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Sample records for brain receptors mitogenesis

  1. Endothelium in brain: Receptors, mitogenesis, and biosynthesis in glial cells

    Energy Technology Data Exchange (ETDEWEB)

    MacCumber, M.W.; Ross, C.A.; Snyder, S.H. (Johns Hopkins Univ. School of Medicine, Baltimore, MD (USA))

    1990-03-01

    The authors have explored the cellular loci of endothelin (ET) actions and formation in the brain, using cerebellar mutant mice was well as primary and continuous cell cultures. A glial role is favored by several observations: (1) mutant mice lacking neuronal Purkinje cells display normal ET receptor binding and enhanced stimulation by ET of inositolphospholipid turnover; (ii) in weaver mice lacking neuronal granule cells, ET stimulation of inositolphospholipid turnover is not significantly diminished; (iii) C{sub 6} glioma cells and primary cultures of cerebellar astroglia exhibit substantial ET receptor binding and ET-induced stimulation of inositolphospholipid turnover; (iv) ET promotes mitogenesis of C{sub 6} glioma cells and primary cerebellar astroglia; and (v) primary cultures of cerebellar astroglia contain ET mRNA. ET also appears to have a neuronal role, since it stimulates inositolphospholipid turnover in primary cultures of cerebellar granule cells, and ET binding declines in granule cell-deficient mice. Thus, ET can be produced by glia and act upon both glia and neurons in a paracrine fashion.

  2. Heterologous desensitization of bombesin-induced mitogenesis by prolonged exposure to vasopressin: a post-receptor signal transduction block.

    OpenAIRE

    Millar, J B; Rozengurt, E

    1989-01-01

    Prolonged exposure of quiescent Swiss 3T3 cells to vasopressin prevents mitogenic stimulation on subsequent addition of bombesin. This heterologous desensitization is selective and can be mimicked by vasopressin agonists, including [Lys8]vasopressin and oxytocin but not by the V1-type-specific vasopressin receptor antagonist [Pmp1,O-Me-Tyr2,Arg8]vasopressin [where Pmp is 1-(beta-mercapto-beta,beta-cyclopenthamethylene propionic acid)]. Furthermore, vasopressin-induced loss of responsiveness t...

  3. Mutation of a Src phosphorylation site in the PDGF beta-receptor leads to increased PDGF-stimulated chemotaxis but decreased mitogenesis

    DEFF Research Database (Denmark)

    Hansen, Klaus; Johnell, M; Siegbahn, A; Rorsman, C; Engström, U; Wernstedt, C; Heldin, C H; Rönnstrand, L

    1996-01-01

    phosphorylated by Src. Cell lines expressing a beta-receptor mutant, in which Tyr934 was replaced with a phenyalanine residue, showed reduced mitogenic signaling in response to PDGF-BB. In contrast, the mutant receptor mediated increased signals for chemotaxis and actin reorganization. Whereas the motility...... responses of cells expressing wild-type beta-receptors were attenuated by inhibition of phosphatidylinositol 3'-kinase, those of cells expressing the mutant receptor were only slightly influenced. In contrast, PDGF-BB-induced chemotaxis of the cells with the mutant receptor was attenuated by inhibition of...... protein kinase C, whereas the chemotaxis of cells expressing the wild-type beta-receptor was less affected. Moreover, the PDGF-BB-stimulated tyrosine phosphorylation of phospholipase C-gamma was increased in the mutant receptor cells compared with wild-type receptor cells. In conclusion, the...

  4. The NK-1 Receptor Antagonist L-732,138 Induces Apoptosis and Counteracts Substance P-Related Mitogenesis in Human Melanoma Cell Lines

    International Nuclear Information System (INIS)

    It has been recently demonstrated that substance P (SP) and neurokinin-1 (NK-1) receptor antagonists induce cell proliferation and cell inhibition in human melanoma cells, respectively. However, the antitumor action of the NK-1 receptor antagonist L-732,138 on such cells is unknown. The aim of this study was to demonstrate an antitumor action of L-732,138 against three human melanoma cell lines (COLO 858, MEL HO, COLO 679). We found that L-732,138 elicits cell growth inhibition in a concentration dependent manner in the melanoma cells studied. Moreover, L-732,138 blocks SP mitogen stimulation. The specific antitumor action of L-732,138 occurred through the NK-1 receptor and melanoma cell death was by apoptosis. These findings indicate that the NK-1 receptor antagonist L-732,138 could be a new antitumor agent in the treatment of human melanoma

  5. Glycine receptors and brain development

    OpenAIRE

    Avila, Ariel; Nguyen, Laurent; Rigo, Jean-Michel

    2013-01-01

    Glycine receptors (GlyRs) are ligand-gated chloride ion channels that mediate fast inhibitory neurotransmission in the spinal cord and the brainstem. There, they are mainly involved in motor control and pain perception in the adult. However, these receptors are also expressed in upper regions of the central nervous system, where they participate in different processes including synaptic neurotransmission. Moreover, GlyRs are present since early stages of brain development and might influence ...

  6. Cannabinoid receptor localization in brain

    Energy Technology Data Exchange (ETDEWEB)

    Herkenham, M.; Lynn, A.B.; Little, M.D.; Johnson, M.R.; Melvin, L.S.; de Costa, B.R.; Rice, K.C. (National Institute of Mental Health, Bethesda, MD (USA))

    1990-03-01

    (3H)CP 55,940, a radiolabeled synthetic cannabinoid, which is 10-100 times more potent in vivo than delta 9-tetrahydrocannabinol, was used to characterize and localize a specific cannabinoid receptor in brain sections. The potencies of a series of natural and synthetic cannabinoids as competitors of (3H)CP 55,940 binding correlated closely with their relative potencies in several biological assays, suggesting that the receptor characterized in our in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience. Autoradiography of cannabinoid receptors in brain sections from several mammalian species, including human, reveals a unique and conserved distribution; binding is most dense in outflow nuclei of the basal ganglia--the substantia nigra pars reticulata and globus pallidus--and in the hippocampus and cerebellum. Generally high densities in forebrain and cerebellum implicate roles for cannabinoids in cognition and movement. Sparse densities in lower brainstem areas controlling cardiovascular and respiratory functions may explain why high doses of delta 9-tetrahydrocannabinol are not lethal.

  7. NMDA receptor function, memory, and brain aging

    OpenAIRE

    Newcomer, John W.; Farber, Nuri B.; Olney, John W.

    2000-01-01

    An increasing level of N-methyl-D-aspartate (NMDA) receptor hypofunction within the brain is associated with memory and learning impairments, with psychosis, and ultimately with excitotoxic brain injury. As the brain ages, the NMDA receptor system becomes progressively hypofunctional, contributing to decreases in memory and learning performance. In those individuals destined to develop Alzheimer's disease, other abnormalities (eg, amyloidopathy and oxidative stress) interact to increase the N...

  8. Distribution of melatonin receptor in human fetal brain

    Institute of Scientific and Technical Information of China (English)

    WANG Guo-quan; SHAO Fu-yuan; ZHAO Ying; LIU Zhi-min

    2001-01-01

    Objective: To study the distribution of 2 kinds of melatonin receptor subtypes (mtl and MT2) in human fetal brain. Methods: The fetal brain tissues were sliced and the distribution ofmelatonin receptors in human fetal brain were detected using immunohistochemistry and in situ hybridization. Results: Melatonin receptor mtl existed in the cerebellun and hypothalamus, melatonin receptor MT2 exists in hypothalamus, occipital and medulla. Conclusion: Two kinds of melatonin receptors, mtl and MT2 exist in the membrane and cytosol of brain cells, indicating that human fetal brain is a target organ of melatonin.

  9. Brain CB2 Receptors: Implications for Neuropsychiatric Disorders

    Directory of Open Access Journals (Sweden)

    Michelle Roche

    2010-08-01

    Full Text Available Although previously thought of as the peripheral cannabinoid receptor, it is now accepted that the CB2 receptor is expressed in the central nervous system on microglia, astrocytes and subpopulations of neurons. Expression of the CB2 receptor in the brain is significantly lower than that of the CB1 receptor. Conflicting findings have been reported on the neurological effects of pharmacological agents targeting the CB2 receptor under normal conditions. Under inflammatory conditions, CB2 receptor expression in the brain is enhanced and CB2 receptor agonists exhibit potent anti-inflammatory effects. These findings have prompted research into the CB2 receptor as a possible target for the treatment of neuroinflammatory and neurodegenerative disorders. Neuroinflammatory alterations are also associated with neuropsychiatric disorders and polymorphisms in the CB2 gene have been reported in depression, eating disorders and schizophrenia. This review will examine the evidence to date for a role of brain CB2 receptors in neuropsychiatric disorders.

  10. GABAA receptor downregulation in brains of subjects with autism

    OpenAIRE

    Fatemi, S. Hossein; Reutiman, Teri J.; Folsom, Timothy D.; Thuras, Paul D.

    2008-01-01

    Gamma-aminobutyric acid A (GABAA) receptors are ligand-gated ion channels responsible for mediation of fast inhibitory action of GABA in the brain. Preliminary reports have demonstrated altered expression of GABA receptors in the brains of subjects with autism suggesting GABA/glutamate system dysregulation. We investigated the expression of four GABAA receptor subunits and observed significant reductions in GABRA1, GABRA2, GABRA3, and GABRB3 in parietal cortex (Brodmann's Area 40(BA40)), whil...

  11. Risperidone treatment increases CB1 receptor binding in rat brain

    DEFF Research Database (Denmark)

    Secher, Anna; Husum, Henriette; Holst, Birgitte;

    2010-01-01

    showed that risperidone treatment altered CB(1) receptor binding in the rat brain. Risperidone-induced adiposity and metabolic dysfunction in the clinic may be explained by increased CB(1) receptor density in brain regions involved in appetite and regulation of metabolic function....... positively correlated with visceral fat mass. Risperidone treatment increased CB(1) receptor binding in the arcuate nucleus (40%), hippocampus (25-30%) and amygdala (35%) without concurrent alterations in the CB(1) receptor mRNA. Risperidone treatment increased adiponectin mRNA. CONCLUSION: The present study...

  12. Basic calcium phosphate crystal-induced Egr-1 expression stimulates mitogenesis in human fibroblasts

    International Nuclear Information System (INIS)

    Previously, we have reported that basic calcium phosphate (BCP) crystals stimulate mitogenesis and synthesis of matrix metalloproteinases in cultured human foreskin and synovial fibroblasts. However, the detailed mechanisms involved are still unclear. In the present study, using RT-PCR and Egr-1 promoter analysis we showed that BCP crystals could stimulate early growth response gene Egr-1 transcription through a PKCα-dependent p44/p42 MAPK pathway. Using a retrovirus gene expression system (Clontech) to overexpress Egr-1 in human fibroblast BJ-1 cells resulted in promotion of mitogenesis measured either by MTT cell proliferation analysis or by direct cell counting. The results demonstrate that Egr-1 may play a key role in mediating BCP crystal-induced synovial fibroblast mitogenesis

  13. The meth brain: methamphetamines alter brain functions via NMDA receptors

    Czech Academy of Sciences Publication Activity Database

    Proft, Juliane; Weiss, Norbert

    2015-01-01

    Roč. 34, č. 1 (2015), s. 1-3. ISSN 0231-5882 R&D Projects: GA ČR GA15-13556S Institutional support: RVO:61388963 Keywords : ion channel * methamphetamine * piriform cortex * NMDA receptor * AMPA receptor Subject RIV: CE - Biochemistry Impact factor: 1.173, year: 2014

  14. Distribution of corticotropin-releasing factor receptors in primate brain

    International Nuclear Information System (INIS)

    The distribution and properties of receptors for corticotropin-releasing factor (CRF) were analyzed in the brain of cynomolgus monkeys. Binding of [125I]tyrosine-labeled ovine CRF to frontal cortex and amygdala membrane-rich fractions was saturable, specific, and time- and temperature-dependent, reaching equilibrium in 30 min at 230C. Scatchard analysis of the binding data indicated one class of high-affinity sites with a K/sub d/ of 1 nM and a concentration of 125 fmol/mg. As in the rat pituitary and brain, CRF receptors in monkey cerebral cortex and amygdala were coupled to adenylate cyclase. Autoradiographic analysis of specific CRF binding in brain sections revealed that the receptors were widely distributed in the cerebral cortex and limbic system. Receptor density was highest in the pars tuberalis of the pituitary and throughout the cerebral cortex, specifically in the prefrontal, frontal, orbital, cingulate, insular, and temporal areas, and in the cerebellar cortex. A low binding density was present in the superior colliculus, locus coeruleus, substantia gelatinosa, preoptic area, septal area, and bed nucleus of the stria terminalis. These data demonstrate that receptors for CRF are present within the primate brain at areas related to the central control of visceral function and behavior, suggesting that brain CRF may serve as a neurotransmitter in the coordination of endocrine and neural mechanisms involved in the response to stress

  15. Kappa-opioid receptor signaling and brain reward function

    OpenAIRE

    Bruijnzeel, Adrie W.

    2009-01-01

    The dynorphin-like peptides have profound effects on the state of the brain reward system and human and animal behavior. The dynorphin-like peptides affect locomotor activity, food intake, sexual behavior, anxiety-like behavior, and drug intake. Stimulation of kappa-opioid receptors, the endogenous receptor for the dynorphin-like peptides, inhibits dopamine release in the striatum (nucleus accumbens and caudate putamen) and induces a negative mood state in humans and animals. The administrati...

  16. Repeated swim stress alters brain benzodiazepine receptors measured in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Weizman, R.; Weizman, A.; Kook, K.A.; Vocci, F.; Deutsch, S.I.; Paul, S.M.

    1989-06-01

    The effects of repeated swim stress on brain benzodiazepine receptors were examined in the mouse using both an in vivo and in vitro binding method. Specific in vivo binding of (/sup 3/H)Ro15-1788 to benzodiazepine receptors was decreased in the hippocampus, cerebral cortex, hypothalamus, midbrain and striatum after repeated swim stress (7 consecutive days of daily swim stress) when compared to nonstressed mice. In vivo benzodiazepine receptor binding was unaltered after repeated swim stress in the cerebellum and pons medulla. The stress-induced reduction in in vivo benzodiazepine receptor binding did not appear to be due to altered cerebral blood flow or to an alteration in benzodiazepine metabolism or biodistribution because there was no difference in (14C)iodoantipyrine distribution or whole brain concentrations of clonazepam after repeated swim stress. Saturation binding experiments revealed a change in both apparent maximal binding capacity and affinity after repeated swim stress. Moreover, a reduction in clonazepam's anticonvulsant potency was also observed after repeated swim stress (an increase in the ED50 dose for protection against pentylenetetrazol-induced seizures), although there was no difference in pentylenetetrazol-induced seizure threshold between the two groups. In contrast to the results obtained in vivo, no change in benzodiazepine receptor binding kinetics was observed using the in vitro binding method. These data suggest that environmental stress can alter the binding parameters of the benzodiazepine receptor and that the in vivo and in vitro binding methods can yield substantially different results.

  17. Repeated swim stress alters brain benzodiazepine receptors measured in vivo

    International Nuclear Information System (INIS)

    The effects of repeated swim stress on brain benzodiazepine receptors were examined in the mouse using both an in vivo and in vitro binding method. Specific in vivo binding of [3H]Ro15-1788 to benzodiazepine receptors was decreased in the hippocampus, cerebral cortex, hypothalamus, midbrain and striatum after repeated swim stress (7 consecutive days of daily swim stress) when compared to nonstressed mice. In vivo benzodiazepine receptor binding was unaltered after repeated swim stress in the cerebellum and pons medulla. The stress-induced reduction in in vivo benzodiazepine receptor binding did not appear to be due to altered cerebral blood flow or to an alteration in benzodiazepine metabolism or biodistribution because there was no difference in [14C]iodoantipyrine distribution or whole brain concentrations of clonazepam after repeated swim stress. Saturation binding experiments revealed a change in both apparent maximal binding capacity and affinity after repeated swim stress. Moreover, a reduction in clonazepam's anticonvulsant potency was also observed after repeated swim stress [an increase in the ED50 dose for protection against pentylenetetrazol-induced seizures], although there was no difference in pentylenetetrazol-induced seizure threshold between the two groups. In contrast to the results obtained in vivo, no change in benzodiazepine receptor binding kinetics was observed using the in vitro binding method. These data suggest that environmental stress can alter the binding parameters of the benzodiazepine receptor and that the in vivo and in vitro binding methods can yield substantially different results

  18. Liver fatty acid-binding protein: specific mediator of the mitogenesis induced by two classes of carcinogenic peroxisome proliferators.

    OpenAIRE

    S H Khan; Sorof, S

    1994-01-01

    Peroxisome proliferators (PP) are a diverse group of chemicals that induce dramatic increases in peroxisomes in rodent hepatocytes, followed by hypertrophy, hepatomegaly, alterations in lipid metabolism, mitogenesis, and finally hepatocarcinomas. Termed nongenotoxic carcinogens, they do not interact with DNA, are not mutagenic in bacterial assays, and fail to elicit many of the phenotypes associated with classic genotoxic carcinogens. We report here that the mitogenesis induced by the major P...

  19. Autoradiographic visualization of substance P receptors in rat brain

    International Nuclear Information System (INIS)

    The distribution of central substance P receptors was characterized by light microscopic autoradiography. Using [125I]physalaemin as a receptor probe, the authors found the distibution to vary approx. 100-fold between high regions such as the olfactory bulb and low regions such as the cerebellum. Similar autoradiograms were generated using [125I]Bolton Hunter substance P or [3H]substance P. One particular advantage of radiolabeled physalaemin relative to the other substance P receptor probes, however, is the low background values. The discrete regional distribution of substance P and its receptors in the CNS suggests that substance P may function as an important regulatory peptide in certain brain areas such as olfactory and limbic regions. (Auth.)

  20. In vivo study of drug interaction with brain benzodiazepine receptor

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, O.; Shinotoh, H.; Ito, T.; Suzuki, K.; Hashimoto, K.; Yamasaki, T.

    1985-05-01

    The possibility of direct estimation of in vivo Bz receptor occupancy in brain was evaluated using C-11, or H-3-flumazepil (Ro15-1788). In animal experiments, 1 ..mu..Ci of H-3-Ro15-1788 was injected at 0.5 or 20 hr after i.v. injection of various dosage of clonazepam. Then radioactivity in cerebral cortex, cerebellum and blood at 5 min. after injection of the tracer was compared. Competitive inhibition of in vivo binding was clearly observed when clonazepam was pretreated at 0.5 hr before injection of the tracer. On the other hand, brain radioactivity was increased when clonazepam was administered at 20 hr before injection of the tracer. This increase in binding of H-3-Ro15-1788 might be caused by rebound of Bz receptor function by treatment with Bz agonist, and this rebound may have an important role in physiological function. Clinical investigation concerning drug interaction with brain Bz receptor was performed in normal volunteer and patients with neurological disorders. The distribution of C-11-Ro15-1788 in the brain of patients chronically treated with clonazepam were significantly heterogeneous. However, cerebral blood flow estimated with N-13 NH3 of these patients were normal.

  1. In vivo study of drug interaction with brain benzodiazepine receptor

    International Nuclear Information System (INIS)

    The possibility of direct estimation of in vivo Bz receptor occupancy in brain was evaluated using C-11, or H-3-flumazepil (Ro15-1788). In animal experiments, 1 μCi of H-3-Ro15-1788 was injected at 0.5 or 20 hr after i.v. injection of various dosage of clonazepam. Then radioactivity in cerebral cortex, cerebellum and blood at 5 min. after injection of the tracer was compared. Competitive inhibition of in vivo binding was clearly observed when clonazepam was pretreated at 0.5 hr before injection of the tracer. On the other hand, brain radioactivity was increased when clonazepam was administered at 20 hr before injection of the tracer. This increase in binding of H-3-Ro15-1788 might be caused by rebound of Bz receptor function by treatment with Bz agonist, and this rebound may have an important role in physiological function. Clinical investigation concerning drug interaction with brain Bz receptor was performed in normal volunteer and patients with neurological disorders. The distribution of C-11-Ro15-1788 in the brain of patients chronically treated with clonazepam were significantly heterogeneous. However, cerebral blood flow estimated with N-13 NH3 of these patients were normal

  2. Brain dopamine D-2 receptors in senile dementia

    International Nuclear Information System (INIS)

    Brain dopamine D-2 receptors were analysed in the caudate nucleus, putamen and nucleus accumbens in 49 patients with different types of neuropathologically verified dementia and in 39 controls by the binding of 3H-spiroperidol. The binding was significantly decreased in all brain areas in patients with Alzheimer's disease (AD), while the changes in patients with multi-infarct dementia (MID) or combined dementia (CD) were non-significant. According to a Scatchard analysis, this decrease in binding was due to the reduced number of receptors. On the other hand, the binding of 3H-spiroperidol was significantly increased in those patients who had received neuroleptic drugs. Significant correlations between 3H-spiroperidol binding and neuropathological changes were seen only in AD patients in the nucleus accumbens. The nucleus accumbens was also the only brain area in which there was a significant correlation between dopamine D-2 and the number of muscarinic receptors in AD patients. The findings of this study on dopamine D-2 receptors suggest the involvement of the nigrostriatal dopaminergic system in AD but not in the other two major types of dementia. (Author)

  3. Melanocortin 4 Receptor and Dopamine D2 Receptor Expression in Brain Areas Involved in Food Intake

    OpenAIRE

    Yoon, Ye Ran; Baik, Ja-Hyun

    2015-01-01

    Background The melanocortin 4 receptor (MC4R) is involved in the regulation of homeostatic energy balance by the hypothalamus. Recent reports showed that MC4R can also control the motivation for food in association with a brain reward system, such as dopamine. We investigated the expression levels of MC4R and the dopamine D2 receptor (D2R), which is known to be related to food rewards, in both the hypothalamus and brain regions involved in food rewards. Methods We examined the expression leve...

  4. Mapping the calcitonin receptor in human brain stem.

    Science.gov (United States)

    Bower, Rebekah L; Eftekhari, Sajedeh; Waldvogel, Henry J; Faull, Richard L M; Tajti, János; Edvinsson, Lars; Hay, Debbie L; Walker, Christopher S

    2016-05-01

    The calcitonin receptor (CTR) is relevant to three hormonal systems: amylin, calcitonin, and calcitonin gene-related peptide (CGRP). Receptors for amylin and calcitonin are targets for treating obesity, diabetes, and bone disorders. CGRP receptors represent a target for pain and migraine. Amylin receptors (AMY) are a heterodimer formed by the coexpression of CTR with receptor activity-modifying proteins (RAMPs). CTR with RAMP1 responds potently to both amylin and CGRP. The brain stem is a major site of action for circulating amylin and is a rich site of CGRP binding. This study aimed to enhance our understanding of these hormone systems by mapping CTR expression in the human brain stem, specifically the medulla oblongata. Widespread CTR-like immunoreactivity was observed throughout the medulla. Dense CTR staining was noted in several discrete nuclei, including the nucleus of the solitary tract, the hypoglossal nucleus, the cuneate nucleus, spinal trigeminal nucleus, the gracile nucleus, and the inferior olivary nucleus. CTR staining was also observed in the area postrema, the lateral reticular nucleus, and the pyramidal tract. The extensive expression of CTR in the medulla suggests that CTR may be involved in a wider range of functions than currently appreciated. PMID:26911465

  5. Sigma-1 Receptor Modulates Neuroinflammation After Traumatic Brain Injury.

    Science.gov (United States)

    Dong, Hui; Ma, Yunfu; Ren, Zengxi; Xu, Bin; Zhang, Yunhe; Chen, Jing; Yang, Bo

    2016-07-01

    Traumatic brain injury (TBI) remains a significant clinical problem and contributes to one-third of all injury-related deaths. Activated microglia-mediated inflammatory response is a distinct characteristic underlying pathophysiology of TBI. Here, we evaluated the effect and possible mechanisms of the selective Sigma-1 receptor agonist 2-(4-morpholinethyl)-1-phenylcyclohexanecarboxylate (PRE-084) in mice TBI model. A single intraperitoneal injection 10 μg/g PRE-084, given 15 min after TBI significantly reduced lesion volume, lessened brain edema, attenuated modified neurological severity score, increased the latency time in wire hang test, and accelerated body weight recovery. Moreover, immunohistochemical analysis with Iba1 staining showed that PRE-084 lessened microglia activation. Meanwhile, PRE-084 reduced nitrosative and oxidative stress to proteins. Thus, Sigma-1 receptors play a major role in inflammatory response after TBI and may serve as useful target for TBI treatment in the future. PMID:26228028

  6. Angiotensin II AT1 receptor blockers as treatments for inflammatory brain disorders

    OpenAIRE

    Saavedra, Juan M.

    2012-01-01

    The effects of brain AngII (angiotensin II) depend on AT1 receptor (AngII type 1 receptor) stimulation and include regulation of cerebrovascular flow, autonomic and hormonal systems, stress, innate immune response and behaviour. Excessive brain AT1 receptor activity associates with hypertension and heart failure, brain ischaemia, abnormal stress responses, blood–brain barrier breakdown and inflammation. These are risk factors leading to neuronal injury, the incidence and progression of neurod...

  7. Modulation of brain opioid receptors by zinc and histidine

    International Nuclear Information System (INIS)

    The effect of zinc and several trace elements was studied on the binding of the opioid receptor antagonist [3H]-naloxone and the agonists [3H]-DAGO, [3H]-DSTLE, and [3H]-EKC, specific for the mu, delta and kappa receptors, respectively, in several areas of the rat brain. Physiological concentrations of zinc were inhibitory to the binding of naloxone, DAGO, and EKC, whereas delta receptors were insensitive to this inhibition. Copper, cadmium, and mercury also inhibited the binding of all the ligands studied to their receptors. Histidine was most effective in preventing the inhibitory effects of zinc and copper, whereas it was less effective on cadmium, and without any effect on the inhibit was less effective on cadmium, and without any effect on the inhibition caused by mercury. Its metabolites histamine and imidazoleacetic acid, and also citrate were ineffective. Magnesium and manganese were stimulatory to opioid receptor binding, whereas cobalt and nickel had dual effects. Concentrations of zinc less that its IC50 totally prevented the stimulatory effects of magnesium and manganese on the mu and delta receptors on which zinc alone had no effects. The reducing reagents dithiothreitol and B-mercaptoethanol partially protected against zinc inhibition, and the oxidizing reagent dithiobisnitrobenzoic acid even potentiated the inhibitory effects of zinc on DSTLE and DAGO binding, although to different extents

  8. Modulation of brain opioid receptors by zinc and histidine

    Energy Technology Data Exchange (ETDEWEB)

    Hanissian, S.H.

    1988-01-01

    The effect of zinc and several trace elements was studied on the binding of the opioid receptor antagonist ({sup 3}H)-naloxone and the agonists ({sup 3}H)-DAGO, ({sup 3}H)-DSTLE, and ({sup 3}H)-EKC, specific for the mu, delta and kappa receptors, respectively, in several areas of the rat brain. Physiological concentrations of zinc were inhibitory to the binding of naloxone, DAGO, and EKC, whereas delta receptors were insensitive to this inhibition. Copper, cadmium, and mercury also inhibited the binding of all the ligands studied to their receptors. Histidine was most effective in preventing the inhibitory effects of zinc and copper, whereas it was less effective on cadmium, and without any effect on the inhibit was less effective on cadmium, and without any effect on the inhibition caused by mercury. Its metabolites histamine and imidazoleacetic acid, and also citrate were ineffective. Magnesium and manganese were stimulatory to opioid receptor binding, whereas cobalt and nickel had dual effects. Concentrations of zinc less that its IC{sub 50} totally prevented the stimulatory effects of magnesium and manganese on the mu and delta receptors on which zinc alone had no effects. The reducing reagents dithiothreitol and B-mercaptoethanol partially protected against zinc inhibition, and the oxidizing reagent dithiobisnitrobenzoic acid even potentiated the inhibitory effects of zinc on DSTLE and DAGO binding, although to different extents.

  9. Oxytocin and Estrogen Receptor β in the Brain: An Overview

    Directory of Open Access Journals (Sweden)

    Alexandra eAcevedo-Rodriguez

    2015-10-01

    Full Text Available Oxytocin is a neuropeptide synthesized primarily by neurons of the paraventricular and supraoptic nuclei of the hypothalamus. These neurons have axons that project into the posterior pituitary and release oxytocin into the bloodstream to promote labor and lactation; however, oxytocin neurons also project to other brain areas where it plays a role in numerous brain functions. Oxytocin binds to the widely expressed oxytocin receptor, and, in doing so, it regulates homeostatic processes, social recognition and fear conditioning. In addition to these functions, oxytocin decreases neuroendocrine stress signaling and anxiety-related and depression-like behaviors. Steroid hormones differentially modulate stress responses and alter oxytocin receptor expression. In particular, estrogen receptor β activation has been found to both reduce anxiety-related behaviors and increase oxytocin peptide transcription, suggesting a role for oxytocin in this estrogen receptor β mediated anxiolytic effect. Further research is needed to identify modulators of oxytocin signaling and the pathways utilized and to elucidate molecular mechanisms controlling oxytocin expression to allow better therapeutic manipulations of this system in patient populations.

  10. Effects of antidepressant drugs on different receptors in the brain

    International Nuclear Information System (INIS)

    Radioligand receptor binding techniques were used to characterize the effects of different structural types of antidepressant drugs on neurotransmitter receptors. The tricyclic antidepressants more or less potently inhibited the binding to rat brain preparations of several different radiolabelled ligands ([3H]WB4101, [3H]QNB, [3H]d-LSD, [3H]mepyramine). The potency of the nontricyclic antidepressants varied greatly. Mianserin, potently displaced [3H]mepyramine, [3H]d-LSD and [3H]WB4101 while it was very weak on [3H]QNB-binding. Nomifensine and the specific 5-HT uptake inhibitors zimelidine and alaproclate had very low affinity for these receptors. All the antidepressants tested were practically devoid of activity on [3H]DHA binding, [3H]spiroperidol binding, [3H]flunitrazepam binding, [3H]muscimol binding and [3H]naloxone binding. The implications of these findings for biogenic amine theories of affective disorders are discussed. (Auth.)

  11. Sex Differences in Serotonin 1 Receptor Binding in Rat Brain

    Science.gov (United States)

    Fischette, Christine T.; Biegon, Anat; McEwen, Bruce S.

    1983-10-01

    Male and female rats exhibit sex differences in binding by serotonin 1 receptors in discrete areas of the brain, some of which have been implicated in the control of ovulation and of gonadotropin release. The sex-specific changes in binding, which occur in response to the same hormonal (estrogenic) stimulus, are due to changes in the number of binding sites. Castration alone also affects the number of binding sites in certain areas. The results lead to the conclusion that peripheral hormones modulate binding by serotonin 1 receptors. The status of the serotonin receptor system may affect the reproductive capacity of an organism and may be related to sex-linked emotional disturbances in humans.

  12. Breast cancer surface receptors predict risk for developing brain metastasis and subsequent prognosis

    OpenAIRE

    Grewal, Jai; Kesari, Santosh

    2008-01-01

    Determining the status of breast cancer surface receptors (estrogen receptor, progesterone receptor, HER2/neu) has become routine in the care of patients with this disease and has proven to be helpful in guiding treatment. For this reason, breast cancer has become a model for molecularly guided therapy in solid tumors. Emerging data support that these receptors are associated with risk for developing brain metastases. Additionally, once brain metastases have occurred these receptors may also ...

  13. Relationship between changes of N-methyl-D-aspartate receptor activity and brain edema after brain injury in rats

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective: To investigate the relationship between the changes of N-methyl-D-aspartate (NMDA) receptor activity and brain edema after injury in rats.   Methods: The brain injury models were made by using a free-falling body. The treatment model was induced by means of injecting AP5 into lateral ventricle before brain injury; water contents in brain cortex were measured with dry-wet method; and NMDA receptor activity was detected with a radio ligand binding assay.   Results: The water contents began to increase at 30 minutes and reached the peak at 6 hours after brain injury. The maximal binding (Bmax) of NMDA receptor increased significantly at 15 minutes and reached the peak at 30 minutes, then decreased gradually and had the lowest value 6 hours after brain injury. Followed the treatment with AP5, NMDA receptor activity in the injured brain showed a normal value; and the water contents were lower than that of AP5-free injury group 24 hours after brain injury.   Conclusions: It suggests that excessive activation of NMDA receptor may be one of the most important factors to induce the secondary cerebral impairments, and AP5 may protect the brain from edema after brain injury.

  14. Imaging of neuropsychiatric disorders. The usefulness of new brain receptor radiopharmaceuticals

    International Nuclear Information System (INIS)

    Until now, imaging of brain receptors have been only possible with positron emission tomography (PET), because there have been no high specific activity, high receptor affinity tracers available for clinical use with single photon emission tomography (SPECT). During the recent years fair number of new receptor ligands have been developed. For dopaminergic system there, are ligands for studying both presynaptic and postsynaptic sites, benzodiazepine receptors can be imaged with high quality ligands and also serotonergic receptors can be imaged. Very intensive work is underway for developing muscarinic receptor ligands, as well as for many other brain receptors

  15. Differential role of tumor necrosis factor receptors in mouse brain inflammatory responses in cryolesion brain injury

    DEFF Research Database (Denmark)

    Quintana, Albert; Giralt, Mercedes; Rojas, Santiago;

    2005-01-01

    Tumor necrosis factor-alpha (TNF-alpha) is one of the mediators dramatically increased after traumatic brain injury that leads to the activation, proliferation, and hypertrophy of mononuclear, phagocytic cells and gliosis. Eventually, TNF-alpha can induce both apoptosis and necrosis via intracell......Tumor necrosis factor-alpha (TNF-alpha) is one of the mediators dramatically increased after traumatic brain injury that leads to the activation, proliferation, and hypertrophy of mononuclear, phagocytic cells and gliosis. Eventually, TNF-alpha can induce both apoptosis and necrosis via...... intracellular signaling. This cytokine exerts its functions via interaction with two receptors: type-1 receptor (TNFR1) and type-2 receptor (TNFR2). In this work, the inflammatory response after a freeze injury (cryolesion) in the cortex was studied in wild-type (WT) animals and in mice lacking TNFR1 (TNFR1 KO...... affected by TNFR1 deficiency. Overall, these results suggest that TNFR1 is involved in the early establishment of the inflammatory response and that its deficiency causes a decreased inflammatory response and tissue damage following brain injury....

  16. In vivo PET imaging of brain nicotinic cholinergic receptors

    International Nuclear Information System (INIS)

    Neuronal acetylcholine receptors (nAChRs) are widely distributed throughout the central nervous system where they modulate a number of CNS functions including neurotransmitter release, cognitive function, anxiety, analgesia and control of cerebral blood flow. In the brain, a major subtype is composed of the α4β2 subunit combination. Density of this subtype has been shown to be decreased in patients with neuro-degenerative disease such as Alzheimer and Parkinson's disease (AD and PD), and mutated receptors has been described in some familial epilepsy. Thus, in vivo mapping of the nicotinic nAChRs by Positron Emission Tomography (PET) are of great interest to monitor the evolution of these pathologies and changes in the neuronal biochemistry induced by therapeutic agents. Recently, a new compound, 3-[2(S)-2-azetidinyl-methoxy]pyridine (A-85380) has been synthesised and labelled with fluorine-18, [18F]fluoro-A-85380 (Dolle et al., 1999). The [18F]fluoro-A-85380 has been shown to bind with high affinity t o nAChRs in vitro (Saba et al., 2004), and its toxicity was low and compatible with it s use at tracer dose in human PET studies (Valette, 2002). PET studies in baboons showed that, after in vivo administration of [ 18F]fluoro-A-85380 at a tracer dose, the distribution of the radioactivity in the brain reflect the distribution of the 18F]fluoro-A-8538 0 combined with its low toxicity make possible the imaging of the nicotinic receptor s in human by PET (Bottlaender 2003). Studies were performed in healthy non-smoker volunteers to evaluate the brain kinetics of [18F]fluoro-A-85380 and to assess the quantification of its nAChRs binding in the human brain with PET (Gallezot et a., 2005). The [18F]fluoro-A-85380 was also used in epileptic patients to whom a mutation in the α4 or β2 nAChRs subunit have been identified. We found that, in these patients, the pattern of the brain distribution of the radiotracer was found different when compared to the healthy subjects

  17. Cognitive disorder and changes in cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor following brain injury

    Institute of Scientific and Technical Information of China (English)

    Weiliang Zhao; Dezhi Kang; Yuanxiang Lin

    2008-01-01

    BACKGROUND: Learning and memory damage is one of the most permanent and the severest symptoms of traumatic brain injury; it can seriously influence the normal life and work of patients. Some research has demonstrated that cognitive disorder is closely related to nicotine cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor. OBJECTIVE: To summarize the cognitive disorder and changes in nicotine cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor following brain injury. RETRIEVAL STRATEGY: A computer-based online search was conducted in PUBMED for English language publications containing the key words "brain injured, cognitive handicap, acetylcholine, N-methyl-D aspartate receptors, neural cell adhesion molecule, brain-derived neurotrophic factor" from January 2000 to December 2007. There were 44 papers in total. Inclusion criteria: ① articles about changes in nicotine cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor following brain injury; ② articles in the same researching circle published in authoritative journals or recently published. Exclusion criteria: duplicated articles.LITERATURE EVALUATION: References were mainly derived from research on changes in these four factors following brain injury. The 20 included papers were clinical or basic experimental studies. DATA SYNTHESIS: After craniocerebral injury, changes in these four factors in brain were similar to those during recovery from cognitive disorder, to a certain degree. Some data have indicated that activation of nicotine cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor could greatly improve cognitive disorder following brain injury. However, there are still a lot of questions remaining; for example, how do these

  18. Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: Therapeutic implications.

    Science.gov (United States)

    Saavedra, Juan M; Sánchez-Lemus, Enrique; Benicky, Julius

    2011-01-01

    Poor adaptation to stress, alterations in cerebrovascular function and excessive brain inflammation play critical roles in the pathophysiology of many psychiatric and neurological disorders such as major depression, schizophrenia, post traumatic stress disorder, Parkinson's and Alzheimer's diseases and traumatic brain injury. Treatment for these highly prevalent and devastating conditions is at present very limited and many times inefficient, and the search for novel therapeutic options is of major importance. Recently, attention has been focused on the role of a brain regulatory peptide, Angiotensin II, and in the translational value of the blockade of its physiological AT(1) receptors. In addition to its well-known cardiovascular effects, Angiotensin II, through AT(1) receptor stimulation, is a pleiotropic brain modulatory factor involved in the control of the reaction to stress, in the regulation of cerebrovascular flow and the response to inflammation. Excessive brain AT(1) receptor activity is associated with exaggerated sympathetic and hormonal response to stress, vulnerability to cerebrovascular ischemia and brain inflammation, processes leading to neuronal injury. In animal models, inhibition of brain AT(1) receptor activity with systemically administered Angiotensin II receptor blockers is neuroprotective; it reduces exaggerated stress responses and anxiety, prevents stress-induced gastric ulcerations, decreases vulnerability to ischemia and stroke, reverses chronic cerebrovascular inflammation, and reduces acute inflammatory responses produced by bacterial endotoxin. These effects protect neurons from injury and contribute to increase the lifespan. Angiotensin II receptor blockers are compounds with a good margin of safety widely used in the treatment of hypertension and their anti-inflammatory and vascular protective effects contribute to reduce renal and cardiovascular failure. Inhibition of brain AT(1) receptors in humans is also neuroprotective

  19. Staphylococcal enterotoxin induced mitogenesis: toxin binding and cell-cell interactions.

    Science.gov (United States)

    Buxser, E S; Bonventre, P F; Archer, D L

    1983-07-01

    The binding characteristics of 125I-labelled staphylococcal enterotoxin A (125I-SEA), a T-cell mitogen, to murine lymphoid cell subpopulations were analyzed. Both T- and B-lymphocytes from murine spleens possess specific binding sites for SEA, as do T-lymphocytes from thymus. B-lymphocytes appear to have a greater capacity for binding of 125-SEA than do T-lymphocytes from either thymus or spleen. Enterotoxin did not specifically bind to thioglycollate-induced peritoneal exudate cells (PECs), used as a source of macrophages. Adherent PECs however, incorporated 125-ISEA by fluid phase endocytosis. When exposed to SEA and thoroughly washed, macrophages stimulate lymphocyte mitogenesis in spleen or thymus cell cultures not directly exposed to toxin. Maximum mitogenic stimulation took place only when both PECs and lymphocytes were exposed to SEA. The presence of splenic B-lymphocytes enhanced the mitogenic response of thymus derived T-cells to SEA. Thus, B-lymphocytes appear to contribute to SEA mitogenesis. These data suggest that mitogenic stimulation and possibly other immunological phenomena associated with SEA occur as a result of complex interactions between cellular components of the immune system. PMID:6605472

  20. Kappa opioid receptors stimulate phosphoinositide turnover in rat brain

    International Nuclear Information System (INIS)

    The effects of various subtype-selective opioid agonists and antagonists on the phosphoinositide (PI) turnover response were investigated in the rat brain. The κ-agonists U-50,488H and ketocyclazocine produced a concentration-dependent increase in the accumulation of IP's in hippocampal slices. The other κ-agonists Dynorphin-A (1-13) amide, and its protected analog D[Ala]2-dynorphin-A (1-13) amide also produced a significant increase in the formation of [3H]-IP's, whereas the μ-selective agonists [D-Ala2-N-Me-Phe4-Gly5-ol]-enkephalin and morphine and the δ-selective agonist [D-Pen2,5]-enkephalin were ineffective. The increase in IP's formation elicited by U-50,488H was partially antagonized by naloxone and more completely antagonized by the κ-selective antagonists nor-binaltorphimine and MR 2266. The formation of IP's induced by U-50,488H varies with the regions of the brain used, being highest in hippocampus and amygdala, and lowest in striatum and pons-medullar. The results indicate that brain κ- but neither μ- nor δ- receptors are coupled to the PI turnover response

  1. Kappa opioid receptors stimulate phosphoinositide turnover in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Periyasamy, S.; Hoss, W. (Univ. of Toledo, OH (USA))

    1990-01-01

    The effects of various subtype-selective opioid agonists and antagonists on the phosphoinositide (PI) turnover response were investigated in the rat brain. The {kappa}-agonists U-50,488H and ketocyclazocine produced a concentration-dependent increase in the accumulation of IP's in hippocampal slices. The other {kappa}-agonists Dynorphin-A (1-13) amide, and its protected analog D(Ala){sup 2}-dynorphin-A (1-13) amide also produced a significant increase in the formation of ({sup 3}H)-IP's, whereas the {mu}-selective agonists (D-Ala{sup 2}-N-Me-Phe{sup 4}-Gly{sup 5}-ol)-enkephalin and morphine and the {delta}-selective agonist (D-Pen{sup 2,5})-enkephalin were ineffective. The increase in IP's formation elicited by U-50,488H was partially antagonized by naloxone and more completely antagonized by the {kappa}-selective antagonists nor-binaltorphimine and MR 2266. The formation of IP's induced by U-50,488H varies with the regions of the brain used, being highest in hippocampus and amygdala, and lowest in striatum and pons-medullar. The results indicate that brain {kappa}- but neither {mu}- nor {delta}- receptors are coupled to the PI turnover response.

  2. Interleukin-1 receptors in mouse brain: Characterization and neuronal localization

    International Nuclear Information System (INIS)

    The cytokine interleukin-1 (IL-1) has a variety of effects in brain, including induction of fever, alteration of slow wave sleep, and alteration of neuroendocrine activity. To examine the potential sites of action of IL-1 in brain, we used iodine-125-labeled recombinant human interleukin-1 [( 125I]IL-1) to identify and characterize IL-1 receptors in crude membrane preparations of mouse (C57BL/6) hippocampus and to study the distribution of IL-1-binding sites in brain using autoradiography. In preliminary homogenate binding and autoradiographic studies, [125I]IL-1 alpha showed significantly higher specific binding than [125I]IL-1 beta. Thus, [125I]IL-1 alpha was used in all subsequent assays. The binding of [125I]IL-1 alpha was linear over a broad range of membrane protein concentrations, saturable, reversible, and of high affinity, with an equilibrium dissociation constant value of 114 +/- 35 pM and a maximum number of binding sites of 2.5 +/- 0.4 fmol/mg protein. In competition studies, recombinant human IL-1 alpha, recombinant human IL-1 beta, and a weak IL-1 beta analog. IL-1 beta +, inhibited [125I]IL-1 alpha binding to mouse hippocampus in parallel with their relative bioactivities in the T-cell comitogenesis assay, with inhibitory binding affinity constants of 55 +/- 18, 76 +/- 20, and 2940 +/- 742 pM, respectively; rat/human CRF and human tumor necrosis factor showed no effect on [125I]IL-1 alpha binding. Autoradiographic localization studies revealed very low densities of [125I]IL-1 alpha-binding sites throughout the brain, with highest densities present in the molecular and granular layers of the dentate gyrus of the hippocampus and in the choroid plexus. Quinolinic acid lesion studies demonstrated that the [125I]IL-1 alpha-binding sites in the hippocampus were localized to intrinsic neurons

  3. GABA[subscript A] Receptor Downregulation in Brains of Subjects with Autism

    Science.gov (United States)

    Fatemi, S. Hossein; Reutiman, Teri J.; Folsom, Timothy D.; Thuras, Paul D.

    2009-01-01

    Gamma-aminobutyric acid A (GABA[subscript A]) receptors are ligand-gated ion channels responsible for mediation of fast inhibitory action of GABA in the brain. Preliminary reports have demonstrated altered expression of GABA receptors in the brains of subjects with autism suggesting GABA/glutamate system dysregulation. We investigated the…

  4. In vivo PET imaging of brain nicotinic cholinergic receptors

    Energy Technology Data Exchange (ETDEWEB)

    Bottlaender, M.; Valette, H.; Saba, W.; Schollhorn-Peyronneau, M.A.; Dolle, F.; Syrota, A. [Service Hospitalier Frederic Joliot (CEA/DSV/DRM), 91 - Orsay (France)

    2006-07-01

    Neuronal acetylcholine receptors (nAChRs) are widely distributed throughout the central nervous system where they modulate a number of CNS functions including neurotransmitter release, cognitive function, anxiety, analgesia and control of cerebral blood flow. In the brain, a major subtype is composed of the {alpha}4{beta}2 subunit combination. Density of this subtype has been shown to be decreased in patients with neuro-degenerative disease such as Alzheimer and Parkinson's disease (AD and PD), and mutated receptors has been described in some familial epilepsy. Thus, in vivo mapping of the nicotinic nAChRs by Positron Emission Tomography (PET) are of great interest to monitor the evolution of these pathologies and changes in the neuronal biochemistry induced by therapeutic agents. Recently, a new compound, 3-[2(S)-2-azetidinyl-methoxy]pyridine (A-85380) has been synthesised and labelled with fluorine-18, [{sup 18}F]fluoro-A-85380 (Dolle et al., 1999). The [{sup 18}F]fluoro-A-85380 has been shown to bind with high affinity t o nAChRs in vitro (Saba et al., 2004), and its toxicity was low and compatible with it s use at tracer dose in human PET studies (Valette, 2002). PET studies in baboons showed that, after in vivo administration of [ {sup 18}F]fluoro-A-85380 at a tracer dose, the distribution of the radioactivity in the brain reflect the distribution of the < 4R2 nAChRs. Competition and pre-blocking studies, using nicotinic agonists, confirm that the radiotracer binds specifically to the heteromeric nAChRs in the brain (Valette et al., 1999). The in vivo, characteristics of the [{sup 18}F]fluoro-A-8538 0 combined with its low toxicity make possible the imaging of the nicotinic receptor s in human by PET (Bottlaender 2003). Studies were performed in healthy non-smoker volunteers to evaluate the brain kinetics of [{sup 18}F]fluoro-A-85380 and to assess the quantification of its nAChRs binding in the human brain with PET (Gallezot et a., 2005). The [{sup 18}F

  5. The function of histamine receptor H4R in the brain revealed by interaction partners.

    Science.gov (United States)

    Moya-Garcia, Aurelio A; Rodriguez, Carlos E; Morilla, Ian; Sanchez-Jimenez, Francisca; Ranea, Juan A G

    2011-01-01

    The histamine H4 receptor is mainly expressed in haematopoietic cells, hence is linked to inflammatory and immune system conditions. It has been recently discovered that the receptor is expressed also in the mammalian central nervous system (CNS), but its role in the brain remains unclear. We address the potential functions of the histamine H4 receptor in the human brain using a 'guilty by association' logic, by close examination of protein-protein functional associations networks in the human proteome. PMID:21622255

  6. A mu–delta opioid receptor brain atlas reveals neuronal co-occurrence in subcortical networks

    OpenAIRE

    Erbs, Eric; Faget, Lauren; Scherrer, Gregory; Matifas, Audrey; Filliol, Dominique; Vonesch, Jean-Luc; Koch, Marc; Kessler, Pascal; Hentsch, Didier; Birling, Marie-Christine; Koutsourakis, Manoussos; Vasseur, Laurent; Veinante, Pierre; Kieffer, Brigitte L.; Massotte, Dominique

    2014-01-01

    Opioid receptors are G protein-coupled receptors (GPCRs) that modulate brain function at all levels of neural integration, including autonomic, sensory, emotional and cognitive processing. Mu (MOR) and delta (DOR) opioid receptors functionally interact in vivo, but whether interactions occur at circuitry, cellular or molecular levels remains unsolved. To challenge the hypothesis of MOR/DOR heteromerization in the brain, we generated redMOR/greenDOR double knock-in mice and report dual recepto...

  7. Excitatory amino acid neurotoxicity and modulation of glutamate receptor expression in organotypic brain slice cultures

    DEFF Research Database (Denmark)

    Zimmer, J; Kristensen, Bjarne Winther; Jakobsen, B; Noraberg, J

    2000-01-01

    -induced excitotoxicity and KA-glutamate receptor subunit mRNA expression after long-term exposure to low, non-toxic doses of KA and NBQX. We conclude that organotypic brain slice cultures, combined with standardized procedures for quantitation of cell damage and receptor subunit changes is of great potential use for...... studies of excitotoxic, glutamate receptor-induced neuronal cell death, receptor modulation and related neuroprotection....

  8. Brain-specific interleukin-1 receptor accessory protein in sleep regulation

    OpenAIRE

    Taishi, Ping; Davis, Christopher J.; Bayomy, Omar; Zielinski, Mark R.; Liao, Fan; Clinton, James M.; Smith, Dirk E.; Krueger, James M.

    2011-01-01

    Interleukin (IL)-1β is involved in several brain functions, including sleep regulation. It promotes non-rapid eye movement (NREM) sleep via the IL-1 type I receptor. IL-1β/IL-1 receptor complex signaling requires adaptor proteins, e.g., the IL-1 receptor brain-specific accessory protein (AcPb). We have cloned and characterized rat AcPb, which shares substantial homologies with mouse AcPb and, compared with AcP, is preferentially expressed in the brain. Furthermore, rat somatosensory cortex Ac...

  9. Autoradiographic analysis of alpha 1-noradrenergic receptors in the human brain postmortem. Effect of suicide

    International Nuclear Information System (INIS)

    In vitro quantitative autoradiography of alpha 1-noradrenergic receptors, using tritiated prazosin as a ligand, was performed on 24 human brains postmortem. Twelve brains were obtained from suicide victims and 12 from matched controls. We found significant lower binding to alpha 1 receptors in several brain regions of the suicide group as compared with matched controls. This decrease in receptor density was evident in portions of the prefrontal cortex, as well as the temporal cortex and in the caudate nucleus. Age, sex, presence of alcohol, and time of death to autopsy did not affect prazosin binding, in our sample, as measured by autoradiography

  10. Nonneural Androgen Receptors Affect Sexual Differentiation of Brain and Behavior.

    Science.gov (United States)

    Swift-Gallant, Ashlyn; Coome, Lindsay A; Ramzan, Firyal; Monks, D Ashley

    2016-02-01

    Testosterone, acting via estrogenic and androgenic pathways, is the major endocrine mechanism promoting sexual differentiation of the mammalian nervous system and behavior, but we have an incomplete knowledge of which cells and tissues mediate these effects. To distinguish between neural and nonneural actions of androgens in sexual differentiation of brain and behavior, we generated a loxP-based transgenic mouse, which overexpresses androgen receptors (ARs) when activated by Cre. We used this transgene to overexpress AR globally in all tissues using a cytomegalovirus (CMV)-Cre driver (CMV-AR), and we used a Nestin-Cre driver to overexpress AR only in neural tissue (Nes-AR). We then examined whether neural or global AR overexpression can affect socio-sexual behaviors using a resident-intruder paradigm. We found that both neural and global AR overexpression resulted in decreased aggressive behaviors and increased thrusting during mounting of intruders, consistent with a neural site of action. Global, but not neural, AR overexpression in males led to an increase in same-sex anogenital investigation. Together, these results suggest novel roles for nonneural AR in sexual differentiation of mice, and indicate that excess AR can lead to a paradoxical reduction of male-typical behavior. PMID:26636184

  11. Stimulation of brain muscarinic acetylcholine receptors acutely reverses radiogenic hypodipsia

    International Nuclear Information System (INIS)

    A sufficiently large dose of ionizing radiation produces changes in water consumption. However, the direction, durations, and physiological substrates of these alterations remain in question. Here we report a 5-d hypodipsia in rats exposed to 600 rads 60Co but a more transient, albeit larger, reduction in drinking after 1000 60Co. Brain cholinergic neurons have been implicated as mediators of thirst. Therefore, we explored the role of hypothalamic muscarinic receptors in the production of radiation-induced hypodipsia. This was accomplished through the intrahypothalamic injection of carbachol (a muscarinic agonist) or atropine (a muscarinic antagonist) in irradiated rats. Intracranial carbachol produced acute reversal of radiogenic hypodipsia while atropine potentiated the hypodipsia. These post-irradiation drug-induced behaviors were similar to those observed after the same drug treatments before irradiation. Since cholinergic neuronal functions persist and are labile (can be pharmacologically stimulated and blocked) after irradiation, this suggests that other neuronal systems and/or neurochemicals may be more prominently involved in radiogenic hypodipsia

  12. Porcine brain natriuretic peptide receptor in bovine adrenal cortex

    International Nuclear Information System (INIS)

    The action of porcine brain natriuretic peptide (pBNP) on the steroidogenesis was investigated in cultured bovine adrenocortical cells. Porcine BNP induced a significant dose-dependent inhibition of both ACTH- and A II-stimulated aldosterone secretion. 10/sup /minus/8/M and 10/sup /minus/7/M pBNP also significantly inhibited ACTH-stimulated cortisol and dehydroepiandrosterone (DHEA) secretions. Binding studies of [125I]-pBNP to bovine adrenocortical membrane fractions showed that adrenal cortex had high-affinity and low-capacity pBNP binding sites, with a dissociation constant (Kd) of 1.70 x 10/sup /minus/10/M and a maximal binding capacity (Bmax) of 19.9 fmol/mg protein. Finally, the 135 Kd radioactive band was specially visualized in the affinity labeling of bovine adrenal cortex with disuccinimidyl suberate (DSS). These results suggest that pBNP may have receptor-mediated suppressive actions on bovine adrenal steroidogenesis, similar to that in atrial natriuretic peptide

  13. Porcine brain natriuretic peptide receptor in bovine adrenal cortex

    Energy Technology Data Exchange (ETDEWEB)

    Higuchi, K.; Hashiguchi, T.; Ohashi, M.; Takayanagi, R.; Haji, M.; Matsuo, H.; Nawata, H.

    1989-01-01

    The action of porcine brain natriuretic peptide (pBNP) on the steroidogenesis was investigated in cultured bovine adrenocortical cells. Porcine BNP induced a significant dose-dependent inhibition of both ACTH- and A II-stimulated aldosterone secretion. 10/sup /minus/8/M and 10/sup /minus/7/M pBNP also significantly inhibited ACTH-stimulated cortisol and dehydroepiandrosterone (DHEA) secretions. Binding studies of (/sup 125/I)-pBNP to bovine adrenocortical membrane fractions showed that adrenal cortex had high-affinity and low-capacity pBNP binding sites, with a dissociation constant (Kd) of 1.70 x 10/sup /minus/10/M and a maximal binding capacity (Bmax) of 19.9 fmol/mg protein. Finally, the 135 Kd radioactive band was specially visualized in the affinity labeling of bovine adrenal cortex with disuccinimidyl suberate (DSS). These results suggest that pBNP may have receptor-mediated suppressive actions on bovine adrenal steroidogenesis, similar to that in atrial natriuretic peptide (ANP).

  14. Targeting neurotransmitter receptors with nanoparticles in vivo allows single-molecule tracking in acute brain slices

    Science.gov (United States)

    Varela, Juan A.; Dupuis, Julien P.; Etchepare, Laetitia; Espana, Agnès; Cognet, Laurent; Groc, Laurent

    2016-03-01

    Single-molecule imaging has changed the way we understand many biological mechanisms, particularly in neurobiology, by shedding light on intricate molecular events down to the nanoscale. However, current single-molecule studies in neuroscience have been limited to cultured neurons or organotypic slices, leaving as an open question the existence of fast receptor diffusion in intact brain tissue. Here, for the first time, we targeted dopamine receptors in vivo with functionalized quantum dots and were able to perform single-molecule tracking in acute rat brain slices. We propose a novel delocalized and non-inflammatory way of delivering nanoparticles (NPs) in vivo to the brain, which allowed us to label and track genetically engineered surface dopamine receptors in neocortical neurons, revealing inherent behaviour and receptor activity regulations. We thus propose a NP-based platform for single-molecule studies in the living brain, opening new avenues of research in physiological and pathological animal models.

  15. Positron Emission Tomography (PET Quantification of GABAA Receptors in the Brain of Fragile X Patients.

    Directory of Open Access Journals (Sweden)

    Charlotte D'Hulst

    Full Text Available Over the last several years, evidence has accumulated that the GABAA receptor is compromised in animal models for fragile X syndrome (FXS, a common hereditary form of intellectual disability. In mouse and fly models, agonists of the GABAA receptor were able to rescue specific consequences of the fragile X mutation. Here, we imaged and quantified GABAA receptors in vivo in brain of fragile X patients using Positron Emission Topography (PET and [11C]flumazenil, a known high-affinity and specific ligand for the benzodiazepine site of GABAA receptors. We measured regional GABAA receptor availability in 10 fragile X patients and 10 control subjects. We found a significant reduction of on average 10% in GABAA receptor binding potential throughout the brain in fragile X patients. In the thalamus, the brain region showing the largest difference, the GABAA receptor availability was even reduced with 17%. This is one of the first reports of a PET study of human fragile X brain and directly demonstrates that the GABAA receptor availability is reduced in fragile X patients. The study reinforces previous hypotheses that the GABAA receptor is a potential target for rational pharmacological treatment of fragile X syndrome.

  16. Scaffolding of Fyn Kinase to the NMDA Receptor Determines Brain Region Sensitivity to Ethanol

    OpenAIRE

    Yaka, Rami; Phamluong, Khanhky; Ron, Dorit

    2003-01-01

    Alcohol (ethanol) abuse is a major societal problem. Although ethanol is a structurally simple, diffusible molecule, its sites of action are surprisingly selective, and the molecular mechanisms underlying specificity in ethanol actions are not understood. The NMDA receptor channel is one of the main targets for ethanol in the brain. We report here that the brain region-specific compartmentalization of Fyn kinase determines NMDA receptor sensitivity to ethanol. We demonstrate that, in the hipp...

  17. Eph Receptor and Ephrin Signaling in Developing and Adult Brain of the Honeybee (Apis mellifera)

    OpenAIRE

    Vidovic, Maria; Nighorn, Alan; Koblar, Simon; Maleszka, Ryszard

    2007-01-01

    Roles for Eph receptor tyrosine kinase and ephrin signaling in vertebrate brain development are well established. Their involvement in the modulation of mammalian synaptic structure and physiology is also emerging. However, less is known of their effects on brain development and their function in adult invertebrate nervous systems. Here, we report on the characterization of Eph receptor and ephrin orthologs in the honeybee, Apis mellifera (Am), and their role in learning and memory. In situ h...

  18. Localization of androgen receptors and estrogen receptors in the same cells of the songbird brain

    Energy Technology Data Exchange (ETDEWEB)

    Gahr, M. (Univ. of Kaiserslautern (Germany, F.R.))

    1990-12-01

    Estrogens and androgens each have unique effects but act together for the neural differentiation and control of sexual behaviors in male vertebrates, such as the canary. The neuronal basis for these synergistic effects is elusive because the spatial relation between estrogen target cells and androgen target cells is unknown. This study localized estrogen receptor (ER)-containing cells by using immunocytochemistry and androgen receptor (AR)-containing cells by using autoradiography in the same sections of the male canary brain. Three cell types, those containing only ER, those containing only AR, and those containing both ER and AR, were found in tissue-specific frequencies. The midbrain nucleus intercollicularis exhibited the highest number of cells expressing both ER and AR, whereas ER and AR are expressed only in disjunctive cell populations in the forebrain nucleus hyperstriatalis ventrale, pars caudale. Synergistic effects of androgens and estrogens for the neural behavorial control could result from cells containing both ER and AR (intracellular) and from neural circuits containing ER and AR in different cells (intercellular).

  19. 123I-iomazenil brain receptor SPECT in focal epilepsy. In comparison with 99mTc-HMPAO brain SPECT, MRI and Video/EEG monitoring

    International Nuclear Information System (INIS)

    Purpose: To evaluate the clinical value of 123I-Iomazenil brain receptor SPECT in diagnosis of focal epilepsy in comparison with 99mTc-HMPAO brain SPECT, MRI and Video/EEG monitoring. Methods 123I-Iomazenil brain receptor SPECT was performed on 40 patients with focal epilepsy. The results were compared with those obtained by 99mTc-HMPAO brain SPECT, MRI and Video/EEG monitoring. Results: In 40 patients, the sensitivity of Video/EEG monitoring for localization of epileptogenic area was 95% (38/40). The sensitivity of 123I-iomazenil brain receptor SPECT, 99mTc-HMPAO brain SPECT and MRI for localization of epileptogenic area compared with Video/EEG monitoring ('gold standard') was 65.8%(25/38), 55.3%(21/38) and 47.4%(18/38), respectively. The localization of epileptogenic area with 123I-Iomazenil brain receptor SPECT was in concordance with Video/EEG monitoring in 20 patients, 99mTc-HMPAO brain SPECT in 15 patients and MRI in 16 patients, respectively. The sensitivity of 123I-Iomazenil brain receptor SPECT combined with MRI for localization of epileptogenic area was 84.2%(32/38). Conclusions: 123I-Iomazenil brain receptor SPECT is a useful method in detecting and localizing epileptogenic area. The combination of 123I-Iomazenil brain receptor SPECT and MRI has a high sensitivity for detecting epileptogenic area

  20. Distinct angiotensin II receptor in primary cultures of glial cells from rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Raizada, M.K.; Phillips, M.I.; Crews, F.T.; Sumners, C.

    1987-07-01

    Angiotensin II (Ang-II) has profound effects on the brain. Receptors for Ang-II have been demonstrated on neurons, but no relationship between glial cells and Agn-II has been established. Glial cells (from the hypothalamus and brain stem of 1-day-old rat brains) in primary culture have been used to demonstrate the presence of specific Ang-II receptors. Binding of /sup 125/I-Ang-II to glial cultures was rapid, reversible, saturable, and specific for Ang-II. The rank order of potency of /sup 125/I-Ang-II binding was determined. Scatchard analysis revealed a homogeneous population of high-affinity binding sites with a B/sub max/ of 110 fmol/mg of protein. Light-microscopic autoradiography of /sup 125/I-Ang-II binding supported the kinetic data, documenting specific Ang-II receptors on the glial cells. Ang-II stimulated a dose-dependent hydrolysis of phosphatidylinositols in glial cells, an effect mediated by Ang-II receptors. However, Ang-II failed to influence (/sup 3/H) norepinephrine uptake, and catecholamines failed to regulate Ang-II receptors, effects that occur in neurons. These observations demonstrate the presence of specific Ang-II receptors on the glial cells in primary cultures derived from normotensive rat brain. The receptors are kinetically similar to, but functionally distinct from, the neuronal Ang-II receptors.

  1. Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders.

    Science.gov (United States)

    Saavedra, Juan M

    2012-11-01

    The effects of brain AngII (angiotensin II) depend on AT(1) receptor (AngII type 1 receptor) stimulation and include regulation of cerebrovascular flow, autonomic and hormonal systems, stress, innate immune response and behaviour. Excessive brain AT(1) receptor activity associates with hypertension and heart failure, brain ischaemia, abnormal stress responses, blood-brain barrier breakdown and inflammation. These are risk factors leading to neuronal injury, the incidence and progression of neurodegerative, mood and traumatic brain disorders, and cognitive decline. In rodents, ARBs (AT(1) receptor blockers) ameliorate stress-induced disorders, anxiety and depression, protect cerebral blood flow during stroke, decrease brain inflammation and amyloid-β neurotoxicity and reduce traumatic brain injury. Direct anti-inflammatory protective effects, demonstrated in cultured microglia, cerebrovascular endothelial cells, neurons and human circulating monocytes, may result not only in AT(1) receptor blockade, but also from PPARγ (peroxisome-proliferator-activated receptor γ) stimulation. Controlled clinical studies indicate that ARBs protect cognition after stroke and during aging, and cohort analyses reveal that these compounds significantly reduce the incidence and progression of Alzheimer's disease. ARBs are commonly used for the therapy of hypertension, diabetes and stroke, but have not been studied in the context of neurodegenerative, mood or traumatic brain disorders, conditions lacking effective therapy. These compounds are well-tolerated pleiotropic neuroprotective agents with additional beneficial cardiovascular and metabolic profiles, and their use in central nervous system disorders offers a novel therapeutic approach of immediate translational value. ARBs should be tested for the prevention and therapy of neurodegenerative disorders, in particular Alzheimer's disease, affective disorders, such as co-morbid cardiovascular disease and depression, and traumatic

  2. Melanocortin MC4 receptor agonists alleviate brain damage in abdominal compartment syndrome in the rat.

    Science.gov (United States)

    Liu, Dong; Zhang, Hong-Guang; Zhao, Zi-Ai; Chang, Ming-Tao; Li, Yang; Yu, Jian; Zhang, Ye; Zhang, Lian-Yang

    2015-02-01

    Intra-abdominal hypertension (IAH) is accompanied by high morbidity and mortality in surgical departments and ICUs. However, its specific pathophysiology is unclear. IAH not only leads to intra-abdominal tissue damage but also causes dysfunction in distal organs, such as the brain. In this study, we explore the protective effects of melanocortin 4 receptor agonists in IAH-induced brain injury. The IAH rat models were induced by hemorrhagic shock/resuscitation (with the mean arterial pressure (MAP) maintained at 30 mm Hg for 90 min followed by the reinfusion of the withdrawn blood with lactated Ringer's solution). Then, air was injected into the peritoneal cavity of the rats to maintain an intra-abdominal pressure of 20 mm Hg for 4 h. The effects of the melanocortin 4 receptor agonist RO27-3225 in alleviating the rats' IAH brain injuries were observed, which indicated that RO27-3225 could reduce brain edema, the expressions of the IL-1β and TNF-α inflammatory cytokines, the blood-brain barrier's permeability and the aquaporin4 (AQP4) and matrix metalloproteinase 9 (MMP9) levels. Moreover, the nicotinic acetylcholine receptor antagonist chlorisondamine and the selective melanocortin 4 receptor antagonist HS024 can negate the protective effects of the RO27-3225. The MC4R agonist can effectively reduce the intracerebral proinflammatory cytokine gene expression and alleviate the brain injury caused by blood-brain barrier damage following IAH. PMID:25616531

  3. [3H]Ethylketocyclazocine binding to mouse brain membranes: evidence for a kappa opioid receptor type

    International Nuclear Information System (INIS)

    The binding of the putative kappa agonist ethylketocyclazocine (EKC) to synaptosomal membranes of mouse brain was studied. This benzomorphan was able to bind to different opioid receptors. A portion of this binding was not inhibited by the agonist naloxone, even at high concentrations (10 microM). This population of receptors, to which opioate alkaloids and opiod peptides display very low affinity, is probably the sigma receptor. Another class of binding sites was identified by the simultaneous addition of the selective agonists Sandoz FK-33824 and D-Ala2-D-Leu5-enkephalin, which blocked the access of EKC to mu and delta opioid receptors, respectively, leaving a portion of naloxone-displaceable benzomorphan binding still detectable. Analysis of this remaining binding revealed a small population of receptors of high affinity, the kappa receptor. Therefore, EKC binds to the mu, delta, kappa and sigma receptors in the mouse brain, with similar affinities for the mu and kappa (0.22 and 0.15 nM). These results confirm the existence of a kappa opioid receptor type in the mouse brain

  4. GABA(A) receptor downregulation in brains of subjects with autism.

    Science.gov (United States)

    Fatemi, S Hossein; Reutiman, Teri J; Folsom, Timothy D; Thuras, Paul D

    2009-02-01

    Gamma-aminobutyric acid A (GABA(A)) receptors are ligand-gated ion channels responsible for mediation of fast inhibitory action of GABA in the brain. Preliminary reports have demonstrated altered expression of GABA receptors in the brains of subjects with autism suggesting GABA/glutamate system dysregulation. We investigated the expression of four GABA(A) receptor subunits and observed significant reductions in GABRA1, GABRA2, GABRA3, and GABRB3 in parietal cortex (Brodmann's Area 40 (BA40)), while GABRA1 and GABRB3 were significantly altered in cerebellum, and GABRA1 was significantly altered in superior frontal cortex (BA9). The presence of seizure disorder did not have a significant impact on GABA(A) receptor subunit expression in the three brain areas. Our results demonstrate that GABA(A) receptors are reduced in three brain regions that have previously been implicated in the pathogenesis of autism, suggesting widespread GABAergic dysfunction in the brains of subjects with autism. PMID:18821008

  5. Is there a gender difference of somatostatin-receptor density in the human brain?

    Science.gov (United States)

    Pichler, Robert; Maschek, Wilhelmine; Crespillo, Carmen; Esteva, Isabel; Soriguer, Federico

    2002-01-01

    Animal experiments and observations in human brains have convincingly shown that sexual differentiation not only concerns the genitalia but also the brain. This has been investigated also in the light of a possible explanation of a presumed biological aetiology of transsexuality. The volume of the central subdivision of the bed nucleus of the stria terminalis, a brain area that is essential for sexual behaviour, has been reported to be larger in men than in women. Additionally, the number of somatostatin expressing neurons in this region was shown to be higher in men than in women. As neuronal production of somatostatin is involved the idea is striking whether somatostatin-receptor density in the cortex of cerebral hemispheres might be related to gender identity. We investigated in vivo the density of somatostatin-receptors in selected regions of the human brain in both sexes by means of receptor scintigraphy. Basal ganglia tracer uptake of 111-In-Pentreotide was equally low in both genders at 0,80% +/ 0,26 (related to tracer uptake of the whole brain layer). Temporal cortex accumulated at 2,9% +/ 1,1 in men and at 2,3% +/ 0,76 in women. Frontal brain region had an uptake of 3,0% +/ 1,4 in male and of 2,5% +/ 1,3 in female. This shows a tendency in males for relatively augmented uptake indicating higher somatostatin receptor density in temporal and frontal cerebral cortex. PMID:12500167

  6. A search for functional histamine H4 receptors in the human, guinea pig and mouse brain.

    Science.gov (United States)

    Feliszek, Monika; Speckmann, Valerie; Schacht, Daniel; von Lehe, Marec; Stark, Holger; Schlicker, Eberhard

    2015-01-01

    Histamine H4 receptors are expressed in immune cells, but their potential role in the brain is less clear. Although H4 transcripts have been identified in human and rat brain, the presence of H4 receptors on the protein level has so far not been proven since appropriate antibodies fulfilling the strict criteria for G protein-coupled receptors are missing. Here, we searched for functional H4 receptors in human, guinea pig and mouse cortex. We studied whether H4 receptor activation is associated with increased GTPγS binding and reduced noradrenaline release. The latter two effects have been previously shown for H3 receptors, which, like the H4 receptors, are coupled to G i/o protein. G protein activation was studied using (35)S-GTPγS binding in cortical membranes. The electrically induced (3)H-noradrenaline release was determined in superfused cortical slices. The H4 agonist 4-methylhistamine failed to affect (35)S-GTPγS binding and/or noradrenaline release in human, guinea pig and mouse cortex although an H 3 receptor-mediated increase in (35)S-GTPγS binding and inhibition of noradrenaline release occurred in parallel experiments. In conclusion, functional H4 receptors increasing (35)S-GTPγS binding and/or decreasing noradrenaline release are not found in human, guinea pig and mouse cortex. PMID:25300787

  7. Localization and characterization of brain somatostatin receptors as studied with somatostatin-14 and somatostatin-28 receptor radioautography

    International Nuclear Information System (INIS)

    The localization and characterization of receptors for somatostatin-14 (S-14) and somatostatin-28 (S-28) were studied in the rat brain using the iodinated agonists [Tyr0,D-Trp8]S-14 and [Leu8,D-Trp22,Tyr25]S-28 as tracers. By radioautography, the distribution of receptors for both S-14 and S-28 appeared very similar with high levels of binding in the deep layers of the cortex, the cingulate cortex, the claustrum, the locus coeruleus and most structures of the limbic system. Generally, there was a correlation between the localization of somatostatin receptors and that of immunoreactive somatostatin, as evaluated by immunocytochemistry. However, in some areas, an inverse correlation between receptor and peptide concentrations was observed. (Auth.)

  8. Light microscopic localization of brain opiate receptors: a general autoradiographic method which preserves tissue quality

    International Nuclear Information System (INIS)

    A general technique is described for using slide-mounted unfixed tissue sections to characterize and visualize drug and neurotransmitter receptors in brain or other tissues. The preparation of material, from fresh frozen, unfixed brain to dried sections securely attached to slides, is described in detail. The tissue can be kept intact during incubation at varying temperatures in solutions containing radiolabeled ligand, ions, buffers, and allosteric effectors. Strategies are described for determining optimal stereospecific binding with highest signal-to-noise ratios and for determining that a meaningful receptor is being studied. Dry formaldehyde fixation by vapors from heated paraformaldehyde preserves the tissue quality and traps the ligand near its site on the receptor, permitting subsequent histological processing through alcohols, solvents, and aqueous media, including liquid nuclear track emulsion. Visualization of [3H]naloxone- or [3H]enkephalin-labeled opiate receptor distributions in rat and human brains is achieved by tritium-sensitive film or by classical wet emulsion autoradiography. The advantages of the film include its ease of use and the ability to quantify receptor density by densitometry which can be computer-assisted. The advantage of the emulsion is the greater resolution and the concomitant appearance of morphology in cell-stained sections. Examples of correlations of opiate receptor distributions which underlying cytoarchitecture illustrate the potential for receptor localization studies

  9. Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions.

    Science.gov (United States)

    Mahfouz, Ahmed; Lelieveldt, Boudewijn P F; Grefhorst, Aldo; van Weert, Lisa T C M; Mol, Isabel M; Sips, Hetty C M; van den Heuvel, José K; Datson, Nicole A; Visser, Jenny A; Reinders, Marcel J T; Meijer, Onno C

    2016-03-01

    Steroid receptors are pleiotropic transcription factors that coordinate adaptation to different physiological states. An important target organ is the brain, but even though their effects are well studied in specific regions, brain-wide steroid receptor targets and mediators remain largely unknown due to the complexity of the brain. Here, we tested the idea that novel aspects of steroid action can be identified through spatial correlation of steroid receptors with genome-wide mRNA expression across different regions in the mouse brain. First, we observed significant coexpression of six nuclear receptors (NRs) [androgen receptor (Ar), estrogen receptor alpha (Esr1), estrogen receptor beta (Esr2), glucocorticoid receptor (Gr), mineralocorticoid receptor (Mr), and progesterone receptor (Pgr)] with sets of steroid target genes that were identified in single brain regions. These coexpression relationships were also present in distinct other brain regions, suggestive of as yet unidentified coordinate regulation of brain regions by, for example, glucocorticoids and estrogens. Second, coexpression of a set of 62 known NR coregulators and the six steroid receptors in 12 nonoverlapping mouse brain regions revealed selective downstream pathways, such as Pak6 as a mediator for the effects of Ar and Gr on dopaminergic transmission. Third, Magel2 and Irs4 were identified and validated as strongly responsive targets to the estrogen diethylstilbestrol in the mouse hypothalamus. The brain- and genome-wide correlations of mRNA expression levels of six steroid receptors that we provide constitute a rich resource for further predictions and understanding of brain modulation by steroid hormones. PMID:26811448

  10. The corticosterone synthesis inhibitor metyrapone decreases dopamine D1 receptors in the rat brain

    International Nuclear Information System (INIS)

    Experiments were performed to examine the effect of metyrapone, an inhibitor of corticosterone synthesis, on the level of dopamine D1 receptors and their transcripts in the caudate-putamen, nucleus accumbens and olfactory tubercle of the rat brain. The binding to dopamine D1 receptors was measured by receptor autoradiography using the specific D1 receptor antagonist [3H]SCH 23390. The level of dopamine D1 receptor messenger RNA was determined by in situ hybridization histochemistry. The results obtained have shown that metyrapone (two injections of 150 and 50 mg/kg, i.p., given 20 and 3 h before killing, respectively) induced a decrease in the D1 receptor-specific binding in the studied areas of the rat brain. In the caudate-putamen, the decrease in [3H]SCH 23390 binding was stronger in the medial (31-39%) than in the lateral part (24-27%). Decreases similar to those in the caudate-putamen were observed in the nucleus accumbens (21%) and olfactory tubercle (32%). Furthermore, metyrapone decreased the level of dopamine D1 receptor messenger RNA in the caudate-putamen (17-28%), nucleus accumbens (20%) and olfactory tubercle (18%).In conclusion, our study indicates that glucocorticoids might be involved in the regulation of dopamine D1 receptor level in the rat brain, since metyrapone (which inhibits the synthesis of these hormones) decreases the messenger RNA encoding D1 receptor synthesis, as well as the specific binding to this receptor. (Copyright (c) 1997 Elsevier Science B.V., Amsterdam. All rights reserved.)

  11. Brain regional differences in CB1 receptor adaptation and regulation of transcription

    OpenAIRE

    Lazenka, M.F.; Selley, D.E.; Sim-Selley, L.J.

    2012-01-01

    Cannabinoid CB1 receptors (CB1Rs) are expressed throughout the brain and mediate the central effects of cannabinoids, including Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of marijuana. Repeated THC administration produces tolerance to cannabinoid-mediated effects, although the magnitude of tolerance varies by effect. Consistent with this observation, CB1R desensitization and downregulation, as well induction of immediate early genes (IEGs), varies by brain region. Zif268...

  12. High abundance androgen receptor in goldfish brain: characteristics and seasonal changes

    International Nuclear Information System (INIS)

    Testosterone (T) exerts its actions in brain directly via androgen receptors or, after aromatization to estradiol, via estrogen receptors. Brain aromatase activity in teleost fish is 100-1000 times greater than in mammals and would be expected to significantly reduce the quantity of androgen available for receptor binding. Experiments were carried out on the goldfish Carassius auratus to determine if androgen receptors are present in teleost brain and whether their physicochemical properties reflect elevated aromatase. Cytosolic and nuclear extracts were assayed with the use of [3H]T and charcoal, Sephadex LH-20, or DNA-cellulose chromatography to separate bound and free steroids. Binding activity was saturable and had an equally high affinity for T and 5 alpha-dihydrotestosterone. Although mibolerone was a relatively weak competitor, the putative teleost androgen 11-ketotestosterone, methyltrienolone (R1881), estradiol, progesterone, and cortisol were poor ligands. Characteristics that distinguish this receptor from a steroid-binding protein in goldfish serum are the presence of binding activity in both nuclear and cytosolic extracts, a low rate of ligand-receptor dissociation, electrophoretic mobility, sedimentation properties in low vs. high salt, and tissue distribution. DNA cellulose-adhering and nonadhering forms were detected, but these did not differ in other variables measured. Although goldfish androgen receptors resembled those of mammals in all important physicochemical characteristics, they were unusually abundant compared to levels in rat brain, but comparable to levels in prostate and other male sex hormone target organs. Moreover, there were seasonal variations in total receptors, with a peak at spawning (April) 4- to 5-fold higher than values in reproductively inactive fish

  13. Memory consolidation and amnesia modify 5-HT6 receptors expression in rat brain: an autoradiographic study.

    Science.gov (United States)

    Meneses, A; Manuel-Apolinar, L; Castillo, C; Castillo, E

    2007-03-12

    Traditionally, the search for memory circuits has been centered on examinations of amnesic and AD patients, cerebral lesions and, neuroimaging. A complementary alternative might be the use of autoradiography with radioligands. Indeed, ex vivo autoradiographic studies offer the advantage to detect functionally active receptors altered by pharmacological tools and memory formation. Hence, herein the 5-HT(6) receptor antagonist SB-399885 and the amnesic drugs scopolamine or dizocilpine were used to manipulate memory consolidation and 5-HT(6) receptors expression was determined by using [(3)H]-SB-258585. Thus, memory consolidation was impaired in scopolamine and dizocilpine treated groups relative to control vehicle but improved it in SB-399885-treated animals. SB-399885 improved memory consolidation seems to be associated with decreased 5-HT(6) receptors expression in 15 out 17 brain areas. Scopolamine or dizocilpine decreased 5-HT(6) receptors expression in nine different brain areas and increased it in CA3 hippocampus or other eight areas, respectively. In brain areas thought to be in charge of procedural memory such basal ganglia (i.e., nucleus accumbens, caudate putamen, and fundus striate) data showed that relative to control animals amnesic groups showed diminished (scopolamine) or augmented (dizocilpine) 5-HT(6) receptor expression. SB-399885 showing improved memory displayed an intermediate expression in these same brain regions. A similar intermediate expression occurs with regard to amygdala, septum, and some cortical areas in charge of explicit memory storage. However, relative to control group amnesic and SB-399885 rats in the hippocampus, region where explicit memory is formed, showed a complex 5-HT(6) receptors expression. In conclusion, these results indicate neural circuits underlying the effects of 5-HT(6) receptor antagonists in autoshaping task and offer some general clues about cognitive processes in general. PMID:17267053

  14. Lactate Receptor Sites Link Neurotransmission, Neurovascular Coupling, and Brain Energy Metabolism

    DEFF Research Database (Denmark)

    Lauritzen, Knut H; Morland, Cecilie; Puchades, Maja; Holm-Hansen, Signe; Hagelin, Else Marie; Lauritzen, Fredrik; Attramadal, Håvard; Storm-Mathisen, Jon; Gjedde, Albert; Bergersen, Linda H

    The G-protein-coupled lactate receptor, GPR81 (HCA1), is known to promote lipid storage in adipocytes by downregulating cAMP levels. Here, we show that GPR81 is also present in the mammalian brain, including regions of the cerebral neocortex and hippocampus, where it can be activated by physiolog...... GPR81 receptors, can act as a volume transmitter that links neuronal activity, cerebral energy metabolism and energy substrate availability....

  15. Effects of Gender and Estrogen Receptors on Iron-Induced Brain Edema Formation.

    Science.gov (United States)

    Xie, Qing; Xi, Guohua; Keep, Richard F; Hua, Ya

    2016-01-01

    Our previous studies have shown that female mice have less brain edema and better recovery in neurological deficits after intracerebral hemorrhage (ICH) and that 17β-estradiol treatment in male mice markedly reduces ICH-induced brain edema. In this study, we investigated the role of gender and the estrogen receptors (ERs) in iron-induced brain edema. There were three parts in this study: (1) either male or female mice received an injection of 10 μL FeCl2 (1 mM) into the right caudate; (2) females received an intracaudate injection of FeCl2 or saline with 1 μg of ICI 182,780 (antagonists of ERs) or vehicle; and (3) males were treated with the ER regulator tamoxifen (5 mg/kg subcutaneously) or vehicle 1 h after FeCl2 injection. Mice were euthanized 24 h later for brain edema determination. FeCl2 induced lower brain edema in females than in males. Co-injection of ICI 182,780 with FeCl2 aggravated iron-induced brain edema in female mice. ICI 182,780 itself did not induce brain edema at the dose of 1 μg. Tamoxifen treatment reduced FeCl2-induced brain edema in male mice. In conclusion, iron induced less brain edema in female mice than in males. ER modification can affect iron-induced brain edema. PMID:26463972

  16. Luteolin inhibits GABAA receptors in HEK cells and brain slices

    Science.gov (United States)

    Shen, Mei-Lin; Wang, Chen-Hung; Chen, Rita Yu-Tzu; Zhou, Ning; Kao, Shung-Te; Wu, Dong Chuan

    2016-01-01

    Modulation of the A type γ-aminobutyric acid receptors (GABAAR) is one of the major drug targets for neurological and psychological diseases. The natural flavonoid compound luteolin (2-(3,4-Dihydroxyphenyl)- 5,7-dihydroxy-4-chromenone) has been reported to have antidepressant, antinociceptive, and anxiolytic-like effects, which possibly involve the mechanisms of modulating GABA signaling. However, as yet detailed studies of the pharmacological effects of luteolin are still lacking, we investigated the effects of luteolin on recombinant and endogenous GABAAR-mediated current responses by electrophysiological approaches. Our results showed that luteolin inhibited GABA-mediated currents and slowed the activation kinetics of recombinant α1β2, α1β2γ2, α5β2, and α5β2γ2 receptors with different degrees of potency and efficacy. The modulatory effect of luteolin was likely dependent on the subunit composition of the receptor complex: the αβ receptors were more sensitive than the αβγ receptors. In hippocampal pyramidal neurons, luteolin significantly reduced the amplitude and slowed the rise time of miniature inhibitory postsynaptic currents (mIPSCs). However, GABAAR-mediated tonic currents were not significantly influenced by luteolin. These data suggested that luteolin has negative modulatory effects on both recombinant and endogenous GABAARs and inhibits phasic rather than tonic inhibition in hippocampus. PMID:27292079

  17. Increased brain dopamine and dopamine receptors in schizophrenia

    International Nuclear Information System (INIS)

    In postmortem samples of caudate nucleus and nucleus accumbens from 48 schizophrenic patients, there were significant increases in both the maximum number of binding sites (Bmax) and the apparent dissociation constant (KD) for tritiated spiperone. The increase in apparent KD probably reflects the presence of residual neuroleptic drugs, but changes in Bmax for tritiated spiperone reflect genuine changes in receptor numbers. The increases in receptors were seen only in patients in whom neuroleptic medication had been maintained until the time of death, indicating that they may be entirely iatrogenic. Dopamine measurements for a larger series of schizophrenic and control cases (n greater than 60) show significantly increased concentrations in both the nucleus accumbens and caudate nucleus. The changes in dopamine were not obviously related to neuroleptic medication and, unlike the receptor changes, were most severe in younger patients

  18. In vivo brain dopaminergic receptor site mapping using 75Se-labeled pergolide analogs: the effects of various dopamine receptor agonists and antagonists

    International Nuclear Information System (INIS)

    Perogolide mesylate is a new synthetic ergoline derivative which is reported to possess agonistic activity at central dopamine receptor sites in the brain. The authors have synthesized a [75Se]-radiolabeled pergolide mesylate derivative, [75Se]-pergolide tartrate, which, after i.v. administration to mature male rats, showed a time course differentiation in the uptake of this radiolabeled compound in isolated peripheral and central (brain) tissues that are known to be rich in dopamine receptor sites. Further studies were conducted in which the animals were preexposed to the dopamine receptor agonist SKF-38393, as well as the dopamine receptor antagonists (+)-butaclamol, (-)-butaclamol, (+/-)-butaclamol and (-)-chloroethylnorapomorphine, to substantiate the specific peripheral and central localization patterns of [75Se]-pergolide tartrate. Further investigations were also conducted in which the animals received an i.v. administration of N-isopropyl-l-123-p-iodoamphetamine ([123I]-iodoamphetamine). However, [123I]-iodoamphetamine did not demonstrate a specific affinity for any type of receptor site in the brain. These investigations further substantiated the fact that [75Se]-pergolide tartrate does cross the blood-brain barrier is quickly localized at specific dopamine receptor sites in the intact rat brain and that this localization pattern can be affected by preexposure to different dopamine receptor agonists and antagonists. Therefore, these investigations provided further evidence that [75Se]-pergolide tartrate and other radiolabeled ergoline analogs might be useful as brain dopamine receptor localization radiopharmaceuticals

  19. In vivo brain dopaminergic receptor site mapping using /sup 75/Se-labeled pergolide analogs: the effects of various dopamine receptor agonists and antagonists

    Energy Technology Data Exchange (ETDEWEB)

    Weaver, A.

    1986-01-01

    Perogolide mesylate is a new synthetic ergoline derivative which is reported to possess agonistic activity at central dopamine receptor sites in the brain. The authors have synthesized a (/sup 75/Se)-radiolabeled pergolide mesylate derivative, (/sup 75/Se)-pergolide tartrate, which, after i.v. administration to mature male rats, showed a time course differentiation in the uptake of this radiolabeled compound in isolated peripheral and central (brain) tissues that are known to be rich in dopamine receptor sites. Further studies were conducted in which the animals were preexposed to the dopamine receptor agonist SKF-38393, as well as the dopamine receptor antagonists (+)-butaclamol, (-)-butaclamol, (+/-)-butaclamol and (-)-chloroethylnorapomorphine, to substantiate the specific peripheral and central localization patterns of (/sup 75/Se)-pergolide tartrate. Further investigations were also conducted in which the animals received an i.v. administration of N-isopropyl-l-123-p-iodoamphetamine ((/sup 123/I)-iodoamphetamine). However, (/sup 123/I)-iodoamphetamine did not demonstrate a specific affinity for any type of receptor site in the brain. These investigations further substantiated the fact that (/sup 75/Se)-pergolide tartrate does cross the blood-brain barrier is quickly localized at specific dopamine receptor sites in the intact rat brain and that this localization pattern can be affected by preexposure to different dopamine receptor agonists and antagonists. Therefore, these investigations provided further evidence that (/sup 75/Se)-pergolide tartrate and other radiolabeled ergoline analogs might be useful as brain dopamine receptor localization radiopharmaceuticals.

  20. Distribution of androgen receptor in microdissected brain areas of the female baboon (Papio cynocephalus).

    Science.gov (United States)

    Handa, R J; Roselli, C E; Resko, J A

    1988-03-29

    We measured androgen receptors in the brain and pituitary of 4 female baboons (Papio cynocephalus) by the in vitro binding of methyltrienolone (R1881) to cytosols from 17 brain subregions as well as anterior and posterior pituitaries. High levels of AR were detected in anterior (22.1 +/- 7.1 (S.E.M.) fmol/mg protein) and posterior pituitary (12.6 +/- 3.3 fmol/mg protein). In brain tissue, the highest androgen receptor levels were found in the infundibular nucleus/median eminence (9.4 +/- 2.3 fmol/mg protein), ventromedial nucleus (6.3 +/- 1.7 fmol/mg protein) and periventricular area (4.9 +/- 1.3 fmol/mg protein). Saturation analysis of anterior pituitary and brain tissue (pool of hypothalamic, preoptic area, amygdala and septum remaining after microdissection of brain nuclei) showed that [3H]R1881 binds to the androgen receptor with high specificity and affinity (Kd = 1.25 x 10(-10) M, 0.45 x 10(-10) M, in anterior pituitary and HPA cytosol, respectively). Serum testosterone levels were low in all animals (0.59 +/- 0.26 ng/ml). With these data we described the quantitative distribution of androgen receptor in the pituitary and in specific brain nuclei in a species of nonhuman primate. The distribution is similar in many respects to that described in the male rat and the data suggest a conservation of androgen receptor distribution across species. PMID:3259151

  1. Acetylcholine receptor-inducing factor from chicken brain increases the level of mRNA encoding the receptor α subunit

    International Nuclear Information System (INIS)

    A 42-kDa glycoprotein isolated from chicken brain, referred to as acetylcholine receptor-inducing activity (ARIA), that stimulates the rate of incorporation of acetylcholine receptors into the surface of chicken myotubes may play a role in the nerve-induced accumulation of receptors at developing neuromuscular synapses. Using nuclease-protection assays, the authors have found that ARIA causes a 2- to 16-fold increase in the level of mRNA encoding the α subunit of the receptor, with little or no change in the levels of γ- and δ-subunit messengers. ARIA also increases the amount of a putative nuclear precursor of α-subunit mRNA, consistent with an activation of gene transcription. These results suggest that the concentration of α subunit may limit the rate of biosynthesis of the acetylcholine receptors in chicken myotubes. They also indicate that neuronal factors can regulate the expression of receptor subunit genes in a selective manner. Tetrodotoxin, 8-bromo-cAMP, and forskolin also increase the amount of α-subunit mRNA, with little change in the amount of γ- and δ-subunit mRNAs. Unlike ARIA, however, these agents have little effect on the concentration of the α-subunit nuclear precursor

  2. Somatostatin-receptor positive brain stem glioma visualized by octreoscan.

    Science.gov (United States)

    Pichler, Robert; Pichler, Josef; Mustafa, Hamdy; Nussbaumer, Karin; Zaunmüller, Thomas; Topakian, Raffi

    2007-06-01

    In diffuse brainstem gliomas often surgical biopsies cannot be obtained. The diagnosis relies upon imaging criteria, first line being MRI. Gliomas generally express somatostatin receptors (SSTR), which might enable receptor imaging. We present the case of a female adolescent with acute onset of hallucinations, dysphagia and diplopia. MRI detected a suggestive large pontine glioma. This lesion presented with marked In-111-pentreotide tracer uptake. SSTR-scan provided information about SSTR-expression, tumour viability and extension. Radiopeptide therapy for selected patients might be discussed. PMID:17627256

  3. The SH3 domain, but not the catalytic domain, is required for phospholipase C-γ1 to mediate epidermal growth factor-induced mitogenesis

    OpenAIRE

    Xie, Zhongjian; Chen, Ying; Pennypacker, Sally D.; Zhou, Zhiguang; PENG, DAN

    2010-01-01

    Phospholipase C-γ1 (PLC-γ1) is a multiple-domain protein and plays an important role in epidermal growth factor (EGF)-induced cell mitogenesis, but the underlying mechanism is unclear. We have previously demonstrated that PLC-γ1 is required for EGF-induced mitogenesis of squamous cell carcinoma (SCC) cells, but the mitogenic function of PLC-γ1 is independent of its lipase activity. Earlier studies suggest that the Src homology 3 (SH3) domain of PLC-γ1 possesses mitogenic activity. In the pres...

  4. Apparent target size of rat brain benzodiazepine receptor, acetylcholinesterase, and pyruvate kinase is highly influenced by experimental conditions

    International Nuclear Information System (INIS)

    Radiation inactivation is a method to determine the apparent target size of molecules. In this report we examined whether radiation inactivation of various enzymes and brain receptors is influenced by the preparation of samples preceding irradiation. The apparent target sizes of endogenous acetylcholinesterase and pyruvate kinase from rat brain and from rabbit muscle and benzodiazepine receptor from rat brain were investigated in some detail. In addition the target sizes of alcohol dehydrogenase (from yeast and horse liver), beta-galactosidase (from Escherichia coli), lactate dehydrogenase (endogenous from rat brain), and 5-HT2 receptors, acetylcholine muscarine receptors, and [35S] butyl bicyclophosphorothionate tertiary binding sites from rat brain were determined. The results show that apparent target sizes are highly influenced by the procedure applied for sample preparation before irradiation. The data indicate that irradiation of frozen whole tissue as opposed to lyophilized tissue or frozen tissue homogenates will estimate the smallest and most relevant functional target size of a receptor or an enzyme

  5. Brain receptors for thyrotropin releasing hormone in morphine tolerant-dependent rats

    International Nuclear Information System (INIS)

    The effect of chronic treatment of rats with morphine and its subsequent withdrawal on the brain receptors for thyrotropin releasing hormone (TRH) labeled with 3H-(3MeHis2)TRH (MeTRH). Male Sprague Dawley rats were implanted with 4 morphine pellets (each containing 75 mg morphine base) during a 3-day period. Placebo pellet implanted rats served as controls. Both tolerance to and dependence on morphine developed as a result of this procedure. For characterization of brain TRH receptors, the animals were sacrificed 72 h after the implantation of first pellet. In another set of animals the pellets were removed and were sacrificed 24 h later. The binding of 3H-MeTRH to membranes prepared from brain without the cerebellum was determined. 3H-MeTRH bound to brain membranes prepared from placebo pellet implanted rats at a single high affinity site with a B/sub max/ value of 33.50 +/- 0.97 fmol/mg protein and a K/sub d/ of 5.18 +/- 0.21 nM. Implantation of morphine pellets did not alter the B/sub max/ value of 3H-MeTRH but decreased the K/sub d/ value significantly. Abrupt or naloxone precipitated withdrawal of morphine did not alter B/sub max/ or the K/sub d/ values. The binding of 3H-MeTRH to brain areas was also determined. The results suggest that the development of tolerance to morphine is associated with enhanced sensitivity of brain TRH receptors, however abrupt withdrawal of morphine does not change the characteristics of brain TRH receptors

  6. Brain receptors for thyrotropin releasing hormone in morphine tolerant-dependent rats

    Energy Technology Data Exchange (ETDEWEB)

    Bhargava, H.N.; Das, S.

    1986-03-01

    The effect of chronic treatment of rats with morphine and its subsequent withdrawal on the brain receptors for thyrotropin releasing hormone (TRH) labeled with /sup 3/H-(3MeHis/sup 2/)TRH (MeTRH). Male Sprague Dawley rats were implanted with 4 morphine pellets (each containing 75 mg morphine base) during a 3-day period. Placebo pellet implanted rats served as controls. Both tolerance to and dependence on morphine developed as a result of this procedure. For characterization of brain TRH receptors, the animals were sacrificed 72 h after the implantation of first pellet. In another set of animals the pellets were removed and were sacrificed 24 h later. The binding of /sup 3/H-MeTRH to membranes prepared from brain without the cerebellum was determined. /sup 3/H-MeTRH bound to brain membranes prepared from placebo pellet implanted rats at a single high affinity site with a B/sub max/ value of 33.50 +/- 0.97 fmol/mg protein and a K/sub d/ of 5.18 +/- 0.21 nM. Implantation of morphine pellets did not alter the B/sub max/ value of /sup 3/H-MeTRH but decreased the K/sub d/ value significantly. Abrupt or naloxone precipitated withdrawal of morphine did not alter B/sub max/ or the K/sub d/ values. The binding of /sup 3/H-MeTRH to brain areas was also determined. The results suggest that the development of tolerance to morphine is associated with enhanced sensitivity of brain TRH receptors, however abrupt withdrawal of morphine does not change the characteristics of brain TRH receptors.

  7. Localization of D1 and D2 dopamine receptors in brain with subtype-specific antibodies.

    Science.gov (United States)

    Levey, A I; Hersch, S M; Rye, D B; Sunahara, R K; Niznik, H B; Kitt, C A; Price, D L; Maggio, R; Brann, M R; Ciliax, B J

    1993-10-01

    Five or more dopamine receptor genes are expressed in brain. However, the pharmacological similarities of the encoded D1-D5 receptors have hindered studies of the localization and functions of the subtypes. To better understand the roles of the individual receptors, antibodies were raised against recombinant D1 and D2 proteins and were shown to bind to the receptor subtypes specifically in Western blot and immunoprecipitation studies. Each antibody reacted selectively with the respective receptor protein expressed both in cells transfected with the cDNAs and in brain. By immunocytochemistry, D1 and D2 had similar regional distributions in rat, monkey, and human brain, with the most intense staining in striatum, olfactory bulb, and substantia nigra. Within each region, however, the precise distributions of each subtype were distinct and often complementary. D1 and D2 were differentially enriched in striatal patch and matrix compartments, in selective layers of the olfactory bulb, and in either substantia nigra pars compacta or reticulata. Electron microscopy demonstrated that D1 and D2 also had highly selective subcellular distributions. In the rat neostriatum, the majority of D1 and D2 immunoreactivity was localized in postsynaptic sites in subsets of spiny dendrites and spine heads in rat neostriatum. Presynaptic D1 and D2 receptors were also observed, indicating both subtypes may regulate neurotransmitter release. D1 was also present in axon terminals in the substantia nigra. These results provide a morphological substrate for understanding the pre- and postsynaptic functions of the genetically defined D1 and D2 receptors in discrete neuronal circuits in mammalian brain. PMID:8415621

  8. The Prorenin and (Prorenin Receptor: New Players in the Brain Renin-Angiotensin System?

    Directory of Open Access Journals (Sweden)

    Wencheng Li

    2012-01-01

    Full Text Available It is well known that the brain renin-angiotensin (RAS system plays an essential role in the development of hypertension, mainly through the modulation of autonomic activities and vasopressin release. However, how the brain synthesizes angiotensin (Ang II has been a debate for decades, largely due to the low renin activity. This paper first describes the expression of the vasoconstrictive arm of RAS components in the brain as well as their physiological and pathophysiological significance. It then focus on the (prorenin receptor (PRR, a newly discovered component of the RAS which has a high level in the brain. We review the role of prorenin and PRR in peripheral organs and emphasize the involvement of brain PRR in the pathogenesis of hypertension. Some future perspectives in PRR research are heighted with respect to novel therapeutic target for the treatment of hypertension and other cardiovascular diseases.

  9. Use of intact rat brain cells as a model to study regulation of muscarinic acetylcholine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Lee, J.H.; El-Fakahany, E.E.

    1985-08-12

    Intact rat brain cells were dissociated and used to study the regulation of muscarinic acetylcholine receptors upon exposure to muscarinic receptor agonists. Incubation of cells with carbamylcholine resulted in a time-dependent decrease in subsequent (/sup 3/H)N-methylscopolamine specific binding, an effect which reached a steady state after 3 hr at 37/sup 0/C. This effect of carbamylcholine was dependent on the concentration of the agonist in the incubation medium and was due to a reduction in the maximal binding capacity of the receptor with no decrease in the affinity of the remaining receptors. This preparation might be useful in future studies to elucidate the mechanisms underlying the regulation of muscarinic acetylcholine receptors in the central nervous system. 20 references, 3 tables.

  10. Brain mineralocorticoid receptors as resilience factor under adverse life conditions?

    NARCIS (Netherlands)

    Kanatsou, S.

    2016-01-01

    Studies in human cohorts have underlined the importance of gene-environment interactions for brain structure and function during development and in adulthood. Such interactions can make the difference between staying healthy or succumbing to disease, e.g. depression or posttraumatic stress disorder.

  11. Brain dopamine receptors in relation to clinical PET-studies

    International Nuclear Information System (INIS)

    A number of published PET Models are discussed with regard to their structure and some of the underlying assumptions. Results of experiments with spiperone and N-methylspiperone in the rat and human brain, which challenge some of these assumptions, are summarized. (author). 37 refs.; 6 figs.; 1 tab

  12. Toll-like receptors in brain development and homeostasis

    DEFF Research Database (Denmark)

    Larsen, Peter H; Holm, Thomas Hellesøe; Owens, Trevor

    2007-01-01

    Toll-like receptors (TLRs) are best known as initiators of the innate immune response to pathogens. Recent reports now reveal intriguing roles for TLRs in the central nervous system (CNS). These include the regulation of neuroinflammation and of neurite outgrowth. The archetypal Toll protein in...

  13. Thrombin binds to murine bone marrow-derived macrophages and enhances colony-stimulating factor-1-driven mitogenesis

    International Nuclear Information System (INIS)

    The binding and mitogenic properties of thrombin have been established in various transformed cell lines. In such systems, thrombin induces cell division in the absence of exogenous growth factors, and the enzyme is considered to act directly as a mitogen. This study explores thrombin's interaction with nontransformed, growth factor-dependent cells. Binding of 125I-alpha-thrombin to colony-stimulating factor (CSF)-1-dependent bone marrow-derived macrophages is saturable, time-dependent, and displaceable by both unlabeled alpha-thrombin, and esterolytically inactive thrombin. Both dissociation studies of pre-bound radio-labeled thrombin and Scatchard analysis assisted by the program Ligand suggest adherence of thrombin-binding data to a multi-site model. There are an estimated 2 x 10(4) high affinity sites (Kd = 7 x 10(-9)M) and 2 x 10(6) low affinity sites (Kd = 9 x 10(-7)M) per cell. Quiescent bone marrow-derived macrophages were cultured with either 10(-8)M thrombin, 1000 units of CSF-1/ml, or both and [3H]thymidine incorporation was determined. Thrombin alone did not induce mitogenesis. CSF-1 induced mitogenesis with peak [3H] thymidine incorporation occurring 24 h after addition of the mitogen. This CSF-1-dependent mitogenic influence was enhanced greater than 2-fold by treatment with thrombin

  14. An autoradiographic analysis of cholinergic receptors in mouse brain after chronic nicotine treatment

    International Nuclear Information System (INIS)

    Quantitative autoradiographic procedures were used to examine the effects of chronic nicotine infusion on the number of central nervous system nicotinic cholinergic receptors. Female DBA mice were implanted with jugular cannulas and infused with saline or various doses of nicotine (0.25, 0.5, 1.0 or 2.0 mg/kg/hr) for 10 days. The animals were then sacrificed and the brains were removed and frozen in isopentane. Cryostat sections were collected and prepared for autoradiographic procedures as previously described. Nicotinic cholinergic receptors were labeled with L-[3H]nicotine or alpha-[125I]bungarotoxin; [3H]quinuclidinyl benzilate was used to measure muscarinic cholinergic receptor binding. Chronic nicotine infusion increased the number of sites labeled by [3H]nicotine in most brain areas. However, the extent of the increase in binding as well as the dose-response curves for the increase were widely different among brain regions. After the highest treatment dose, binding was increased in 67 of 86 regions measured. Septal and thalamic regions were most resistant to change. Nicotinic binding measured by alpha-[125I]bungarotoxin also increased after chronic treatment, but in a less robust fashion. At the highest treatment dose, only 26 of 80 regions were significantly changes. Muscarinic binding was not altered after chronic nicotine treatment. These data suggest that brain regions are not equivalent in the mechanisms that regulate alterations in nicotinic cholinergic receptor binding after chronic nicotine treatment

  15. Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants

    Science.gov (United States)

    In rodents, hypothalamic brain-derived neurotrophic factor (BDNF) expression appears to be regulated by melanocortin-4 receptor (MC4R) activity. The impact of MC4R genetic variation on circulating BDNF in humans is unknown. The objective of this study is to compare BDNF concentrations of subjects wi...

  16. Combined autoradiographic-immunocytochemical analysis of opioid receptors and opioid peptide neuronal systems in brain

    International Nuclear Information System (INIS)

    Using adjacent section autoradiography-immunocytochemistry, the distribution of [3H]naloxone binding sites was studied in relation to neuronal systems containing [Leu]enkephalin, dynorphin A, or beta-endorphin immunoreactivity in rat brain. Brain sections from formaldehyde-perfused rats show robust specific binding of [3H]naloxone, the pharmacological (mu-like) properties of which appear unaltered. In contrast, specific binding of the delta ligand [3H]D-Ala2,D-Leu5-enkephalin was virtually totally eliminated as a result of formaldehyde perfusion. Using adjacent section analysis, the authors have noted associations between [3H]naloxone binding sites and one, two, or all three opioid systems in different brain regions; however, in some areas, no apparent relationship could be observed. Within regions, the relationship was complex. The complexity of the association between [3H]naloxone binding sites and the multiple opioid systems, and previous reports of co-localization of mu and kappa receptors in rat brain, are inconsistent with a simple-one-to-one relationship between a given opioid precursor and opioid receptor subtype. Instead, since differential processing of the three precursors gives rise to peptides of varying receptor subtype potencies and selectivities, the multiple peptide-receptor relationships may point to a key role of post-translational processing in determining the physiological consequences of opioid neurotransmission

  17. Estrogen provides neuroprotection against brain edema and blood brain barrier disruption through both estrogen receptors α and β following traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Vida Naderi

    2015-02-01

    Full Text Available Objective(s:Estrogen (E2 has neuroprotective effects on blood-brain-barrier (BBB after traumatic brain injury (TBI. In order to investigate the roles of estrogen receptors (ERs in these effects, ER-α antagonist (MPP and, ER-β antagonist (PHTPP, or non-selective estrogen receptors antagonist (ICI 182780 were administered. Materials and Methods: Ovariectomized rats were divided into 10 groups, as follows: Sham, TBI, E2, oil, MPP+E2, PHTPP+E2, MPP+PHTPP+E2, ICI+E2, MPP, and DMSO. E2 (33.3 µg/Kg or oil were administered 30 min after TBI. 1 dose (150 µg/Kg of each of MPP, PHTPP, and (4 mg/kg ICI182780 was injected two times, 24 hr apart, before TBI and estrogen treatment. BBB disruption (Evans blue content and brain edema (brain water content evaluated 5 hr and 24 hr after the TBI were evaluated, respectively. Results: The results showed that E2 reduced brain edema after TBI compared to vehicle (P

  18. Evidence that the EphA2 receptor exacerbates ischemic brain injury.

    Directory of Open Access Journals (Sweden)

    John Thundyil

    Full Text Available Ephrin (Eph signaling within the central nervous system is known to modulate axon guidance, synaptic plasticity, and to promote long-term potentiation. We investigated the potential involvement of EphA2 receptors in ischemic stroke-induced brain inflammation in a mouse model of focal stroke. Cerebral ischemia was induced in male C57Bl6/J wild-type (WT and EphA2-deficient (EphA2(-/- mice by middle cerebral artery occlusion (MCAO; 60 min, followed by reperfusion (24 or 72 h. Brain infarction was measured using triphenyltetrazolium chloride staining. Neurological deficit scores and brain infarct volumes were significantly less in EphA2(-/- mice compared with WT controls. This protection by EphA2 deletion was associated with a comparative decrease in brain edema, blood-brain barrier damage, MMP-9 expression and leukocyte infiltration, and higher expression levels of the tight junction protein, zona occludens-1. Moreover, EphA2(-/- brains had significantly lower levels of the pro-apoptotic proteins, cleaved caspase-3 and BAX, and higher levels of the anti-apoptotic protein, Bcl-2 as compared to WT group. We confirmed that isolated WT cortical neurons express the EphA2 receptor and its ligands (ephrin-A1-A3. Furthermore, expression of all four proteins was increased in WT primary cortical neurons following 24 h of glucose deprivation, and in the brains of WT mice following stroke. Glucose deprivation induced less cell death in primary neurons from EphA2(-/- compared with WT mice. In conclusion, our data provide the first evidence that the EphA2 receptor directly contributes to blood-brain barrier damage and neuronal death following ischemic stroke.

  19. The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity.

    Science.gov (United States)

    Miner, Jonathan J; Daniels, Brian P; Shrestha, Bimmi; Proenca-Modena, Jose L; Lew, Erin D; Lazear, Helen M; Gorman, Matthew J; Lemke, Greg; Klein, Robyn S; Diamond, Michael S

    2015-12-01

    The TAM receptors Tyro3, Axl and Mertk are receptor tyrosine kinases that dampen host innate immune responses following engagement with their ligands Gas6 and Protein S, which recognize phosphatidylserine on apoptotic cells. In a form of apoptotic mimicry, many enveloped viruses display phosphatidylserine on the outer leaflet of their membranes, enabling TAM receptor activation and downregulation of antiviral responses. Accordingly, we hypothesized that a deficiency of TAM receptors would enhance antiviral responses and protect against viral infection. Unexpectedly, mice lacking Mertk and/or Axl, but not Tyro3, exhibited greater vulnerability to infection with neuroinvasive West Nile and La Crosse encephalitis viruses. This phenotype was associated with increased blood-brain barrier permeability, which enhanced virus entry into and infection of the brain. Activation of Mertk synergized with interferon-β to tighten cell junctions and prevent virus transit across brain microvascular endothelial cells. Because TAM receptors restrict pathogenesis of neuroinvasive viruses, these findings have implications for TAM antagonists that are currently in clinical development. PMID:26523970

  20. Characterization of atrial natriuretic peptide receptors in brain microvessel endothelial cells

    Science.gov (United States)

    Whitson, P. A.; Huls, M. H.; Sams, C. F.

    1991-01-01

    Atrial natriuretic peptide (ANP) binding and ANP-induced increases in cyclic guanosine monophosphate (cGMP) levels have been observed in brain microvessels (Chabrier et al., 1987; Steardo and Nathanson, 1987), suggesting that this fluid-regulating hormone may play a role in the fluid homeostasis of the brain. This study was initiated to characterize the ANP receptors in primary cultures of brain microvessel endothelial cells (BMECs). The apparent equilibrium dissociation constant, Kd, for ANP increased from 0.25 nM to 2.5 nM, and the number of ANP binding sites as determined by Scatchard analysis increased from 7,100 to 170,000 sites/cell between 2 and 10 days of culture following monolayer formation. Time- and concentration-dependent studies on the stimulation of cGMP levels by ANP indicated that guanylate cyclase-linked ANP receptors were present in BMECs. The relative abilities of ANP, brain natriuretic peptide (BNP), and a truncated analog of ANP containing amino acids 5-27 (ANP 5-27) to modulate the accumulation of cGMP was found to be ANP greater than BNP much greater than ANP 5-27. Affinity cross-linking with disuccinimidyl suberate and radiolabeled ANP followed by gel electrophoresis under reducing conditions demonstrated a single band corresponding to the 60-70 kD receptor, indicating the presence of the nonguanylate cyclase-linked ANP receptor. Radiolabeled ANP binding was examined in the presence of various concentrations of either ANP, BNP, or ANP 5-27 and suggested that a large proportion of the ANP receptors present in blood-brain barrier endothelial cells bind all of these ligands similarly. These data indicate both guanylate cyclase linked and nonguanylate cyclase linked receptors are present on BMECs and that a higher proportion of the nonguanylate cyclase linked receptors is expressed. This in vitro culture system may provide a valuable tool for the examination of ANP receptor expression and function in blood-brain barrier endothelial cells.

  1. Somatostatin receptor scintigraphy in brain tumors and pituitary tumors: First experiences

    International Nuclear Information System (INIS)

    This preliminary study embraced 45 patients with meningiomas, brain tumors or pituitary tumors, which were imaged by planar and tomographic scintigraphy after intravenous injection of 111Indium-labeled octreotide. In all of the meningiomas studied (unifocal and multifocal tumors in various locations), a high density of somatostatin receptors was detected by scintigraphy. Pituitary tumors were slightly positive in 50% of cases only, independent of the endocrine activity. Gliomas with an intact blood-brain barrier showed no enhanced tracer uptake in vivo, while gliomas with distributed blood-brain barrier had a high activity uptake. We conclude that in vivo somatostatin receptor scintigraphy, although not tumor-specific, may aid in the preoperative diagnosis and staging of intracranial tumors, especially skull base tumors. (orig.)

  2. Maps of receptor binding parameters in the human brain - a kinetic analysis of pet measurements

    International Nuclear Information System (INIS)

    A kinetic method is described for the estimation of neuroreceptor density as well as the rate constants for association and dissociation of rapidly equilibrating radioligands. The method is exemplified by positron emission tomographic measurements of the human brain using 11C-raclopride, a D2 dopamine receptor antagonist, and 11C-Ro 15-1788, a benzodiazepine receptor antagonist. Using a linear non iterative algorithm, regional binding characteristics were calculated and displayed poixel by pixel in brain maps. Data from repeated experiments on the same subject with different amounts of the unlabeled ligand were utilized. The binding characteristics were determined according to a two step procedure in which the time course of the free radioligand concentration was estimated from a reference region considered to be free of specific receptor binding sites. Alternative methods to determine the concentration of free radioligand are discussed. (orig.)

  3. Purification of the neurotensin receptor from bovine brain

    International Nuclear Information System (INIS)

    The neurotensin receptor protein, solubilized with digitonin/asolectin from bovine cerebral cortex membranes, was purified to apparent homogeneity by affinity chromatography using immobilized neurotensin. The product exhibits saturable and specific binding of [3,11-tyrosyl-3,5-3H] neurotensin with an apparent affinity (K/sub d/ = 5.5 nM) comparable to that measured in intact membranes and crude soluble extracts. The affinity-purified material, after reduction with 100 mM dithiothreitol, in denaturing gel electrophoresis showed a single polypeptide of M/sub r/ 72,000. Under nonreducing conditions the apparent M/sub r/, however, was 50,000, suggesting the presence of intramolecular disulfide bonds. The purified neurotensin receptor was judged to be homogenous, in that (i) only a single polypeptide was detectable; and (ii) the overall purification was 30,000-50,000-fold, giving a specific neurotensin-binding activity close to the theoretical maximum

  4. Sphingosine 1-phosphate receptor 5 mediates the immune quiescence of the human brain endothelial barrier

    Directory of Open Access Journals (Sweden)

    van Doorn Ruben

    2012-06-01

    Full Text Available Abstract Background The sphingosine 1-phosphate (S1P receptor modulator FTY720P (Gilenya® potently reduces relapse rate and lesion activity in the neuroinflammatory disorder multiple sclerosis. Although most of its efficacy has been shown to be related to immunosuppression through the induction of lymphopenia, it has been suggested that a number of its beneficial effects are related to altered endothelial and blood–brain barrier (BBB functionality. However, to date it remains unknown whether brain endothelial S1P receptors are involved in the maintenance of the function of the BBB thereby mediating immune quiescence of the brain. Here we demonstrate that the brain endothelial receptor S1P5 largely contributes to the maintenance of brain endothelial barrier function. Methods We analyzed the expression of S1P5 in human post-mortem tissues using immunohistochemistry. The function of S1P5 at the BBB was assessed in cultured human brain endothelial cells (ECs using agonists and lentivirus-mediated knockdown of S1P5. Subsequent analyses of different aspects of the brain EC barrier included the formation of a tight barrier, the expression of BBB proteins and markers of inflammation and monocyte transmigration. Results We show that activation of S1P5 on cultured human brain ECs by a selective agonist elicits enhanced barrier integrity and reduced transendothelial migration of monocytes in vitro. These results were corroborated by genetically silencing S1P5 in brain ECs. Interestingly, functional studies with these cells revealed that S1P5 strongly contributes to brain EC barrier function and underlies the expression of specific BBB endothelial characteristics such as tight junctions and permeability. In addition, S1P5 maintains the immunoquiescent state of brain ECs with low expression levels of leukocyte adhesion molecules and inflammatory chemokines and cytokines through lowering the activation of the transcription factor NFκB. Conclusion Our

  5. Aging-induced changes in brain regional serotonin receptor binding: Effect of Carnosine.

    Science.gov (United States)

    Banerjee, S; Poddar, M K

    2016-04-01

    Monoamine neurotransmitter, serotonin (5-HT) has its own specific receptors in both pre- and post-synapse. In the present study the role of carnosine on aging-induced changes of [(3)H]-5-HT receptor binding in different brain regions in a rat model was studied. The results showed that during aging (18 and 24 months) the [(3)H]-5-HT receptor binding was reduced in hippocampus, hypothalamus and pons-medulla with a decrease in their both Bmax and KD but in cerebral cortex the [(3)H]-5-HT binding was increased with the increase of its only Bmax. The aging-induced changes in [(3)H]-5-HT receptor binding with carnosine (2.0 μg/kg/day, intrathecally, for 21 consecutive days) attenuated in (a) 24-month-aged rats irrespective of the brain regions with the attenuation of its Bmax except hypothalamus where both Bmax and KD were significantly attenuated, (b) hippocampus and hypothalamus of 18-month-aged rats with the attenuation of its Bmax, and restored toward the [(3)H]-5-HT receptor binding that observed in 4-month-young rats. The decrease in pons-medullary [(3)H]-5-HT binding including its Bmax of 18-month-aged rats was promoted with carnosine without any significant change in its cerebral cortex. The [(3)H]-5-HT receptor binding with the same dosages of carnosine in 4-month-young rats (a) increased in the cerebral cortex and hippocampus with the increase in their only Bmax whereas (b) decreased in hypothalamus and pons-medulla with a decrease in their both Bmax and KD. These results suggest that carnosine treatment may (a) play a preventive role in aging-induced brain region-specific changes in serotonergic activity (b) not be worthy in 4-month-young rats in relation to the brain regional serotonergic activity. PMID:26808776

  6. Acute liver failure-induced death of rats is delayed or prevented by blocking NMDA receptors in brain.

    Science.gov (United States)

    Cauli, Omar; Rodrigo, Regina; Boix, Jordi; Piedrafita, Blanca; Agusti, Ana; Felipo, Vicente

    2008-09-01

    Developing procedures to delay the mechanisms of acute liver failure-induced death would increase patients' survival by allowing time for liver regeneration or to receive a liver for transplantation. Hyperammonemia is a main contributor to brain herniation and mortality in acute liver failure (ALF). Acute ammonia intoxication in rats leads to N-methyl-D-aspartate (NMDA) receptor activation in brain. Blocking these receptors prevents ammonia-induced death. Ammonia-induced activation of NMDA receptors could contribute to ALF-induced death. If this were the case, blocking NMDA receptors could prevent or delay ALF-induced death. The aim of this work was to assess 1) whether ALF leads to NMDA receptors activation in brain in vivo and 2) whether blocking NMDA receptors prevents or delays ALF-induced death of rats. It is shown, by in vivo brain microdialysis, that galactosamine-induced ALF leads to NMDA receptors activation in brain. Blocking NMDA receptors by continuous administration of MK-801 or memantine through miniosmotic pumps affords significant protection against ALF-induced death, increasing the survival time approximately twofold. Also, when liver injury is not 100% lethal (1.5 g/kg galactosamine), blocking NMDA receptors increases the survival rate from 23 to 62%. This supports that blocking NMDA receptors could have therapeutic utility to improve survival of patients with ALF. PMID:18599589

  7. Adenosine A2A Receptors Modulate Acute Injury and Neuroinflammation in Brain Ischemia

    Directory of Open Access Journals (Sweden)

    Felicita Pedata

    2014-01-01

    Full Text Available The extracellular concentration of adenosine in the brain increases dramatically during ischemia. Adenosine A2A receptor is expressed in neurons and glial cells and in inflammatory cells (lymphocytes and granulocytes. Recently, adenosine A2A receptor emerged as a potential therapeutic attractive target in ischemia. Ischemia is a multifactorial pathology characterized by different events evolving in the time. After ischemia the early massive increase of extracellular glutamate is followed by activation of resident immune cells, that is, microglia, and production or activation of inflammation mediators. Proinflammatory cytokines, which upregulate cell adhesion molecules, exert an important role in promoting recruitment of leukocytes that in turn promote expansion of the inflammatory response in ischemic tissue. Protracted neuroinflammation is now recognized as the predominant mechanism of secondary brain injury progression. A2A receptors present on central cells and on blood cells account for important effects depending on the time-related evolution of the pathological condition. Evidence suggests that A2A receptor antagonists provide early protection via centrally mediated control of excessive excitotoxicity, while A2A receptor agonists provide protracted protection by controlling massive blood cell infiltration in the hours and days after ischemia. Focus on inflammatory responses provides for adenosine A2A receptor agonists a wide therapeutic time-window of hours and even days after stroke.

  8. Effects of imipramine treatment on delta-opioid receptors of the rat brain cortex and striatum.

    Science.gov (United States)

    Varona, Adolfo; Gil, Javier; Saracibar, Gonzalo; Maza, Jose Luis; Echevarria, Enrique; Irazusta, Jon

    2003-01-01

    Imipramine (CAS 113-52-0) is being utilized widely for the treatment of major depression. In recent years, there has been evidence of the involvement of the endogenous opioid system in major depression and its treatment. There is some evidence indicating that opioid receptors could be involved in the antidepressant mechanism of action. Regarding this topic, mood-related behavior of endogenous enkephalins seems to be mediated by delta-opioid receptors. In this work, the effects of subacute (5 day) and chronic (15 day) treatments of imipramine on the density and the affinity of the delta-receptors in the striatum and in the parietal and frontal cortices of the rat brain are described. Studied parameters (Bmax and Kd) were calculated by a saturation binding assay with the delta-opioid agonists [3H]-DPDPE (tyrosyl-2,6-3H(N)-(2-D-penicillamine-5-D-penicillamine)-enkephalin) as specific ligand and DSLET ([D-serine2]-D-leucine-enkephalin-threonine) as non-radioactive competing ligand. It was found that 15 days treatment significantly decreased the delta-opioid receptor density,without changing the affinity, in the frontal cortex of the rat brain. That decrease was confirmed by delta-opioid receptor immunostaining. These results suggest that delta-opioid receptors could play a role in the chronic action mechanism of imipramine. PMID:12608010

  9. Imaging dopamine and opiate receptors in the human brain in health and disease

    International Nuclear Information System (INIS)

    Chemical activity accompanies mental activity, but only recently has it been possible to begin to examine its nature. In 1983 the first imaging of a neuroreceptor in the human brain was accomplished with carbon-11 methyl spipeone, a ligand that binds preferentially to dopamine-2 receptors, 80% of which are located in the caudate nucleus and putamen. Quantitative imaging of serotonin-2, opiate, benzodiazapine and muscarinic cholinergic receptors has subsequently been accomplished. In studies of normal men and women, it has been found that dopamine and serotonin receptor activity decreases dramatically with age, such a decrease being more pronounced in men than in women and greater in the case of dopamine receptors than serotonin-2 receptors. Preliminary studies in patients with neuropsychiatric disorders suggests that dopamine-2 receptor activity is diminished in the caudate nucleus of patients with Huntington's disease. Positron tomography permits quantitative assay of picomolar quantities of neuroreceptors within the living human brain. Studies of patients with Parkinson's disease, Alzheimer's disease, depression, anxiety, schizophrenia, acute and chronic pain states and drug addiction are now in progress

  10. Purification of high affinity benzodiazepine receptor binding site fragments from rat brain

    International Nuclear Information System (INIS)

    In central nervous system benzodiazepine recognition sites occur on neuronal cell surfaces as one member of a multireceptor complex, including recognition sites for benzodiazepines, gamma aminobutyric acid (GABA), barbiturates and a chloride ionophore. During photoaffinity labelling, the benzodiazepine agonist, 3H-flunitrazepam, is irreversibly bound to central benzodiazepine high affinity recognition sites in the presence of ultraviolet light. In these studies a 3H-flunitrazepam radiolabel was used to track the isolation and purification of high affinity agonist binding site fragments from membrane-bound benzodiazepine receptor in rat brain. The authors present a method for limited proteolysis of 3H-flunitrazepam photoaffinity labeled rat brain membranes, generating photolabeled benzodiazepine receptor fragments containing the agonist binding site. Using trypsin chymotrypsin A4, or a combination of these two proteases, they have demonstrated the extent and time course for partial digestion of benzodiazepine receptor, yielding photolabeled receptor binding site fragments. These photolabeled receptor fragments have been further purified on the basis of size, using ultrafiltration, gel permeation chromatography, and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) as well as on the basis of hydrophobicity, using a high performance liquid chromatography (HPLC) precolumn, several HPLC elution schemes, and two different HPLC column types. Using these procedures, they have purified three photolabeled benzodiazepine receptor fragments containing the agonist binding site which appear to have a molecular weight of less than 2000 daltons each

  11. Selective effects of carbamate pesticides on rat neuronal nicotinic acetylcholine receptors and rat brain acetylcholinesterase

    International Nuclear Information System (INIS)

    Effects of commonly used carbamate pesticides on rat neuronal nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes have been investigated using the two-electrode voltage clamp technique. The potencies of these effects have been compared to the potencies of the carbamates to inhibit rat brain acetylcholinesterase. The potency order of six carbamates to inhibit α4β4 nicotinic receptors is fenoxycarb > EPTC > carbaryl, bendiocarb > propoxur > aldicarb with IC50 values ranging from 3 μM for fenoxycarb to 165 μM for propoxur and >1 mM for aldicarb. Conversely, the potency order of these carbamates to inhibit rat brain acetylcholinesterase is bendiocarb > propoxur, aldicarb > carbaryl >> EPTC, fenoxycarb with IC50 values ranging from 1 μM for bendiocarb to 17 μM for carbaryl and >>1 mM for EPTC and fenoxycarb. The α4β2, α3β4, and α3β2 nicotinic acetylcholine receptors are inhibited by fenoxycarb, EPTC, and carbaryl with potency orders similar to that for α4β4 receptors. Comparing the potencies of inhibition of the distinct subtypes of nicotinic acetylcholine receptors shows that the α3β2 receptor is less sensitive to inhibition by fenoxycarb and EPTC. The potency of inhibition depends on the carbamate as well as on a combination of α and β subunit properties. It is concluded that carbamate pesticides affect different subtypes of neuronal nicotinic receptors independently of acetylcholinesterase inhibition. This implicates that neuronal nicotinic receptors are additional targets for some carbamate pesticides and that these receptors may contribute to carbamate pesticide toxicology, especially after long-term exposure

  12. BDNF modulates GABAA receptors microtransplanted from the human epileptic brain to Xenopus oocytes

    Science.gov (United States)

    Palma, E.; Torchia, G.; Limatola, C.; Trettel, F.; Arcella, A.; Cantore, G.; Di Gennaro, G.; Manfredi, M.; Esposito, V.; Quarato, P. P.; Miledi, R.; Eusebi, F.

    2005-01-01

    Cell membranes isolated from brain tissues, obtained surgically from six patients afflicted with drug-resistant temporal lobe epilepsy and from one nonepileptic patient afflicted with a cerebral oligodendroglioma, were injected into frog oocytes. By using this approach, the oocytes acquire human GABAA receptors, and we have shown previously that the “epileptic receptors” (receptors transplanted from epileptic brains) display a marked run-down during repetitive applications of GABA. It was found that exposure to the neurotrophin BDNF increased the amplitude of the “GABA currents” (currents elicited by GABA) generated by the epileptic receptors and decreased their run-down; both events being blocked by K252A, a neurotrophin tyrosine kinase receptor B inhibitor. These effects of BDNF were not mimicked by nerve growth factor. In contrast, the GABAA receptors transplanted from the nonepileptic human hippocampal uncus (obtained during surgical resection as part of the nontumoral tissue from the oligodendroglioma margins) or receptors expressed by injecting rat recombinant α1β2γ2 GABAA receptor subunit cDNAs generated GABA currents whose time-course and run-down were not altered by BDNF. Loading the oocytes with the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetate-acetoxymethyl ester (BAPTA-AM), or treating them with Rp-8-Br-cAMP, an inhibitor of the cAMP-dependent PKA, did not alter the GABA currents. However, staurosporine (a broad spectrum PK inhibitor), bisindolylmaleimide I (a PKC inhibitor), and U73122 (a phospholipase C inhibitor) blocked the BDNF-induced effects on the epileptic GABA currents. Our results indicate that BDNF potentiates the epileptic GABAA currents and antagonizes their use-dependent run-down, thus strengthening GABAergic inhibition, probably by means of activation of tyrosine kinase receptor B receptors and of both PLC and PKC. PMID:15665077

  13. The effect of ZMS on brain M receptor in aged rats

    International Nuclear Information System (INIS)

    Objective: The purpose of this work was to study the effect of ZMS, an active component of Yin tonic, Zhimu, on brain M2 receptor density of aged animals and its correlation with the effect on learning/memory ability. Methods: A dual-site competitive binding assay using 3H-quinuclidinyl benzilate (QNB) as non selective radioligand and unlabelled Methoctramine as selective competitive agent was established for measuring M2 receptor density in aged rats. Results: In addition to the change of total density of M receptors, the density of a subtype of M receptors, M2 receptor in brain was significantly decreased in aged rats [(231.8 +- 115.9) fmol·mg-1 (x-bar +- s) in young rats and (97.9 +- 46.3) fmol·mg-1 in aged rats]. When the aged rats were treated with ZMS for two months, in addition to the up-regulation of total M receptors, the M2 receptor was up-regulated significantly [being (213 +- 77) mg at a ZMS dose of 3.6 mg·kg-1·d-'1, and (212 +- 72) mg at a ZMS dose of 18 mg·kg-1·d-1]. When the correlation between M2 or total M receptor densities and the learning/memory ability measured by Y-maze performance was examined with linear regression, the correlation coefficient was remarkable (0.721 and 0.505, respectively). Conclusions: ZMS has the ability of up-regulating M2 receptor and this may be an important factor for the improvement of learning and memory by ZMS

  14. Characterization of tyramine and octopamine receptors in the insect (Locusta migratoria migratorioides) brain.

    Science.gov (United States)

    Hiripi, L; Juhos, S; Downer, R G

    1994-01-01

    The kinetic and pharmacological properties of [3H]tyramine and [3H]octopamine binding to membrane preparations of locust (Locusta migratoria migratorioides) brain were studied to characterize the tyramine and octopamine receptors. [3H]Tyramine and [3H]octopamine bind specifically and reversibly to the locust brain membrane with equilibrium achieved after 20 min. The dissociation of [3H]tyramine is monophasic while that of the [3H]octopamine shows a biphasic tendency. Scatchard analysis of the saturation curves reveals a single high affinity binding site for each of tyramine and octopamine. The mean (+/- S.E.M.) values of Kd and Bmax are 6.11 +/- 0.71 nM and 21.45 +/- 3.0 fmol/mg tissue for tyramine and 5.65 +/- 0.91 nM and 15.0 +/- 2.4 fmol/mg tissue for octopamine, respectively. Pharmacological analysis of the binding suggests the presence of both tyramine and octopamine receptors in the locust brain. alpha-Adrenergic agonists and antagonists have a high affinity to the octopamine but not the tyramine receptor whereas dopaminergic drugs have a higher affinity to the tyramine receptor than the octopamine receptor. No highly effective inhibitors of tyramine binding were identified. The serotonergic blockers, mianserin, LSD, BOL are effective blockers for both tyramine and octopamine receptors, whereas the serotonergic antagonist gramine is more active against the octopamine than the serotonin receptor. The results suggest that a G-protein binding mechanism is involved in the expression of both the tyramine and octopamine effects. PMID:7907928

  15. Selective vulnerabilities of N-methyl-D-aspartate (NMDA receptors during brain aging

    Directory of Open Access Journals (Sweden)

    Brenna L Brim

    2010-03-01

    Full Text Available N-methyl-D-aspartate (NMDA receptors are present in high density within the cerebral cortex and hippocampus and play an important role in learning and memory. NMDA receptors are negatively affected by aging, but these effects are not uniform in many different ways. This review discusses the selective age-related vulnerabilities of different binding sites of the NMDA receptor complex, different subunits that comprise the complex, and the expression and functions of the receptor within different brain regions. Spatial reference, passive avoidance, and working memory, as well as place field stability and expansion all involve NMDA receptors. Aged animals show deficiencies in these functions, as compared to young, and some studies have identified an association between age-associated changes in the expression of NMDA receptors and poor memory performance. A number of diet and drug interventions have shown potential for reversing or slowing the effects of aging on the NMDA receptor. On the other hand, there is mounting evidence that the NMDA receptors that remain within aged individuals are not always associated with good cognitive functioning. This may be due to a compensatory response of neurons to the decline in NMDA receptor expression or a change in the subunit composition of the remaining receptors. These studies suggest that developing treatments that are aimed at preventing or reversing the effects of aging on the NMDA receptor may aid in ameliorating the memory declines that are associated with aging. However, we need to be mindful of the possibility that there may also be negative consequences in aged individuals.

  16. Single nanoparticle tracking of [Formula: see text]-methyl-d-aspartate receptors in cultured and intact brain tissue.

    Science.gov (United States)

    Varela, Juan A; Ferreira, Joana S; Dupuis, Julien P; Durand, Pauline; Bouchet, Delphine; Groc, Laurent

    2016-10-01

    Recent developments in single-molecule imaging have revealed many biological mechanisms, providing high spatial and temporal resolution maps of molecular events. In neurobiology, these techniques unveiled that plasma membrane neurotransmitter receptors and transporters laterally diffuse at the surface of cultured brain cells. The photostability of bright nanoprobes, such as quantum dots (QDs), has given access to neurotransmitter receptor tracking over long periods of time with a high spatial resolution. However, our knowledge has been restricted to cultured systems, i.e., neurons and organotypic slices, therefore lacking several aspects of the intact brain rheology and connectivity. Here, we used QDs to track single glutamatergic [Formula: see text]-methyl-d-aspartate receptors (NMDAR) in acute brain slices. By delivering functionalized nanoparticles in vivo through intraventricular injections to rats expressing genetically engineered-tagged NMDAR, we successfully tracked the receptors in native brain tissue. Comparing NMDAR tracking to different classical brain preparations (acute brain slices, cultured organotypic brain slices, and cultured neurons) revealed that the surface diffusion properties shared several features and are also influenced by the nature of the extracellular environment. Together, we describe the experimental procedures to track plasma membrane NMDAR in dissociated and native brain tissue, paving the way for investigations aiming at characterizing receptor diffusion biophysics in intact tissue and exploring the physiopathological roles of receptor surface dynamics. PMID:27429996

  17. Evidence for the presence of beta 3-adrenergic receptor mRNA in the human brain.

    Science.gov (United States)

    Rodriguez, M; Carillon, C; Coquerel, A; Le Fur, G; Ferrara, P; Caput, D; Shire, D

    1995-04-01

    The beta 3-adrenergic receptor (AR) is widely distributed in peripheral tissues, but up to now it has not been detected in the central nervous system. By using the polymerase chain reaction (PCR) technique, we found the beta 3-AR mRNA to be present in all the regions of the human brain we investigated. The quantities found were very low compared to those of the beta 1-AR and beta 2-AR mRNAs, being hardly detectable in adult brain. In contrast, the brain of very young infants contained about 100 times more beta 3-AR mRNA than the adult brain, whereas the amounts of beta 1-AR and beta 2-AR transcripts were essentially the same. In addition, using PCR we have cloned a central beta 3-AR coding region from a human frontal cortex cDNA library and have found it to be identical to the corresponding peripheral sequence. PMID:7609625

  18. The NMDA receptor changes during reperfusion after local ischemia in the rat brain

    International Nuclear Information System (INIS)

    Objective: To study the changes of N-methyl-D-aspartate(NMDA) receptor in the rat brain during reperfusion after local ischemia. Methods: The rat cerebral focal ischemia/reperfusion model after middle cerebral artery occlusion (MCAO) was made by the intraluminal suture method. After ischemia and reperfusion models were completed, the rat brain was removed immediately and dissected under the frozen state. After incubation with 3H-MK-801 which was used as a radioactive ligand, the samples were exposed on the hypersensitive film at the room temperature. Regions of interest (ROIs) were set bilaterally in each autoradiographic brain image. LEICAQ-550IWL imaging analysis system was used to detect the density of NMDA receptor. The ratios of the receptor density between affected and unaffected side in the same ROI were compared. Before receptor binding assay, the middle section of the ischemic cortex was separated, homogenized and centrifugated. After binding with the radioligand, radioactivity was measured by liquid scintillation counter. Scatchard plot was made from the liquid scintillation counter and affinity (Kd) and maximal binding (Bmax) changes of NMDA receptor were calculated. The results of Kd and Bmax were compared between groups. Results: NMDA receptor density in the corresponding ROI increased significantly during 2 h ischemia and 2 h reperfusion in comparison with the result of the sham group, which showed that the NMDA receptor channel was opened abundantly. The opening of the channel was mainly caused by the increase of the excitatory amino acids. There was significant decrease in the degree of channel opening in the 24 h and 72 h reperfusion groups in corresponding ROIs and no difference was found between two groups. The value of Kd in ischemia and reperfusion groups did not change. Bmax of NMDA receptor increased obviously during 2 h reperfusion and decreased obviously during 24 h and 72 h reperfusion. Conclusions: During the ischemia reperfusion, the

  19. Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-d-aspartate receptor subunits and d-serine ☆

    OpenAIRE

    Savignac, Helene M.; Corona, Giulia; Mills, Henrietta; Chen, Li; Spencer, Jeremy P.E.; Tzortzis, George; Burnet, Philip W. J.

    2013-01-01

    The influence of the gut microbiota on brain chemistry has been convincingly demonstrated in rodents. In the absence of gut bacteria, the central expression of brain derived neurotropic factor, (BDNF), and N-methyl-d-aspartate receptor (NMDAR) subunits are reduced, whereas, oral probiotics increase brain BDNF, and impart significant anxiolytic effects. We tested whether prebiotic compounds, which increase intrinsic enteric microbiota, also affected brain BDNF and NMDARs. In addition, we exami...

  20. Inhibition of Acetylcholinesterase Modulates NMDA Receptor Antagonist Mediated Alterations in the Developing Brain

    Directory of Open Access Journals (Sweden)

    Ivo Bendix

    2014-03-01

    Full Text Available Exposure to N-methyl-d-aspartate (NMDA receptor antagonists has been demonstrated to induce neurodegeneration in newborn rats. However, in clinical practice the use of NMDA receptor antagonists as anesthetics and sedatives cannot always be avoided. The present study investigated the effect of the indirect cholinergic agonist physostigmine on neurotrophin expression and the extracellular matrix during NMDA receptor antagonist induced injury to the immature rat brain. The aim was to investigate matrix metalloproteinase (MMP-2 activity, as well as expression of tissue inhibitor of metalloproteinase (TIMP-2 and brain-derived neurotrophic factor (BDNF after co-administration of the non-competitive NMDA receptor antagonist MK801 (dizocilpine and the acetylcholinesterase (AChE inhibitor physostigmine. The AChE inhibitor physostigmine ameliorated the MK801-induced reduction of BDNF mRNA and protein levels, reduced MK801-triggered MMP-2 activity and prevented decreased TIMP-2 mRNA expression. Our results indicate that AChE inhibition may prevent newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways and by modulating the extracellular matrix.

  1. Sexually dimorphic development and binding characteristics of NMDA receptors in the brain of the platyfish

    Science.gov (United States)

    Flynn, K. M.; Schreibman, M. P.; Yablonsky-Alter, E.; Banerjee, S. P.

    1999-01-01

    This study investigated age- and gender-specific variations in properties of the glutamate N-methyl-d-aspartate receptor (NMDAR) in a freshwater teleost, the platyfish (Xiphophorus maculatus). Prior localization of the immunoreactive (ir)-R1 subunit of the NMDAR protein (R1) in cells of the nucleus olfactoretinalis (NOR), a primary gonadotropin-releasing hormone (GnRH)-containing brain nucleus in the platyfish, suggests that NMDAR, as in mammals, is involved in modulation of the platyfish brain-pituitary-gonad (BPG) axis. The current study shows that the number of cells in the NOR displaying ir-R1 is significantly increased in pubescent and mature female platyfish when compared to immature and senescent animals. In males, there is no significant change in ir-R1 expression in the NOR at any time in their lifespan. The affinity of the noncompetitive antagonist ((3)H)MK-801 for the NMDAR is significantly increased in pubescent females while maximum binding of ((3)H)MK-801 to the receptor reaches a significant maximum in mature females. In males, both MK-801 affinity and maximum binding remain unchanged throughout development. This is the first report of gender differences in the association of NMDA receptors with neuroendocrine brain areas during development. It is also the first report to suggest NMDA receptor involvement in the development of the BPG axis in a nonmammalian vertebrate. Copyright 1999 Academic Press.

  2. Neuropeptide Y stimulates DNA synthesis in human vascular smooth muscle cells through neuropeptide Y Y1 receptors

    DEFF Research Database (Denmark)

    Nilsson, T; Edvinsson, L

    2000-01-01

    was potently antagonised by the NPY Y1 receptor antagonist BIBP3226 ((R)-N2-(diphenylacetyl)-N-[(4-hydroxy-phenyl)methyl]-D-arginine-a mide), indicating the effect to be mediated via the NPY Y1 receptor. Noradrenaline (NA) also induced mitogenesis, Emax 35 +/- 10% relative to control. When added...

  3. Cell surface modulation of gene expression in brain cells by down regulation of glucocorticoid receptors

    Energy Technology Data Exchange (ETDEWEB)

    McGinnis, J.F.; de Vellis, J.

    1981-02-01

    The concentration of glycerol-3-phosphate dehydrogenase (GPDH; sn-glycerol-3-phosphate:NAD/sup +/ 2-oxidoreductase, EC 1.1.1.8) had previously been determined to be regulated by glucocorticoids in rat brain cells in vivo and in cell culture. We now demonstrate that concanavalin A (Con A) can inhibit the induction of GPDH in a dose-dependent manner in C6 rat glioma cells and in primary cultures of rat brain oligodendrocytes. The inhibition specifically prevents the appearance of new molecules of GPDH, although Con A does not significantly inhibit protein synthesis in these cells, nor does it affect the activity of another solube enzyme, lactate dehydrogenase. The ability to block enzyme induction is not limited to Con A, because other lectins also inhibit induction. The molecular mechanism by which Con A inhibits GPDH induction appears to be by the down regulation of the cytoplasmic glucocorticoid receptors, because exposure to Con A results in the loss of more than 90% of the receptor activity. Con A does not inhibit the receptor assay and no direct interaction between the receptor and Con A could be demonstrated. This down regulation is not tumor cell specific and appears to be a general phenomenon, because it occurs in normal oligodendrocytes and even in normal astrocytes (a cell type in which the gene for GPDH is not expressed). The down regulation of glucocorticoid receptors in normal brain cells suggests two important corollaries. First, it demonstrates the existence of a rate-limiting step controlling the glucocorticoid-dependent gene expression in brain cells and possibly represents a regulatory site common to all glucocorticoid target cells. Second, it suggests that the response to glucocorticoids of oligodendrocytes and astrocytes can be regulated in vivo by cell surface contact with endogenous lectins, neighboring cells, or both.

  4. A generic model for 11C labelled radiopharmaceuticals for imaging receptors in the human brain

    International Nuclear Information System (INIS)

    A large number of radiopharmaceuticals labelled with 11C (half-time 0.340 h) are being developed for positron emission tomographic studies of different types of receptor in the human brain. For most of these agents the available biokinetic data are insufficient to construct realistic compound-specific biokinetic models for calculating the internal radiation dose delivered to persons undergoing investigation. A generic model for brain receptor substances that predicts the internal dose with sufficient accuracy for general radiation protection purposes has, therefore, been developed. Biokinetic data for 13 11C radiopharmaceuticals used clinically for imaging different brain receptors indicate that, despite differences in chemical structure, their uptake and retention in the human brain and other tissues is broadly similar. The proposed model assumes instantaneous deposition of 5% of the injected radioactivity in the brain, with the remaining radioactivity being rapidly and uniformly distributed throughout all other tissues. Elimination from all tissues is assumed to occur with a half-time of 2 h. It is further assumed that 75% of the injected 11C is excreted in the urine, and 25% via the gall bladder, with a half-time of 2 h. This model yields an effective dose of 4.5 x 10-3mSv/MBq, with doses of 3.2 x 10-2, 1.7 x 10-2, 8.7 X 10-3, 5.2 x 10-3, and 3.8 x 10-3mGy MBq-1 to the urinary bladder, gall bladder, kidneys, brain and ovaries, respectively. These doses are well within the range of those reported using compound-specific models for the radiopharmaceuticals studied. (author)

  5. Autoradiographic visualization of insulin-like growth factor-II receptors in rat brain

    International Nuclear Information System (INIS)

    The documented presence of IGF-II in brain and CSF prompted us to investigate the distribution of receptors for IGF-II in rat brain slices. Human 125-I-IGF-II (10 pM) was incubated for 16 hrs at 40C with slide-mounted rat brain slices in the absence and presence of unlabeled human IGF-II (67 nM) or human insulin (86 nM). Slides were washed, dried, and exposed to X-ray film for 4-7 days. The results showed dense labeling in the granular layers of the olfactory bulbs, deep layers of the cerebral cortex, pineal gland, anterior pituitary, hippocampus (pyramidal cells CA1-CA2 and dentate gyrus), and the granule cell layers of the cerebellum. Unlabeled IGF-II eliminated most of the binding of these brain regions while insulin produced only a minimal reduction in the amount of 125I-IGF-II bound. These results indicate that a specific neural receptor for IGS-II is uniquely distributed in rat brain tissue and supports the notion that this peptide might play an important role in normal neuronal functioning

  6. Effects of vitamin B-6 nutrition on benzodiazepine (BDZ) receptor binding in the developing rat brain

    International Nuclear Information System (INIS)

    A dietary deficiency of vitamin B-6 promotes seizure activity in neonatal animals and human infants. Previous studied have shown that neonatal vitamin B-6 deprivation results in reduced levels of brain gamma-aminobutyric acid (GABA) and increased binding at the GABA site of the GABA/BDZ receptor complex. Since the GABA and BDZ receptors are allosterically linked, this study was undertaken to determine if vitamin B-6 deprivation had an effect on BDZ receptor binding. Benzodiazepine receptor binding isotherms using 3H-flunitrazepam as ligand were performed in the presence and absence of 10 μM GABA. The results indicate a significant increase in the binding affinity (Kd) in the presence of GABA in cerebellar membranes from deficient rat pups at 14 days of age with no effect on receptor number (Bmax). By 28 days of age, the increase in Kd was no longer present. No change in Kd or Bmax was observed in cortical tissue from deficient animals at 14 or 28 days of age. Preliminary studies of GABA-enhancement of 3H-flunitrazepam binding indicate that vitamin B-6 deficiency also induces alterations in the ability of GABA to enhance BZD receptor binding. In summary, these results indicate that the effects of vitamin B-6 deprivation on BDZ receptor binding are region specific and age related

  7. [Studying specific effects of nootropic drugs on glutamate receptors in the rat brain].

    Science.gov (United States)

    Firstova, Iu Iu; Vasil'eva, E V; Kovalev, G I

    2011-01-01

    The influence of nootropic drugs of different groups (piracetam, phenotropil, nooglutil, noopept, semax, meclofenoxate, pantocalcine, and dimebon) on the binding of the corresponding ligands to AMPA, NMDA, and mGlu receptors of rat brain has been studied by the method of radio-ligand binding in vitro. It is established that nooglutil exhibits pharmacologically significant competition with a selective agonist of AMPA receptors ([G-3H]Ro 48-8587) for the receptor binding sites (with IC50 = 6.4 +/- 0.2 microM), while the competition of noopept for these receptor binding sites was lower by an order of magnitude (IC50 = 80 +/- 5.6 microM). The heptapeptide drug semax was moderately competitive with [G-3H]LY 354740 for mGlu receptor sites (IC50 = 33 +/- 2.4 microM). Dimebon moderately influenced the specific binding of the ligand of NMDA receptor channel ([G-3H]MK-801) at IC50 = 59 +/- 3.6 microM. Nootropic drugs of the pyrrolidone group (piracetam, phenotropil) as well as meclofenoxate, pantocalcine (pantogam) in a broad rage of concentrations (10(-4)-10(-10) M) did not affect the binding of the corresponding ligands to glutamate receptors (IC50 100 pM). Thus, the direct neurochemical investigation was used for the first time to qualitatively characterize the specific binding sites for nooglutil and (to a lower extent) noopept on AMPA receptors, for semax on metabotropic glutamate receptors, and for dimebon on the channel region of NMDA receptors. The results are indicative of a selective action of some nootropes on the glutamate family. PMID:21476267

  8. Effects of white spirits on rat brain 5-HT receptor functions and synaptic remodeling

    DEFF Research Database (Denmark)

    Lam, Henrik Rye; Plenge, P.; Jørgensen, O.S.

    2001-01-01

    ratio in forebrain, whereas NCAM increased in hippocampus and the NCAM/SNAP-25 ratio decreased in entorhinal cortex. Dearomatized white spirit did not affect NCAM, SNAP-25, or NCAM/SNAP-25 ratio in any brain region. The affected 5-HT receptor expression and synaptic plasticity marker proteins indicate......Previously, inhalation exposure to different types of white spirit (i.e. complex mixtures of aliphatic, aromatic, alkyl aromatic, and naphthenic hydrocarbons) has been shown to induce neurochemical effects in rat brains. Especially, the serotonergic system was involved at the global, regional, and...

  9. Changes in sensitivity of brain dopamine and serotonin receptors during long-term treatment with carbidine

    Energy Technology Data Exchange (ETDEWEB)

    Zharkovskii, A.M.; Allikmets, L.K.; Chereshka, K.S.; Zharkovskaya, T.A.

    1986-04-01

    The authors study the state of the dopamine and serotonin receptors of the brain during chronic administration of carbidine to animals. Parts of the brain from two rats were pooled and binding of tritium-spiperone and tritium-LSD was determined. Statistical analysis of the data for apomorphine sterotypy was carried out and the Student's test was used for analysis of the remaining data. It is shown that after discontinuation of carbidine binding of tritium-spiperone and tritium-LSD in the cortex was reduced.

  10. The Vitamin D Receptor (VDR) Gene Polymorphisms in Turkish Brain Cancer Patients

    OpenAIRE

    Bahar Toptaş; Ali Metin Kafadar; Canan Cacina; Saime Turan; Leman Melis Yurdum; Nihal Yiğitbaşı; Muhammed Oğuz Gökçe; Ümit Zeybek; Ilhan Yaylım

    2013-01-01

    Objective. It has been stated that brain cancers are an increasingly serious issue in many parts of the world. The aim of our study was to determine a possible relationship between Vitamin D receptor (VDR) gene polymorphisms and the risk of glioma and meningioma. Methods. We investigated the VDR Taq-I and VDR Fok-I gene polymorphisms in 100 brain cancer patients (including 44 meningioma cases and 56 glioma cases) and 122 age-matched healthy control subjects. This study was performed by polyme...

  11. Characterization of 5-HT1D receptor binding sites in post-mortem human brain cortex.

    OpenAIRE

    Martial, J; de Montigny, C; Cecyre, D; Quirion, R

    1991-01-01

    The present study provides further evidence for the presence of serotonin1D (5-HT1D) receptors in post-mortem human brain. Receptor binding parameters in temporal cortex homogenates were assessed using [3H]5-HT in the presence of 100 nM 8-OH-DPAT, 1 microM propranolol and 1 microM mesulergine to prevent labelling of the 5-HT1A, 5-HT1B and 5-HT1C sites, respectively. Under these conditions, [3H]5-HT apparently bound to a class of high affinity (Kd = 5.0 +/- 1.0 nM) low capacity (Bmax = 96 +/- ...

  12. Brain aromatase (Cyp19A2) and estrogen receptors, in larvae and adult pejerrey fish Odontesthes bonariensis: Neuroanatomical and functional relations

    Science.gov (United States)

    Strobl-Mazzulla, P. H.; Lethimonier, C.; Gueguen, M.M.; Karube, M.; Fernandino, J.I.; Yoshizaki, G.; Patino, R.; Strussmann, C.A.; Kah, O.; Somoza, G.M.

    2008-01-01

    Although estrogens exert many functions on vertebrate brains, there is little information on the relationship between brain aromatase and estrogen receptors. Here, we report the cloning and characterization of two estrogen receptors, ?? and ??, in pejerrey. Both receptors' mRNAs largely overlap and were predominantly expressed in the brain, pituitary, liver, and gonads. Also brain aromatase and estrogen receptors were up-regulated in the brain of estradiol-treated males. In situ hybridization was performed to study in more detail, the distribution of the two receptors in comparison with brain aromatase mRNA in the brain of adult pejerrey. The estrogen receptors' mRNAs exhibited distinct but partially overlapping patterns of expression in the preoptic area and the mediobasal hypothalamus, as well as in the pituitary gland. Moreover, the estrogen receptor ??, but not ??, were found to be expressed in cells lining the preoptic recess, similarly as observed for brain aromatase. Finally, it was shown that the onset expression of brain aromatase and both estrogen receptors in the head of larvae preceded the morphological differentiation of the gonads. Because pejerrey sex differentiation is strongly influenced by temperature, brain aromatase expression was measured during the temperature-sensitive window and was found to be significantly higher at male-promoting temperature. Taken together these results suggest close neuroanatomical and functional relationships between brain aromatase and estrogen receptors, probably involved in the sexual differentiation of the brain and raising interesting questions on the origin (central or peripheral) of the brain aromatase substrate. ?? 2008 Elsevier Inc.

  13. Physiology and physiopathology of central type Benzodiazepine receptors: Study in the monkey and in human brain using positron emission tomography

    International Nuclear Information System (INIS)

    A new non-invasive technique that allows to study in a living subject central type benzodiazepine receptors is developed. A combined approach is applied using a specific positron-emitting radiotracer for the in vivo labelling of the receptors and positron emission tomography allowing, by external detection, a quantitative determination of tissue radioactivity. The radioligand used for the in vivo labelling of benzodiazepine receptors is the antagonist RO 15-1788 labelled with carbon 11. The various stages of the study are described: in vivo characterization in the monkey of central type benzodiazepine receptors; characterization of central type benzodiazepine receptors in human brain using selective molecules for the BZ1 benzodiazepine subclass; demonstration of the heterogeneity of central type benzodiazepine receptors in the brain; study of pathological alteration of benzodiazepine receptors in experimental epilepsy

  14. Brain α7 nicotinic acetylcholine receptors in MPTP-lesioned monkeys and parkinsonian patients.

    Science.gov (United States)

    Morissette, Marc; Morin, Nicolas; Grégoire, Laurent; Rajput, Alex; Rajput, Ali H; Di Paolo, Thérèse

    2016-06-01

    L-DOPA-induced dyskinesias (LID) appear in the majority of Parkinson's disease (PD) patients. Nicotinic acetylcholine (nACh) receptor-mediated signaling has been implicated in PD and LID and modulation of brain α7 nACh receptors might be a potential therapeutic target for PD. This study used [(125)I]α-Bungarotoxin autoradiography to investigate α7 nACh receptors in LID in post-mortem brains from PD patients (n=14) and control subjects (n=11), and from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys treated with saline (n=5), L-DOPA (n=4) or L-DOPA+2-methyl-6-(phenylethynyl)pyridine (MPEP) (n=5), and control monkeys (n=4). MPEP is the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist; it reduced the development of LID in these monkeys. [(125)I]α-Bungarotoxin specific binding to striatal and pallidal α7 nACh receptors were only increased in L-DOPA-treated dyskinetic MPTP monkeys as compared to controls, saline and L-DOPA+MPEP MPTP monkeys; dyskinesia scores correlated positively with this binding. The total group of Parkinsonian patients had higher [(125)I]α-Bungarotoxin specific binding compared to controls in the caudate nucleus but not in the putamen. PD patients without motor complications had higher [(125)I]α-Bungarotoxin specific binding compared to controls only in the caudate nucleus. PD patients with LID only had higher [(125)I]α-Bungarotoxin specific binding compared to controls in the caudate nucleus and compared to those without motor complications and controls in the putamen. PD patients with wearing-off only, had [(125)I]α-Bungarotoxin specific binding at control values in the caudate nucleus and lower in the putamen. Reduced motor complications were associated with normal striatal α7 nACh receptors, suggesting the potential of this receptor to manage motor complications in PD. PMID:27038656

  15. Effect of sabcomeline on muscarinic and dopamine receptor binding in intact mouse brain

    International Nuclear Information System (INIS)

    Sabcomeline [(R-(Z)-(+)-α-(methoxyiamino)- 1-azabicyclo[2.2.2]octane-3-acetonitrile)] is a potent and functionally selective muscarinic M1 receptor partial agonist. However, little is known of the binding properties of sabcomeline under in vivo conditions. In this study, muscarinic receptor occupancy by sabcomeline in mouse brain regions and heart was estimated using [3H]quinuclidinyl benzilate (QNB) and [3H]N-methylpiperidyl benzilate (NMPB) as radioligands. In the cerebral cortex, hippocampus, and striatum, the estimated IC50 value of sabcomeline for [3H]NMPB binding was almost 0.2 mg/kg. Sabcomeline was not a selective ligand to M1 receptors as compared with biperiden in vivo. In the cerebral cortex, maximum receptor occupancy was observed about 1 hr after intravenous injection of sabcomeline (0.3 mg/kg), and the binding availability of mACh receptors had almost returned to the control level by 3-4 hr. These findings indicated that the binding kinetics of sabcomeline is rather rapid in mouse brain. Examination of dopamine D2 receptor binding revealed that sabcomeline affected the kinetics of both [3H]raclopride and [3H]N-methylspiperone (NMSP) binding in the striatum. It significantly decreased the k3 and k4 of [3H]raclopride binding resulting in an increase in binding potential (BP=k3/k4=Bmax/Kd) in sabcomeline-treated mice, and an approximately 15% decrease in k3 of [3H]NMSP binding was also observed. Although the mechanism is still unclear, sabcomeline altered dopamine D2 receptor affinity or availability by modulations via neural networks. (author)

  16. Radiochemical evaluation of a new brain receptor imaging agent

    International Nuclear Information System (INIS)

    We report about the radiochemical evaluation of a new serotonin-1A (5-HT1A) receptor imaging agent. The new derivative of WAY 100635, viz. C1-(2 methoxyphenyl)-(4- mercaptoethyl)-piperazine, was labelled with technetium-99m using thiocresol through 99mTc(V)-glucoheptonate precursor. The labelling was carried out at room temperature within 10 minutes using 370-740 MBq of 99mTc-pertechnetate. The specific activity of the '2+1+1' mixed ligand complex was about 40 GBq/ml. The labelling efficiency and the stability of the labelled compound were monitored by ITLC-SG, solvent extraction and reverse-phase HPLC. The labelling efficiency exceeded 95% and remained high about 4 hours if stored at room temperature or in a refrigerator at 4 deg C. The results give evidence of a high labelling efficiency and stability of the ligand used. The labelled ligand seems to hold promise within the family of existing radiopharmaceuticals

  17. Ultrastructural localization of cholinergic muscarinic receptors in rat brain cortical capillaries

    OpenAIRE

    Luiten, PGM; DEJONG, GI; VANDERZEE, EA; vanDijken, H; van Dijken, H.

    1996-01-01

    Cholinergic innervation of the cerebrovasculature is known to regulate vascular tone, perfusion rate and permeability of the microvascular wall. Notably the cholinergic innervation of cerebral capillaries is of interest since these capillaries form the blood-brain barrier. Although there is a general consensus as to the presence of nicotinic and muscarinic receptors in the domain of the capillary wall, their precise anatomical position is unknown. The subcellular localization of muscarinic re...

  18. Main subunits of ionotropic glutamate receptors are expressed in isolated rat brain microvessels

    Czech Academy of Sciences Publication Activity Database

    Šťastný, František; Schwendt, M.; Lisý, Václav; Ježová, D.

    2002-01-01

    Roč. 24, č. 1 (2002), s. 93-96. ISSN 0161-6412 R&D Projects: GA ČR GA305/99/1317; GA ČR GA309/99/0211 Grant ostatní: VEGA(SK) 2/6084 Institutional research plan: CEZ:AV0Z5011922 Keywords : Glutamate receptor * gene expression and binding * blood-brain barrier Subject RIV: FH - Neurology Impact factor: 0.969, year: 2002

  19. Autoradiographic localization of putative nicotinic receptors in the rat brain using 125I-neuronal bungarotoxin

    International Nuclear Information System (INIS)

    Neuronal bungarotoxin (NBT), a snake venom neurotoxin, selectively blocks nicotinic receptors in many peripheral and central neuronal preparations. alpha-Bungarotoxin (alpha BT), on the other hand, a second toxin isolated from the venom of the same snake, is an ineffective nicotinic antagonist in most vertebrate neuronal preparations studied thus far. To examine central nicotinic receptors recognized by NBT, we have characterized the binding of 125I-labeled NBT (125I-NBT) to rat brain membranes and have mapped the distribution of 125I-NBT binding in brain sections using quantitative light microscopic autoradiography. The binding of 125I-NBT was found to be saturable, of high affinity, and heterogeneously distributed in the brain. Pharmacological studies suggested that more than one population of sites is labeled by 125I-NBT. For example, one component of 125I-NBT binding was also recognized by alpha BT, while a second component, not recognized by alpha BT, was recognized by the nicotinic agonist nicotine. The highest densities of these alpha BT-insensitive, nicotine-sensitive sites were found in the fasciculus retroflexus, the lateral geniculate nucleus, the medial terminal nucleus of the accessory optic tract, and the olivary pretectal nucleus. alpha BT-sensitive NBT binding sites were found in highest density in the lateral geniculate nucleus, the subthalamic nucleus, the dorsal tegmental nucleus, and the medial mammillary nucleus (lateral part). The number of brain regions with a high density of 125I-NBT binding sites, blocked either by alpha BT or by nicotine, is low when compared with results obtained using other approaches to studying the central distribution of nicotinic receptors, such as labeling with 3H-nicotine or labeling with cDNA probes to mRNAs coding for putative receptor subunits

  20. Brain volumes in late life: gender, hormone treatment, and estrogen receptor variants.

    OpenAIRE

    Ryan, Joanne; Artero, Sylvaine; Carrière, Isabelle; Scali, Jacqueline; Maller, Jerome; Meslin, Chantal; Ritchie, Karen; Scarabin, Pierre-Yves; Ancelin, Marie-Laure

    2014-01-01

    Structural imaging studies suggest gender differences in brain volumes; however, whether hormone treatment (HT) can protect against age-related structural changes remains unknown, and no prior neuroimaging study has investigated potential interactions between HT and estrogen receptor (ESR) polymorphisms. Magnetic resonance imaging was used to measure gray and white matter, hippocampal volume, corpus callosum, cerebrospinal fluid (CSF), total intracranial volume (ICV) and white matter lesions ...

  1. Quantitative Molecular Imaging of Neuronal Nicotinic Acetylcholine Receptors in the Human Brain with A-85380 Radiotracers

    OpenAIRE

    Lotfipour, Shahrdad; Mandelkern, Mark; Brody, Arthur L.

    2011-01-01

    Neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated in a spectrum of cognitive functions as well as psychiatric and neurodegenerative disorders, including tobacco addiction and Alzheimer's Disease. The examination of neuronal nAChRs in living humans is a relatively new field. Researchers have developed brain-imaging radiotracers for nAChRs, with radiolabeled A-85380 compounds having the most widespread use. We provide a brief background on nAChRs, followed by a discussion...

  2. Effects of visual deprivation during brain development on expression of AMPA receptor subunits in rat’s hippocampus

    Directory of Open Access Journals (Sweden)

    Sayyed Alireza Talaei

    2015-06-01

    Conclusion: Dark rearing of rats during critical period of brain development changes the relative expression and also arrangement of both AMPA receptor subunits, GluR1 and GluR2 in the hippocampus, age dependently.

  3. Notch receptor expression in neurogenic regions of the adult zebrafish brain.

    Directory of Open Access Journals (Sweden)

    Vanessa de Oliveira-Carlos

    Full Text Available The adult zebrash brain has a remarkable constitutive neurogenic capacity. The regulation and maintenance of its adult neurogenic niches are poorly understood. In mammals, Notch signaling is involved in stem cell maintenance both in embryonic and adult CNS. To better understand how Notch signaling is involved in stem cell maintenance during adult neurogenesis in zebrafish we analysed Notch receptor expression in five neurogenic zones of the adult zebrafish brain. Combining proliferation and glial markers we identified several subsets of Notch receptor expressing cells. We found that 90 [Formula: see text] of proliferating radial glia express notch1a, notch1b and notch3. In contrast, the proliferating non-glial populations of the dorsal telencephalon and hypothalamus rarely express notch3 and about half express notch1a/1b. In the non-proliferating radial glia notch3 is the predominant receptor throughout the brain. In the ventral telencephalon and in the mitotic area of the optic tectum, where cells have neuroepithelial properties, notch1a/1b/3 are expressed in most proliferating cells. However, in the cerebellar niche, although progenitors also have neuroepithelial properties, only notch1a/1b are expressed in a high number of PCNA [Formula: see text] cells. In this region notch3 expression is mostly in Bergmann glia and at low levels in few PCNA [Formula: see text] cells. Additionally, we found that in the proliferation zone of the ventral telencephalon, Notch receptors display an apical high to basal low gradient of expression. Notch receptors are also expressed in subpopulations of oligodendrocytes, neurons and endothelial cells. We suggest that the partial regional heterogeneity observed for Notch expression in progenitor cells might be related to the cellular diversity present in each of these neurogenic niches.

  4. Immuno-localization of galanin receptor-1 (GALR1) in rat brain

    International Nuclear Information System (INIS)

    Full text: Galanin is expressed in discrete areas throughout the central nervous system and has several putative physiological actions including effects on hormone secretion, reproduction and cognition, via actions at multiple G-protein-coupled receptors. Currently, three galanin receptors - GalR1, -R2, -R3 - have been identified that differ in pharmacology, signalling and distribution. The distribution of [125I]-galanin binding sites presumably represents multiple receptors and so the precise regional and cellular localization of each receptor subtype is unknown. This study examined the distribution in rat brain of GalR1 receptors by immunohistochemistry, using polyclonal antibodies raised against short peptide sequences from the third intracellular loop and the proximal C-terminal. Adult rats were deeply anaesthetized (pentobarbitone 60 mg/kg, ip.) and perfusion-fixed with 4% paraformaldehyde. Specific GalR1 immunoreactivity (IR) was detected in neurons in various brain regions including cells within the olfactory bulb, piriform cortex, dorsomedial thalamus, hypothalamus (PVN, SON, ARC), midbrain/pons (intense staining in ventrolateral/medial PAG) and medulla. The localization pattern was qualitatively similar with both antisera and was consistent with that observed for GalR1 mRNA in normal rat brain. Recent evidence also reveals that GalR1- mRNA and -IR levels are coordinately altered after neuronal stimulation. These studies demonstrate a method for the identification of GalR1-containing cells that should assist in better differentiating the phenotype of galanin-receptive neurons. Copyright (2002) Australian Neuroscience Society

  5. Localization of receptors for bombesin-like peptides in the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Moody, T.W.; Getz, R.; O' Donohue, T.L.; Rosenstein, J.M.

    1988-01-01

    BN-like peptides and receptors are present in discrete areas of the mammalian brain. By radioimmunoassay, endogenous BN/GRP, neuromedin B, and ranatensin-like peptides are present in the rat brain. High-to-moderate concentrations of BN/GRP are present in the rat hypothalamus and thalamus, whereas moderate-to-high densities of neuromedin B and ranatensin-like peptides are present in the olfactory bulb and hippocampus, as well as in the hypothalamus and thalamus. While the distribution of neuromedin B and ranatensin-like peptides appears similar, it is distinct from that of BN/GRP. When released from CNS neurons, these peptides may interact with receptors for BN-like peptides. BN, GRP, ranatensin, and neuromedin B inhibit specific (/sup 125/I-Tyr4)BN binding with high affinity. By use of in vitro autoradiographic techniques to detect binding of (/sup 125/I-Tyr4)BN to receptors for BN-like peptides, high grain densities were found in the olfactory bulb and tubercle, the nucleus accumbens, the suprachiasmatic and paraventricular nucleus of the hypothalamus, the central medial and paraventricular thalamic nuclei, the hippocampus, the dentate gyrus, and the amygdala of the rat brain. Some of these receptors may be biologically active and mediate the biological effects of BN-like peptides. For example, when BN is directly injected into the nucleus accumbens, pronounced grooming results and the effects caused by BN are reversed by spantide and (D-Phe12)BN. Thus, the putative BN receptor antagonists may serve as useful agents to investigate the biological significance of BN-like peptides in the CNS.

  6. Phosphatase inhibitors remove the run-down of γ-aminobutyric acid type A receptors in the human epileptic brain

    Science.gov (United States)

    Palma, E.; Ragozzino, D. A.; Di Angelantonio, S.; Spinelli, G.; Trettel, F.; Martinez-Torres, A.; Torchia, G.; Arcella, A.; Di Gennaro, G.; Quarato, P. P.; Esposito, V.; Cantore, G.; Miledi, R.; Eusebi, F.

    2004-01-01

    The properties of γ-aminobutyric acid (GABA) type A receptors (GABAA receptors) microtransplanted from the human epileptic brain to the plasma membrane of Xenopus oocytes were compared with those recorded directly from neurons, or glial cells, in human brains slices. Cell membranes isolated from brain specimens, surgically obtained from six patients afflicted with drug-resistant temporal lobe epilepsy (TLE) were injected into frog oocytes. Within a few hours, these oocytes acquired GABAA receptors that generated GABA currents with an unusual run-down, which was inhibited by orthovanadate and okadaic acid. In contrast, receptors derived from membranes of a nonepileptic hippocampal uncus, membranes from mouse brain, or recombinant rat α1β2γ2-GABA receptors exhibited a much less pronounced GABA-current run-down. Moreover, the GABAA receptors of pyramidal neurons in temporal neocortex slices from the same six epileptic patients exhibited a stronger run-down than the receptors of rat pyramidal neurons. Interestingly, the GABAA receptors of neighboring glial cells remained substantially stable after repetitive activation. Therefore, the excessive GABA-current run-down observed in the membrane-injected oocytes recapitulates essentially what occurs in neurons, rather than in glial cells. Quantitative RT-PCR analyses from the same TLE neocortex specimens revealed that GABAA-receptor β1, β2, β3, and γ2 subunit mRNAs were significantly overexpressed (8- to 33-fold) compared with control autopsy tissues. Our results suggest that an abnormal GABA-receptor subunit transcription in the TLE brain leads to the expression of run-down-enhanced GABAA receptors. Blockage of phosphatases stabilizes the TLE GABAA receptors and strengthens GABAergic inhibition. It may be that this process can be targeted to develop new treatments for intractable epilepsy. PMID:15218107

  7. The serotonin receptor 7 and the structural plasticity of brain circuits

    Science.gov (United States)

    Volpicelli, Floriana; Speranza, Luisa; di Porzio, Umberto; Crispino, Marianna; Perrone-Capano, Carla

    2014-01-01

    Serotonin (5-hydroxytryptamine, 5-HT) modulates numerous physiological processes in the nervous system. Together with its function as neurotransmitter, 5-HT regulates neurite outgrowth, dendritic spine shape and density, growth cone motility and synapse formation during development. In the mammalian brain 5-HT innervation is virtually ubiquitous and the diversity and specificity of its signaling and function arise from at least 20 different receptors, grouped in 7 classes. Here we will focus on the role 5-HT7 receptor (5-HT7R) in the correct establishment of neuronal cytoarchitecture during development, as also suggested by its involvement in several neurodevelopmental disorders. The emerging picture shows that this receptor is a key player contributing not only to shape brain networks during development but also to remodel neuronal wiring in the mature brain, thus controlling cognitive and emotional responses. The activation of 5-HT7R might be one of the mechanisms underlying the ability of the CNS to respond to different stimuli by modulation of its circuit configuration. PMID:25309369

  8. The serotonin receptor 7 and the structural plasticity of brain circuits

    Directory of Open Access Journals (Sweden)

    Floriana eVolpicelli

    2014-09-01

    Full Text Available Serotonin (5-hydroxytryptamine, 5-HT modulates numerous physiological processes in the nervous system. Together with its function as neurotrasmitter, 5-HT regulates neurite outgrowth, dendritic spine shape and density, growth cone motility and synapse formation during development. In the mammalian brain 5-HT innervation is virtually ubiquitous and the diversity and specificity of its signaling and function arise from at least 20 different receptors, grouped in 7 classes. Here we will focus on the role 5-HT7 receptor (5-HT7R in the correct establishment of neuronal cytoarchitecture during development, as also suggested by its involvement in several neurodevelopmental disorders. The emerging picture shows that this receptor is a key player contributing not only to shape brain networks during development but also to remodel neuronal wiring in the mature brain, thus controlling cognitive and emotional responses. The activation of 5-HT7R might be one of the mechanisms underlying the ability of the CNS to respond to different stimuli by modulation of its circuit configuration.

  9. Blockage of transient receptor potential vanilloid 4 inhibits brain edema in middle cerebral artery occlusion mice

    Directory of Open Access Journals (Sweden)

    Pinghui eJie

    2015-04-01

    Full Text Available Brain edema is an important pathological process during stroke. Activation of transient receptor potential vanilloid 4 (TRPV4 causes an up-regulation of matrix metalloproteinases (MMPs in lung tissue. MMP can digest the endothelial basal lamina to destroy blood brain barrier, leading to vasogenic brain edema. Herein, we tested whether TRPV4-blockage could inhibit brain edema through inhibiting MMPs in middle cerebral artery occlusion (MCAO mice. We found that the brain water content and Evans blue extravasation at 48 h post-MCAO were reduced by a TRPV4 antagonist HC-067047. The increased MMP-2/9 protein in hippocampus of MCAO mice was attenuated by HC-067046, but only the increased MMP-9 activity was blocked by HC-067047. The loss of zonula occluden-1 (ZO-1 and occludin protein in MCAO mice was also attenuated by HC-067047. Moreover, MMP-2/9 protein increased in mice treated with a TRPV4 agonist GSK1016790A, but only MMP-9 activity was increased by GSK1016790A. Finally, ZO-1 and occludin protein was decreased by GSK1016790A, which was reversed by an MMP-9 inhibitor. We conclude that blockage of TRPV4 may inhibit brain edema in cerebral ischemia through inhibiting MMP-9 activation and the loss of tight junction protein.

  10. Developmentally Regulated Expression of the Nerve Growth Factor Receptor Gene in the Periphery and Brain

    Science.gov (United States)

    Buck, C. R.; Martinez, Humberto J.; Black, Ira B.; Chao, Moses V.

    1987-05-01

    Nerve growth factor (NGF) regulates development and maintenance of function of peripheral sympathetic and sensory neurons. A potential role for the trophic factor in brain has been detected only recently. The ability of a cell to respond to NGF is due, in part, to expression of specific receptors on the cell surface. To study tissue-specific expression of the NGF receptor gene, we have used sensitive cRNA probes for detection of NGF receptor mRNA. Our studies indicate that the receptor gene is selectively and specifically expressed in sympathetic (superior cervical) and sensory (dorsal root) ganglia in the periphery, and by the septum-basal forebrain centrally, in the neonatal rat in vivo. Moreover, examination of tissues from neonatal and adult rats reveals a marked reduction in steady-state NGF receptor mRNA levels in sensory ganglia. In contrast, a 2- to 4-fold increase was observed in the basal forebrain and in the sympathetic ganglia over the same time period. Our observations suggest that NGF receptor mRNA expression is developmentally regulated in specific areas of the nervous system in a differential fashion.

  11. Disruption of estrogen receptor beta in mice brain results in pathological alterations resembling Alzheimer disease

    Institute of Scientific and Technical Information of China (English)

    Qing-hong ZHANG; Yan-hong HUANG; Yu-zhen HU; Geng-ze WEI; Xue-feng HAN; Shun-yan LU; Yu-feng ZHAO

    2004-01-01

    AIM: To study the pathological characteristics of the mice with estrogen receptor β (ERβ) disruption in brain.METHODS: Immunohistochemistry method was applied in the study. RESULTS: β-Amyloid peptide(Aβ42) and apolipoprotein E (ApoE) immunoreactive substances were accumulated notably in cortex and limbic structures such as the hippocampus and amygdala in brain, resembling the pathological changes of human Alzheimer disease (AD). Aβ formed cloudy-like deposits in parenchyma of brain, while apoE also deposited along or surrounding the blood vessels. CONCLUSIONS: ERβ is crucial to the development of neural degenerative disease, so modulation of Aβ metabolism via ERβ signal pathway might be beneficial for AD prevention or therapy.

  12. Implications of astrocytes in mediating the protective effects of Selective Estrogen Receptor Modulators upon brain damage

    Directory of Open Access Journals (Sweden)

    George E. Barreto

    2015-04-01

    Full Text Available Selective Estrogen Receptor Modulators (SERMs are steroidal or non-steroidal compounds that are already used in clinical practice for the treatment of breast cancer, osteoporosis and menopausal symptoms. While SERMs actions in the breast, bone, and uterus have been well characterized, their actions in the brain are less well understood. Previous works have demonstrated the beneficial effects of SERMs in different chronic neurodegenerative diseases like Alzheimer, Parkinson’s disease and Multiple sclerosis, as well as acute degeneration as stroke and traumatic brain injury. Moreover, these compounds exhibit similar protective actions as those of estradiol in the Central Nervous System, overt any secondary effect. For these reasons, in the past few years, there has been a growing interest in the neuroprotective effects exerted directly or indirectly by SERMs in the SNC. In this context, astrocytes play an important role in the maintenance of brain metabolism, and antioxidant support to neurons, thus indicating that better protection of astrocytes are an important asset targeting neuronal protection. Moreover, various clinical and experimental studies have reported that astrocytes are essential for the neuroprotective effects of SERMs during neuronal injuries, as these cells express different estrogen receptors in cell membrane, demonstrating that part of SERMs effects upon injury may be mediated by astrocytes. The present work highlights the current evidence on the protective mechanisms of SERMs, such as tamoxifen and raloxifene, in the SNC, and their modulation of astrocytic properties as promising therapeutic targets during brain damage.

  13. Expression of hippocampal brain-derived neurotrophic factor and its receptors in Stanley consortium brains

    OpenAIRE

    Dunham, Jason S.; Deakin, J. F. William; Miyajima, Fabio; Payton, Tony; Toro, Carla Tatiana

    2009-01-01

    Several lines of evidence implicate BDNF in the pathophysiology of psychiatric illness. BDNF polymorphisms have also been associated with the risk of schizophrenia and mood disorders. We therefore investigated whether levels of (pro)BDNF and receptor proteins, TrkB and p75, are altered in hippocampus in schizophrenia and mood disorder and whether polymorphisms in each gene influenced protein expression. Formalin-fixed paraffin-embedded hippocampal sections from subjects with...

  14. [3H]methylcarbamylcholine, a new radioligand for studying brain nicotinic receptors

    International Nuclear Information System (INIS)

    A new radioligand, [3H]methylcarbamylcholine, has been developed for the study of the nicotinic cholinergic and nicotine-like binding sites in rat brain membranes. A Scatchard analysis with the radioligand yielded a Ksub(d) of 1.1 x 10-9 M and a Bsub(max) of 4.0 x 10-14 moles/mg protein which compares with a lower affinity site for (-)-[3H]nicotine having a Ksub(d) of 3 x 10-9 M and a Bsub(max) of 2x 10-14 moles/mg. Comparable values for the Ksub(d) were obtained from a Hill plot and from calculations based on rate constants for association and dissociation. A comparison of the binding affinities of various nicotine analogues, nicotinic cholinergic agents, and other neurotropic agents revealed a close similarity between the two radioligands, with the exception that quaternization of nicotine or carbamate esters increased affinity by at least an order of magnitude with [3H]methylcarbamylcholine and resulted in a comparable decrease in affinity with [3H]nicotine as the ligand. The binding of [3H]methylcarbamylcholine, like [3H]nicotine, was not displaceable by muscarinic cholinergic antagonists. It was concluded that, although [3H]methylcarbamylcholine and [3H]nicotine bind to a common receptor in brain, the functional and chemical characteristics of the receptor(s) differ in some respects from peripheral nicotinic cholinergic receptors. (author)

  15. Effects of isomers of apomorphines on dopamine receptors in striatal and limbic tissue of rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Kula, N.S.; Baldessarini, R.J.; Bromley, S.; Neumeyer, J.L.

    1985-09-16

    The optical isomers of apomorphine (APO) and N-propylnorapomorphine (NPA) were interacted with three biochemical indices of dopamine (Da) receptors in extrapyramidal and limbic preparations of rat brain tissues. There were consistent isomeric preferences for the R(-) configuration of both DA analogs in stimulation adenylate cyclase (D-1 sites) and in competing for high affinity binding of /sup 3/H-spiroperidol (D-2 sites) and of /sup 3/H-ADTN (DA agonist binding sites) in striatal tissue, with lesser isomeric differences in the limbic tissue. The S(+) apomorphines did not inhibit stimulation of adenylate cyclase by DA. The tendency for greater activity of higher apparent affinity of R(-) apomorphines in striatum may reflect the evidently greater abundance of receptor sites in that region. There were only small regional differences in interactions of the apomorphine isomers with all three receptor sites, except for a strong preference of (-)NPA for striatal D-2 sites. These results do not parallel our recent observations indicating potent and selective antidopaminergic actions of S(+) apomorphines in the rat limbic system. They suggest caution in assuming close parallels between current biochemical functional, especially behavioral, methods of evaluating dopamine receptors of mammalian brain.

  16. Multiple opioid receptor binding in dissociated intact guinea pig brain cells

    Energy Technology Data Exchange (ETDEWEB)

    Tam, S.W.; James, D.W.

    1986-03-05

    Dissociated intact guinea pig brain cells were prepared by the method of Rogers and El-Fakahany. Over 95% of these cells are viable as demonstrated by their exclusion of the dye trypan blue. Opioid receptor binding assays were performed in a modified Kreb-Ringers physiological buffer. The following radiolabeled ligands and conditions were used to selectively labeled multiple opioid receptors: mu binding, 1 nM (/sup 3/H)naloxone + 20 nM DADLE + 300 nM U50,488H; kappa binding, 4 nM (-)-(/sup 3/H)-EKC + 100 nM DAGO + 500 nM DADLE; delta binding, 2 nM (/sup 3/H)-DADLE + 100 nM DAGO + 300 nM U50,488H; sigma binding, 4 nM (+)-(/sup 3/H)SKF 10,047. The intact brain cells in physiological buffer demonstrated specific binding for mu, kappa, delta, and sigma receptors. The relative binding potency of naloxone for each of the receptor types is arbitrarily set at 1.

  17. Multiple opioid receptor binding in dissociated intact guinea pig brain cells

    International Nuclear Information System (INIS)

    Dissociated intact guinea pig brain cells were prepared by the method of Rogers and El-Fakahany. Over 95% of these cells are viable as demonstrated by their exclusion of the dye trypan blue. Opioid receptor binding assays were performed in a modified Kreb-Ringers physiological buffer. The following radiolabeled ligands and conditions were used to selectively labeled multiple opioid receptors: mu binding, 1 nM [3H]naloxone + 20 nM DADLE + 300 nM U50,488H; kappa binding, 4 nM (-)-[3H]-EKC + 100 nM DAGO + 500 nM DADLE; delta binding, 2 nM [3H]-DADLE + 100 nM DAGO + 300 nM U50,488H; sigma binding, 4 nM (+)-[3H]SKF 10,047. The intact brain cells in physiological buffer demonstrated specific binding for mu, kappa, delta, and sigma receptors. The relative binding potency of naloxone for each of the receptor types is arbitrarily set at 1

  18. Discrete mapping of brain Mu and delta opioid receptors using selective peptides: Quantitative autoradiography, species differences and comparison with kappa receptors

    Energy Technology Data Exchange (ETDEWEB)

    Sharif, N.A.; Hughes, J. (Addenbrookes Hospital Site, Cambridge (England))

    1989-05-01

    The opioid peptides, (3H)DAGO and (3H)DPDPE, bound to rat and guinea pig brain homogenates with a high, nanomolar affinity and to a high density of mu and delta receptors, respectively. (3H)DAGO binding to mu receptors was competitively inhibited by unlabelled opioids with the following rank order of potency: DAGO greater than morphine greater than DADLE greater than naloxone greater than etorphine much greater than U50488 much greater than DPDPE. In contrast, (3H)DPDPE binding to delta receptors was inhibited by compounds with the following rank order of potency: DPDPE greater than DADLE greater than etorphine greater than dynorphin(1-8) greater than naloxone much greater than U50488 much greater than DAGO. These profiles were consistent with specific labelling of the mu and delta opioid receptors, respectively. In vitro autoradiographic techniques coupled with computer-assisted image analyses revealed a discrete but differential anatomical localization of mu and delta receptors in the rat and guinea pig brain. In general, mu and delta receptor density in the rat exceeded that in the guinea pig brain and differed markedly from that of kappa receptors in these species. However, while mu receptors were distributed throughout the brain with hotspots in the fore-, mid- and hindbrain of the two rodents, the delta sites were relatively diffusely distributed, and were mainly concentrated in the forebrain with particularly high levels within the olfactory bulb (OB), n. accumbens and striatum. Notable regions of high density of mu receptors in the rat and guinea pig brain were the accessory olfactory bulb, striatal patches and streaks, amygdaloid nuclei, ventral hippocampal subiculum and dentate gyrus, numerous thalamic nuclei, geniculate bodies, central grey, superior and inferior colliculi, solitary and pontine nuclei and s. nigra.

  19. Discrete mapping of brain Mu and delta opioid receptors using selective peptides: Quantitative autoradiography, species differences and comparison with kappa receptors

    International Nuclear Information System (INIS)

    The opioid peptides, [3H]DAGO and [3H]DPDPE, bound to rat and guinea pig brain homogenates with a high, nanomolar affinity and to a high density of mu and delta receptors, respectively. [3H]DAGO binding to mu receptors was competitively inhibited by unlabelled opioids with the following rank order of potency: DAGO greater than morphine greater than DADLE greater than naloxone greater than etorphine much greater than U50488 much greater than DPDPE. In contrast, [3H]DPDPE binding to delta receptors was inhibited by compounds with the following rank order of potency: DPDPE greater than DADLE greater than etorphine greater than dynorphin(1-8) greater than naloxone much greater than U50488 much greater than DAGO. These profiles were consistent with specific labelling of the mu and delta opioid receptors, respectively. In vitro autoradiographic techniques coupled with computer-assisted image analyses revealed a discrete but differential anatomical localization of mu and delta receptors in the rat and guinea pig brain. In general, mu and delta receptor density in the rat exceeded that in the guinea pig brain and differed markedly from that of kappa receptors in these species. However, while mu receptors were distributed throughout the brain with hotspots in the fore-, mid- and hindbrain of the two rodents, the delta sites were relatively diffusely distributed, and were mainly concentrated in the forebrain with particularly high levels within the olfactory bulb (OB), n. accumbens and striatum. Notable regions of high density of mu receptors in the rat and guinea pig brain were the accessory olfactory bulb, striatal patches and streaks, amygdaloid nuclei, ventral hippocampal subiculum and dentate gyrus, numerous thalamic nuclei, geniculate bodies, central grey, superior and inferior colliculi, solitary and pontine nuclei and s. nigra

  20. Leptin receptor-positive and leptin receptor-negative proopiomelanocortin neurons innervate an identical set of brain structures.

    Science.gov (United States)

    Lima, Leandro B; Metzger, Martin; Furigo, Isadora C; Donato, J

    2016-09-01

    Neurons that express the prohormone proopiomelanocortin (POMC) in the arcuate hypothalamic nucleus (Arc) are engaged in the regulation of energy balance and glucose homeostasis. Additionally, POMC neurons are considered key first-order cells regulated by leptin. Interestingly, in the Arc, POMC cells that express the leptin receptor (POMC/LepR+ cells) are found side by side with POMC cells not directly responsive to leptin (POMC/LepR- cells). However, it remains unknown whether these distinct populations innervate different target regions. Therefore, the objective of the present study was to compare the projections of POMC/LepR+ and POMC/LepR- neurons. Using genetically modified LepR-reporter mice to identify leptin receptor-expressing cells and immunohistochemistry to stain POMC-derived peptides (α-MSH or β-endorphin) we confirmed that approximately 80% of Arc β-endorphin-positive neurons co-expressed leptin receptors. POMC/LepR+ and POMC/LepR- axons were intermingled in all of their target regions. As revealed by confocal microscopy, we found an elevated degree of co-localization between α-MSH+ axons and the reporter protein (tdTomato) in all brain regions analyzed, with co-localization coefficients ranging from 0.889 to 0.701. Thus, these two populations of POMC neurons seem to project to the same set of brain structures, although one of the two subtypes of POMC axons was sometimes found to be more abundant than the other in distinct subregions of the same nucleus. Therefore, POMC/LepR+ and POMC/LepR- cells may target separate neuronal populations and consequently activate distinct neuronal circuits within some target nuclei. These findings contribute to unravel the neuronal circuits involved in the regulation of energy balance and glucose homeostasis. PMID:27321158

  1. In vivo imaging of brain androgen receptors in rats: a [18F]FDHT PET study

    International Nuclear Information System (INIS)

    Introduction: Steroid hormones like androgens play an important role in the development and maintenance of several brain functions. Androgens can act through androgen receptors (AR) in the brain. This study aims to demonstrate the feasibility of positron emission tomography (PET) with 16β-[18F]fluoro-5α-dihydrotestosterone ([18F]FDHT) to image AR expression in the brain. Methods: Male Wistar rats were either orchiectomized to inhibit endogenous androgen production or underwent sham-surgery. Fifteen days after surgery, rats were subjected to a 90-min dynamic [18F]FDHT PET scan with arterial blood sampling. In a subset of orchiectomized rats, 1 mg/kg dihydrotestosterone was co-injected with the tracer in order to saturate the AR. Plasma samples were analyzed for the presence of radioactive metabolites by radio-TLC. Pharmacokinetic modeling was performed to quantify brain kinetics of the tracer. After the PET scan, the animals were terminated for ex-vivo biodistribution. Results: PET imaging and ex vivo biodistribution studies showed low [18F]FDHT uptake in all brain regions, except pituitary. [18F]FDHT uptake in the surrounding cranial bones was high and increased over time. [18F]FDHT was rapidly metabolized in rats. Metabolism was significantly faster in orchiectomized rats than in sham-orchiectomized rats. Quantitative analysis of PET data indicated substantial spill-over of activity from cranial bones into peripheral brain regions, which prevented further analysis of peripheral brain regions. Logan graphical analysis and kinetic modeling using 1- and 2-tissue compartment models showed reversible and homogenously distributed tracer uptake in central brain regions. [18F]FDHT uptake in the brain could not be blocked by endogenous androgens or administration of dihydrotestosterone. Conclusion: The results of this study indicate that imaging of AR availability in rat brain with [18F]FDHT PET is not feasible. The low AR expression in the brain, the rapid metabolism of

  2. Sigma1 and dopamine D2 receptor occupancy in the mouse brain after a single administration of haloperidol and two dopamine D2-like receptor ligands

    International Nuclear Information System (INIS)

    We investigated sigma1 and dopamine D2 receptor occupancy in mouse brain after a single injection of haloperidol, nemonapride, or spiperone using [11C]SA4503 and [11C]raclopride, respectively. Co-injection of the three compounds significantly blocked the uptake of each radioligand. Six hours later, only haloperidol blocked [11C]SA4503 uptake, while all three reduced [11C]raclopride uptake. Sigma1 receptor occupancy by haloperidol was reduced to 19% at day 2 when D2 receptor occupancy disappeared. [11C]SA4503 would be applicable to the investigation of sigma1 receptor occupancy of antispychotic drugs using PET

  3. {beta}-adrenergic receptor density and adenylate cyclase activity in lead-exposed rat brain after cessation of lead exposure

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Huoy-Rou [I-Shou University, Department of Biomedical Engineering, Dashu Shiang, Kaohsiung County (Taiwan); Tsao, Der-An [Fooyin University of Technology, Department of Medical Technology (Taiwan); Yu, Hsin-Su [Taiwan University, Department of Dermatology, College of Medicine (Taiwan); Ho, Chi-Kung [Kaohsiung Medical University, Occupational Medicine (Taiwan); Kaohsiung Medical University, Graduate Institute of Medicine, Research Center for Occupational Disease (Taiwan)

    2005-01-01

    To understanding the reversible or irreversible harm to the {beta}-adrenergic system in the brain of lead-exposed rats, this study sets up an animal model to estimate the change in the sympathetic nervous system of brain after lead exposure was withdrawn. We address the following topics in this study: (a) the relationship between withdrawal time of lead exposure and brain {beta}-adrenergic receptor, blood lead level, and brain lead level in lead-exposed rats after lead exposure was stopped; and (b) the relationship between lead level and {beta}-adrenergic receptor and cyclic AMP (c-AMP) in brain. Wistar rats were chronically fed with 2% lead acetate and water for 2 months. Radioligand binding was assayed by a method that fulfilled strict criteria of {beta}-adrenergic receptor using the ligand [{sup 125}I]iodocyanopindolol. The levels of lead were determined by electrothermal atomic absorption spectrometry. The c-AMP level was determined by radioimmunoassay. The results showed a close relationship between decreasing lead levels and increasing numbers of brain {beta}-adrenergic receptors and brain adenylate cyclase activity after lead exposure was withdrawn. The effect of lead exposure on the {beta}-adrenergic system of the brain is a partly reversible condition. (orig.)

  4. Brain stem adenosine receptors modulate centrally mediated hypotensive responses in conscious rats: A review

    Directory of Open Access Journals (Sweden)

    Noha N. Nassar

    2015-05-01

    Full Text Available Adenosine is implicated in the modulation of cardiovascular responses either at the peripheral or at central level in experimental animals. However, there are no dedicated reviews on the involvement of adenosine in mediating the hypotensive response of centrally administered clonidine in general and specifically in aortically barodenervated rats (ABD. The conscious ABD rat model exhibits surgically induced baroreflex dysfunction and exaggerated hypotensive response, compared with conscious sham-operated (SO rats. The current review focuses on, the role of adenosine receptors in blood pressure (BP regulation and their possible crosstalk with other receptors e.g. imidazoline (I1 and alpha (α2A adrenergic receptor (AR. The former receptor is a molecular target for clonidine, whose hypotensive effect is enhanced approx. 3-fold in conscious ABD rats. We also discussed how the balance between the brain stem adenosine A1 and A2A receptors is regulated by baroreceptors and how such balance influences the centrally mediated hypotensive responses. The use of the ABD rat model yielded insight into the downstream signaling cascades following clonidine-evoked hypotension in a surgical model of baroreflex dysfunction.

  5. [3H]Haloperidol labels brain dopamine receptors after its injection into the internal carotid artery of the rat

    International Nuclear Information System (INIS)

    Pulse injection of [3H]haloperidol (0.1 μCi; 0.003 μg) into the internal carotid artery of the rat specifically labelled dopamine receptors in striatum and olfactory tubercle, as indicated by the kinetics of, and the effects of neuroleptic drugs on, the ligand disposition. The described method may prove useful for labelling brain receptors with ligands which readily cross the blood-brain barrier but which do not selectively mark their receptors if injected systemically. (Auth.)

  6. Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects.

    Directory of Open Access Journals (Sweden)

    Emmanuel S Onaivi

    Full Text Available BACKGROUND: Addiction and major depression are mental health problems associated with stressful events in life with high relapse and reoccurrence even after treatment. Many laboratories were not able to detect the presence of cannabinoid CB2 receptors (CB2-Rs in healthy brains, but there has been demonstration of CB2-R expression in rat microglial cells and other brain associated cells during inflammation. Therefore, neuronal expression of CB2-Rs had been ambiguous and controversial and its role in depression and substance abuse is unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study we tested the hypothesis that genetic variants of CB2 gene might be associated with depression in a human population and that alteration in CB2 gene expression may be involved in the effects of abused substances including opiates, cocaine and ethanol in rodents. Here we demonstrate that a high incidence of (Q63R but not (H316Y polymorphism in the CB2 gene was found in Japanese depressed subjects. CB2-Rs and their gene transcripts are expressed in the brains of naïve mice and are modulated following exposure to stressors and administration of abused drugs. Mice that developed alcohol preference had reduced CB2 gene expression and chronic treatment with JWH015 a putative CB2-R agonist, enhanced alcohol consumption in stressed but not in control mice. The direct intracerebroventricular microinjection of CB2 anti-sense oligonucleotide into the mouse brain reduced mouse aversions in the plus-maze test, indicating the functional presence of CB2-Rs in the brain that modifies behavior. We report for the using electron microscopy the sub cellular localization of CB2-Rs that are mainly on post-synaptic elements in rodent brain. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate the functional expression of CB2-Rs in brain that may provide novel targets for the effects of cannabinoids in depression and substance abuse disorders beyond neuro-immunocannabinoid activity.

  7. Fourteenβ-(bromoacetamido)morphine irreversibly labels μ opioid receptors in rat brain membranes

    International Nuclear Information System (INIS)

    The binding properties of 14β-(bromoacetamido)morphine (BAM) and the ability of BAM to irreversibly inhibit opioid binding to rat brain membranes were examined to characterize the affinity and selectivity of BAM as an irreversible affinity ligand for opioid receptors. BAM had the same receptor selectivity as morphine, with a 3-5-fold decrease in affinity for the different types of opioid receptors. When brain membranes were incubated with BAM, followed by extensive washing, opioid binding was restored to control levels. However, when membranes were incubated with dithiothreitol (DTT), followed by BAM, and subsequently washed, 90% of the 0.25 nM [3H][D-Ala2,(Me)Phe4,Gly(ol)5]enkephalin (DAGO) binding was irreversibly inhibited as a result of the specific alkylation of a sulfhydryl group at the μ binding site. This inhibition was dependent on the concentrations of both DTT and BAM. The μ receptor specificity of BAM alkylation was demonstrated by the ability of BAM alkylated membranes to still bind the δ-selective peptide [3H][D-penicillamine2,D-penicillamine5]enkephalin (DPDPE) and (-)-[3H]bremazocine in the presence of μ and δ blockers, selective for κ binding sites. Morphine and naloxone partially protected the binding site from alkylation with BAM, while ligands that did not bind to the μs site did not afford protection. These studies have demonstrated that when a disulfide bond at or near μ opioid binding sites was reduced, BAM could then alkylate this site, resulting in the specific irreversible labeling of μ opioid receptors

  8. Apo-ghrelin receptor (apo-GHSR1a Regulates Dopamine Signaling in the Brain

    Directory of Open Access Journals (Sweden)

    Andras eKern

    2014-08-01

    Full Text Available The orexigenic peptide hormone ghrelin is synthesized in the stomach and its receptor growth hormone secretagogue receptor (GHSR1a is expressed mainly in the central nervous system (CNS. In this review we confine our discussion to the physiological role of GHSR1a in the brain. Paradoxically, despite broad expression of GHSR1a in the CNS, other than trace amounts in the hypothalamus, ghrelin is undetectable in the brain. In our efforts to elucidate the function of the ligand-free ghrelin receptor (apo-GHSR1a we identified subsets of neurons that co-express GHSR1a and dopamine receptors. In this review we focus on interactions between apo-GHSR1a and dopamine-2 receptor (DRD2 and formation of GHSR1a:DRD2 heteromers in hypothalamic neurons that regulate appetite, and discuss implications for the treatment of Prader-Willi syndrome. GHSR1a antagonists of distinct chemical structures, a quinazolinone and a triazole, respectively enhance and inhibit dopamine signaling through GHSR1a:DRD2 heteromers by an allosteric mechanism. This finding illustrates a potential strategy for designing the next generation of drugs for treating eating disorders as well as psychiatric disorders caused by abnormal dopamine signaling. Treatment with a GHSR1a antagonist that enhances dopamine/DRD2 activity in GHSR1a:DRD2 expressing hypothalamic neurons has the potential to inhibit the uncontrollable hyperphagia associated with Prader-Willi syndrome. DRD2 antagonists are prescribed for treating schizophrenia, but these block dopamine signaling in all DRD2 expressing neurons and are associated with adverse side effects, including enhanced appetite and excessive weight gain. A GHSR1a antagonist of structural class that allosterically blocks dopamine/DRD2 action in GHSR1a:DRD2 expressing neurons would have no effect on neurons expressing DRD2 alone; therefore, the side effects of DRD2 antagonists would potentially be reduced thereby enhancing patient compliance.

  9. Fourteen. beta. -(bromoacetamido)morphine irreversibly labels. mu. opioid receptors in rat brain membranes

    Energy Technology Data Exchange (ETDEWEB)

    Bidlack, J.M.; Frey, D.K.; Seyed-Mozaffari, A.; Archer, S. (Univ. of Rochester School of Medicine and Dentistry, NY (USA))

    1989-05-16

    The binding properties of 14{beta}-(bromoacetamido)morphine (BAM) and the ability of BAM to irreversibly inhibit opioid binding to rat brain membranes were examined to characterize the affinity and selectivity of BAM as an irreversible affinity ligand for opioid receptors. BAM had the same receptor selectivity as morphine, with a 3-5-fold decrease in affinity for the different types of opioid receptors. When brain membranes were incubated with BAM, followed by extensive washing, opioid binding was restored to control levels. However, when membranes were incubated with dithiothreitol (DTT), followed by BAM, and subsequently washed, 90% of the 0.25 nM ({sup 3}H)(D-Ala{sup 2},(Me)Phe{sup 4},Gly(ol){sup 5})enkephalin (DAGO) binding was irreversibly inhibited as a result of the specific alkylation of a sulfhydryl group at the {mu} binding site. This inhibition was dependent on the concentrations of both DTT and BAM. The {mu} receptor specificity of BAM alkylation was demonstrated by the ability of BAM alkylated membranes to still bind the {delta}-selective peptide ({sup 3}H)(D-penicillamine{sup 2},D-penicillamine{sup 5})enkephalin (DPDPE) and (-)-({sup 3}H)bremazocine in the presence of {mu} and {delta} blockers, selective for {kappa} binding sites. Morphine and naloxone partially protected the binding site from alkylation with BAM, while ligands that did not bind to the {mu}s site did not afford protection. These studies have demonstrated that when a disulfide bond at or near {mu} opioid binding sites was reduced, BAM could then alkylate this site, resulting in the specific irreversible labeling of {mu} opioid receptors.

  10. Radiochemical and biological evaluation of a new brain serotonin1A receptor imaging agent

    International Nuclear Information System (INIS)

    Radiochemical and biological evaluations are made of a new bidentate radioligand as a potential brain serotonin1A (5-HT1A) receptor imaging agent. The bidentate part of the complex was a derivative of the well known serotonin1A receptor antagonist molecule, namely WAY 100635; the monodentate parts were thiocresol, thiosalicylic acid and thio-2-naphthol. The labelling procedure was performed through the 99mTc(V)-glucoheptonate precursor. The bidentate + monodentate complex formed during the reaction in the case of thiocresol was identified as 99TcO(o-CH3-C6H4-N(CH2-CH2)2N-CH2CH2S)( p-C6H4CH3)2 (99mTc-1). Its labelling efficiency and stability were determined by thin layer chromatography, the organic solvent extraction method and high performance liquid chromagraphy. The biodistribution of the labelled compound was found by using male Wistar rats. On the basis of these data, kinetic curves were constructed for different organs and the dosimetry for humans was calculated. The brain uptake and pharmacokinetics were followed by planar and single photon emission computed tomography (SPECT) imaging in rats. Average brain count density was calculated and different regional count densities (counts/gram tissue) were obtained for the hippocampus and other receptor-rich regions. A detailed SPECT study was carried out after administration of 99mTc-1 to a cynomolgus monkey (Macaca cynomolgus). The results found show that, of three investigated aromatic thiol compounds, the labelling efficiency was the highest in the case of thiocresol as the monodentate part. Therefore all further studies were carried out using thiocresol. The labelling efficiency of this bidentate complex was about 80%, and the molecule was stable for up to one hour. The biodistribution data show that more than 0.1% of the injected dose is present in the rat brains a few minutes after administration, and the metabolic pathway is through the hepatobiliary system. From the results obtained with the study of the

  11. Mapping adenosine A1 receptors in the cat brain by positron emission tomography with [11C]MPDX

    International Nuclear Information System (INIS)

    We evaluated the potential of [11C]MPDX as a radioligand for mapping adenosine A1 receptors in comparison with previously proposed [11C]KF15372 in cat brain by PET. Two tracers showed the same brain distribution. Brain uptake of [11C]MPDX (Ki=4.2 nM) was much higher and washed out faster than that of [11C]KF15372 (Ki=3.0 nM), and was blocked by carrier-loading or displaced with an A1 antagonist. The regional A1 receptor distribution evaluated with kinetic analysis is consistent with that previously measured in vitro. [11C]MPDX PET has a potential for mapping adenosine A1 receptors in brain

  12. Weight loss after bariatric surgery normalizes brain opioid receptors in morbid obesity.

    Science.gov (United States)

    Karlsson, H K; Tuulari, J J; Tuominen, L; Hirvonen, J; Honka, H; Parkkola, R; Helin, S; Salminen, P; Nuutila, P; Nummenmaa, L

    2016-08-01

    Positron emission tomography (PET) studies suggest opioidergic system dysfunction in morbid obesity, while evidence for the role of the dopaminergic system is less consistent. Whether opioid dysfunction represents a state or trait in obesity remains unresolved, but could be assessed in obese subjects undergoing weight loss. Here we measured brain μ-opioid receptor (MOR) and dopamine D2 receptor (D2R) availability in 16 morbidly obese women twice-before and 6 months after bariatric surgery-using PET with [(11)C]carfentanil and [(11)C]raclopride. Data were compared with those from 14 lean control subjects. Receptor-binding potentials (BPND) were compared between the groups and between the pre- and postoperative scans among the obese subjects. Brain MOR availability was initially lower among obese subjects, but weight loss (mean=26.1 kg, s.d.=7.6 kg) reversed this and resulted in ~23% higher MOR availability in the postoperative versus preoperative scan. Changes were observed in areas implicated in reward processing, including ventral striatum, insula, amygdala and thalamus (P'ssystem plays an important role in the pathophysiology of human obesity. Because bariatric surgery and concomitant weight loss recover downregulated MOR availability, lowered MOR availability is associated with an obese phenotype and may mediate excessive energy uptake. Our results highlight that understanding the opioidergic contribution to overeating is critical for developing new treatments for obesity. PMID:26460230

  13. Intact brain cells: a novel model system for studying opioid receptor binding

    Energy Technology Data Exchange (ETDEWEB)

    Rogers, N.F.; El-Fakahany, E.E.

    1985-07-29

    The use of a novel tissue preparation to study opioid receptor binding in viable, intact cells derived from whole brains of adult rats is presented. Mechanically dissociated and sieved cells, which were not homogenized at any stage of the experimental protocol, and iso-osmotic physiological buffer were used in these experiments. This system was adapted in order to avoid mechanical and chemical disruption of cell membranes, cytoskeletal ultrastructure or receptor topography by homogenization or by the use of nonphysiological buffers, and to mimic in vivo binding conditions as much as possible. Using (/sup 3/H)naloxone as the radioligand, the studies showed saturable and stereospecific high-affinity binding of this opioid antagonist in intact cells, which in turn showed consistently high viability. (/sup 3/H)Naloxone binding was also linear over a wide range of tissue concentrations. This technique provides a very promising model for future studies of the binding of opioids and of many other classes of drugs to brain tissue receptors in a more physiologically relevant system than those commonly used to date.

  14. Chronic brief restraint decreases in vivo binding of benzodiazepine receptor ligand to mouse brain.

    Science.gov (United States)

    Mosaddeghi, M; Burke, T F; Moerschbaecher, J M

    1993-01-01

    This study examines the effects of chronic brief restraint on in vivo benzodiazepine (BZD) receptor binding in mouse brain. Three groups of mice were used. Mice in group 1 were neither restrained nor injected (ACUTE control). Mice in group 2 were restrained for 5-6 s by grabbing the back skin and holding the subject upside-down at a 45 degrees angle as if to be injected (CHRONIC SHAM control) for 7 d. Mice in group 3 (CHRONIC SALINE) received daily single intraperitoneal (ip) injections of saline (5 mL/kg) for 7 d. On d 8 BZD receptors were labeled in vivo by administration of 3 microCi [3H]flumazenil (ip). The levels of ligand bound in vivo to cerebral cortex (CX), cerebellum (CB), brain stem (BS), striatum (ST), hippocampus (HP), and hypothalamus (HY) were determined. Results indicated that the level of binding was significantly (p stress produces a decrease in BZD receptor binding sites. PMID:8385464

  15. Intact brain cells: a novel model system for studying opioid receptor binding

    International Nuclear Information System (INIS)

    The use of a novel tissue preparation to study opioid receptor binding in viable, intact cells derived from whole brains of adult rats is presented. Mechanically dissociated and sieved cells, which were not homogenized at any stage of the experimental protocol, and iso-osmotic physiological buffer were used in these experiments. This system was adapted in order to avoid mechanical and chemical disruption of cell membranes, cytoskeletal ultrastructure or receptor topography by homogenization or by the use of nonphysiological buffers, and to mimic in vivo binding conditions as much as possible. Using [3H]naloxone as the radioligand, the studies showed saturable and stereospecific high-affinity binding of this opioid antagonist in intact cells, which in turn showed consistently high viability. [3H]Naloxone binding was also linear over a wide range of tissue concentrations. This technique provides a very promising model for future studies of the binding of opioids and of many other classes of drugs to brain tissue receptors in a more physiologically relevant system than those commonly used to date

  16. Site-specific effects of the nonsteroidal anti-inflammatory drug lysine clonixinate on rat brain opioid receptors.

    Science.gov (United States)

    Ortí, E; Coirini, H; Pico, J C

    1999-04-01

    In addition to effects in the periphery through inhibition of prostaglandin synthesis, several lines of evidence suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) act in the central nervous system. The possibility that the central action of NSAIDs involves regulation of opioid receptors was investigated by quantitative autoradiography of mu, delta, and kappa sites in rat brain slices. Increased (p lysine clonixinate. Labeling of delta receptors was lower in the lateral septum, and kappa sites decreased in thalamic nuclei. These effects were not mediated through direct interaction with opioid-binding sites, since receptor-binding assays using rat brain membranes confirmed that clonixinate up to 1 x 10(-4) mol/l does not inhibit mu, delta, and kappa receptor specific binding. Central effects of NSAIDs might, therefore, involve interaction with the opioid receptor system through indirect mechanisms. PMID:10077738

  17. Angiotensin II receptor subtypes are coupled with distinct signal-transduction mechanisms in neurons and astrocytes from rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Sumners, C.; Wei Tang; Zelezna, B.; Raizada, M.K. (Univ. of Florida, Gainesville (United States))

    1991-09-01

    Both neurons and astrocytes contain specific receptors for angiotensin II (AII). The authors used selective ligands for the AT{sub 1} and AT{sub 2} types of AII receptors to investigate the expression of functional receptor subtypes in astrocyte cultures and neuron cultures from 1-day-old (neonatal) rat brain. In astrocyte cultures, competition of {sup 125}I-labeled AII ({sup 125}I-AII) specific binding with AT{sub 1} (DuP753) or AT{sub 2} {l brace}PD123177, CGP42112A, (Phe(p-NH{sub 2}){sup 6})AII{r brace} selective receptor ligands revealed a potency series of AII > DuP753 > > > CGP42112A > (Phe(p-NH{sub 2}){sup 6})AII > PD123177. These results suggest a predominance of the AT{sub 1} receptor subtype in neonatal astrocytes. {sup 125}I-AII specific binding to neonate neuronal cultures was reduced 73-84% by 1 {mu} MPD123177, and the residual {sup 125}I-AII specific binding was eliminated by DuP753. The results suggest that astrocyte cultures from neonatal rat brains contain predominantly AT{sub 1} receptors that are coupled to a stimulation of inositophospholipid hydrolysis. In contrast, neuron cultures from neonatal rat brain contain mostly AT{sub 2} receptors that are coupled to a reduction in basal cGMP levels, but a smaller population of AT{sub 1} receptors is also present in these neurons.

  18. Human blood-brain barrier insulin-like growth factor receptor

    International Nuclear Information System (INIS)

    Insulin-like growth factor (IGF)-1 and IGF-2, may be important regulatory molecules in the CNS. Possible origins of IGFs in brain include either de novo synthesis or transport of circulating IGFs from blood into brain via receptor mediated transcytosis mechanisms at the brain capillary endothelial wall, ie, the blood-brain barrier (BBB). In the present studies, isolated human brain capillaries are used as an in vitro model system of the human BBB and the characteristics of IGF-1 or IGF-2 binding to this preparation were assessed. The total binding of IGF-2 at 37 degrees C exceeded 130% per mg protein and was threefold greater than the total binding for IGF-1. However, at 37 degrees C nonsaturable binding equaled total binding, suggesting that endocytosis is rate limiting at physiologic temperatures. Binding studies performed at 4 degrees C slowed endocytosis to a greater extent than membrane binding, and specific binding of either IGF-1 or IGF-2 was detectable. Scatchard plots for either peptide were linear and the molar dissociation constant of IGF-1 and IGF-2 binding was 2.1 +/- 0.4 and 1.1 +/- 0.1 nmol/L, respectively. Superphysiologic concentrations of porcine insulin inhibited the binding of both IGF-1 (ED50 = 2 micrograms/mL) and IGF-2 (ED50 = 0.5 microgram/mL). Affinity cross linking of 125I-IGF-1, 125I-IGF-2, and 125I-insulin to isolated human brain capillaries was performed using disuccinimidylsuberate (DSS). These studies revealed a 141 kd binding site for both IGF-1 and IGF-2, and a 133 kd binding site for insulin

  19. Obesity is associated with high serotonin 4 receptor availability in the brain reward circuitry

    DEFF Research Database (Denmark)

    Haahr, M. E.; Rasmussen, Peter Mondrup; Madsen, K.;

    2012-01-01

    The neurobiology underlying obesity is not fully understood. The neurotransmitter serotonin (5-HT) is established as a satiety-generating signal, but its rewarding role in feeding is less well elucidated. From animal experiments there is now evidence that the 5-HT4 receptor (5-HT4R) is involved in...... food intake, and that pharmacological or genetic manipulation of the receptor in reward-related brain areas alters food intake.Here, we used positron emission tomography in humans to examine the association between cerebral 5-HT4Rs and common obesity.We found in humans a strong positive association...... between body mass index and the 5-HT4R density bilaterally in the two reward ‘hot spots’ nucleus accumbens and ventral pallidum, and additionally in the left hippocampal region and orbitofrontal cortex.These findings suggest that the 5-HT4R is critically involved in reward circuits that regulate people...

  20. Oxytocin receptor gene and racial ingroup bias in empathy-related brain activity.

    Science.gov (United States)

    Luo, Siyang; Li, Bingfeng; Ma, Yina; Zhang, Wenxia; Rao, Yi; Han, Shihui

    2015-04-15

    The human brain responds more strongly to racial ingroup than outgroup individuals' pain. This racial ingroup bias varies across individuals and has been attributed to social experiences. What remains unknown is whether the racial ingroup bias in brain activity is associated with a genetic polymorphism. We investigated genetic associations of racial ingroup bias in the brain activity to racial ingroup and outgroup faces that received painful or non-painful stimulations by scanning A/A and G/G homozygous of the oxytocin receptor gene polymorphism (OXTR rs53576) using functional MRI. We found that G/G compared to A/A individuals showed stronger activity in the anterior cingulate and supplementary motor area (ACC/SMA) in response to racial ingroup members' pain, whereas A/A relative to G/G individuals exhibited greater activity in the nucleus accumbens (NAcc) in response to racial outgroup members' pain. Moreover, the racial ingroup bias in ACC/SMA activity positively predicted participants' racial ingroup bias in implicit attitudes and NAcc activity to racial outgroup individuals' pain negatively predicted participants' motivations to reduce racial outgroup members' pain. Our results suggest that the two variants of OXTR rs53576 are associated with racial ingroup bias in brain activities that are linked to implicit attitude and altruistic motivation, respectively. PMID:25637390

  1. 3,4-methylenedioxyamphetamine upregulates p75 neurotrophin receptor protein expression in the rat brain

    Institute of Scientific and Technical Information of China (English)

    Chaomin Wang; Zugui Peng; Weihong Kuang; Hanyu Zheng; Jiang Long; Xue Wang

    2012-01-01

    The p75 neurotrophin receptor, which is a member of the tumor necrosis factor receptor superfamily, facilitates apoptosis during development and following central nervous system injury. Previous stu-dies have shown that programmed cell death is likely involved in the neurotoxic effects of 3, 4-methylenedioxy-N-methylamphetamine (MDMA), because MDMA induces apoptosis of immor-talized neurons through regulation of proteins belonging to the Bcl-2 family. In the present study, intraperitoneal injection of different doses of MDMA (20, 50, and 100 mg/kg) induced significant behavioral changes, such as increased excitability, increased activity, and irritability in rats. Moreover, changes exhibited dose-dependent adaptation. Following MDMA injection in rat brain tissue, the number of apoptotic cells dose-dependently increased and p75 neurotrophin receptor expression significantly increased in the prefrontal cortex, cerebellum, and hippocampus. These findings confirmed that MDMA induced neuronal apoptosis, and results suggested that this effect was related by upregulated protein expression of the p75 neurotrophin receptor.

  2. High affinity dopamine D2 receptor radioligands. 1. Regional rat brain distribution of iodinated benzamides

    Energy Technology Data Exchange (ETDEWEB)

    Kessler, R.M.; Ansari, M.S.; de Paulis, T.; Schmidt, D.E.; Clanton, J.A.; Smith, H.E.; Manning, R.G.; Gillespie, D.; Ebert, M.H. (Vanderbilt University School of Medicine, Nashville, TN (USA))

    1991-08-01

    Five 125I-labeled substituted benzamides, which are close structural analogues of (S)-sulpiride, eticlopride, and isoremoxipride, were evaluated for their selective in vivo uptake into dopamine D2 receptor rich tissue of the rat brain. Iodopride (KD 0.88 nM), an iodine substituted benzamide structurally related to sulpiride, displayed a maximal striatum: cerebellar uptake ratio of 7.6. Demonstration of saturation of the receptor with (125I)iodopride in striatum required uptake in frontal cortex to be used, rather than cerebellar uptake, to define nonspecific binding. Two other ligands structurally related to eticlopride, iclopride (KD 0.23 nM) and itopride (KD 0.16 nM), displayed maximal striatal: cerebellar uptake ratios of 9.8 and 3.3, respectively. The most potent ligands, epidepride (KD 0.057 nM) and ioxipride (KD 0.070 nM) showed striatal:cerebellar uptake ratios of 234 and 65, respectively. The observed uptake ratios correlated poorly with the affinity constants for the dopamine D2 receptor alone, but were highly correlated (r = 0.92) with the product of the receptor dissociation constant (KD) and the apparent lipophilicity (kw), as determined by reverse-phase HPLC at pH 7.5. Total striatal uptake also appeared dependent on lipophilicity, with maximal uptake occurring for ligands having log kw 2.4-2.8.

  3. High affinity dopamine D2 receptor radioligands. 1. Regional rat brain distribution of iodinated benzamides

    International Nuclear Information System (INIS)

    Five 125I-labeled substituted benzamides, which are close structural analogues of (S)-sulpiride, eticlopride, and isoremoxipride, were evaluated for their selective in vivo uptake into dopamine D2 receptor rich tissue of the rat brain. Iodopride (KD 0.88 nM), an iodine substituted benzamide structurally related to sulpiride, displayed a maximal striatum: cerebellar uptake ratio of 7.6. Demonstration of saturation of the receptor with [125I]iodopride in striatum required uptake in frontal cortex to be used, rather than cerebellar uptake, to define nonspecific binding. Two other ligands structurally related to eticlopride, iclopride (KD 0.23 nM) and itopride (KD 0.16 nM), displayed maximal striatal: cerebellar uptake ratios of 9.8 and 3.3, respectively. The most potent ligands, epidepride (KD 0.057 nM) and ioxipride (KD 0.070 nM) showed striatal:cerebellar uptake ratios of 234 and 65, respectively. The observed uptake ratios correlated poorly with the affinity constants for the dopamine D2 receptor alone, but were highly correlated (r = 0.92) with the product of the receptor dissociation constant (KD) and the apparent lipophilicity (kw), as determined by reverse-phase HPLC at pH 7.5. Total striatal uptake also appeared dependent on lipophilicity, with maximal uptake occurring for ligands having log kw 2.4-2.8

  4. 3,4-methylenedioxyamphetamine upregulates p75 neurotrophin receptor protein expression in the rat brain.

    Science.gov (United States)

    Wang, Chaomin; Peng, Zugui; Kuang, Weihong; Zheng, Hanyu; Long, Jiang; Wang, Xue

    2012-04-25

    The p75 neurotrophin receptor, which is a member of the tumor necrosis factor receptor superfamily, facilitates apoptosis during development and following central nervous system injury. Previous studies have shown that programmed cell death is likely involved in the neurotoxic effects of 3, 4-methylenedioxy-N-methylamphetamine (MDMA), because MDMA induces apoptosis of immortalized neurons through regulation of proteins belonging to the Bcl-2 family. In the present study, intraperitoneal injection of different doses of MDMA (20, 50, and 100 mg/kg) induced significant behavioral changes, such as increased excitability, increased activity, and irritability in rats. Moreover, changes exhibited dose-dependent adaptation. Following MDMA injection in rat brain tissue, the number of apoptotic cells dose-dependently increased and p75 neurotrophin receptor expression significantly increased in the prefrontal cortex, cerebellum, and hippocampus. These findings confirmed that MDMA induced neuronal apoptosis, and results suggested that this effect was related by upregulated protein expression of the p75 neurotrophin receptor. PMID:25722682

  5. Ligands for SPECT and PET imaging of muscarinic-cholinergic receptors of the heart and brain

    Energy Technology Data Exchange (ETDEWEB)

    Knapp, F.F. Jr.; McPherson, D.W.; Luo, H. [and others

    1995-06-01

    Interest in the potential use of cerebral SPECT and PET imaging for determination of the density and activity of muscarinic-cholinergic receptors (mAChR) has been stimulated by the changes in these receptors which occur in many neurological diseases. In addition, the important involvement of mAChR in modulating negative inotropic cardiac activity suggests that such receptor ligands may have important applications in evaluation of changes which may occur in cardiac disease. In this paper, the properties of several key muscarinic receptor ligands being developed or which have been used for clinical SPECT and PET are discussed. In addition, the ORNL development of the new iodinated IQNP ligand based on QNB and the results of in vivo biodistribution studies in rats, in vitro competitive binding studies and ex vivo autoradiographic experiments are described. The use of radioiodinated IQNP may offer several advantages in comparison to IQNB because of its easy and high yield preparation and high brain uptake and the potential usefulness of the {open_quotes}partial{close_quotes} subtype selective IONP isomers. We also describe the development of new IQNP-type analogues which offer the opportunity for radiolabeling with positron-emitting radioisotopes (carbon-11, fluorine-18 and bromine-76) for potential use with PET.

  6. Eph receptor and ephrin signaling in developing and adult brain of the honeybee (Apis mellifera).

    Science.gov (United States)

    Vidovic, Maria; Nighorn, Alan; Koblar, Simon; Maleszka, Ryszard

    2007-02-01

    Roles for Eph receptor tyrosine kinase and ephrin signaling in vertebrate brain development are well established. Their involvement in the modulation of mammalian synaptic structure and physiology is also emerging. However, less is known of their effects on brain development and their function in adult invertebrate nervous systems. Here, we report on the characterization of Eph receptor and ephrin orthologs in the honeybee, Apis mellifera (Am), and their role in learning and memory. In situ hybridization for mRNA expression showed a uniform distribution of expression of both genes across the developing pupal and adult brain. However, in situ labeling with Fc fusion proteins indicated that the AmEphR and Amephrin proteins were differentially localized to cell body regions in the mushroom bodies and the developing neuropiles of the antennal and optic lobes. In adults, AmEphR protein was localized to regions of synaptic contacts in optic lobes, in the glomeruli of antennal lobes, and in the medial lobe of the mushroom body. The latter two regions are involved in olfactory learning and memory in the honeybee. Injections of EphR-Fc and ephrin-Fc proteins into the brains of adult bees, 1 h before olfactory conditioning of the proboscis extension reflex, significantly reduced memory 24 h later. Experimental amnesia in the group injected with ephrin-Fc was apparent 1 h post-training. Experimental amnesia was also induced by post-training injections with ephrin-Fc suggesting a role in recall. This is the first demonstration that Eph molecules function to regulate the formation of memory in insects. PMID:17443785

  7. Effects of white spirits on rat brain 5-HT receptor functions and synaptic remodeling.

    Science.gov (United States)

    Lam, H R; Plenge, P; Jørgensen, O S

    2001-01-01

    Previously, inhalation exposure to different types of white spirit (i.e. complex mixtures of aliphatic, aromatic, alkyl aromatic, and naphthenic hydrocarbons) has been shown to induce neurochemical effects in rat brains. Especially, the serotonergic system was involved at the global, regional, and subcellular levels. This study investigates the effects of two types of white spirit on 5-hydroxytryptamine (5-HT) transporters (5-HTT), 5-HT(2A) and 5-HT(4) receptor expression in forebrain, and on neural cell adhesion molecule (NCAM) and 25-kDa synaptosomal associated protein (SNAP-25) concentrations when applied as indices for synaptic remodeling in forebrain, hippocampus, and entorhinal cortex. Male Wistar rats were exposed to 0, 400, or 800 ppm of aromatic (20 vol.% aromatic hydrocarbons) or dearomatized white spirit (catalytically hydrogenated white spirit) in the inhaled air for 6 h/day, 7 days/week for 3 weeks. The 5-HTT B(max) and K(d) were not affected. Both types of white spirit at 800 ppm decreased B(max) for the 5-HT(2A) receptor. The aromatic type decreased the K(d) of the 5-HT(2A) and 5-HT(4) receptors at 800 ppm. Aromatic white spirit did not affect NCAM or SNAP-25 concentrations or NCAM/SNAP-25 ratio in forebrain, whereas NCAM increased in hippocampus and the NCAM/SNAP-25 ratio decreased in entorhinal cortex. Dearomatized white spirit did not affect NCAM, SNAP-25, or NCAM/SNAP-25 ratio in any brain region. The affected 5-HT receptor expression and synaptic plasticity marker proteins indicate that inhalation exposure to high concentrations of white spirit may be neurotoxic to rats, especially the aromatic white spirit type. PMID:11792528

  8. Tyrosine phosphorylation of a 66KD soluble protein and augmentation of lectin induced mitogenesis by DMSO in human T lymphocytes

    International Nuclear Information System (INIS)

    The authors have demonstrated that induction of mitogenesis in human T lymphocytes is associated with the tyrosine phosphorylation of a 66KD soluble substrate-TPP 66. Since DMSO has been shown to be a non-specific stimulator of tyrosine protein kinases they have examined the effect of DMSO on both activation and tyrosine phosphorylation in human T cells. Human peripheral blood T lymphocytes were isolated by dextran sedimentation, Ficol/Paque centrifugation and nylon wool filtration. Phosphorylation was performed in cells incubated with [32P] orthophosphate followed by DMSO for 30 min. TPP 66 was identified by 2-D PAGE, autoradiography, and HV electrophoresis of the hydrolyzed protein. Concentrations of DMSO from 1% to 50% induced the tyrosine phosphorylation of TPP 66 with maximal stimulation seen at 20%. DMSO alone did not activate the T cells (measured by [3H] thymidine incorporation) when tested at high concentrations for 30 sec to 10 min. (longer incubations were markedly toxic) or low concentrations for 12 to 48 hrs. Low concentrations of DMSO 0.1%-0.5% did however, markedly augment [3H] thymidine incorporation induced by PHA or Con A. These data suggest that tyrosine phosphorylation of TPP 66 alone may not constitute sufficient signal for the activation sequence to begin but the phosphorylation of this soluble substrate may be a critical factor in the propagation of the activation sequence

  9. Selective Estrogen Receptor Modulators regulate reactive microglia after penetrating brain injury

    Directory of Open Access Journals (Sweden)

    George E. Barreto

    2014-06-01

    Full Text Available Following brain injury, microglia assume a reactive-like state and secrete pro-inflammatory molecules that can potentiate damage. A therapeutic strategy that may limit microgliosis is of potential interest. In this context, selective estrogen receptor modulators, such as raloxifene and tamoxifen, are known to reduce microglia activation induced by neuroinflammatory stimuli in young animals. In the present study, we have assessed whether raloxifene and tamoxifen are able to affect microglia activation after brain injury in young and aged animals in time points relevant to clinics, which is hours after brain trauma. Volume fraction of MHC-II+ microglia was estimated according to the point-counting method of Weibel within a distance of 350 μm from the lateral border of the wound, and cellular morphology was measured by fractal analysis. Two groups of animals were studied: 1 young rats, ovariectomized at 2 months of age; and 2 aged rats, ovariectomized at 18 months of age. Fifteen days after ovariectomy animals received a stab wound brain injury and the treatment with estrogenic compounds. Our findings indicate that raloxifene and tamoxifen reduced microglia activation in both young and aged animals. Although the volume fraction of reactive microglia was found lower in aged animals, this was accompanied by important changes in cell morphology, where aged microglia assume a bushier and hyperplasic aspect when compared to young microglia. These data suggest that early regulation of microglia activation provides a mechanism by which SERMs may exert a neuroprotective effect in the setting of a brain trauma.

  10. Characterization of GABA/sub A/ receptor-mediated 36chloride uptake in rat brain synaptoneurosomes

    International Nuclear Information System (INIS)

    γ-Aminobutyric acid (GABA) receptor-mediated 36chloride (36Cl-) uptake was measured in synaptoneurosomes from rat brain. GABA and GABA agonists stimulated 36Cl- uptake in a concentration-dependent manner with the following order of potency: Muscimol>GABA>piperidine-4-sulfonic acid (P4S)>4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP)=3-aminopropanesulfonic acid (3APS)>>taurine. Both P4S and 3APS behaved as partial agonists, while the GABA/sub B/ agonist, baclofen, was ineffective. The response to muscimol was inhibited by bicuculline and picrotoxin in a mixed competitive/non-competitive manner. Other inhibitors of GABA receptor-opened channels or non-neuronal anion channels such as penicillin, picrate, furosemide and disulfonic acid stilbenes also inhibited the response to muscimol. A regional variation in muscimol-stimulated 36Cl- uptake was observed; the largest responses were observed in the cerebral cortex, cerebellum and hippocampus, moderate responses were obtained in the striatum and hypothalamus and the smallest response was observed in the pons-medulla. GABA receptor-mediated 36Cl- uptake was also dependent on the anion present in the media. The muscinol response varied in media containing the following anions: Br->Cl-≥NO3->I-≥SCN->>C3H5OO-≥ClO4->F-, consistent with the relative anion permeability through GABA receptor-gated anion channels and the enhancement of convulsant binding to the GABA receptor-gated Cl- channel. 43 references, 4 figures, 3 tables

  11. Blocking NMDA receptors delays death in rats with acute liver failure by dual protective mechanisms in kidney and brain.

    Science.gov (United States)

    Cauli, Omar; González-Usano, Alba; Cabrera-Pastor, Andrea; Gimenez-Garzó, Carla; López-Larrubia, Pilar; Ruiz-Sauri, Amparo; Hernández-Rabaza, Vicente; Duszczyk, Malgorzata; Malek, Michal; Lazarewicz, Jerzy W; Carratalá, Arturo; Urios, Amparo; Miguel, Alfonso; Torregrosa, Isidro; Carda, Carmen; Montoliu, Carmina; Felipo, Vicente

    2014-06-01

    Treatment of patients with acute liver failure (ALF) is unsatisfactory and mortality remains unacceptably high. Blocking NMDA receptors delays or prevents death of rats with ALF. The underlying mechanisms remain unclear. Clarifying these mechanisms will help to design more efficient treatments to increase patient's survival. The aim of this work was to shed light on the mechanisms by which blocking NMDA receptors delays rat's death in ALF. ALF was induced by galactosamine injection. NMDA receptors were blocked by continuous MK-801 administration. Edema and cerebral blood flow were assessed by magnetic resonance. The time course of ammonia levels in brain, muscle, blood, and urine; of glutamine, lactate, and water content in brain; of glomerular filtration rate and kidney damage; and of hepatic encephalopathy (HE) and intracranial pressure was assessed. ALF reduces kidney glomerular filtration rate (GFR) as reflected by reduced inulin clearance. GFR reduction is due to both reduced renal perfusion and kidney tubular damage as reflected by increased Kim-1 in urine and histological analysis. Blocking NMDA receptors delays kidney damage, allowing transient increased GFR and ammonia elimination which delays hyperammonemia and associated changes in brain. Blocking NMDA receptors does not prevent cerebral edema or blood-brain barrier permeability but reduces or prevents changes in cerebral blood flow and brain lactate. The data show that dual protective effects of MK-801 in kidney and brain delay cerebral alterations, HE, intracranial pressure increase and death. NMDA receptors antagonists may increase survival of patients with ALF by providing additional time for liver transplantation or regeneration. PMID:24338618

  12. Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism.

    Directory of Open Access Journals (Sweden)

    Laurent Kappeler

    2008-10-01

    Full Text Available Mutations that decrease insulin-like growth factor (IGF and growth hormone signaling limit body size and prolong lifespan in mice. In vertebrates, these somatotropic hormones are controlled by the neuroendocrine brain. Hormone-like regulations discovered in nematodes and flies suggest that IGF signals in the nervous system can determine lifespan, but it is unknown whether this applies to higher organisms. Using conditional mutagenesis in the mouse, we show that brain IGF receptors (IGF-1R efficiently regulate somatotropic development. Partial inactivation of IGF-1R in the embryonic brain selectively inhibited GH and IGF-I pathways after birth. This caused growth retardation, smaller adult size, and metabolic alterations, and led to delayed mortality and longer mean lifespan. Thus, early changes in neuroendocrine development can durably modify the life trajectory in mammals. The underlying mechanism appears to be an adaptive plasticity of somatotropic functions allowing individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments. Our results also suggest that tonic somatotropic signaling entails the risk of shortened lifespan.

  13. SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist.

    Science.gov (United States)

    Kennett, G A; Wood, M D; Bright, F; Trail, B; Riley, G; Holland, V; Avenell, K Y; Stean, T; Upton, N; Bromidge, S; Forbes, I T; Brown, A M; Middlemiss, D N; Blackburn, T P

    1997-01-01

    SB 242084 has a high affinity (pKi 9.0) for the cloned human 5-HT2C receptor and 100- and 158-fold selectivity over the closely related cloned human 5-HT2B and 5-HT2A subtypes respectively. SB 242084 had over 100-fold selectivity over a range of other 5-HT, dopamine and adrenergic receptors. In studies of 5-HT-stimulated phosphatidylinositol hydrolysis using SH-SY5Y cells stably expressing the cloned human 5-HT2C receptor, SB 242084 acted as an antagonist with a pKb of 9.3, which closely resembled its corresponding receptor binding affinity. SB 242084 potently inhibited m-chlorophenylpiperazine (mCPP, 7 mgkg i.p. 20 min pre-test)-induced hypolocomotion in rats, a model of in vivo central 5-HT2C receptor function, with an ID50 of 0.11 mg/kg i.p., and 2.0 mg/kg p.o. SB 242084 (0.1-1 mg/kg i.p.) exhibited an anxiolytic-like profile in the rat social interaction test, increasing time spent in social interaction, but having no effect on locomotion. SB 242084 (0.1-1 mg/kg i.p.) also markedly increased punished responding in a rat Geller-Seifter conflict test of anxiety, but had no consistent effect on unpunished responding. A large acute dose of SB 242084 (30 mg/kg p.o.) had no effect on seizure susceptibility in the rat maximal electroshock seizure threshold test. Also, while SB 242084 (2 and 6 mg/kg p.o. 1 hr pre-test) antagonized the hypophagic response to mCPP, neither acute nor subchronic administration of the drug, for 5 days at 2 or 6 mg/kg p.o. twice daily, affected food intake or weight gain. The results suggest that SB 242084 is the first reported selective potent and brain penetrant 5-HT2C receptor antagonist and has anxiolytic-like activity, but does not possess either proconvulsant or hyperphagic properties which are characteristic of mutant mice lacking the 5-HT2C receptor. PMID:9225286

  14. The pharmacokinetics of [11C]methoxy-norchloroprogabidic acid, a potential PET tracer for GABA receptors in the brain

    International Nuclear Information System (INIS)

    We have described the kinetic properties of [11C]methoxy-norchloroprogabidic acid, a potential radioligand for the gamma-aminobutyric acid (GABA) receptor. Early metabolism in mice was negligible. Protein binding in human plasma was 89±7%. Distribution volumes were 89.6±29.4 l whereas the elimination half-life was 41.6±14.3 min. Animal and human positron emission tomography (PET) data demonstrate limited uptake of the activity in brain tissue. Displacement studies in mice suggest a nonsignificant fraction of specific receptor binding. [11C] Methoxy-norchloroprogabidic acid is therefore unsuitable for brain PET

  15. Pet imaging of two monoaminergic neurotransmitter systems in brain : studies of the norepinephrine transporter and dopamine D©ü receptor

    OpenAIRE

    Seneca, Nicholas

    2006-01-01

    Positron emission tomography (PET) has been widely used to study non-invasively function of the brain, pathophysiology of disease and aid in the development of new drugs. PET and selective radiolabeled molecules allow imaging of certain critical components of neurotransmission, such as pre-synaptic transporters and post-synaptic receptors in living brain. The general aim of the present thesis was (i) to measure neuropharmacological interventions using PET (e.g., competition ...

  16. Region-specific alterations in the corticotropin-releasing factor and glucocorticoid receptors in the postmortem brain of suicide victims

    OpenAIRE

    Pandey, Ghanshyam N.

    2012-01-01

    Rationale : Abnormalities of hypothalamic–pituitary–adrenal (HPA) axis in depression and suicide are among the most consistent findings in biological psychiatry. However, the specific molecular mechanism associated with HPA axis abnormality in the brain of depressed or suicidal subjects is not clear. It is believed that abnormal HPA axis is caused by increased levels of corticotropin-releasing factor (CRF) and decreased levels of glucocorticoid receptor (GR) in the brain of depr...

  17. Enhanced water and salt intake in transgenic mice with brain-restricted overexpression of angiotensin (AT1) receptors

    OpenAIRE

    Lazartigues, Eric; Sinnayah, Puspha; Augoyard, Ginette; Gharib, Claude; Johnson, Alan Kim; Davisson, Robin L.

    2008-01-01

    To address the relative contribution of central and peripheral angiotensin II (ANG II) type 1A receptors (AT1A) to blood pressure and volume homeostasis, we generated a transgenic mouse model [neuron-specific enolase (NSE)-AT1A] with brain-restricted overexpression of AT1A receptors. These mice are normotensive at baseline but have dramatically enhanced pressor and bradycardic responses to intracerebroventricular ANG II or activation of endogenous ANG II production. Here our goal was to exami...

  18. Heterogeneity in expression of functional ionotropic glutamate and GABA receptors in astrocytes across brain regions: insights from the thalamus

    OpenAIRE

    Höft, Simon; Griemsmann, Stephanie; Seifert, Gerald; Steinhäuser, Christian

    2014-01-01

    Astrocytes may express ionotropic glutamate and gamma-aminobutyric acid (GABA) receptors, which allow them to sense and to respond to neuronal activity. However, so far the properties of astrocytes have been studied only in a few brain regions. Here, we provide the first detailed receptor analysis of astrocytes in the murine ventrobasal thalamus and compare the properties with those in other regions. To improve voltage-clamp control and avoid indirect effects during drug applications, freshly...

  19. Brain

    Science.gov (United States)

    ... will return after updating. Resources Archived Modules Updates Brain Cerebrum The cerebrum is the part of the ... the outside of the brain and spinal cord. Brain Stem The brain stem is the part of ...

  20. Selective serotonin 5-HT1A receptor biased agonists elicitdistinct brain activation patterns: a pharmacoMRI study.

    Science.gov (United States)

    Becker, G; Bolbos, R; Costes, N; Redouté, J; Newman-Tancredi, A; Zimmer, L

    2016-01-01

    Serotonin 1A (5-HT1A) receptors are involved in several physiological and pathological processes and constitute therefore an important therapeutic target. The recent pharmacological concept of biased agonism asserts that highly selective agonists can preferentially direct receptor signaling to specific intracellular responses, opening the possibility of drugs targeting a receptor subtype in specific brain regions. The present study brings additional support to this concept thanks to functional magnetic resonance imaging (7 Tesla-fMRI) in anaesthetized rats. Three 5-HT1A receptor agonists (8-OH-DPAT, F13714 and F15599) and one 5-HT1A receptor antagonist (MPPF) were compared in terms of influence on the brain blood oxygen level-dependent (BOLD) signal. Our study revealed for the first time contrasting BOLD signal patterns of biased agonists in comparison to a classical agonist and a silent antagonist. By providing functional information on the influence of pharmacological activation of 5-HT1A receptors in specific brain regions, this neuroimaging approach, translatable to the clinic, promises to be useful in exploring the new concept of biased agonism in neuropsychopharmacology. PMID:27211078

  1. Expression of Astrocytic Type 2 Angiotensin Receptor in Central Nervous System Inflammation Correlates With Blood-Brain Barrier Breakdown

    DEFF Research Database (Denmark)

    Füchtbauer, Laila; Toft-Hansen, Henrik; Khorooshi, Reza;

    2010-01-01

    The blood-brain barrier (BBB), a complex of endothelial and glial barriers, controls passage of cells and solutes between the blood and central nervous system (CNS). Blood-brain barrier breakdown refers to entry of cells and/or solutes. We were interested whether the renin-angiotensin system is...... involved during BBB breakdown. We studied the type 2 angiotensin receptor AT(2) because of its suggested neuroprotective role. Two models of brain inflammation were used to distinguish solute versus cellular barrier functions. Both leukocytes and horseradish peroxidase (HRP) accumulated in the perivascular...

  2. Risperidone regulates Dopamine D2-like receptors expression in rat brain in a time-dependent manner

    Directory of Open Access Journals (Sweden)

    Ni Peiyan

    2015-03-01

    Full Text Available Background and Objectives: Antipsychotics can elicit dopamine super-sensitivity by up-regulation of D2-like receptors (DRD2, DRD3, and DRD4 expression. Nevertheless, the expression profile of dopamine D2-like receptors in different brain regions and peripheral blood mononuclear cells (PBMCs, and changes following risperidone administration were still unclear. In this study, we would investigate the expression of D2-like receptors mRNA in different brain regions and the peripheral blood mononuclear cells (PBMCs in rats after 2, 6 weeks risperidone administration. Methods: The experimental rats were given risperidone (0.25mg/kg/day, i.p., and the control rats were given 0.9% NaCl. The rats were sacrificed at 0 week, 2 weeks and 6 weeks after the drug administration. Expression of the dopamine D2-like receptors was quantified by Real-time PCR method. Results: Dopamine D2-like receptors expressed in all the examined regions of rat brain. Their expression significantly increased 2weeks after risperidone administration in different brain regions. However, the changed expression of DRD2 and DRD3 turned back to the basal level 6weeks later, while the increased DRD4 expression remained in left parietal cortex. Meanwhile, DRD2 and DRD3 but not DRD4 expressed in PBMCs, however, the risperidone could not affect their expression. Conclusions: The risperidone could change the dopamine D2-like receptors expression in a time-dependent manner in different brain regions, which might guide the clinical use in the near future.

  3. Regulation of NMDA and AMPA receptors during the maturation phase of chicken brain development

    International Nuclear Information System (INIS)

    Full text: The maturation of chicken forebrain is protracted and occurs well after synapse formation providing a good model for studying mechanisms of brain maturation. Using microslices from immature (10 day) and adult chicken forebrain prepared after decapitation, we have examined functional properties of NMDA and AMPA receptors by measuring agonist-induced uptake of 45Ca2+ . The rate and extent of NMDA induced 45Ca2+ accumulation decreased during maturation with no change in EC50. The rate and extent of the AMPA induced response also decreased with a 60-fold increase in EC50. However, the total NMDA receptor content did not change as indicated by 3 H-MK801 binding and NR1 immunoreactivity in P2 fractions. Similarly, there was no change in the Bmax of 3H-AMPA, though there was a two-fold increase in KD, and little or no change in the immunoreactivity in GluR1, 2, 2/3 or 4. These results suggest that it is the regulation of receptors, their subunit composition and/or their distribution that is responsible for the altered functional responses. To study a population of receptors that is presumed to be functional because it is associated with the postsynaptic junctional complex, we purified subcellular fractions enriched in post-synaptic densities (PSDs). During maturation the concentration of NR1, 2A and 2B subunits decreased and NR2B tyrosine phosphorylation increased in the purified PSDs without a change in the receptor binding proteins PSD95 and SAP102. GluR1, GluR4 and GluR2/3 immunoreactivity did not change in the PSDs but there was an increase in the concentration of GluR2, a decrease in the Ser831 phosphorylation of GluR1 and a decrease in the concentration of the receptor binding protein GRIP. These changes are consistent with the functional changes observed using 45Ca2+ accumulation. Copyright (2002) Australian Neuroscience Society

  4. Phospholipase D signaling in serotonin-induced mitogenesis of pulmonary artery smooth muscle cells.

    Science.gov (United States)

    Liu, Y; Fanburg, B L

    2008-09-01

    We have previously reported the participation of mitogen-activated protein, Rho, and phosphoinositide-3 (PI3) kinases in separate pathways in serotonin (5-HT)-induced proliferation of pulmonary artery smooth muscle cells (SMCs). In this study, we investigated the possible participation of phospholipase D (PLD) and phosphatidic acid (PA) in this growth process. 5-HT stimulated a time-dependent increase in [(3)H]phosphatidylbutanol and PA generation. Exposure of SMCs to 1-butanol or overexpression of an inactive mutant of human PLD1R898R blocked 5-HT-induced proliferation. Furthermore, 1-butanol inhibited 5-HT activation of S6K1 and S6 protein, downstream effectors of mammalian target of rapamycin (mTOR), by 80 and 72%, respectively, and partially blocked activation of extracellular signal-regulated kinase (ERK) by 30% but had no effect on other associated signaling pathways. Exogenous PA caused cellular proliferation and revitalized cyclin D1 expression by 5-HT of the 1-butanol-treated cells. PA also reproduced activations by 5-HT of mTOR, S6K1, and ERK. Transfection with inactive human PLD1 reduced 5-HT-induced activation of S6K1 by approximately 50%. Inhibition of 5-HT receptor 2A (R 2A) with ketaserin blocked PLD activation by 5-HT. Inhibition with PI3-kinase inhibitor failed to block either activation of PLD by 5-HT or PA-dependent S6K1 phosphorylation. Taken together, these results indicate that ligation of the 5-HTR 2A by 5-HT initiates PLD activation in SMCs, and that its product, PA, is an early signaling molecule in 5-HT-induced pulmonary artery SMC proliferation. Signaling by PA produces its downstream effects primarily through the mTOR/S6K1 pathway and to a lesser extent through the ERK pathway. Hydrolysis of cell membrane lipid may be important in vascular effects of 5-HT. PMID:18621911

  5. Molecular mechanisms of the synergy between cysteinyl-leukotrienes and receptor tyrosine kinase growth factors on human bronchial fibroblast proliferation

    Directory of Open Access Journals (Sweden)

    Hajime Yoshisue

    2006-12-01

    Full Text Available We have reported that cysteinyl-leukotrienes (cys-LTs synergise not only with epidermal growth factor (EGF but also with platelet-derived growth factor (PDGF and fibroblast growth factor (FGF to induce mitogenesis in human bronchial fibroblasts. We now describe the molecular mechanisms underlying this synergism. Mitogenesis was assessed by incorporation of [3H]thymidine into DNA and changes in protein phosphorylation by Western blotting. Surprisingly, no CysLT receptor antagonists (MK-571, montelukast, BAY u9773 prevented the synergistic mitogenesis. LTD4 did not cause phosphorylation of EGFR nor did it augment EGF-induced phosphorylation of EGFR, and the synergy between LTD4 and EGF was not blocked by the metalloproteinase inhibitor GM6001 or by an HB-EGF neutralising antibody. The EGFR-selective kinase inhibitor, AG1478, suppressed the synergy by LTD4 and EGF, but had no effect on the synergy with PDGF and FGF. While inhibitors of mitogen-activated protein kinase, phosphatidylinositol 3-kinase and protein kinase C (PKC prevented the synergy, these drugs also inhibited mitogenesis elicited by EGF alone. In contrast, pertussis toxin (PTX efficiently inhibited the potentiating effect of LTD4 on EGF-induced mitogenesis, as well as that provoked by PDGF or FGF, but had no effect on mitogenesis elicited by the growth factors alone. Whereas LTD4 alone did not augment phosphorylation of extracellular signal-regulated kinase (Erk-1/2 and Akt, it increased phosphorylation of PKC in a Gi-dependent manner. Addition of LTD4 prolonged the duration of EGF-induced phosphorylation of Erk-1/2 and Akt, both of which were sensitive to PTX. The effect of cys-LTs involves a PTX-sensitive and PKC-mediated intracellular pathway leading to sustained growth factor-dependent phosphorylation of Erk-1/2 and Akt.

  6. Radioiodinated tracers for the evaluation of dopamine receptors in the neonatal rat brain after hypoxic-ischemic injury

    International Nuclear Information System (INIS)

    In order to evaluate in vivo SPET for assessing cerebral function after hypoxic-ischemic injury in human neonates, we studied D1 and D2 dopamine receptors in a rat model. Seven-day-old rats underwent permanent unilateral common carotid ligation followed by exposure to 8% O2. Two weeks later, in brains with no visible loss of hemispheric volume, striatal dopaminergic receptors were studied, with [125I]TISCH and [125I]IBZM for the D1 and D2 dopamine receptors, respectively. Using [125I]TISCH, we observed no modifications of D1 receptors, but in contrast, ex vivo and in vitro autoradiographic experiments showed a 40% decrease in the striatal binding of [125I]IBZM on both the ipsilateral and the contralateral side to the carotid ligation. These alterations were detected with IBZM, a D2 dopamine receptor ligand usable for SPET imaging. (orig./MG)

  7. G-protein-coupled estrogen receptor 1 is involved in brain development during zebrafish (Danio rerio) embryogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Yanan; Liu, Xiaochun [State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Provincial Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275 (China); Zhu, Pei; Li, Jianzhen; Sham, Kathy W.Y. [School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong (China); Cheng, Shuk Han [Department of Biology and Chemistry, City University of Hong Kong, Kowloon, Hong Kong (China); Li, Shuisheng; Zhang, Yong [State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Provincial Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275 (China); Cheng, Christopher H.K., E-mail: chkcheng@cuhk.edu.hk [School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong (China); Lin, Haoran, E-mail: lsslhr@mail.sysu.edu.cn [State Key Laboratory of Biocontrol, Institute of Aquatic Economic Animals and Guangdong Provincial Key Laboratory for Aquatic Economic Animals, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275 (China); College of Ocean, Hainan University, Haikou 570228, Hainan (China)

    2013-05-24

    Highlights: •The Gper expression was detected in the developing brain of zebrafish. •Gper morpholino knockdown induced apoptosis of brain cells. •Gper morpholino knockdown reduced expression in neuron markers. •Zebrafish Gper may be involved in neuronal development. -- Abstract: G-protein-coupled estrogen receptor 1 (Gper, formerly known as GPR30) is found to be a trophic and protective factor in mediating action of estrogen in adult brain, while its role in developing brain remains to be elucidated. Here we present the expression pattern of Gper and its functions during embryogenesis in zebrafish. Both the mRNA and protein of Gper were detected throughout embryogenesis. Whole mount in situ hybridization (WISH) revealed a wide distribution of gper mRNAs in various regions of the developing brain. Gper knockdown by specific morpholinos resulted in growth retardation in embryos and morphological defects in the developing brain. In addition, induced apoptosis, decreased proliferation of the brain cells and maldevelopment of sensory and motor neurons were also found in the morphants. Our results provide novel insights into Gper functions in the developing brain, revealing that Gper can maintain the survival of the brain cells, and formation and/or differentiation of the sensory and motor neurons.

  8. G-protein-coupled estrogen receptor 1 is involved in brain development during zebrafish (Danio rerio) embryogenesis

    International Nuclear Information System (INIS)

    Highlights: •The Gper expression was detected in the developing brain of zebrafish. •Gper morpholino knockdown induced apoptosis of brain cells. •Gper morpholino knockdown reduced expression in neuron markers. •Zebrafish Gper may be involved in neuronal development. -- Abstract: G-protein-coupled estrogen receptor 1 (Gper, formerly known as GPR30) is found to be a trophic and protective factor in mediating action of estrogen in adult brain, while its role in developing brain remains to be elucidated. Here we present the expression pattern of Gper and its functions during embryogenesis in zebrafish. Both the mRNA and protein of Gper were detected throughout embryogenesis. Whole mount in situ hybridization (WISH) revealed a wide distribution of gper mRNAs in various regions of the developing brain. Gper knockdown by specific morpholinos resulted in growth retardation in embryos and morphological defects in the developing brain. In addition, induced apoptosis, decreased proliferation of the brain cells and maldevelopment of sensory and motor neurons were also found in the morphants. Our results provide novel insights into Gper functions in the developing brain, revealing that Gper can maintain the survival of the brain cells, and formation and/or differentiation of the sensory and motor neurons

  9. Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood-brain barrier

    DEFF Research Database (Denmark)

    Eftekhari, Sajedeh; Salvatore, Christopher A; Johansson, Sara;

    2015-01-01

    ) and related this to the expression of CGRP and its receptor in rhesus trigeminal ganglion. Pituitary adenylate cyclase-activating polypeptide (PACAP) and glutamate were examined and related to the CGRP system. Furthermore, we examined if the trigeminal ganglion is protected by the blood-brain barrier...

  10. Protease activated receptor signaling is required for African trypanosome traversal of human brain microvascular endothelial cells.

    Directory of Open Access Journals (Sweden)

    Dennis J Grab

    Full Text Available BACKGROUND: Using human brain microvascular endothelial cells (HBMECs as an in vitro model for how African trypanosomes cross the human blood-brain barrier (BBB we recently reported that the parasites cross the BBB by generating calcium activation signals in HBMECs through the activity of parasite cysteine proteases, particularly cathepsin L (brucipain. In the current study, we examined the possible role of a class of protease stimulated HBMEC G protein coupled receptors (GPCRs known as protease activated receptors (PARs that might be implicated in calcium signaling by African trypanosomes. METHODOLOGY/PRINCIPAL FINDINGS: Using RNA interference (RNAi we found that in vitro PAR-2 gene (F2RL1 expression in HBMEC monolayers could be reduced by over 95%. We also found that the ability of Trypanosoma brucei rhodesiense to cross F2RL1-silenced HBMEC monolayers was reduced (39%-49% and that HBMECs silenced for F2RL1 maintained control levels of barrier function in the presence of the parasite. Consistent with the role of PAR-2, we found that HBMEC barrier function was also maintained after blockade of Galpha(q with Pasteurella multocida toxin (PMT. PAR-2 signaling has been shown in other systems to have neuroinflammatory and neuroprotective roles and our data implicate a role for proteases (i.e. brucipain and PAR-2 in African trypanosome/HBMEC interactions. Using gene-profiling methods to interrogate candidate HBMEC pathways specifically triggered by brucipain, several pathways that potentially link some pathophysiologic processes associated with CNS HAT were identified. CONCLUSIONS/SIGNIFICANCE: Together, the data support a role, in part, for GPCRs as molecular targets for parasite proteases that lead to the activation of Galpha(q-mediated calcium signaling. The consequence of these events is predicted to be increased permeability of the BBB to parasite transmigration and the initiation of neuroinflammation, events precursory to CNS disease.

  11. Distribution and Abundance of Glucocorticoid and Mineralocorticoid Receptors throughout the Brain of the Great Tit (Parus major)

    Science.gov (United States)

    Senft, Rebecca A.; Meddle, Simone L.; Baugh, Alexander T.

    2016-01-01

    The glucocorticoid stress response, regulated by the hypothalamic-pituitary-adrenal (HPA) axis, enables individuals to cope with stressors through transcriptional effects in cells expressing the appropriate receptors. The two receptors that bind glucocorticoids—the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR)—are present in a variety of vertebrate tissues, but their expression in the brain is especially important. Neural receptor patterns have the potential to integrate multiple behavioral and physiological traits simultaneously, including self-regulation of glucocorticoid secretion through negative feedback processes. In the present work, we quantified the expression of GR and MR mRNA throughout the brain of a female great tit (Parus major), creating a distribution map encompassing 48 regions. This map, the first of its kind for P. major, demonstrated a widespread but not ubiquitous distribution of both receptor types. In the paraventricular nucleus of the hypothalamus (PVN) and the hippocampus (HP)—the two brain regions that we sampled from a total of 25 birds, we found high GR mRNA expression in the former and, unexpectedly, low MR mRNA in the latter. We examined the covariation of MR and GR levels in these two regions and found a strong, positive relationship between MR in the PVN and MR in the HP and a similar trend for GR across these two regions. This correlation supports the idea that hormone pleiotropy may constrain an individual’s behavioral and physiological phenotype. In the female song system, we found moderate GR in hyperstriatum ventrale, pars caudalis (HVC), and moderate MR in robust nucleus of the arcopallium (RA). Understanding intra- and interspecific patterns of glucocorticoid receptor expression can inform us about the behavioral processes (e.g. song learning) that may be sensitive to stress and stimulate future hypotheses concerning the relationships between receptor expression, circulating hormone concentrations

  12. The brain 5-HT4 receptor binding is down-regulated in the Flinders Sensitive Line depression model and in response to paroxetine administration

    DEFF Research Database (Denmark)

    Licht, Cecilie Löe; Marcussen, Anders Bue; Wegener, Gregers;

    2009-01-01

    The 5-hydroxytryptamine (5-HT(4)) receptor may be implicated in depression and is a new potential target for antidepressant treatment. We have investigated the brain 5-HT(4) receptor [(3)H]SB207145 binding in the Flinders Sensitive Line rat depression model by quantitative receptor autoradiograph...

  13. Guidance of Drosophila Mushroom Body Axons Depends upon DRL-Wnt Receptor Cleavage in the Brain Dorsomedial Lineage Precursors

    Directory of Open Access Journals (Sweden)

    Elodie Reynaud

    2015-05-01

    Full Text Available In vivo axon pathfinding mechanisms in the neuron-dense brain remain relatively poorly characterized. We study the Drosophila mushroom body (MB axons, whose α and β branches connect to different brain areas. We show that the Ryk family WNT5 receptor, DRL (derailed, which is expressed in the dorsomedial lineages, brain structure precursors adjacent to the MBs, is required for MB α branch axon guidance. DRL acts to capture and present WNT5 to MB axons rather than transduce a WNT5 signal. DRL’s ectodomain must be cleaved and shed to guide α axons. DRL-2, another Ryk, is expressed within MB axons and functions as a repulsive WNT5 signaling receptor. Finally, our biochemical data support the existence of a ternary complex composed of the cleaved DRL ectodomain, WNT5, and DRL-2. Thus, the interaction of MB-extrinsic and -intrinsic Ryks via their common ligand acts to guide MB α axons.

  14. Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain

    DEFF Research Database (Denmark)

    Borg, J; Cervenka, S; Kuja-Halkola, R; Matheson, G J; Jönsson, E G; Lichtenstein, P; Henningsson, S; Ichimiya, T; Larsson, H; Stenkrona, P; Halldin, C; Farde, L

    2016-01-01

    and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [(11)C]raclopride binding to the D2- and D3-dopamine receptor and [(11)C]WAY100635 binding to the......The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about...... binding and a major contribution of environmental factors (pairwise shared and unique individual; 0.70-0.75) on neocortical 5-HT1A receptor binding. Our findings indicate that individual variation in neuroreceptor availability in the adult brain is the end point of a nature-nurture interplay, and call for...

  15. Localization of glucocorticoid receptor messenger ribonucleic acid in hippocampus of rat brain using in situ hybridization

    International Nuclear Information System (INIS)

    An in situ hybridization procedure was applied to quantify glucocorticoid receptor (GR) mRNAs in the hippocampus of rat brain. Hybridization was carried out using a radiolabeled antisense probe complementary to the rat liver GR gene. The specificity of the method was validated by showing: 1) a high cellular grain density in sections hybridized with an antisense but not a sense probe; 2) agreement between the experimental and theoretical temperature at which 50% of the hybrids melted, and 3) a high signal distribution of GR mRNA in the hippocampus, a region of brain known to preferentially concentrate steroid hormones. Within the hippocampus, however, subregional differences in hybridization densities were observed. Quantitative autoradiography indicated that the average neuronal silver grain number was highest in the pyramidal cell layers of CA2 and CA4 and lowest in those of CA1 and CA3. Also, there was a significant difference in the average grain number between all of the cell fields except for that between CA2 and CA4. These results show that contiguous but neuroanatomically distinct cell fields of the hippocampus express different levels of GR transcripts, and indicate that differential regulation of GR expression occurs in subpopulations of hippocampal neurons

  16. The Vitamin D Receptor (VDR Gene Polymorphisms in Turkish Brain Cancer Patients

    Directory of Open Access Journals (Sweden)

    Bahar Toptaş

    2013-01-01

    Full Text Available Objective. It has been stated that brain cancers are an increasingly serious issue in many parts of the world. The aim of our study was to determine a possible relationship between Vitamin D receptor (VDR gene polymorphisms and the risk of glioma and meningioma. Methods. We investigated the VDR Taq-I and VDR Fok-I gene polymorphisms in 100 brain cancer patients (including 44 meningioma cases and 56 glioma cases and 122 age-matched healthy control subjects. This study was performed by polymerase chain reaction-based restriction fragment length polymorphism (RF LP. Results. VDR Fok-I ff genotype was significantly increased in meningioma patients (15.9% compared with controls (2.5%, and carriers of Fok-I ff genotype had a 6.47-fold increased risk for meningioma cases. There was no significant difference between patients and controls for VDR Taq-I genotypes and alleles. Conclusions. We suggest that VDR Fok-I genotypes might affect the development of meningioma.

  17. High-affinity cannabinoid binding site in brain: A possible marijuana receptor

    Energy Technology Data Exchange (ETDEWEB)

    Nye, J.S.

    1988-01-01

    The mechanism by which delta{sup 9} tetrahydrocannabinol (delta{sup 9}THC), the major psychoactive component of marijuana or hashish, produces its potent psychological and physiological effects is unknown. To find receptor binding sites for THC, we designed a water-soluble analog for use as a radioligand. 5{prime}-Trimethylammonium-delta{sup 8}THC (TMA) is a positively charged analog of delta-{sup 8}THC modified on the 5{prime} carbon, a portion of the molecule not important for its psychoactivity. We have studied the binding of ({sup 3}H)-5{prime}-trimethylammonium-delta-{sup 8}THC (({sup 3}H)TMA) to rat neuronal membranes. ({sup 3}H)TMA binds saturably and reversibly to brain membranes with high affinity to apparently one class of sites. Highest binding site density occurs in brain, but several peripheral organs also display specific binding. Detergent solubilizes the sites without affecting their pharmacologial properties. Molecular sieve chromatography reveals a bimodal peak of ({sup 3}H)TMA binding activity of approximately 60,000 daltons apparent molecular weight.

  18. High-affinity cannabinoid binding site in brain: A possible marijuana receptor

    International Nuclear Information System (INIS)

    The mechanism by which delta9 tetrahydrocannabinol (delta9THC), the major psychoactive component of marijuana or hashish, produces its potent psychological and physiological effects is unknown. To find receptor binding sites for THC, we designed a water-soluble analog for use as a radioligand. 5'-Trimethylammonium-delta8THC (TMA) is a positively charged analog of delta-8THC modified on the 5' carbon, a portion of the molecule not important for its psychoactivity. We have studied the binding of [3H]-5'-trimethylammonium-delta-8THC ([3H]TMA) to rat neuronal membranes. [3H]TMA binds saturably and reversibly to brain membranes with high affinity to apparently one class of sites. Highest binding site density occurs in brain, but several peripheral organs also display specific binding. Detergent solubilizes the sites without affecting their pharmacologial properties. Molecular sieve chromatography reveals a bimodal peak of [3H]TMA binding activity of approximately 60,000 daltons apparent molecular weight

  19. Quantitative autoradiography of [3H]CTOP binding to mu opioid receptors in rat brain

    International Nuclear Information System (INIS)

    [3H]H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 ([3H]CTOP), a potent and highly selective mu opioid antagonist, was used to localize the mu receptors in rat brain by light microscopic autoradiography. Radioligand binding studies with [3H]CTOP using slide-mounted tissue sections of rat brain produced a Kd value of 1.1 nM with a Bmax value of 79.1 fmol/mg protein. Mu opioid agonists and antagonists inhibited [3H]CTOP binding with high affinity (IC50 values of 0.2-2.4nM), while the delta agonist DPDPE, delta antagonist ICI 174,864, and kappa agonist U 69,593 were very weak inhibitors of [3H]CTOP binding. Light microscopic autoradiography of [3H]CTOP binding sites revealed regions of high density and regions of moderate labeling. The cerebral cortex showed a low density of [3H]CTOP binding

  20. Aluminum access to the brain: A role for transferrin and its receptor

    International Nuclear Information System (INIS)

    The toxicity of aluminum in plant and animal cell biology is well established, although poorly understood. Several recent studies have identified aluminum as a potential, although highly controversial, contributory factor in the pathology of Alzheimer's disease, amyotrophic lateral sclerosis, and dialysis dementia. For example, aluminum has been found in high concentrations in senile plaques and neurofibrillary tangles, which occur in the brains of subjects with Alzheimer's disease. However, a mechanism for the entry of aluminum (Al3+) into the cells of the central nervous system (CNS) has yet to be found. Here the authors describe a possible route of entry for aluminum into the cells of the CNS via the same high-affinity receptor-ligand system that has been postulated for iron (Fe3) aluminum is able to gain access to the central nervous system under normal physiological conditions. Furthermore, these data suggest that the interaction between transferrin and its receptor may function as a general metal ion regulatory system in the CNS, extending beyond its postulated role in iron regulation

  1. [3H]opipramol labels a novel binding site and sigma receptors in rat brain membranes

    International Nuclear Information System (INIS)

    Opipramol (OP), a clinically effective antidepressant with a tricyclic structure, is inactive as an inhibitor of biogenic amine uptake. [3H]Opipramol binds saturably to rat brain membranes (apparent KD = 4 nM, Bmax = 3 pmol/mg of protein). [3H]Opipramol binding can be differentiated into haloperidol-sensitive and -resistant components, with Ki values for haloperidol of 1 nM (Bmax = 1 pmol/mg of protein) and 350 nM (Bmax = 1.9 pmol/mg of protein), respectively. The drug specificity of the haloperidol-sensitive component is the same as that of sigma receptors labeled with (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperdine. The haloperidol-resistant component does not correspond to any known neurotransmitter receptor or uptake recognition site. It displays high affinity for phenothiazines and related structures such as perphenazine, clopenthixol, and flupenthixol, whose potencies are comparable to that of opipramol. Because certain of these drugs are more potent at the haloperidol-resistant opipramol site than in exerting any other action, it is possible that this opipramol-selective site may mediate their therapeutic effects

  2. In vitro blood-brain barrier permeability predictions for GABAA receptor modulating piperine analogs.

    Science.gov (United States)

    Eigenmann, Daniela Elisabeth; Dürig, Carmen; Jähne, Evelyn Andrea; Smieško, Martin; Culot, Maxime; Gosselet, Fabien; Cecchelli, Romeo; Helms, Hans Christian Cederberg; Brodin, Birger; Wimmer, Laurin; Mihovilovic, Marko D; Hamburger, Matthias; Oufir, Mouhssin

    2016-06-01

    The alkaloid piperine from black pepper (Piper nigrum L.) and several synthetic piperine analogs were recently identified as positive allosteric modulators of γ-aminobutyric acid type A (GABAA) receptors. In order to reach their target sites of action, these compounds need to enter the brain by crossing the blood-brain barrier (BBB). We here evaluated piperine and five selected analogs (SCT-66, SCT-64, SCT-29, LAU397, and LAU399) regarding their BBB permeability. Data were obtained in three in vitro BBB models, namely a recently established human model with immortalized hBMEC cells, a human brain-like endothelial cells (BLEC) model, and a primary animal (bovine endothelial/rat astrocytes co-culture) model. For each compound, quantitative UHPLC-MS/MS methods in the range of 5.00-500ng/mL in the corresponding matrix were developed, and permeability coefficients in the three BBB models were determined. In vitro predictions from the two human BBB models were in good agreement, while permeability data from the animal model differed to some extent, possibly due to protein binding of the screened compounds. In all three BBB models, piperine and SCT-64 displayed the highest BBB permeation potential. This was corroborated by data from in silico prediction. For the other piperine analogs (SCT-66, SCT-29, LAU397, and LAU399), BBB permeability was low to moderate in the two human BBB models, and moderate to high in the animal BBB model. Efflux ratios (ER) calculated from bidirectional permeability experiments indicated that the compounds were likely not substrates of active efflux transporters. PMID:27018328

  3. Increased expression of receptor for advanced glycation end-products worsens focal brain ischemia in diabetic rats

    Institute of Scientific and Technical Information of China (English)

    Ying Xing; Jinting He; Weidong Yu; Lingling Hou; Jiajun Chen

    2012-01-01

    A rat model of diabetes mellitus was induced by a high fat diet, followed by focal brain ischemia induced using the thread method after 0.5 month. Immunohistochemistry showed that expression of receptor for advanced glycation end-products was higher in the ischemic cortex of diabetic rats compared with non-diabetic rats with brain ischemia. Western blot assay revealed increased phosphorylated c-Jun N-terminal kinase expression, and unchanged phosphorylated extracellular signal-regulated protein kinase protein expression in the ischemic cortex of diabetic rats compared with non-diabetic rats with brain ischemia. Additionally, phosphorylated p38 mitogen-activated protein kinase protein was not detected in any rats in the two groups. Severity of limb hemiplegia was worse in diabetic rats with brain ischemia compared with ischemia alone rats. The results suggest that increased expression of receptor for advanced glycation end-products can further activate the c-Jun N-terminal kinase pathway in mitogen-activated protein kinase, thereby worsening brain injury associated with focal brain ischemia in diabetic rats.

  4. Change in the properties of the opiate receptors of the brain under conditions of habituation of rats to morphine

    Energy Technology Data Exchange (ETDEWEB)

    Zaitsev, S.V.; Sergeeva, M.G.; Chichenkov, O.N.; Petrov, V.E.; Varfolomeev, S.D.

    1987-02-20

    The influence of prolonged administration of morphine on the properties of the opiate receptors of the rat brain was investigated. For this purpose they conducted an analysis of the isotherms of binding of labeled ..mu..-, sigma-, and chi-ligands: morphine, D-Ala/sup 2/, D-Leu/sup 5/-enkephalin, and ethylketocyclazocin, with membrane preparations of the brains of rats tolerant to morphine, as well as the control animals. For a quantitative determination of the dissociation constants of the ligand-receptor complexes (K) and the concentration of the reagents ((Q)), they used differential method and the method of simulation modeling. It was shown that the values of K and (Q) for individual animals are subjected to substantial dispersion, whereas the ratios (Q)/K undergo minor individual fluctuations, both in the control group and in the group of rats tolerant to morphine. This permits the ratio (Q)/K to be singled out as one of the main parameters for comparing the properties of opiate receptors of various groups of animals. Using this criterion, as well as the method of simulated modeling, it was shown that the development of tolerance is accompanied by a change in the properties of the delta-receptors (the ratio (Q)/K decreases by a factor of more than two). In contrast to the delta-receptors, no significant influence of the tolerance on the properties of the ..mu..- and chi-receptors, as well as the ultrahigh-affinity ligand binding sites, was detected.

  5. Change in the properties of the opiate receptors of the brain under conditions of habituation of rats to morphine

    International Nuclear Information System (INIS)

    The influence of prolonged administration of morphine on the properties of the opiate receptors of the rat brain was investigated. For this purpose they conducted an analysis of the isotherms of binding of labeled μ-, σ-, and chi-ligands: morphine, D-Ala2, D-Leu5-enkephalin, and ethylketocyclazocin, with membrane preparations of the brains of rats tolerant to morphine, as well as the control animals. For a quantitative determination of the dissociation constants of the ligand-receptor complexes (K) and the concentration of the reagents ([Q]), they used differential method and the method of simulation modeling. It was shown that the values of K and [Q] for individual animals are subjected to substantial dispersion, whereas the ratios [Q]/K undergo minor individual fluctuations, both in the control group and in the group of rats tolerant to morphine. This permits the ratio [Q]/K to be singled out as one of the main parameters for comparing the properties of opiate receptors of various groups of animals. Using this criterion, as well as the method of simulated modeling, it was shown that the development of tolerance is accompanied by a change in the properties of the δ-receptors (the ratio [Q]/K decreases by a factor of more than two). In contrast to the δ-receptors, no significant influence of the tolerance on the properties of the μ- and chi-receptors, as well as the ultrahigh-affinity ligand binding sites, was detected

  6. Neural effects of gut- and brain-derived glucagon-like peptide-1 and its receptor agonist.

    Science.gov (United States)

    Katsurada, Kenichi; Yada, Toshihiko

    2016-04-01

    Glucagon-like peptide-1 (GLP-1) is derived from both the enteroendocrine L cells and preproglucagon-expressing neurons in the nucleus tractus solitarius (NTS) of the brain stem. As GLP-1 is cleaved by dipeptidyl peptidase-4 yielding a half-life of less than 2 min, it is plausible that the gut-derived GLP-1, released postprandially, exerts its effects on the brain mainly by interacting with vagal afferent neurons located at the intestinal or hepatic portal area. GLP-1 neurons in the NTS widely project in the central nervous system and act as a neurotransmitter. One of the physiological roles of brain-derived GLP-1 is restriction of feeding. GLP-1 receptor agonists have recently been used to treat type 2 diabetic patients, and have been shown to exhibit pleiotropic effects beyond incretin action, which involve brain functions. GLP-1 receptor agonist administered in the periphery is stable because of its resistance to dipeptidyl peptidase-4, and is highly likely to act on the brain by passing through the blood-brain barrier (BBB), as well as interacting with vagal afferent nerves. Central actions of GLP-1 have various roles including regulation of feeding, weight, glucose and lipid metabolism, cardiovascular functions, cognitive functions, and stress and emotional responses. In the present review, we focus on the source of GLP-1 and the pathway by which peripheral GLP-1 informs the brain, and then discuss recent findings on the central effects of GLP-1 and GLP-1 receptor agonists. PMID:27186358

  7. Antibodies to the α1-adrenergic receptor cause vascular impairments in rat brain as demonstrated by magnetic resonance angiography.

    Directory of Open Access Journals (Sweden)

    Peter Karczewski

    Full Text Available BACKGROUND: Circulating agonistic autoantibodies acting at G protein-coupled receptors have been associated with numerous sever pathologies in humans. Antibodies directed predominantly against the α(1-adrenergig receptor were detected in patients suffering from widespread diseases such as hypertension and type 2 diabetes. Their deleterious action has been demonstrated for peripheral organs. We postulate that antibodies to the α(1-adrenergig receptor are relevant pathomolecules in diseases of the central nervous system associated with vascular impairments. METHODOLOGY/PRINCIPAL FINDINGS: Using a rat model we studied the long-term action of antibodies against the α(1-adrenergig receptor either induced by immunization with a receptor peptide or applied by intravenous injection. The vasculature in the rat brains was investigated by time-of-flight magnetic resonance angiography using a 9.4 Tesla small animal MR imaging system. Visual examination of maximum-intensity-projections (MIPs of brain angiographs revealed the development of vascular defects in antibody- exposed animals between three and eight months of treatment. Relative vascular areas were derived from representative MIP image sections by grayscale analysis and used to form an index of vascular circulation. Animals exposed to the action of α(1-adrenergig receptor antibodies showed significantly reduced vascular areas (p<0.05. Calculated index values indicated attenuated blood flow in both antibody-treated cohorts compared to their respective controls reaching with (relative units ± standard error, n = 10 0.839 ± 0.026 versus 0.919 ± 0.026 statistical significance (p<0.05 for peptide-immunized rats. CONCLUSION/SIGNIFICANCE: We present evidence that antibodies to the α(1-adrenergig receptor cause cerebrovascular impairments in the rat. Our findings suggest the pathological significance of these antibodies in pathologies of the human central nervous system linked to impairments of

  8. Metabolism of [123I]epidepride may affect brain dopamine D2 receptor imaging with single-photon emission tomography

    International Nuclear Information System (INIS)

    Iodine-123 labelled epidepride is a novel radiopharmaceutical for the study of cerebral dopamine D2 receptors using single-photon emission tomography (SPET). A lipophilic labelled metabolite of [123I]epidepride which may enter the brain and hamper the quantitation of receptors has been observed in human plasma. In the present study, gradient high-performance liquid chromatography (HPLC) was used to investigate the plasma concentration of the lipophilic labelled metabolite and its correlation to SPET imaging of striatal dopamine D2 receptors. A linear regression fit showed a negative correlation between the amount of the lipophilic labelled metabolite and the striatum to cerebellum ratio (n=16, R=-0.58, P2 receptors with SPET using [123I]epidepride. (orig.)

  9. Temporal expression of transporters and receptors in a rat primary co-culture blood-brain barrier model.

    Science.gov (United States)

    Liu, Houfu; Li, Yang; Lu, Sijie; Wu, Yiwen; Sahi, Jasminder

    2014-10-01

    1. The more relevant primary co-cultures of brain microvessel endothelial cells and astrocytes (BMEC) are less utilized for screening of potential CNS uptake when compared to intestinal and renal cell lines. 2. In this study, we characterized the temporal mRNA expression of major CNS transporters and receptors, including the transporter regulators Pxr, Ahr and Car in a rat BMEC co-cultured model. Permeability was compared with the Madin-Darby canine kidney (MDCKII)-MDR1 cell line and rat brain in situ perfusion model. 3. Our data demonstrated differential changes in expression of individual transporters and receptors over the culture period. Expression of ATP-binding cassette transporters was better retained than that of solute carrier transporters. The insulin receptor (IR) was best maintained among investigated receptors. AhR demonstrated high mRNA expression in rat brain capillaries and expression was better retained than Pxr or Car in culture. Mdr1b expression was up-regulated during primary culture, albeit Mdr1a mRNA levels were much higher. P-gp and Bcrp-1 were highly expressed and functional in this in vitro system. 4. Permeability measurements with 18 CNS marketed drugs demonstrated weak correlation between rBMEC model and rat in situ permeability and moderate correlation with MDCKII-MDR1 cells. 5. We have provided appropriate methodologies, as well as detailed and quantitative characterization data to facilitate improved understanding and rational use of this in vitro rat BBB model. PMID:24827375

  10. Magnetic resonance analysis of the effects of acute ammonia intoxication on rat brain. Role of NMDA receptors.

    Science.gov (United States)

    Cauli, Omar; López-Larrubia, Pilar; Rodrigues, Tiago B; Cerdán, Sebastián; Felipo, Vicente

    2007-11-01

    Acute ammonia intoxication leads to rapid death, which is prevented by blocking N-methyl-d-aspartate (NMDA) receptors. The subsequent mechanisms leading to death remain unclear. Brain edema seems an important step. The aim of this work was to study the effects of acute ammonia intoxication on different cerebral parameters in vivo using magnetic resonance and to assess which effects are mediated by NMDA receptors activation. To assess edema induction, we injected rats with ammonium acetate and measured apparent diffusion coefficient (ADC) in 16 brain areas. We also analyzed the effects on T1, T2, and T2* maps and whether these effects are prevented by blocking NMDA receptors. The effects of acute ammonia intoxication are different in different brain areas. T1 relaxation time is reduced in eight areas. T2 relaxation time is reduced only in ventral thalamus and globus pallidus. ADC values increased in hippocampus, caudate-putamen, substantia nigra and cerebellar cortex, reflecting vasogenic edema. ADC decreased in hypothalamus, reflecting cytotoxic edema. Myo-inositol increased in cerebellum and substantia nigra, reflecting vasogenic edema. N-acetyl-aspartate decreased in cerebellum, reflecting neuronal damage. Changes in N-acetyl-aspartate, T1 and T2 are prevented by blocking NMDA receptors with MK-801 while changes in ADC or myo-inositol (induction of edema) are not. PMID:17727627

  11. Electrophysiological characterization, solubilization and purification of the Tityus gamma toxin receptor associated with the gating component of the Na+ channel from rat brain.

    OpenAIRE

    Barhanin, J; Pauron, D; Lombet, A; Norman, R I; Vijverberg, H. P.; Giglio, J. R.; Lazdunski, M

    1983-01-01

    Electrophysiological studies with neuroblastoma cells have shown that toxin gamma from the venom of the scorpion Tityus serrulatus is a new toxin specific for the gating system of the Na+ channel. The procedure which solubilizes the tetrodotoxin receptor from rat brain also solubilizes the Tityus gamma toxin receptor. Binding experiments on the solubilized receptor with a radioiodinated derivative of Tityus gamma toxin have shown: (i) that the TiTx gamma-receptor complex is very stable with a...

  12. Dopamine D1, D2, D3 receptors, vesicular monoamine transporter type-2 (VMAT2 and dopamine transporter (DAT densities in aged human brain.

    Directory of Open Access Journals (Sweden)

    Jianjun Sun

    Full Text Available The dopamine D(1, D(2, D(3 receptors, vesicular monoamine transporter type-2 (VMAT2, and dopamine transporter (DAT densities were measured in 11 aged human brains (aged 77-107.8, mean: 91 years by quantitative autoradiography. The density of D(1 receptors, VMAT2, and DAT was measured using [(3H]SCH23390, [(3H]dihydrotetrabenazine, and [(3H]WIN35428, respectively. The density of D(2 and D(3 receptors was calculated using the D(3-preferring radioligand, [(3H]WC-10 and the D(2-preferring radioligand [(3H]raclopride using a mathematical model developed previously by our group. Dopamine D(1, D(2, and D(3 receptors are extensively distributed throughout striatum; the highest density of D(3 receptors occurred in the nucleus accumbens (NAc. The density of the DAT is 10-20-fold lower than that of VMAT2 in striatal regions. Dopamine D(3 receptor density exceeded D(2 receptor densities in extrastriatal regions, and thalamus contained a high level of D(3 receptors with negligible D(2 receptors. The density of dopamine D(1 linearly correlated with D(3 receptor density in the thalamus. The density of the DAT was negligible in the extrastriatal regions whereas the VMAT2 was expressed in moderate density. D(3 receptor and VMAT2 densities were in similar level between the aged human and aged rhesus brain samples, whereas aged human brain samples had lower range of densities of D(1 and D(2 receptors and DAT compared with the aged rhesus monkey brain. The differential density of D(3 and D(2 receptors in human brain will be useful in the interpretation of PET imaging studies in human subjects with existing radiotracers, and assist in the validation of newer PET radiotracers having a higher selectivity for dopamine D(2 or D(3 receptors.

  13. Androgen receptors in brain and pituitary of female rats: cyclic changes and comparisons with the male.

    Science.gov (United States)

    Handa, R J; Reid, D L; Resko, J A

    1986-03-01

    The in vitro binding of a synthetic androgen, methyltrienolone ([3H]-R1881), to brain and pituitary (PIT) cytosol and nuclear extracts was determined in male and female rats. Purified cytosol was prepared from PIT or hypothalamic-preoptic area-amygdala (HPA) and incubated in the presence of 0.1 to 10 nM [3H]-R1881. Scatchard analysis revealed the presence of a single, saturable, high-affinity binding site in PIT cytosol with a dissociation constant (Kd) of 0.42 X 10(-10) M in females and 0.95 X 10(-10) M in intact males. The Kd of HPA cytosol was much less in castrated males [0.47 +/- 0.05 (SEM) X 10(-10)M, n = 7] and females (0.63 +/- 0.1 X 10(-10) M, n = 4) than in intact males (5.8 +/- 1.1 X 10(-10) M, n = 8). Treatment of castrated males with dihydrotestosterone (DHT) for 24 h (250 micrograms/100 g of body weight) increased the Kd of HPA cytosol only slightly (1.6 X 10(-10) M, mean of two replicates). Scatchard analysis of salt-extracted nuclear androgen receptor (ARn) showed a single, high-affinity binding site with similar Kd values in PIT and HPA of intact and castrated, DHT-treated male rats (PIT Kd = 7.3 X 10(-10) M, 9.3 X 10(-10) M; HPA Kd = 1.5 X 10(-9) M, 1.3 X 10(-9) M, respectively). Competition studies involving a range of several radioinert steroids revealed that the binding of [3H]-R1881 to cytosol (ARc) and nuclear extract was specific for androgen receptor when triamcinolone acetonide (10 microM) was added. The ARc and ARn levels were quantified in PIT, preoptic area (POA), hypothalamus (HT), amygdala, hippocampus, and cortex by single point estimation. Significantly (p less than 0.01) greater amounts of ARc were detected in PIT of ovariectomized females (32.7 +/- 2.9 fmol/mg of protein) than in that of orchidectomized males (22.33 +/- 1.6 fmol/mg of protein). The highest levels in the brain were seen in HT and POA. Pituitary ARc in females varied throughout the estrous cycle. Significantly (p less than 0.01) greater amounts were detected on

  14. Antidepressant drugs transactivate TrkB neurotrophin receptors in the adult rodent brain independently of BDNF and monoamine transporter blockade.

    Directory of Open Access Journals (Sweden)

    Tomi Rantamäki

    Full Text Available BACKGROUND: Antidepressant drugs (ADs have been shown to activate BDNF (brain-derived neurotrophic factor receptor TrkB in the rodent brain but the mechanism underlying this phenomenon remains unclear. ADs act as monoamine reuptake inhibitors and after prolonged treatments regulate brain bdnf mRNA levels indicating that monoamine-BDNF signaling regulate AD-induced TrkB activation in vivo. However, recent findings demonstrate that Trk receptors can be transactivated independently of their neurotrophin ligands. METHODOLOGY: In this study we examined the role of BDNF, TrkB kinase activity and monoamine reuptake in the AD-induced TrkB activation in vivo and in vitro by employing several transgenic mouse models, cultured neurons and TrkB-expressing cell lines. PRINCIPAL FINDINGS: Using a chemical-genetic TrkB(F616A mutant and TrkB overexpressing mice, we demonstrate that ADs specifically activate both the maturely and immaturely glycosylated forms of TrkB receptors in the brain in a TrkB kinase dependent manner. However, the tricyclic AD imipramine readily induced the phosphorylation of TrkB receptors in conditional bdnf⁻/⁻ knock-out mice (132.4±8.5% of control; P = 0.01, indicating that BDNF is not required for the TrkB activation. Moreover, using serotonin transporter (SERT deficient mice and chemical lesions of monoaminergic neurons we show that neither a functional SERT nor monoamines are required for the TrkB phosphorylation response induced by the serotonin selective reuptake inhibitors fluoxetine or citalopram, or norepinephrine selective reuptake inhibitor reboxetine. However, neither ADs nor monoamine transmitters activated TrkB in cultured neurons or cell lines expressing TrkB receptors, arguing that ADs do not directly bind to TrkB. CONCLUSIONS: The present findings suggest that ADs transactivate brain TrkB receptors independently of BDNF and monoamine reuptake blockade and emphasize the need of an intact tissue context for the

  15. Aldosterone-induced oxidative stress and inflammation in the brain are mediated by the endothelial cell mineralocorticoid receptor.

    Science.gov (United States)

    Dinh, Quynh N; Young, Morag J; Evans, Megan A; Drummond, Grant R; Sobey, Christopher G; Chrissobolis, Sophocles

    2016-04-15

    Elevated aldosterone levels, which promote cerebral vascular oxidative stress, inflammation, and endothelial dysfunction, may increase stroke risk, independent of blood pressure and other risk factors. The main target receptor of aldosterone, the mineralocorticoid receptor (MR), is expressed in many cell types, including endothelial cells. Endothelial cell dysfunction is thought to be an initiating step contributing to cardiovascular disease and stroke; however the importance of MR expressed on endothelial cells in the brain is unknown. Here we have examined whether endothelial cell MR mediates cerebral vascular oxidative stress and brain inflammation during aldosterone excess. In male mice, aldosterone (0.72mg/kg/day, 14 days) caused a small increase (~14mmHg) in blood pressure. The MR blocker spironolactone (25mg/kg/d, ip) abolished this increase, whereas endothelial cell MR-deficiency had no effect. Aldosterone increased superoxide production capacity in cerebral arteries, and also mRNA expression of the pro-inflammatory cytokines chemokine (C-C motif) ligand 7 (CCL7), CCL8 and interleukin (IL)-1β in the brain. These increases were prevented by both spironolactone treatment and endothelial cell MR-deficiency; whereas IL-1β expression was blocked by spironolactone only. Endothelial cell MR mediates aldosterone-induced increases in cerebrovascular superoxide levels and chemokine expression in the brain, but not blood pressure or brain IL-1β. Endothelial cell-targeted MR antagonism may represent a novel approach to treat cerebrovascular disease and stroke, particularly during conditions of aldosterone excess. PMID:26923165

  16. Cysteamine-induced depletion of brain somatostatin is associated with up-regulation of cerebrocortical somatostatin receptors

    International Nuclear Information System (INIS)

    Cysteamine (CSH) administered as a single sc injection to rats produced rapid depletion of cerebrocortical Somatostatin-14 like immunoreactivity (S-14 LI) with a significant 48% reduction occurring within 5 min and maximum (72%) decrease at 4 h. The depletion of S-14 LI was associated with a 1.7 fold increase in Bmax of the cerebrocortical S-14 receptors 5 min after CSH administration and a concomitant but slower increase in the affinity of these receptors. Incubation of intact synaptosomes with 1 mM CSH at 37 C in vitro for 60 min also caused a rapid depletion of S-14 LI, but there was no change in the Bmax or Kd of the S-14 receptors for up to 30 min beyond which time a 2.8-fold decrease in the affinity of S-14 receptors was observed. Higher concentrations of CSH (greater than or equal to 10 mM) added during the incubation of synaptosomes in vitro completely abolished the specific binding of these receptors. The pituitary S-14 receptors were studied 30 min after CSH administration and unlike the cerebrocortical S-14 receptors at this time did not exhibit any change in Bmax or affinity. When added at the time of the binding assay CSH (1 mM) was without a direct effect on cerebrocortical as well as pituitary membrane S-14 receptors. Furthermore, addition of CSH at the time of binding assay did not destroy the integrity of [125I-Tyr11]S-14. It is concluded that administration of CSH to rats in vivo depletes brain S-14 LI and up-regulates synaptosomal S-14 receptors. Exposure of synaptosomes to CSH in vitro for 30 min also depletes S-14 LI but has no effect on S-14 receptors. CSH has a direct inhibitory effect on S-14 receptor binding after prolonged in vitro incubation. Pituitary S-14 receptors unlike those in the brain are unaffected by S-14 LI depletion at least acutely

  17. Technetium 99 m spiperone dithiocarbamate study as a potential agent for brain pathologies diagnosis related to D 2 dopamine receptors

    International Nuclear Information System (INIS)

    Psycho-pharmacology has been discovering much about the D 2 dopamine receptors and their interrelationship to brain pathologies such as Parkinson's Disease, Schizophrenia and Huntington Disease. Those biological receptors have got affinity with dopamine endogenous agent, so that they complex and, in non pathological individuals, the biological receptors contribute to bring the levels of dopamine and free acetylcholine into equilibrium. The D 2 antagonistic psychotropic agents because of having got strong affinity with those receptors, have been being transformed into radiopharmaceuticals to diagnose these pathological disease of Central Nervous System. The Spiperone Dithiocarbamate complex studied by us, is a potential diagnosis agent because of being highly lipo-soluble and having close relationship with D 2 receptors. Besides, it is a photon emitter, allowing the use of SPECT (Single Photon Emission Computed Tomography) technique which is economically less expensive if compared to the PET (Positron Emission Tomography) technique. The Spiperone Dithiocarbamate (SPDC) is synthesized from Spiperone and its complexation with Technetium-99 m has been prepared with its reaction parameters after being studied and improved. The SPDC-99m Tc complex biological distribution have made in Wistar rats and the uptake of spleen, heart, liver stomach, lung, kidney, blood, intestine and brain have been resolved. The plasmatic clearance curve has been based on Wistar rats data and the know-how of the kit (for label SPDC with Tc) has been achieved. (author). 5 figs, 4 tabs

  18. Uncertainty analysis for absorbed dose from a brain receptor imaging agent

    Energy Technology Data Exchange (ETDEWEB)

    Aydogan, B.; Miller, L.F. [Univ. of Tennessee, Knoxville, TN (United States). Nuclear Engineering Dept.; Sparks, R.B. [Oak Ridge Inst. for Science and Education, TN (United States); Stubbs, J.B. [Radiation Dosimetry Systems of Oak Ridge, Inc., Knoxville, TN (United States)

    1999-01-01

    Absorbed dose estimates are known to contain uncertainties. A recent literature search indicates that prior to this study no rigorous investigation of uncertainty associated with absorbed dose has been undertaken. A method of uncertainty analysis for absorbed dose calculations has been developed and implemented for the brain receptor imaging agent {sup 123}I-IPT. The two major sources of uncertainty considered were the uncertainty associated with the determination of residence time and that associated with the determination of the S values. There are many sources of uncertainty in the determination of the S values, but only the inter-patient organ mass variation was considered in this work. The absorbed dose uncertainties were determined for lung, liver, heart and brain. Ninety-five percent confidence intervals of the organ absorbed dose distributions for each patient and for a seven-patient population group were determined by the ``Latin Hypercube Sampling`` method. For an individual patient, the upper bound of the 95% confidence interval of the absorbed dose was found to be about 2.5 times larger than the estimated mean absorbed dose. For the seven-patient population the upper bound of the 95% confidence interval of the absorbed dose distribution was around 45% more than the estimated population mean. For example, the 95% confidence interval of the population liver dose distribution was found to be between 1.49E+0.7 Gy/MBq and 4.65E+07 Gy/MBq with a mean of 2.52E+07 Gy/MBq. This study concluded that patients in a population receiving {sup 123}I-IPT could receive absorbed doses as much as twice as large as the standard estimated absorbed dose due to these uncertainties.

  19. Widespread Expression of Erythropoietin Receptor in Brain and Its Induction by Injury

    Science.gov (United States)

    Ott, Christoph; Martens, Henrik; Hassouna, Imam; Oliveira, Bárbara; Erck, Christian; Zafeiriou, Maria-Patapia; Peteri, Ulla-Kaisa; Hesse, Dörte; Gerhart, Simone; Altas, Bekir; Kolbow, Tekla; Stadler, Herbert; Kawabe, Hiroshi; Zimmermann, Wolfram-Hubertus; Nave, Klaus-Armin; Schulz-Schaeffer, Walter; Jahn, Olaf; Ehrenreich, Hannelore

    2015-01-01

    Erythropoietin (EPO) exerts potent neuroprotective, neuroregenerative and procognitive functions. However, unequivocal demonstration of erythropoietin receptor (EPOR) expression in brain cells has remained difficult since previously available anti-EPOR antibodies (EPOR-AB) were unspecific. We report here a new, highly specific, polyclonal rabbit EPOR-AB directed against different epitopes in the cytoplasmic tail of human and murine EPOR and its characterization by mass spectrometric analysis of immuno-precipitated endogenous EPOR, Western blotting, immunostaining and flow cytometry. Among others, we applied genetic strategies including overexpression, Lentivirus-mediated conditional knockout of EpoR and tagged proteins, both on cultured cells and tissue sections, as well as intracortical implantation of EPOR-transduced cells to verify specificity. We show examples of EPOR expression in neurons, oligodendroglia, astrocytes and microglia. Employing this new EPOR-AB with double-labeling strategies, we demonstrate membrane expression of EPOR as well as its localization in intracellular compartments such as the Golgi apparatus. Moreover, we show injury-induced expression of EPOR. In mice, a stereotactically applied stab wound to the motor cortex leads to distinct EpoR expression by reactive GFAP-expressing cells in the lesion vicinity. In a patient suffering from epilepsy, neurons and oligodendrocytes of the hippocampus strongly express EPOR. To conclude, this new analytical tool will allow neuroscientists to pinpoint EPOR expression in cells of the nervous system and to better understand its role in healthy conditions, including brain development, as well as under pathological circumstances, such as upregulation upon distress and injury. PMID:26349059

  20. Data on Arc and Zif268 expression in the brain of the α-2A adrenergic receptor knockout mouse.

    Science.gov (United States)

    Sanders, Jeff

    2016-06-01

    The α2-adrenergic receptor (α2-AR) is widely distributed in the brain with distinct roles for α2-AR subtypes (A, B and C). In this article, data are provided on Activity Regulated Cytoskeleton Associated Protein (Arc) and Zif268 expression in the brain of the α2A-AR knockout (α2A-AR KO) mouse. These data are supplemental to an original research article examining Arc and Zif268 expression in rats injected with the α2-AR antagonist, RX821002 (http://dx.doi.org/10.1016/j.neulet.2015.12.002. [1]). PMID:26952134

  1. Inhibition of Type I Insulin-Like Growth Factor Receptor Signaling Attenuates the Development of Breast Cancer Brain Metastasis

    OpenAIRE

    Saldana, Sandra M.; Lee, Heng-Huan; Lowery, Frank J; Khotskaya, Yekaterina B.; Xia, Weiya; Zhang, Chenyu; Chang, Shih-Shin; Chou, Chao-Kai; Steeg, Patricia S; Yu, Dihua; Hung, Mien-Chie

    2013-01-01

    Brain metastasis is a common cause of mortality in cancer patients, yet potential therapeutic targets remain largely unknown. The type I insulin-like growth factor receptor (IGF-IR) is known to play a role in the progression of breast cancer and is currently being investigated in the clinical setting for various types of cancer. The present study demonstrates that IGF-IR is constitutively autophosphorylated in brain-seeking breast cancer sublines. Knockdown of IGF-IR results in a decrease of ...

  2. Coexpression of N-methyl-D-aspartate and phencyclidine receptors in Xenopus oocytes injected with rat brain mRNA.

    OpenAIRE

    Kushner, L; Lerma, J.; Zukin, R S; Bennett, M V

    1988-01-01

    Recent evidence suggest that the N-methyl-D-aspartate (N-Me-D-Asp) channel is functionally and structurally associated with the phencyclidine (PCP) receptor, which mediates the psychotomimetic effects of PCP, sigma opioids, and dioxalanes. To investigate the relationship between N-Me-D-Asp and PCP receptors on a molecular level, we injected mRNA isolated from adult rat brain into Xenopus oocytes. In injected oocytes N-Me-D-Asp application (with glycine) evoked a partially desentizing inward c...

  3. Altered expression of metabotropic glutamate receptor 1 alpha after acute diffuse brain injury Effect of the competitive antagonist 1-aminoindan-1, 5-dicarboxylic acid

    Institute of Scientific and Technical Information of China (English)

    Fei Cao; Mantao Chen; Gu Li; Ke Ye; Xin Huang; Xiujue Zheng

    2012-01-01

    The diffuse brain injury model was conducted in Sprague-Dawley rats, according to Marmarou's free-fall attack. The water content in brain tissue, expression of metabotropic glutamate receptor 1α mRNA and protein were significantly increased after injury, reached a peak at 24 hours, and then gradually decreased. After treatment with the competitive antagonist of metabotropic glutamate receptor 1α, (RS)-1-aminoindan-1, 5-dicarboxylic acid, the water content of brain tissues decreased between 12-72 hours after injury, and neurological behaviors improved at 2 weeks. These experimental findings suggest that the 1-aminoindan-1, 5-dicarboxylic acid may result in marked neuroprotection against diffuse brain injury.

  4. Brain interleukin-1β and the intrinsic receptor antagonist control peripheral Toll-like receptor 3-mediated suppression of spontaneous activity in rats.

    Directory of Open Access Journals (Sweden)

    Masanori Yamato

    Full Text Available During acute viral infections such as influenza, humans often experience not only transient fever, but also prolonged fatigue or depressive feelings with a decrease in social activity for days or weeks. These feelings are thought to be due to neuroinflammation in the brain. Recent studies have suggested that chronic neuroinflammation is a precipitating event of various neurological disorders, but the mechanism determining the duration of neuroinflammation has not been elucidated. In this study, neuroinflammation was induced by intraperitoneal injection of polyriboinosinic:polyribocytidylic acid (poly I:C, a Toll-like receptor-3 agonist that mimics viral infection in male Sprague-Dawley rats, and then investigated how the neuroinflammation shift from acute to the chronic state. The rats showed transient fever and prolonged suppression of spontaneous activity for several days following poly I:C injection. NS-398, a cyclooxygenase-2 inhibitor, completely prevented fever, but did not improve spontaneous activity, indicating that suppression of spontaneous activity was not induced by the arachidonate cascade that generated the fever. The animals overexpressed interleukin (IL-1β and IL-1 receptor antagonist (IL-1ra in the brain including the cerebral cortex. Blocking the IL-1 receptor in the brain by intracerebroventricular (i.c.v. infusion of recombinant IL-1ra completely blocked the poly I:C-induced suppression of spontaneous activity and attenuated amplification of brain interferon (IFN-α expression, which has been reported to produce fatigue-like behavior by suppressing the serotonergic system. Furthermore, i.c.v. infusion of neutralizing antibody for IL-1ra prolonged recovery from suppression of spontaneous activity. Our findings indicated that IL-1β is the key trigger of neuroinflammation and that IL-1ra prevents the neuroinflammation entering the chronic state.

  5. Increased efflux of amyloid-β peptides through the blood-brain barrier by muscarinic acetylcholine receptor inhibition reduces pathological phenotypes in mouse models of brain amyloidosis.

    Science.gov (United States)

    Paganetti, Paolo; Antoniello, Katia; Devraj, Kavi; Toni, Nicolas; Kieran, Dairin; Madani, Rime; Pihlgren, Maria; Adolfsson, Oskar; Froestl, Wolfgang; Schrattenholz, André; Liebner, Stefan; Havas, Daniel; Windisch, Manfred; Cirrito, John R; Pfeifer, Andrea; Muhs, Andreas

    2014-01-01

    The formation and accumulation of toxic amyloid-β peptides (Aβ) in the brain may drive the pathogenesis of Alzheimer's disease. Accordingly, disease-modifying therapies for Alzheimer's disease and related disorders could result from treatments regulating Aβ homeostasis. Examples are the inhibition of production, misfolding, and accumulation of Aβ or the enhancement of its clearance. Here we show that oral treatment with ACI-91 (Pirenzepine) dose-dependently reduced brain Aβ burden in AβPPPS1, hAβPPSL, and AβPP/PS1 transgenic mice. A possible mechanism of action of ACI-91 may occur through selective inhibition of muscarinic acetylcholine receptors (AChR) on endothelial cells of brain microvessels and enhanced Aβ peptide clearance across the blood-brain barrier. One month treatment with ACI-91 increased the clearance of intrathecally-injected Aβ in plaque-bearing mice. ACI-91 also accelerated the clearance of brain-injected Aβ in blood and peripheral tissues by favoring its urinal excretion. A single oral dose of ACI-91 reduced the half-life of interstitial Aβ peptide in pre-plaque mhAβPP/PS1d mice. By extending our studies to an in vitro model, we showed that muscarinic AChR inhibition by ACI-91 and Darifenacin augmented the capacity of differentiated endothelial monolayers for active transport of Aβ peptide. Finally, ACI-91 was found to consistently affect, in vitro and in vivo, the expression of endothelial cell genes involved in Aβ transport across the Blood Brain Brain (BBB). Thus increased Aβ clearance through the BBB may contribute to reduced Aβ burden and associated phenotypes. Inhibition of muscarinic AChR restricted to the periphery may present a therapeutic advantage as it avoids adverse central cholinergic effects. PMID:24072071

  6. Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration

    Science.gov (United States)

    Burk, Raymond F.; Hill, Kristina E.; Motley, Amy K.; Winfrey, Virginia P.; Kurokawa, Suguru; Mitchell, Stuart L.; Zhang, Wanqi

    2014-01-01

    Selenoprotein P (Sepp1) and its receptor, apolipoprotein E receptor 2 (apoER2), account for brain retaining selenium better than other tissues. The primary sources of Sepp1 in plasma and brain are hepatocytes and astrocytes, respectively. ApoER2 is expressed in varying amounts by tissues; within the brain it is expressed primarily by neurons. Knockout of Sepp1 or apoER2 lowers brain selenium from ∼120 to ∼50 ng/g and leads to severe neurodegeneration and death in mild selenium deficiency. Interactions of Sepp1 and apoER2 that protect against this injury have not been characterized. We studied Sepp1, apoER2, and brain selenium in knockout mice. Immunocytochemistry showed that apoER2 mediates Sepp1 uptake at the blood-brain barrier. When Sepp1−/− or apoER2−/− mice developed severe neurodegeneration caused by mild selenium deficiency, brain selenium was ∼35 ng/g. In extreme selenium deficiency, however, brain selenium of ∼12 ng/g was tolerated when both Sepp1 and apoER2 were intact in the brain. These findings indicate that tandem Sepp1-apoER2 interactions supply selenium for maintenance of brain neurons. One interaction is at the blood-brain barrier, and the other is within the brain. We postulate that Sepp1 inside the blood-brain barrier is taken up by neurons via apoER2, concentrating brain selenium in them.—Burk, R. F., Hill, K. E., Motley, A. K., Winfrey, V. P., Kurokawa, S., Mitchell, S. L., Zhang, W. Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration. PMID:24760755

  7. Localization of dopamine receptors in the tree shrew brain using [3H]-SCH23390 and [125I]-epidepride.

    Science.gov (United States)

    Mijnster, M J; Isovich, E; Flügge, G; Fuchs, E

    1999-09-11

    The tree shrew is a mammalian species, which is phylogenetically related to insectivores and primates. The aim of the present study was to investigate the distribution of dopamine receptor D1- and D2-like binding sites in the brain of this non-rodent, non-primate mammal. Using in vitro autoradiography and employing the radioligands [3H]-SCH23390 and [125I]-epidepride, dopamine receptors were mapped and quantified. Significant findings with regard to the D1-like binding pattern include the presence of a "patchy" binding in the striatum. In the cortex, D1-like binding sites were observed in both the superficial and the deep layers. In the hippocampal formation, D1-like binding sites were seen primarily in the CAI region and not in the dentate gyrus. These characteristics of the D1 pattern in the tree shrew brain are shared by cat and monkey and human brain, but not by rodent brain. Significant findings with regard to the D2-like binding pattern include the presence of D2-like binding in the claustrum. In addition, the striatum demonstrated "patchy" D2-like binding. These characteristics of the D2 pattern in the tree shrew brain are shared by cat and monkey and human brain, but not by rodent brain. On the other hand, the significant densities of D2-like binding sites in the glomerular layer of the tree shrew olfactory bulb is a finding that discriminates tree shrews from higher evolutionary species who lack such binding. Overall, the evidence coincides with the view that tree shrews are phylogenetically related to primates. PMID:10546993

  8. Pattern of brain metastatic disease according to HER-2 and ER receptor status in breast cancer patients

    International Nuclear Information System (INIS)

    Aims: To document the type, location, extent, and complications of brain metastases in patients with breast cancer and identify associations with oestrogen receptor (ER) negative and human epidermal growth factor receptor 2 (HER-2) receptor expression. Materials and methods: Breast cancer patients with known brain metastases were included in this retrospective study, if cross-sectional imaging of the brain [computed tomography (CT)] was available to review and HER-2 and ER status was known. Two neuroradiologists, who were blinded to the receptor status, separately and for each patient, documented on a proforma the location, number, and dimensions of the deposits and the presence or absence of hydrocephalus. Adjudication was sought where there was discrepancy between the two reports. ER status, HER-2 receptor status, and patient age were also documented. The results were analysed using two-sided Fisher's exact tests with Lancaster's mid-P correction and associations were sought between the tumour characteristics and the pattern of brain disease. Results: Sixty patients were included in the study. There was an association between young age (<40 years) and HER-2 positivity [10 of 24 (41.7%) versus three of 36 (8.3%); p = 0.002]. In ER-negative women, HER-2 positivity was found to be associated with a larger number (six or more) of metastases [11 of 18 (61%) versus nine of 25 (36%); p = 0.049], more brain stem metastases [11 of 18 (61%) versus three of 26 (11.5%); p = 0.035], more frequent occurrence of hydrocephalus [7 of 12 (36.8%) versus three of 26 (11.5%); p = 0.049], and a higher incidence of occipital metastases [12 of 18 (66.7%) versus eight of 26 (30.8%); p = 0.029]. Conclusion: ER-negative HER-2-positive women are more likely to present with a larger number of lesions, more brain stem/occipital metastases, and hydrocephalus, which may predispose them to unfavourable outcomes following treatment

  9. Interaction of a vasopressin antagonist with vasopressin receptors in the septum of the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Dorsa, D.M.; Brot, M.D.; Shewey, L.M.; Meyers, K.M.; Szot, P.; Miller, M.A.

    1988-01-01

    The ability of d(CH2)5-Tyr(Me)-arginine-8-vasopressin, an antagonist of peripheral pressoric (V1-type) vasopressin receptors, to label vasopressin binding sites in the septum of the rat brain was evaluated. Using crude membrane preparations from the septum, /sup 3/H-arginine-8-vasopressin (AVP) specifically labels a single class of binding sites with a Kd of 2.9 nM and maximum binding site concentration of 19.8 fmole/mg protein. /sup 3/H-Antag also labels a single class of membrane sites but with higher affinity (Kd = 0.47 nM) and lower capacity (10.1 fmole/mg protein) than /sup 3/H-AVP. The rank order of potency of various competitor peptides for /sup 3/H-AVP and /sup 3/H-Antag binding was similar. Oxytocin was 100-1,000 fold less potent than AVP in competing for binding with both ligands. /sup 3/H-AVP and /sup 3/H-Antag showed similar labeling patterns when incubated with septal tissue slices. Unlabeled Antag also effectively antagonized vasopressin-stimulated phosphatidylinositol hydrolysis in septal tissue slices.

  10. Panel discussion: cCinical pet neurotransmitter metabolism and receptor binding studies of brain

    International Nuclear Information System (INIS)

    Following presentations on applications and results of PET imaging in Parkinson's disease (PD), Alzheimer's disease (AD), and refractory temporal lobe epilepsy, additional aspects of PET use in evaluating neurologic disease were discussed. Several questions addressed imaging of the dopamine (DA) synapse in PD. Discussion centered around reasons for focal hypometabolism of the association cortex in AD but not of the striatum in PD as well as potential applications of metabolic and presynaptic DA measurements in the diagnostic evaluation of Parkinsonian syndromes. The specificity of fluoroDOPA (FD) uptake following PD treatment by adrenal or substantia nigra transplantation was addressed. Blood-brain-barrier disruption and the metabolic instability of FD were discussed as underlying causes of increased tracer accumulation reported in the literature. The session then turned to dementia and the problem of establishing a definite diagnosis.The roles of PET and SPECT imaging in these areas is relatively new but is very promising. The session concluded with discussion of the possibility of activation studies with neurotransmitter ligands. The design and interpretation of such studies are quite complex. Physiologic stimulation studies frequently result in altered local cerebral perfusion; it will be necessary to distinguish differences in ligand distribution arising form blood flow changes from possible alterations in receptor availability. These interactions may also confound radioligand studies following pharmacologic interventions with unlabeled drugs

  11. Selective estrogen receptor modulators decrease reactive astrogliosis in the injured brain: Effects of aging and prolonged depletion of ovarian hormones

    OpenAIRE

    Barreto, G.; Santos-Galindo, M.; Diz-Chaves, Yolanda; Pernía, Olga; Carrero, P; Azcoitia, I.; Garcia-Segura, Luis M.

    2009-01-01

    After brain injury, astrocytes acquire a reactive phenotype characterized by a series of morphological and molecular modifications, including the expression of the cytoskeletal protein vimentin. Previous studies have shown that estradiol down-regulates reactive astrogliosis. In this study we assessed whether raloxifene and tamoxifen, two selective estrogen receptor modulators, have effects similar to estradiol in astrocytes. We also assessed whether aging and the timing of estrogenic therapy ...

  12. A High Soy Diet Enhances Neurotropin Receptor and Bcl-XL Gene Expression in the Brains of Ovariectomized Female Rats

    OpenAIRE

    Lovekamp-Swan, Tara; Glendenning, Michele L.; Schreihofer, Derek A.

    2007-01-01

    Estrogen is a powerful neuroprotective agent with the ability to induce trophic and antiapoptotic genes. However, concerns about negative overall health consequences of estrogen replacement after menopause have led to the adoption of other strategies to obtain estrogen’s benefits in the brain, including the use of selective estrogen receptor modulators, high soy diets, or isoflavone supplements. This study sought to determine the ability of a high soy diet to induce neuroprotective gene expre...

  13. Binding characteristics of brain-derived neurotrophic factor to its receptors on neurons from the chick embryo

    International Nuclear Information System (INIS)

    Brain-derived neurotrophic factor (BDNF), a protein known to support the survival of embryonic sensory neurons and retinal ganglion cells, was derivatized with 125I-Bolton-Hunter reagent and obtained in a biologically active, radioactive form (125I-BDNF). Using dorsal root ganglion neurons from chick embryos at 9 d of development, the basic physicochemical parameters of the binding of 125I-BDNF with its receptors were established. Two different classes of receptors were found, with dissociation constants of 1.7 x 10(-11) M (high-affinity receptors) and 1.3 x 10(-9) M (low-affinity receptors). Unlabeled BDNF competed with 125I-BDNF for binding to the high-affinity receptors with an inhibition constant essentially identical to the dissociation constant of the labeled protein: 1.2 x 10(-11) M. The association and dissociation rates from both types of receptors were also determined, and the dissociation constants calculated from these kinetic experiments were found to correspond to the results obtained from steady-state binding. The number of high-affinity receptors (a few hundred per cell soma) was 15 times lower than that of low-affinity receptors. No high-affinity receptors were found on sympathetic neurons, known not to respond to BDNF, although specific binding of 125I-BDNF to these cells was detected at a high concentration of the radioligand. These results are discussed and compared with those obtained with nerve growth factor on the same neuronal populations

  14. BLOCKADE OF BRAIN ANGIOTENSIN II AT1 RECEPTORS AMELIORATES STRESS, ANXIETY, BRAIN INFLAMMATION AND ISCHEMIA: THERAPEUTIC IMPLICATIONS

    OpenAIRE

    Saavedra, Juan M.; Sánchez-Lemus, Enrique; BENICKY, Julius

    2010-01-01

    Poor adaptation to stress, alterations in cerebrovascular function and excessive brain inflammation play critical roles in the pathophysiology of many psychiatric and neurological disorders such as major depression, schizophrenia, post traumatic stress disorder, Parkinson's and Alzheimer's diseases and traumatic brain injury. Treatment for these highly prevalent and devastating conditions is at present very limited and many times inefficient, and the search for novel therapeutic options is of...

  15. SPECT imaging of dopamine receptors with [123I]epidepride: characterization of uptake in the human brain

    International Nuclear Information System (INIS)

    Summary. [123I]Epidepride is a new ligand for single photon emission computerized tomography (SPECT) that specifically labels D2-like dopamine receptors with very high affinity. Here, we report on the regional kinetic uptake of [123I]epidepride in the brain of 4 normal volunteers and 3 patients with choreatic movement disorders. In healthy subjects striatal activity peaked at 2.5 hours after injection of the tracer and decreased slowly thereafter. There were no significant differences between left and right brain hemispheres. Activity above background was also measurable in areas corresponding to the thalamus, temporal cortex and frontal cortex. The striatal to cerebellar ratio was about 14 after 2.5 hours and this ratio steadily increased with time. The striatal to cerebellar ratio was clearly reduced in all 3 patients with choreatic movement disorders (from about 14 in control subjects after 2.5 hours to about 7 in choreatic patients). [123I]Epidepride may be a useful SPECT ligand for studying D2 receptors in the living human brain because of its high target to background ratio, its high affinity and the possibility to investigate extrastriatal D2 receptors. (author)

  16. Distribution of the a2, a3, and a5 nicotinic acetylcholine receptor subunits in the chick brain

    Directory of Open Access Journals (Sweden)

    Torrão A.S.

    1997-01-01

    Full Text Available Nicotinic acetylcholine receptors (nAChRs are ionotropic receptors comprised of a and ß subunits. These receptors are widely distributed in the central nervous system, and previous studies have revealed specific patterns of localization for some nAChR subunits in the vertebrate brain. In the present study we used immunohistochemical methods and monoclonal antibodies to localize the a2, a3, and a5 nAChR subunits in the chick mesencephalon and diencephalon. We observed a differential distribution of these three subunits in the chick brain, and showed that the somata and neuropil of many central structures contain the a5 nAChR subunit. The a2 and a3 subunits, on the other hand, exhibited a more restricted distribution than a5 and other subunits previously studied, namely a7, a8 and ß2. The patterns of distribution of the different nAChR subunits suggest that neurons in many brain structures may contain several subtypes of nAChRs and that in a few regions one particular subtype may determine the cholinergic nicotinic responses

  17. PCB disruption of the hypothalamus-pituitary-interrenal axis involves brain glucocorticoid receptor downregulation in anadromous Arctic charr

    Science.gov (United States)

    Aluru, N.; Jorgensen, E.H.; Maule, A.G.; Vijayan, M.M.

    2004-01-01

    We examined whether brain glucocorticoid receptor (GR) modulation by polychlorinated biphenyls (PCBs) was involved in the abnormal cortisol response to stress seen in anadromous Arctic charr (Salvelinus alpinus). Fish treated with Aroclor 1254 (0, 1, 10, and 100 mg/kg body mass) were maintained for 5 mo without feeding in the winter to mimic their seasonal fasting cycle, whereas a fed group with 0 and 100 mg/kg Aroclor was maintained for comparison. Fasting elevated plasma cortisol levels and brain GR content but depressed heat shock protein 90 (hsp90) and interrenal cortisol production capacity. Exposure of fasted fish to Aroclor 1254 resulted in a dose-dependent increase in brain total PCB content. This accumulation in fish with high PCB dose was threefold higher in fasted fish compared with fed fish. PCBs depressed plasma cortisol levels but did not affect in vitro interrenal cortisol production capacity in fasted charr. At high PCB dose, the brain GR content was significantly lower in the fasted fish and this corresponded with a lower brain hsp70 and hsp90 content. The elevation of plasma cortisol levels and upregulation of brain GR content may be an important adaptation to extended fasting in anadromous Arctic charr, and this response was disrupted by PCBs. Taken together, the hypothalamus-pituitary- interrenal axis is a target for PCB impact during winter emaciation in anadromous Arctic charr.

  18. Neuronal nicotinic receptor subtypes in normal ageing, Alzheimer's disease and schizophrenia : Influences of neuropathological mechanisms as studied in human autopsy brain and transgenic mice

    OpenAIRE

    Marutle, Amelia

    2002-01-01

    Neuronal nicotinic acetylcholine receptors (nAChRs) are transmitter-gated ion channel receptors which are widely distributed in the brain. They mediate the effects of several neurotransmitters including ACh, DA, 5-HT and NA and are important for many normal physiological functions in the brain and are also implicated in a number of CNS disorders, such as AD, PD, schizophrenia, Tourette's syndrome and familial epilepsy. The overall aim of this thesis was to characterise chang...

  19. Immunorecognition of estrogen and androgen receptors in the brain and thoracic ganglion mass of mud crab, Scylla paramamosain

    Institute of Scientific and Technical Information of China (English)

    Haihui Ye; Huiyang Huang; Shaojing Li; Guizhong Wang

    2008-01-01

    The brain and the thoracic ganglion of a crustacean can synthesize and secrete gonad-stimulating hormone (GSH) which stimulates the maturation of gonad. In the previous experiments, sex steroid hormones (estradiol, testosterone, progesterone, etc.) have been detected from the crustacean. However, the feedback regulation of sex steroid hormones on the brain and the thoracic ganglion of the crustacean has not been reported so far. In the present experiment, monoclonal antibodies were applied to investigate the immunorecognition of estrogen receptor (ER) and androgen receptor (AR) in the brain and the thoracic ganglion mass of Scylla paramamosain. The results showed that the distribution of the immunopositive substances of ER and AR was extremely similar. They distributed in the protocerebrum, deutocerebrum and tritocerebrum of the brain, and mainly in protocerebrum. In the thoracic ganglion mass, immunopositive substances distributed in the subesophageal ganglion, thoracic ganglion and abdominal ganglion, and mostly in subesophageal ganglion. Immunopositive substances of ER and AR mostly existed in the cytoplasm of neurons. The present study will provide morphological evidence for the origin and the evolution of ER and AR. In addition, the immunoreactivities of ER and AR suggested that the estrogen and androgen may be involved in the feedback regulation of crustacean neuroendocrine.

  20. Synthesis and evaluation of [/sup 125/I]iodothienoperidol as a potential receptor site directed brain imaging agent

    International Nuclear Information System (INIS)

    This study was undertaken to design and evaluate radioligands for the noninvasive quantification of dopamine receptors in the brain. The approach involved the preparation of the iodothienyl analog I of haloperidol II, a well characterized dopamine antagonist which has been labeled with F-18 and C-11. The synthesis involved the addition of 5-trimethylstannyl-2-thienyllithium so the piperidone intermediate. The product was characterized by spectroscopic and analytic methods and radioiodinated via electrophilic iododestannylation to yield the product in 75-85% isolated yield. The tissue distribution of the radiochemical was evaluated in rats as a function of time, 0.25-2 hrs, and in the presence or absence of haloperidol (1 mg/kg) to measure receptor binding. The results indicated that the 0.25 h uptake in the brain was high (2.2% ID) and that the washout of the activity was relatively slow, 1.3% ID present at 2 hr. The Br/B1 values remained relatively constant over that time interval (9.3-12.1:1). Coadministration of 1 mg/kg haloperidol markedly reduced the uptake in the brain at 0.25 and 2 hr (55% and 62%) with much less of an effect on the nontarget tissues. The study indicates that the authors have prepared a radiotracer, labeled with iodine, that demonstrates both good brain uptake and selectivity as well as a specific binding site component

  1. Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography

    International Nuclear Information System (INIS)

    Two substituted benzamides, FLB 524 and raclopride, were labeled with 11C and examined for their possible use as ligands for positron emission tomography (PET) scan studies on dopamine-2 (D-2) receptors in the brains of monkeys and healthy human subjects. Both ligands allowed the in vivo visualization of D-2 receptor binding in the corpus striatum caudate nucleus/putamen complex in PET-scan images. [11C]Raclopride showed a high ratio of specific striatal to nonspecific cerebellar binding, and the kinetics of binding of this ligand made it optimal for PET studies. The in vivo binding of [11C]raclopride in the striatum of cynomolgus monkeys was markedly reduced by displacement with haloperidol. In healthy human subjects, [11C]raclopride binding in the caudate nucleus/putamen was 4- to 5-fold greater than nonspecific binding in the cerebellum. In comparison with previously available ligands for PET-scan studies on central dopamine receptors in man, [11C]raclopride appears to be advantageous with regard to (i) specificity of binding to D-2 receptors, (ii) the high ratio between binding in dopamine-rich (caudate, putamen) and dopamine-poor (cerebellum) human brain regions, and (iii) rapid association and reversibility of specific binding

  2. Expression of galanin and its receptors are perturbed in a rodent model of mild, blast-induced traumatic brain injury.

    Science.gov (United States)

    Kawa, Lizan; Barde, Swapnali; Arborelius, Ulf P; Theodorsson, Elvar; Agoston, Denes; Risling, Mårten; Hökfelt, Tomas

    2016-05-01

    The symptomatology, mood and cognitive disturbances seen in post-traumatic stress disorder (PTSD) and mild blast-induced traumatic brain injury (mbTBI) overlap considerably. However the pathological mechanisms underlying the two conditions are currently unknown. The neuropeptide galanin has been suggested to play a role in the development of stress and mood disorders. Here we applied bio- and histochemical methods with the aim to elucidate the nature of any changes in the expression of galanin and its receptors in a rodent model of mbTBI. In situ hybridization and quantitative polymerase chain reaction studies revealed significant, injury-induced changes, in some cases lasting at least for one week, in the mRNA levels of galanin and/or its three receptors, galanin receptor 1-3 (GalR1-3). Such changes were seen in several forebrain regions, and the locus coeruleus. In the ventral periaqueductal gray GalR1 mRNA levels were increased, while GalR2 were decreased. Analysis of galanin peptide levels using radioimmunoassay demonstrated an increase in several brain regions including the locus coeruleus, dorsal hippocampal formation and amygdala. These findings suggest a role for the galanin system in the endogenous response to mbTBI, and that pharmacological studies of the effects of activation or inhibition of different galanin receptors in combination with functional assays of behavioral recovery may reveal promising targets for new therapeutic strategies in mbTBI. PMID:26928087

  3. Metabolism of [123I]epidepride may affect brain dopamine D2 receptor imaging with single-photon emission tomography.

    Science.gov (United States)

    Bergström, K A; Yu, M; Kuikka, J T; Akerman, K K; Hiltunen, J; Lehtonen, J; Halldin, C; Tiihonen, J

    2000-02-01

    Iodine-123 labelled epidepride is a novel radiopharmaceutical for the study of cerebral dopamine D2 receptors using single-photon emission tomography (SPET). A lipophilic labelled metabolite of [123I]epidepride which may enter the brain and hamper the quantitation of receptors has been observed in human plasma. In the present study, gradient high-performance liquid chromatography (HPLC) was used to investigate the plasma concentration of the lipophilic labelled metabolite and its correlation to SPET imaging of striatal dopamine D2 receptors. A linear regression fit showed a negative correlation between the amount of the lipophilic labelled metabolite and the striatum to cerebellum ratio (n=16, R=-0.58, Pepidepride. PMID:10755727

  4. Expression and distribution of the glucocorticoid receptor DlGR1 in the teleost Dicentrarchus labrax brain

    Directory of Open Access Journals (Sweden)

    Nicolò Parrinello

    2010-01-01

    Full Text Available Cortisol is the main corticosteroid secreted by the interrenal cells of the head kidney and it exerts a role in mantaining the omeostatic status in fish. In teleosts its effects are mediated through intracellular receptors expressed in several tissues, that are ligand-dependent transcription factors by binding to specific tissue DNA sequences. In Dicentrarchus labrax we previously cloned and sequenced a glucocorticoid receptor, DlGR1, isolated from leukocytes of peritoneal cavity. In this work we showed mRNA expression and tissue immunohistochemical localization of brain DlGR1 by in situ hybridization assays, with a riboprobe with DlGR1 cDNA trascriptional activation domain, and by immunohistochemical methods, using a specific antibody for a selected sequence of the receptor tran- scriptional domain. The mRNA and the protein are expressed in pyramidal cells of the optic lobe and in the small globular neurons of the diencephalon.

  5. Origin and consequences of brain Toll-like receptor 4 pathway stimulation in an experimental model of depression

    Directory of Open Access Journals (Sweden)

    Madrigal José LM

    2011-11-01

    Full Text Available Abstract Background There is a pressing need to identify novel pathophysiological pathways relevant to depression that can help to reveal targets for the development of new medications. Toll-like receptor 4 (TLR-4 has a regulatory role in the brain's response to stress. Psychological stress may compromise the intestinal barrier, and increased gastrointestinal permeability with translocation of lipopolysaccharide (LPS from Gram-negative bacteria may play a role in the pathophysiology of major depression. Methods Adult male Sprague-Dawley rats were subjected to chronic mild stress (CMS or CMS+intestinal antibiotic decontamination (CMS+ATB protocols. Levels of components of the TLR-4 signaling pathway, of LPS and of different inflammatory, oxidative/nitrosative and anti-inflammatory mediators were measured by RT-PCR, western blot and/or ELISA in brain prefrontal cortex. Behavioral despair was studied using Porsolt's test. Results CMS increased levels of TLR-4 and its co-receptor MD-2 in brain as well as LPS and LPS-binding protein in plasma. In addition, CMS also increased interleukin (IL-1β, COX-2, PGE2 and lipid peroxidation levels and reduced levels of the anti-inflammatory prostaglandin 15d-PGJ2 in brain tissue. Intestinal decontamination reduced brain levels of the pro-inflammatory parameters and increased 15d-PGJ2, however this did not affect depressive-like behavior induced by CMS. Conclusions Our results suggest that LPS from bacterial translocation is responsible, at least in part, for the TLR-4 activation found in brain after CMS, which leads to release of inflammatory mediators in the CNS. The use of Gram-negative antibiotics offers a potential therapeutic approach for the adjuvant treatment of depression.

  6. Age, sex and NK1 receptors in the human brain -- a positron emission tomography study with [¹¹C]GR205171.

    Science.gov (United States)

    Engman, Jonas; Åhs, Fredrik; Furmark, Tomas; Linnman, Clas; Pissiota, Anna; Appel, Lieuwe; Frans, Örjan; Långström, Bengt; Fredrikson, Mats

    2012-08-01

    The substance P/neurokinin 1 (SP/NK1) system has been implicated in the processing of negative affect. Its role seems complex and findings from animal studies have not been easily translated to humans. Brain imaging studies on NK1 receptor distribution in humans have revealed an abundance of receptors in cortical, striatal and subcortical areas, including the amygdala. A reduction in NK1 receptors with increasing age has been reported in frontal, temporal, and parietal cortices, as well as in hippocampal areas. Also, a previous study suggests sex differences in cortical and subcortical areas, with women displaying fewer NK1 receptors. The present PET study explored NK1 receptor availability in men (n=9) and women (n=9) matched for age varying between 20 and 50years using the highly specific NK1 receptor antagonist [¹¹C]GR205171 and a reference tissue model with cerebellum as the reference region. Age by sex interactions in the amygdala and the temporal cortex reflected a lower NK1 receptor availability with increasing age in men, but not in women. A general age-related decline in NK1 receptor availability was evident in the frontal, temporal, and occipital cortices, as well as in the brainstem, caudate nucleus, and thalamus. Women had lower NK1 receptor availability in the thalamus. The observed pattern of NK1 receptor distribution in the brain might have functional significance for brain-related disorders showing age- and sex-related differences in prevalence. PMID:22225860

  7. Prebiotic feeding elevates central brain derived neurotrophic factor, N-methyl-D-aspartate receptor subunits and D-serine.

    Science.gov (United States)

    Savignac, Helene M; Corona, Giulia; Mills, Henrietta; Chen, Li; Spencer, Jeremy P E; Tzortzis, George; Burnet, Philip W J

    2013-12-01

    The influence of the gut microbiota on brain chemistry has been convincingly demonstrated in rodents. In the absence of gut bacteria, the central expression of brain derived neurotropic factor, (BDNF), and N-methyl-d-aspartate receptor (NMDAR) subunits are reduced, whereas, oral probiotics increase brain BDNF, and impart significant anxiolytic effects. We tested whether prebiotic compounds, which increase intrinsic enteric microbiota, also affected brain BDNF and NMDARs. In addition, we examined whether plasma from prebiotic treated rats released BDNF from human SH-SY5Y neuroblastoma cells, to provide an initial indication of mechanism of action. Rats were gavaged with fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS) or water for five weeks, prior to measurements of brain BDNF, NMDAR subunits and amino acids associated with glutamate neurotransmission (glutamate, glutamine, and serine and alanine enantiomers). Prebiotics increased hippocampal BDNF and NR1 subunit expression relative to controls. The intake of GOS also increased hippocampal NR2A subunits, and frontal cortex NR1 and d-serine. Prebiotics did not alter glutamate, glutamine, l-serine, l-alanine or d-alanine concentrations in the brain, though GOSfeeding raised plasma d-alanine. Elevated levels of plasma peptide YY (PYY) after GOS intake was observed. Plasma from GOS rats increased the release of BDNF from SH-SY5Y cells, but not in the presence of PYY antisera. The addition of synthetic PYY to SH-SY5Y cell cultures, also elevated BDNF secretion. We conclude that prebiotic-mediated proliferation of gut microbiota in rats, like probiotics, increases brain BDNF expression, possibly through the involvement of gut hormones. The effect of GOS on components of central NMDAR signalling was greater than FOS, and may reflect the proliferative potency of GOS on microbiota. Our data therefore, provide a sound basis to further investigate the utility of prebiotics in the maintenance of brain health and

  8. Prevention of Escherichia coli K1 Penetration of the Blood-Brain Barrier by Counteracting the Host Cell Receptor and Signaling Molecule Involved in E. coli Invasion of Human Brain Microvascular Endothelial Cells▿

    OpenAIRE

    Zhu, Longkun; Pearce, Donna; Kim, Kwang Sik

    2010-01-01

    Escherichia coli meningitis is an important cause of mortality and morbidity, and a key contributing factor is our incomplete understanding of the pathogenesis of E. coli meningitis. We have shown that E. coli penetration into the brain requires E. coli invasion of human brain microvascular endothelial cells (HBMEC), which constitute the blood-brain barrier. E. coli invasion of HBMEC involves its interaction with HBMEC receptors, such as E. coli cytotoxic necrotizing factor 1 (CNF1) interacti...

  9. The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke

    DEFF Research Database (Denmark)

    Ruscher, Karsten; Shamloo, Mehrdad; Rickhag, Karl Mattias;

    2011-01-01

    )piperazine dihydrochloride, an agonist of the sigma-1 receptor, starting two days after injury, enhanced the recovery of lost sensorimotor function without decreasing infarct size. The sigma-1 receptor was found in the galactocerebroside enriched membrane microdomains of reactive astrocytes and in neurons. Sigma-1 receptor...... induced sigma-1 receptor expression and actin dependent membrane raft formation, the latter blocked by sigma-1 receptor small interfering RNA silencing and pharmacological inhibition. We conclude that sigma-1 receptor activation stimulates recovery after stroke by enhancing cellular transport...

  10. Kinetic analysis of transport and opioid receptor binding of [3H](-)-cyclofoxy in rat brain in vivo: Implications for human studies

    International Nuclear Information System (INIS)

    [3H]Cyclofoxy (CF: 17-cyclopropylmethyl-3,14-dihydroxy-4,5-alpha-epoxy-6-beta-fluoromorp hinan) is an opioid antagonist with affinity to both mu and kappa subtypes that was synthesized for quantitative evaluation of opioid receptor binding in vivo. Two sets of experiments in rats were analyzed. The first involved determining the metabolite-corrected blood concentration and tissue distribution of CF in brain 1 to 60 min after i.v. bolus injection. The second involved measuring brain washout for 15 to 120 s following intracarotid artery injection of CF. A physiologically based model and a classical compartmental pharmacokinetic model were compared. The models included different assumptions for transport across the blood-brain barrier (BBB); estimates of nonspecific tissue binding and specific binding to a single opiate receptor site were found to be essentially the same with both models. The nonspecific binding equilibrium constant varied modestly in different brain structures (Keq = 3-9), whereas the binding potential (BP) varied over a much broader range (BP = 0.6-32). In vivo estimates of the opioid receptor dissociation constant were similar for different brain structures (KD = 2.1-5.2 nM), whereas the apparent receptor density (Bmax) varied between 1 (cerebellum) and 78 (thalamus) pmol/g of brain. The receptor dissociation rate constants in cerebrum (k4 = 0.08-0.16 min-1; koff = 0.16-0.23 min-1) and brain vascular permeability (PS = 1.3-3.4 ml/min/g) are sufficiently high to achieve equilibrium conditions within a reasonable period of time. Graphical analysis of the data is inappropriate due to the high tissue-loss rate constant for CF in brain. From these findings, CF should be a very useful opioid receptor ligand for the estimation of the receptor binding parameters in human subjects using [18F]CF and positron emission tomography

  11. Postnatal expression of H1-receptor mRNA in the rat brain: correlation to L-histidine decarboxylase expression and local upregulation in limbic seizures.

    Science.gov (United States)

    Lintunen, M; Sallmen, T; Karlstedt, K; Fukui, H; Eriksson, K S; Panula, P

    1998-07-01

    Histamine is implicated in the regulation of brain functions through three distinct receptors. Endogenous histamine in the brain is derived from mast cells and neurons, but the importance of these two pools during early postnatal development is still unknown. The expression of histamine H1-receptor in the rat brain was examined using in situ hybridization during postnatal development and in adults. For comparison, the expression of L-histidine decarboxylase (HDC) in the two pools was revealed. H1-receptor was evenly expressed throughout the brain on the first postnatal days, but resembled the adult, uneven pattern already on postnatal day 5 (P5). HDC was expressed in both mast cells and tuberomammillary neurons from birth until P5, after which the mast cell expression was no more detectable. In adult rat brain, high or moderate levels of H1-receptor expression were found in the hippocampus, zona incerta, medial amygdaloid nucleus and reticular thalamic nucleus. In most areas of the adult brain the expression of H1-receptor mRNA correlates well with binding data and histaminergic innervation. A notable exception is the hypothalamus, with high fibre density but moderate or low H1-receptor expression. Systemic kainic acid administration induced increased expression of H1-receptor mRNA in the caudate-putamen and dentate gyrus, whereas no change was seen in the hippocampal subfields CA1-CA3 or in the entorhinal cortex 6 h after kainic acid injections. This significant increase supports the concept that histaminergic transmission, through H1-receptor, is involved in the regulation of seizure activity in the brain. PMID:9749757

  12. Nine-month follow-up of the insulin receptor signalling cascade in the brain of streptozotocin rat model of sporadic Alzheimer's disease

    OpenAIRE

    Osmanović Barilar, Jelena; Knezović, Ana; Grünblatt, Edna; Riederer, Peter; Šalković-Petrišić, Melita

    2015-01-01

    Sporadic Alzheimer disease (sAD) is associated with impairment of insulin receptor (IR) signalling in the brain. Rats used to model sAD develop insulin-resistant brain state following intracerebroventricular treatment with a betacytotoxic drug streptozotocin (STZ-icv). Brain IR signalling has been explored usually at only one time point in periods ≤3 months after the STZ-icv administration. We have investigated insulin signalling in the rat hippocampus at five time points in periods ≤9 months...

  13. Tumor necrosis factor receptor superfamily member 9 is upregulated in the endothelium and tumor cells in melanoma brain metastasis

    Directory of Open Access Journals (Sweden)

    Patrick N Harter

    2014-12-01

    Full Text Available Aim: The cytokine receptor tumor necrosis factor receptor superfamily member 9 (TNFRSF9 is mainly considered to be a co-stimulatory activation marker in hematopoietic cells. Several preclinical models have shown a dramatic beneficial effect of treatment approaches targeting TNFRSF9 with agonistic antibodies. However, preliminary clinical phase I/II studies were stopped after the occurrence of several severe deleterious side effects. In a previous study, it was demonstrated that TNFRSF9 was strongly expressed by reactive astrocytes in primary central nervous system (CNS tumors, but was largely absent from tumor or inflammatory cells. The aim of the present study was to address the cellular source of TNFRSF9 expression in the setting of human melanoma brain metastasis, a highly immunogenic tumor with a prominent tropism to the CNS. Methods: Melanoma brain metastasis was analyzed in a cohort of 78 patients by immunohistochemistry for TNFRSF9 and its expression was correlated with clinicopathological parameters including sex, age, survival, tumor size, number of tumor spots, and BRAF V600E expression status. Results: Tumor necrosis factor receptor superfamily member 9 was frequently expressed independently on both melanoma and endothelial cells. In addition, TNFRSF9 was also present on smooth muscle cells of larger vessels and on a subset of lymphomonocytic tumor infiltrates. No association between TNFRSF9 expression and patient survival or other clinicopathological parameters was seen. Of note, several cases showed a gradual increase in TNFRSF9 expression on tumor cells with increasing distance from blood vessels, an observation that might be linked to hypoxia-driven TNFRSF9 expression in tumor cells. Conclusion: The findings indicate that the cellular source of TNFRSF9 in melanoma brain metastasis largely exceeds the lymphomonocytic pool, and therefore further careful (re- assessment of potential TNFRSF9 functions in cell types other than

  14. Cannabinoid effects on CB1 receptor density in the adolescent brain: an autoradiographic study using the synthetic cannabinoid HU210.

    Science.gov (United States)

    Dalton, Victoria S; Zavitsanou, Katerina

    2010-11-01

    The short- and long-term behavioral effects of cannabinoids differ in adolescent and adult rodents. Few studies though have examined the underlying neurochemical changes that occur in the brain following adolescent cannabinoid exposure. In this study, we examined the effect of treatment with the synthetic cannabinoid, HU210, on CB1 receptor density in the brain and on body weight in adolescent male rats. Rats were treated daily with 25, 50, or 100 μg/kg HU210 for 4 or 14 days, or received a single dose of 100 μg/kg HU210 and sacrificed 24 h later. Receptor density was investigated using in vitro autoradiography with the CB1 receptor ligand [(3)H] CP55,940. In contrast to adult animals treated under the same paradigm in a previous study, adolescents continued on average, to gain weight over the course of the study. Weight gain was slowest in the 100 μg/kg group and improved dose dependently with controls gaining the most weight. Following the acute dose of HU210, a trend for a reduction in [(3)H] CP55,940 binding and a significant effect of treatment was observed. Statistically significant, dose-dependent, region-specific decreases in binding were observed in all brain regions examined following 4 and 14 days treatment. The pattern of CB1 receptor downregulation was similar to that observed in adults treated with cannabinoids in previous studies; however, its magnitude was smaller in adolescents. This reduced compensatory response may contribute to some acute behavioral effects, the pharmacological cross-tolerance and the long-lasting, adverse psychological consequences of cannabinoid exposure during adolescence. PMID:20842718

  15. Selective Vulnerabilities of N-methyl-D-aspartate (NMDA) Receptors During Brain Aging

    OpenAIRE

    Magnusson, Kathy R.; Brenna L Brim; Das, Siba R.

    2010-01-01

    N-methyl-D-aspartate (NMDA) receptors are present in high density within the cerebral cortex and hippocampus and play an important role in learning and memory. NMDA receptors are negatively affected by aging, but these effects are not uniform in many different ways. This review discusses the selective age-related vulnerabilities of different binding sites of the NMDA receptor complex, different subunits that comprise the complex, and the expression and functions of the receptor within differe...

  16. TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation1

    OpenAIRE

    Ji, Rui; Tian, Shifu; Lu, Helen J.; LU, QINGJUN; Yan ZHENG; Wang, Xiaomin; Ding, Jixiang; Li, Qiutang; Lu, Qingxian

    2013-01-01

    TAM tyrosine kinases play multiple functional roles including regulation of the target genes important in homeostatic regulation of cytokine receptors or Toll-like receptor-mediated signal transduction pathways. Here, we show that TAM receptors affect adult hippocampal neurogenesis and loss of TAM receptors impair hippocampal neurogenesis, largely attributed to exaggerated inflammatory responses by microglia characterized by increased MAP kinase and NF-κB activation and elevated production of...

  17. Oxytocin receptor ligand binding in embryonic tissue and postnatal brain development of the C57BL/6J mouse

    Directory of Open Access Journals (Sweden)

    Elizabeth eHammock

    2013-12-01

    Full Text Available Oxytocin (OXT has drawn increasing attention as a developmentally relevant neuropeptide given its role in the brain regulation of social behavior. It has been suggested that OXT plays an important role in the infant brain during caregiver attachment in nurturing familial contexts, but there is incomplete experimental evidence. Mouse models of OXT system genes have been particularly informative for the role of the OXT system in social behavior, however, the developing brain areas that could respond to ligand activation of the OXT receptor (OXTR have yet to be identified in this species. Here we report new data revealing dynamic ligand-binding distribution of OXTR in the developing mouse brain. Using male and female C57BL/6J mice at postnatal days (P 0, 7, 14, 21, 35, and 60 we quantified OXTR ligand binding in several brain areas which changed across development. Further, we describe OXTR ligand binding in select tissues of the near-term whole embryo at E18.5. Together, these data aid in the interpretation of findings in mouse models of the OXT system and generate new testable hypotheses for developmental roles for OXT in mammalian systems. We discuss our findings in the context of developmental disorders (including autism, attachment biology, and infant physiological regulation.

  18. Activation of P2X(7) receptors stimulates the expression of P2Y(2) receptor mRNA in astrocytes cultured from rat brain.

    Science.gov (United States)

    D'Alimonte, I; Ciccarelli, R; Di Iorio, P; Nargi, E; Buccella, S; Giuliani, P; Rathbone, M P; Jiang, S; Caciagli, F; Ballerini, P

    2007-01-01

    Under pathological conditions brain cells release ATP at concentrations reported to activate P2X(7) ionotropic receptor subtypes expressed in both neuronal and glial cells. In the present study we report that the most potent P2X(7) receptor agonist BzATP stimulates the expression of the metabotropic ATP receptor P2Y(2) in cultured rat brain astrocytes. In other cell types several kinds of stimulation, including stress or injury, induce P2Y(2) expression that, in turn, is involved in different cell reactions. Similarly, it has recently been found that in astrocytes and astrocytoma cells P2Y(2) sites can trigger neuroprotective pathways through the activation of several mechanisms, including the induction of genes for antiapoptotic factors, neurotrophins, growth factors and neuropeptides. Here we present evidence that P2Y(2) mRNA expression in cultured astrocytes peaks 6 h after BzATP exposure and returns to basal levels after 24 h. This effect was mimicked by high ATP concentrations (1 mM) and was abolished by P2X(7)-antagonists oATP and BBG. The BzATP-evoked P2Y(2) receptor up-regulation in cultured astrocytes was coupled to an increased UTP-mediated intracellular calcium response. This effect was inhibited by oATP and BBG and by P2Y(2)siRNA, thus supporting evidence of increased P2Y(2) activity. To further investigate the mechanisms by which P2X(7) receptors mediated the P2Y(2) mRNA up-regulation, the cells were pre-treated with the chelating agent EGTA, or with inhibitors of mitogen-activated kinase (MAPK) (PD98059) or protein kinase C, (GF109203X). Each inhibitor significantly reduced the extent to which BzATP induced P2Y(2) mRNA. Both BzATP and ATP (1 mM) increased ERK1/2 activation. P2X(7)-induced ERK1/2 phosphorylation was unaffected by pre-treatment of astrocytes with EGTA whereas it was inhibited by GF109203X. Phorbol-12-myristate-13-acetate (PMA), an activator of PKCs, rapidly increased ERK1/2 activation. We conclude that activation of P2X(7) receptors in

  19. Mu-Opioid (MOP) receptor mediated G-protein signaling is impaired in specific brain regions in a rat model of schizophrenia.

    Science.gov (United States)

    Szűcs, Edina; Büki, Alexandra; Kékesi, Gabriella; Horváth, Gyöngyi; Benyhe, Sándor

    2016-04-21

    Schizophrenia is a complex mental health disorder. Clinical reports suggest that many patients with schizophrenia are less sensitive to pain than other individuals. Animal models do not interpret schizophrenia completely, but they can model a number of symptoms of the disease, including decreased pain sensitivities and increased pain thresholds of various modalities. Opioid receptors and endogenous opioid peptides have a substantial role in analgesia. In this biochemical study we investigated changes in the signaling properties of the mu-opioid (MOP) receptor in different brain regions, which are involved in the pain transmission, i.e., thalamus, olfactory bulb, prefrontal cortex and hippocampus. Our goal was to compare the transmembrane signaling mediated by MOP receptors in control rats and in a recently developed rat model of schizophrenia. Regulatory G-protein activation via MOP receptors were measured in [(35)S]GTPγS binding assays in the presence of a highly selective MOP receptor peptide agonist, DAMGO. It was found that the MOP receptor mediated activation of G-proteins was substantially lower in membranes prepared from the 'schizophrenic' model rats than in control animals. The potency of DAMGO to activate MOP receptor was also decreased in all brain regions studied. Taken together in our rat model of schizophrenia, MOP receptor mediated G-proteins have a reduced stimulatory activity compared to membrane preparations taken from control animals. The observed distinct changes of opioid receptor functions in different areas of the brain do not explain the augmented nociceptive threshold described in these animals. PMID:26946106

  20. The effect of heart-and kidney-benefiting Chinese herbal medicines on the function of adrenergic receptors in brain tissues of analogue dementia rats

    International Nuclear Information System (INIS)

    Analogue dementia model of rats was produced by electrolytic lesion of brain. α-adrenergic receptors were assayed by radioligand binding assay (RRBA). It was found that Bmax of α1 receptors was decreased obviously in cerebral cortex, hippocampus and cerebellum of analogue dementia rats and was raised obviously by Heart-and Kidney-Benefiting Chinese Herbs as well as by Hydergin. The electrolytic lesion did not change the activity of MAO-B in model rat brains. Neither Heart-and Kidney-Benefiting Chinese Herb Medicines nor Hydergin showed marked effect on brain MAO-B activity of the model rats

  1. Synthesis of radiotracers for studying muscarinic cholinergic receptors in the living human brain using positron emission tomography: [11C]dexetimide and [11C]levetimide

    International Nuclear Information System (INIS)

    The localization and quantitation of muscarinic cholinergic receptors (m-AChR) in the living human brain using a non-invasive method such as positron emission tomography (PET) may provide valuable information about receptor changes which have been observed post mortem in patients with Huntington's chorea and Alzheimer's dementia, as well as normal brain mechanisms mediated by the m-AChR. We chose to label dexetimide as a radiotracer for studying the m-AChR and levetimide as a radiotracer for assessing non-specific binding associated with the in vivo receptor binding studies. (author)

  2. NOVEL SPLICED VARIANTS OF IONOTROPIC GLUTAMATE RECEPTOR GLUR6 IN NORMAL HUMAN FIBROBLAST AND BRAIN CELLS ARE TRANSCRIBED BY TISSUE SPECIFIC PROMOTERS

    OpenAIRE

    Zhawar, Vikramjit K.; Kaur, Gurpreet; deRiel, Jon K.; Kaur, G. Pal; Raj P Kandpal; Athwal, Raghbir S.

    2010-01-01

    The members of the ionotropic glutamate receptor family, namely, a-amino-3-hydroxy-S-methyl-4-isoxazole propionate (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptors, are important mediators of the rapid synaptic transmission in the central nervous system. We have investigated the splicing pattern and expression of the kainate receptor subunit GluR6 in human fibroblast cell lines and brain tissue. We demonstrate the expression of GluR6A variant specifically in brain, and four variants...

  3. Quantification of human brain benzodiazepine receptors using [{sup 18}F]fluoroethylflumazenil: a first report in volunteers and epileptic patients

    Energy Technology Data Exchange (ETDEWEB)

    Leveque, Philippe [Unite de Tomographie par Positrons, Universite Catholique de Louvain, Louvain-la-Neuve (Belgium); Unite de Chimie Pharmaceutique et de Radiopharmacie, CMFA/REMA, Universite Catholique de Louvain, 73-40 Avenue Mounier, 1200, Bruxelles (Belgium); Sanabria-Bohorquez, Sandra [Imaging Research, Merck Research Laboratories, West Point, Philadelphia (United States); Bol, Anne; Volder, Anne de; Labar, Daniel [Unite de Tomographie par Positrons, Universite Catholique de Louvain, Louvain-la-Neuve (Belgium); Rijckevorsel, K. van [Service de Neurologie, Cliniques Universitaires Saint-Luc, Bruxelles (Belgium); Gallez, Bernard [Unite de Chimie Pharmaceutique et de Radiopharmacie, CMFA/REMA, Universite Catholique de Louvain, 73-40 Avenue Mounier, 1200, Bruxelles (Belgium); Unite de Resonance Magnetique Biomedicale, Universite Catholique de Louvain, Bruxelles (Belgium)

    2003-12-01

    Fluorine-18 fluoroethylflumazenil ([{sup 18}F]FEF) is a tracer for central benzodiazepine (BZ) receptors which is proposed as an alternative to carbon-11 flumazenil for in vivo imaging using positron emission tomography (PET) in humans. In this study, [{sup 18}F]FEF kinetic data were acquired using a 60-min two-injection protocol on three normal subjects and two patients suffering from mesiotemporal epilepsy as demonstrated by abnormal magnetic resonance imaging and [{sup 18}F]fluorodeoxyglucose positron emission tomography. First, a tracer bolus injection was performed and [{sup 18}F]FEF rapidly distributed in the brain according to the known BZ receptor distribution. Thirty minutes later a displacement injection of 0.01 mg/kg of unlabelled flumazenil was performed. Activity was rapidly displaced from all BZ receptor regions demonstrating the specific binding of [{sup 18}F]FEF. No displacement was observed in the pons. Plasma input function was obtained from arterial blood sampling, and metabolite analysis was performed by high-performance liquid chromatography. Metabolite quantification revealed a fast decrease in tracer plasma concentration, such that at 5 min post injection about 70% of the total radioactivity in plasma corresponded to [{sup 18}F]FEF, reaching 24% at 30 min post injection. The interactions between [{sup 18}F]FEF and BZ receptors were described using linear compartmental models with plasma input and reference tissue approaches. Binding potential values were in agreement with the known distribution of BZ receptors in human brain. Finally, in two patients with mesiotemporal sclerosis, reduced uptake of [{sup 18}F]FEF was clearly observed in the implicated left hippocampus. (orig.)

  4. The essential role of AMPA receptor GluR2 subunit RNA editing in the normal and diseased brain

    Directory of Open Access Journals (Sweden)

    Amanda Lorraine Wright

    2012-04-01

    Full Text Available AMPA receptors are comprised of different combinations of GluR1-GluR4 (also known as GluA1-GluA4 and GluR-A to GluR-D subunits. The GluR2 subunit is subject to Q/R site RNA editing by the ADAR2 enzyme, which converts a codon for glutamine (Q, present in the GluR2 gene, to a codon for arginine (R found in the mRNA. AMPA receptors are calcium (Ca2+-permeable if they contain the unedited GluR2(Q subunit or if they lack the GluR2 subunit. While most AMPA receptors in the brain contain the edited GluR2(R subunit and are therefore Ca2+-impermeable, recent evidence suggests that Ca2+-permeable GluR2-lacking AMPA receptors are important in synaptic plasticity and learning. However, the presence of Ca2+-permeable AMPA receptors containing unedited GluR2 leads to excitotoxic cell loss. Recent studies have indicated that RNA editing of GluR2 is deregulated in diseases, such as amyotrophic lateral sclerosis (ALS, as well in acute neurodegenerative conditions, such as ischemia. More recently, studies have investigated the regulation of RNA editing and possible causes for its deregulation during disease. In this review, we will explore the role of GluR2 RNA editing in the healthy and diseased brain and outline new insights into the mechanisms that control this process.

  5. Dopamine D1-D2 receptor heteromer signaling pathway in the brain: emerging physiological relevance

    Directory of Open Access Journals (Sweden)

    Hasbi Ahmed

    2011-06-01

    Full Text Available Abstract Dopamine is an important catecholamine neurotransmitter modulating many physiological functions, and is linked to psychopathology of many diseases such as schizophrenia and drug addiction. Dopamine D1 and D2 receptors are the most abundant dopaminergic receptors in the striatum, and although a clear segregation between the pathways expressing these two receptors has been reported in certain subregions, the presence of D1-D2 receptor heteromers within a unique subset of neurons, forming a novel signaling transducing functional entity has been shown. Recently, significant progress has been made in elucidating the signaling pathways activated by the D1-D2 receptor heteromer and their potential physiological relevance.

  6. Location and expression of neurotrophin-3 and its receptor in the brain of human embryos during early development

    Institute of Scientific and Technical Information of China (English)

    Jian Li; Yongjie Mi; Dajun Ma

    2008-01-01

    BACKGROUND: Cell culture in vitro trials have demonstrated that neurotrophin-3 (NT-3) can enhance the survival of sensory neurons and sympathetic neurons, and can also support embryo-derived motor neurons.This effect is dependent on nerve growth factor on the surface of cells. Understanding the role of NT-3 and its receptor in the early development of human embryonic brains will help to investigate the correlation between early survival of nerve cells and the microenvironment of neural regeneration.OBJECTIVE: To observe the proliferation of cerebral neurons in the development of human embryonic brain, and to investigate the location, expression and distribution of NT-3 and its receptor TrkC during human brain development.DESIGN, TIME AND SETTING: An observation study on cells was performed in the Department of Human Anatomy, Histology and Embryology, Chengdu Medical College in September 2007.MATERIALS: Fifteen specimens of fresh human embryo, aged 6 weeks, were used in this study.METHODS: The proliferation of cerebral neurons was detected using proliferating cell nuclear antigen, and the immunocytochemistry ABC technique was applied to observe the location, expression and distribution of NT-3 and its receptor TrkC in the brain of the human embryo.MAIN OUTCOME MEASURES: Location, expression and distribution of NT-3 and its receptor in the brain of the human embryo.RESULTS: In the early period (aged 6 weeks) of human embryonic development, proliferating cell nuclear antigen-positive reactive substances were mainly observed in the nucleus of the forebrain ventricular zone and subventricular zone, and the intensity was stronger in the subventricular zone than the forebrain ventricle.NT-3 positive reactive substance was mainly distributed in the cytoblastema of the forebrain neuroepithelial layer and nerve cell process, while TrkC was mainly distributed in the cell membrane of the forebrain ventricular zone and subventricular zone. During embryonic development, NT-3 and

  7. Measuring specific receptor binding of a PET radioligand in human brain without pharmacological blockade: The genomic plot

    Science.gov (United States)

    Veronese, Mattia; Zanotti-Fregonara, Paolo; Rizzo, Gaia; Bertoldo, Alessandra; Innis, Robert B.; Turkheimer, Federico E.

    2016-01-01

    PET studies allow in vivo imaging of the density of brain receptor species. The PET signal, however, is the sum of the fraction of radioligand that is specifically bound to the target receptor and the non-displaceable fraction (i.e. the non-specifically bound radioligand plus the free ligand in tissue). Therefore, measuring the non-displaceable fraction, which is generally assumed to be constant across the brain, is a necessary step to obtain regional estimates of the specific fractions. The nondisplaceable binding can be directly measured if a reference region, i.e. a region devoid of any specific binding, is available. Many receptors are however widely expressed across the brain, and a true reference region is rarely available. In these cases, the nonspecific binding can be obtained after competitive pharmacological blockade, which is often contraindicated in humans. In this work we introduce the genomic plot for estimating the nondisplaceable fraction using baseline scans only. The genomic plot is a transformation of the Lassen graphical method in which the brain maps of mRNA transcripts of the target receptor obtained from the Allen brain atlas are used as a surrogate measure of the specific binding. Thus, the genomic plot allows the calculation of the specific and nondisplaceable components of radioligand uptake without the need of pharmacological blockade. We first assessed the statistical properties of the method with computer simulations. Then we sought ground-truth validation using human PET datasets of seven different neuroreceptor radioligands, where nonspecific fractions were either obtained separately using drug displacement or available from a true reference region. The population nondisplaceable fractions estimated by the genomic plot were very close to those measured by actual human blocking studies (mean relative difference between 2% and 7%). However, these estimates were valid only when mRNA expressions were predictive of protein levels (i

  8. Contribution of altered signal transduction associated to glutamate receptors in brain to the neurological alterations of hepatic encephalopathy

    Institute of Scientific and Technical Information of China (English)

    Vicente Felipo

    2006-01-01

    Patients with liver disease may present hepatic encephalopathy (HE), a complex neuropsychiatric syndrome covering a wide range of neurological alterations,including cognitive and motor disturbances. HE reduces the quality of life of the patients and is associated with poor prognosis. In the worse cases HE may lead to coma or death.The mechanisms leading to HE which are not well known are being studied using animal models. The neurological alterations in HE are a consequence of impaired cerebral function mainly due to alterations in neurotransmission. We review here some studies indicating that alterations in neurotransmission associated to different types of glutamate receptors are responsible for some of the cognitive and motor alterations present in HE.These studies show that the function of the signal transduction pathway glutamate-nitric oxide-cGMP associated to the NMDA type of glutamate receptors is impaired in brain in vivo in HE animal models as well as in brain of patients died of HE. Activation of NMDA receptors in brain activates this pathway and increases cGMP. In animal models of HE this increase in cGMP induced by activation of NMDA receptors is reduced,which is responsible for the impairment in learning ability in these animal models. Increasing cGMP by pharmacological means restores learning ability in rats with HE and may be a new therapeutic approach to improve cognitive function in patients with HE.However, it is necessary to previously assess the possible secondary effects.Patients with HE may present psychomotor slowing,hypokinesia and bradykinesia. Animal models of HE also show hypolocomotion. It has been shown in rats with HE that hypolocomotion is due to excessive activation of metabotropic glutamate receptors (mGluRs) in substantia nigra pars reticulata. Blocking mGluR1 in this brain area normalizes motor activity in the rats, suggesting that a similar treatment for patients with HE could be useful to treat psychomotor slowing and

  9. Contribution of altered signal transduction associated to glutamate receptors in brain to the neurological alterations of hepatic encephalopathy

    Science.gov (United States)

    Felipo, Vicente

    2006-01-01

    Patients with liver disease may present hepatic enceph-alopathy (HE), a complex neuropsychiatric syndrome covering a wide range of neurological alterations, including cognitive and motor disturbances. HE reduces the quality of life of the patients and is associated with poor prognosis. In the worse cases HE may lead to coma or death. The mechanisms leading to HE which are not well known are being studied using animal models. The neurological alterations in HE are a consequence of impaired cerebral function mainly due to alterations in neurotransmission. We review here some studies indicating that alterations in neurotransmission associated to different types of glutamate receptors are responsible for some of the cognitive and motor alterations present in HE. These studies show that the function of the signal transduction pathway glutamate-nitric oxide-cGMP associated to the NMDA type of glutamate receptors is impaired in brain in vivo in HE animal models as well as in brain of patients died of HE. Activation of NMDA receptors in brain activates this pathway and increases cGMP. In animal models of HE this increase in cGMP induced by activation of NMDA receptors is reduced, which is responsible for the impairment in learning ability in these animal models. Increasing cGMP by pharmacological means restores learning ability in rats with HE and may be a new therapeutic approach to improve cognitive function in patients with HE. However, it is necessary to previously assess the possible secondary effects. Patients with HE may present psychomotor slowing, hypokinesia and bradykinesia. Animal models of HE also show hypolocomotion. It has been shown in rats with HE that hypolocomotion is due to excessive activation of metabotropic glutamate receptors (mGluRs) in substantia nigra pars reticulata. Blocking mGluR1 in this brain area normalizes motor activity in the rats, suggesting that a similar treatment for patients with HE could be useful to treat psychomotor slowing and

  10. Quantitative autoradiography of ligands for dopamine receptors and transporters in brain of Göttingen minipig: comparison with results in vivo

    DEFF Research Database (Denmark)

    Minuzzi, Luciano; Alstrup, Aage Kristian Olsen; Bender, Dirk;

    2006-01-01

    The pig has been used as animal model for positron emission tomography (PET) studies of dopamine (DA) receptors and pharmacological perturbations of DA neurotransmission. However, the binding properties of DA receptors and transporters in pig brain have not been characterized in vitro. Therefore......, the saturation binding parameters of [3H]SCH 23390 for DA D1 receptors and [3H]raclopride for DA D2/3 receptors were measured by quantitative autoradiography in cryostat sections from brain of groups of 8 week old and adult female Göttingen minipigs. The magnitudes of Bmax and Kd for these ligands...... were similar in young and old pigs, and were close to those reported for rat and human brain. Furthermore, gradients in the concentrations of D1 and D2/3 sites in striatum measured in vitro agreed with earlier findings in PET studies. However, the dopamine transporter (DAT) ligand [3H]GBR12935 did not...

  11. PCP-induced alterations in cerebral glucose utilization in rat brain: blockade by metaphit, a PCP-receptor-acylating agent

    Energy Technology Data Exchange (ETDEWEB)

    Tamminga, C.A.; Tanimoto, K.; Kuo, S.; Chase, T.N.; Contreras, P.C.; Rice, K.C.; Jackson, A.E.; O' Donohue, T.L.

    1987-01-01

    The effects of phencyclidine (PCP) on regional cerebral glucose utilization was determined by using quantitative autoradiography with (/sup 14/C)-2-deoxyglucose. PCP increased brain metabolism in selected areas of cortex, particularly limbic, and in the basal ganglia and thalamus, whereas the drug decreased metabolism in areas related to audition. These results are consistent with the known physiology of central PCP neurons and may help to suggest brain areas involved in PCP-mediated actions. Moreover, based on the behavioral similarities between PCP psychosis and an acute schizophrenic episode, these data may be relevant to the understanding of schizophrenia. The PCP-receptor-acylating agent, metaphit, blocked most of these PCP actions. In addition, metaphit by itself was found to diminish glucose utilization rather uniformly throughout brain. These results indicate an antagonist effect of metaphit on the PCP system and suggest a widespread action of metaphit, putatively at a PCP-related site, possibly in connection with the N-methyl-D-aspartate (NMDA) receptor.

  12. Hydrolysis of cytectrene marked by the technetium 99m by acetylcholinesterase in the rat brain and confirmation of fixing the cytectrene on brain receptors

    International Nuclear Information System (INIS)

    Alzheimer's disease is a degenerative neurological disorder that causes progressive and irreversible loss of mental functions. It is the most common form of dementia and is characterized by a decrease in serotonergic neurons that carry the 5HT1A receptors. We showed that the use of cytectrene for the quantitative measurement of the activity of the Acetylcholinesterase in the brain depends on the rate of hydrolysis and the enzymatic specificity. The results showed that the cytectrene can be used as a substrate for a precise and quantitative determination of the activity of this enzyme. We have made hippocampal and cortical neuron cultures in the brain from young rats. After the differentiation of these neurons, some cell cultures are incubated with 8 OH DPAT, a receptor 5HT1A agonist of the serotonin, which are located on the surface of neurons. The neurons are then incubated with a molecule marked with radioactive technetium 99m Tc. These neurons are crushed and radioactivity is read. The results show that for growing neurons in the hippocampus, we have levels of radioactivity cells treated with agonist, below the level of radioactivity of cells treated with the radioactive molecules. The cortical neurons show the same level of radioactivity in the cells treated with agonist for cells treated only with the molecule marked. Our results show a decrease of fixing the molecule marked on 5HT1A receptor neurons in the hippocampus compared to neurons in the cortex. This work will enable us to prove the decrease of neurons in neuronal diseases and to make the diagnosis of these diseases. (author)

  13. The recently identified P2Y-like receptor GPR17 is a sensor of brain damage and a new target for brain repair.

    Directory of Open Access Journals (Sweden)

    Davide Lecca

    Full Text Available Deciphering the mechanisms regulating the generation of new neurons and new oligodendrocytes, the myelinating cells of the central nervous system, is of paramount importance to address new strategies to replace endogenous damaged cells in the adult brain and foster repair in neurodegenerative diseases. Upon brain injury, the extracellular concentrations of nucleotides and cysteinyl-leukotrienes (cysLTs, two families of endogenous signaling molecules, are markedly increased at the site of damage, suggesting that they may act as "danger signals" to alert responses to tissue damage and start repair. Here we show that, in brain telencephalon, GPR17, a recently deorphanized receptor for both uracil nucleotides and cysLTs (e.g., UDP-glucose and LTD(4, is normally present on neurons and on a subset of parenchymal quiescent oligodendrocyte precursor cells. We also show that induction of brain injury using an established focal ischemia model in the rodent induces profound spatiotemporal-dependent changes of GPR17. In the lesioned area, we observed an early and transient up-regulation of GPR17 in neurons expressing the cellular stress marker heat shock protein 70. Magnetic Resonance Imaging in living mice showed that the in vivo pharmacological or biotechnological knock down of GPR17 markedly prevents brain infarct evolution, suggesting GPR17 as a mediator of neuronal death at this early ischemic stage. At later times after ischemia, GPR17 immuno-labeling appeared on microglia/macrophages infiltrating the lesioned area to indicate that GPR17 may also acts as a player in the remodeling of brain circuitries by microglia. At this later stage, parenchymal GPR17+ oligodendrocyte progenitors started proliferating in the peri-injured area, suggesting initiation of remyelination. To confirm a specific role for GPR17 in oligodendrocyte differentiation, the in vitro exposure of cortical pre-oligodendrocytes to the GPR17 endogenous ligands UDP-glucose and LTD(4

  14. Toll-like receptor 4 knockout ameliorates neuroinflammation due to lung-brain interaction in mechanically ventilated mice.

    Science.gov (United States)

    Chen, Ting; Chen, Chang; Zhang, Zongze; Zou, Yufeng; Peng, Mian; Wang, Yanlin

    2016-08-01

    Toll-like receptor 4 (TLR4) is a crucial receptor in the innate immune system, and increasing evidence supports its role in inflammation, stress, and tissue injury, including injury to the lung and brain. We aimed to investigate the effects of TLR4 on neuroinflammation due to the lung-brain interaction in mechanically ventilated mice. Male wild-type (WT) C57BL/6 and TLR4 knockout (TLR4 KO) mice were divided into three groups: (1) control group (C): spontaneous breathing; (2) anesthesia group (A): spontaneous breathing under anesthesia; and (3) mechanical ventilation group (MV): 6h of MV under anesthesia. The behavioral responses of mice were tested with fear conditioning tests. The histological changes in the lung and brain were assessed using hematoxylin-eosin (HE) staining. The level of TLR4 mRNA in tissue was measured using reverse transcription-polymerase chain reaction (RT-PCR). The levels of inflammatory cytokines were measured with an enzyme-linked immunosorbent assay (ELISA). Microgliosis, astrocytosis, and the TLR4 immunoreactivity in the hippocampus were measured by double immunofluorescence. MV mice exhibited impaired cognition, and this impairment was less severe in TLR4 KO mice than in WT mice. In WT mice, MV increased TLR4 mRNA expression in the lung and brain. MV induced mild lung injury, which was prevented in TLR4 KO mice. MV mice exhibited increased levels of inflammatory cytokines, increased microglia and astrocyte activation. Microgliosis was alleviated in TLR4 KO mice. MV mice exhibited increased TLR4 immunoreactivity, which was expressed in microglia and astrocytes. These results demonstrate that TLR4 is involved in neuroinflammation due to the lung-brain interaction and that TLR4 KO ameliorates neuroinflammation due to lung-brain interaction after prolonged MV. In addition, Administration of a TLR4 antagonist (100μg/mice) to WT mice also significantly attenuated neuroinflammation of lung-brain interaction due to prolonged MV. TLR4 antagonism

  15. Adenosine receptors in the immature brain : with special reference to their role in hypoxic ischemia

    OpenAIRE

    Ådén, Ulrika

    2001-01-01

    Although the newborn brain tolerates a much longer period of oxygen deprivation and ischemia than does the adult brain, perinatal hypoxic ischemia probably is an important cause of neurological dysfunction, cerebral palsy and epilepsy later in life. Hence it is important to investigate the mechanisms that modulate the extent of perinatal ischernic brain damage. There is good evidence that endogenous adenosine acts as a neuroprotective agent in models of ischemia in the m...

  16. Insulin Receptor Substrate-1 Activation Mediated p53 Downregulation Protects Against Hypoxic-Ischemia in the Neonatal Brain.

    Science.gov (United States)

    Tu, Yi-Fang; Jiang, Si-Tse; Chow, Yen-Hung; Huang, Chao-Ching; Ho, Chien-Jung; Chou, Ya-Ping

    2016-08-01

    This study determined if dietary restriction (DR) protects against hypoxic-ischemia (HI) in the neonatal brain via insulin receptor substrate-1 (IRS-1)/Akt pathway-mediated downregulation of p53 in the neurovascular unit. On postnatal (P) day 7, HI was induced in rat pups grouped from P1 into normal litter size (NL, 12 pups/dam) and increased litter size (DR, 18 pups/dam). In vivo IRS-1 anti-sense oligonucleotide and IRS-1 overexpressed recombinant adenovirus were given, and neurovascular damage was assessed. In vitro models of oxygen-glucose deprivation (OGD) examined the inhibition and overexpression of IRS-1 on p53 and cell death in neurons and endothelial cells. Compared to NL pups, DR pups had significantly higher IRS-1, p-IRS-1, and pAkt levels, decreased p53, more tight junction proteins, reduced blood-brain barrier (BBB) damage after HI, and less infarct volumes at P21. Immunofluorescence revealed that IRS-1 was upregulated in the endothelial cells and neurons of DR pups. IRS-1 downregulation in DR pups reduced p-Akt, increased p53, worsened BBB damage, and increased brain injury, whereas IRS-1 overexpression in NL pups upregulated p-Akt, decreased p53, attenuated BBB damage, and decreased brain injury. In vitro, IRS-1 downregulation aggravated cell death in neurons and endothelial cells and is associated with decreased p-Akt and increased p53. In contrast, IRS-1 overexpression reduced cell death in endothelial cells with increased p-Akt and decreased p53. In conclusion, DR reduces neurovascular damage after HI in the neonatal brain through an IRS-1/Akt-mediated p53 downregulation, suggesting that IRS-1 signaling is a therapeutic target for hypoxic brain injury in neonates. PMID:26111627

  17. Classical androgen receptors in non-classical sites in the brain

    OpenAIRE

    Sarkey, Sara; Azcoitia, Iñigo; Garcia-Segura, Luis Miguel; Garcia-Ovejero, Daniel; Doncarlos, Lydia L.

    2008-01-01

    Androgen receptors are expressed in many different neuronal populations in the central nervous system where they often act as transcription factors in the cell nucleus. However, recent studies have detected androgen receptor immunoreactivity in neuronal and glial processes of the adult rat neocortex, hippocampal formation, and amygdala as well as in the telencephalon of Eastern Fence and green anole lizards. This review discusses previously published findings on extranuclear androgen receptor...

  18. Changes of metabotropic glutamate receptor subtype 1a in diffuse brain injury with secondary brain insults and the effects of 2-methyl-4-carboxyphenylglycine

    Institute of Scientific and Technical Information of China (English)

    FEI Zhou 费舟; ZHANG Xiang 章翔; LIU En-yu 刘恩渝

    2003-01-01

    Objective: To observe the changes of metabotropic glutamate receptor 1a in rat brain in a rodent model of diffuse head injury with secondary insults and the effects of 2-methyl-4-carboxyphenylglycine (MCPG).Methods: Based on Marmarous rodent model of diffuse brain injury (DBI), hypotension was made by blood withdrawal as secondary brain insults (SBI).105 male SD rats were randomized into A and B groups.The changes of mGluR1a in cerebral cortex were studied by immunohistochemistry and the effect of MCPG by HE.Each group was divided into different subgroups at different time after injury.Results: Compared with that of sham group, the number of mGluR1a positive neuron increased by 12.9±3.2 (P<0.05) 1 day after injury in the injured cerebral cortex in DBI group.However, in DBI and SBI group there was a more significant increase in the number of mGluR1a positive neuron at 4 hours after injury (15.6±3.0, P<0.05)and then the number of mGluR1a positive neuron gradually decreased.Administration of MCPG reduced total cortical necrotic neurons counts on the 7th day after injury (5.21±2.52, P<0.05).Conclusions: Brain injury can increase the gene expression of mGluR1a and the role of mGluR1a may be a key factor in the aggravation of head injury with SBI, and that MCPG may have therapeutic potential in head injury.

  19. Expression of a truncated receptor protein tyrosine phosphatase kappa in the brain of an adult transgenic mouse

    DEFF Research Database (Denmark)

    Shen, P; Canoll, P D; Sap, J;

    1999-01-01

    Receptor protein tyrosine phosphatases (RPTPs) comprise a family of proteins that feature intracellular phosphatase domains and an ectodomain with putative ligand-binding motifs. Several RPTPs are expressed in the brain, including RPTP-kappa which participates in homophilic cell-cell interactions...... developmental processes such as axonal growth and target recognition, as has been demonstrated for certain Drosophila RPTPs. The brain distribution of RPTP-kappa-expressing cells has not been determined, however. In a gene-trap mouse model with a beta-gal+neo (beta-geo) insertion in the endogenous RPTP......-kappa gene, the consequent loss of RPTP-kappa's enzymatic activity does not produce any obvious phenotypic defects [W.C. Skarnes, J.E. Moss, S.M. Hurtley, R.S.P. Beddington, Capturing genes encoding membrane and secreted proteins important for mouse development, Proc. Natl. Acad. Sci. U.S.A. 92 (1995) 6592...

  20. Effects of trihexyphenidyl and L-dopa on brain muscarinic cholinergic receptor binding measured by positron emission tomography

    International Nuclear Information System (INIS)

    The effects of pharmacological intervention on brain muscarinic cholinergic receptor (mAChR) binding were assessed in seven patients with Parkinson's disease by positron emission tomography and carbon-11 labelled N-methyl-4-piperidyl benzilate ([11C]NMPB). [11C]NMPB was injected twice, approximately 2 hours apart, in each patient, to assess the effect of single doses of 4 mg of trihexyphenidyl (n=5) or 400 mg of L-dopa with 57 mg of benserazide (n=2) on the binding parameter of mAChRs (K3). There was a mean 28% inhibition of K3 values in the brain in the presence of trihexyphenidyl, which was assumed to reflect mAChR occupancy. No significant change in K3 was observed in the presence of L-dopa. This study demonstrates the feasibility of measuring mAChR occupancy by an anticholinergic medication with PET

  1. Autoradiographic comparison of [125I]epidepride and [125I]NCQ 298 binding to human brain extrastriated dopamine receptors.

    Science.gov (United States)

    Hall, H; Halldin, C; Jerning, E; Osterlund, M; Farde, L; Sedvall, G

    1997-07-01

    Extrastriatal D2-dopamine receptors can be visualised in the monkey and human brain using the benzamides [11C]- and [76Br]FLB 457 in PET and [123I]epidepride in SPECT but not with the salicylamide analogues [76Br]FLB 463 and [123I]NCQ 298. To clarify the background for the differences in binding seen in vivo, we have compared the in vitro binding of [125I]epidepride and [123I]NCQ 298, using human whole hemisphere autoradiography. The images obtained with any radioligand showed detailed distribution with very dense binding in the putamen and the caudate nucleus and with the same detailed extrastriatal distribution. Thus, the divergent results obtained in vivo cannot be explained by different binding properties of the extrastriatal receptors. PMID:9290072

  2. Autoradiographic comparison of [125I]epidepride and [125I]NCQ 298 binding to human brain extrastriated dopamine receptors

    International Nuclear Information System (INIS)

    Extrastriatal D2-dopamine receptors can be visualized in the monkey and human brain using the benzamides [11C]- and [76Br]FLB 457 in PET and [123I]epidepride in SPECT but not with the salicylamide analogues [76Br]FLB 463 and [123I]NCQ 298. To clarify the background for the differences in binding seen in vivo, we have compared the in vitro binding of [125I]epidepride and [125I]NCQ 298, using human whole hemisphere autoradiography. The images obtained with any radioligand showed detailed distribution with very dense binding in the putamen and the caudate nucleus and with the same detailed extrastriatal distribution. Thus, the divergent results obtained in vivo cannot be explained by different binding properties of the extrastriatal receptors

  3. Structural requirements for galanin interaction with receptors from pancreatic beta cells and from brain tissue of the rat

    Energy Technology Data Exchange (ETDEWEB)

    Lagny-Pourmir, I.; Lorinet, A.M.; Yanaihara, N.; Laburthe, M. (Unite de Recherches sur la Differenciation et la Neuroendocrinologie de Cellules Digestives, Batiment INSERM, Villejuif (France))

    1989-07-01

    The binding activity of several galanin fragments and analogs was measured on specific receptors present in rat brain and the rat pancreatic beta cell line Rin m 5F. In both tissues it was observed that: (1) galanin(3-29), galanin(10-29) and (Ile2)-galanin were ineffective for inhibiting ({sup 125}I) galanin binding and (2) active peptides had the following rank order of potency: galanin(1-29) greater than (Ac-Trp2)-galanin(2-29) greater than galanin(2-29) greater than galanin(1-15) greater than (Phe2)-galanin greater than (Tyr2)-galanin. It was concluded that the N-terminal portion of galanin is very important for interaction with central or peripheral receptors. The aromatic amino acid in position 2 (Trp in native galanin) plays a crucial role.

  4. The effect of ZMS on the coupling of muscarinic receptor to G-proteins activation in rat brain

    International Nuclear Information System (INIS)

    The carbachol-stimulated [35S]GTP γ S binding method was used to observe the effect of ZMS, an active component from Zhimu, on the coupling of M-receptor to G-protein. the effect of ZMS on the ability of learning and memory in aged rats was also observed. It was shown that the carbachol-stimulated elevation of [35S]GTPγS binding was significantly decreased in aged rats as compared with young rats. The carbachol-induced [35S]STPγS binding showed that administration of ZMS at median or high dose have a definite elevation effect on the coupling activity of M-receptors to G-protein in brain, and this elevation was accompanied by an improvement of learning and memory ability

  5. Experimental study on alteration of adrenergic receptors activity in neuronal membranes protein of cerebral cortex following brain trauma in rats

    Institute of Scientific and Technical Information of China (English)

    ZHANG Xin-wei; XU Ru-xiang; QI Yi-long; CHEN Chang-cai

    2001-01-01

    Objective: To define the course of changes taken by α1 and β adrenergic receptors (AR) activity after traumatic brain injury (TBI) and explore the approach for secondary brain injury (SBI) management. Methods: The neuronal membrane protein of cortex were extracted from the rats subject to traumatic brain injury, and the changes of α1- and β-AR activities in the neuronal membranes were examined by radio ligand binding assay (RLBA). Results: α1- and β-AR activities underwent obvious changes, reaching their peak values at 24 h after TBI. α1-AR binding density (Bmax) reduced by 22.6%while the ligand affinity increased by 66.7%, and for β-AR, however, Bmax increased by 116.9% and the ligand affinity reduced by 50.7%. Their antagonists could counteract the changes ofα1- and β-AR activity. Conclusion: The patterns of changes varies between α1- and β-AR activity after TBI, suggesting their different roles in the neuronal membranes after brain trauma, and timely administration of AR antagonists is potentially beneficial in TBI management.

  6. Role of astrocytic leptin receptor subtypes on leptin permeation across hCMEC/D3 human brain endothelial cells

    OpenAIRE

    Hsuchou, Hung; Kastin, Abba J; Tu, Hong; Abbott, N Joan; Couraud, Pierre-Olivier; Pan, Weihong

    2010-01-01

    Astrocytic leptin receptors (ObR) can be upregulated in conditions such as adult-onset obesity. To determine whether the levels and subtypes of astrocytic ObR modulate leptin transport, we co-cultured hCMEC/D3 human brain endothelial cells and C6 astrocytoma cells in the Transwell system, and tested leptin permeation from apical to basolateral chambers. In comparison with hCMEC alone, co-culture of C6 cells reduced the permeability of paracellular markers and leptin. Unexpectedly, ObRb overex...

  7. Prognostic implications of p53 protein, epidermal growth factor receptor, and Ki-67 labelling in brain tumours.

    OpenAIRE

    Jaros, E.; Perry, R H; Adam, L.; Kelly, P J; Crawford, P. J.; Kalbag, R M; Mendelow, A D; Sengupta, R P; Pearson, A D

    1992-01-01

    The expression of p53 protein, epidermal growth factor receptor (EGFR), and Ki-67 nuclear antigen was examined by immunohistochemistry in biopsies of 16 types of human brain tumours, including 43 astrocytomas. P53 protein, almost certainly its mutant form, was expressed in seven of the 16, and EGFR in 11 of the 16 types of tumours. In astrocytomas both the proportion of tumours which expressed p53 or EGFR increased with grade of malignancy as did the mean Ki-67 labelling index (LI): p53-0% in...

  8. P2X7 receptor activation in rat brain cultured astrocytes increases the biosynthetic release of cysteinyl leukotrienes.

    Science.gov (United States)

    Ballerini, P; Ciccarelli, R; Caciagli, F; Rathbone, M P; Werstiuk, E S; Traversa, U; Buccella, S; Giuliani, P; Jang, S; Nargi, E; Visini, D; Santavenere, C; Di Iorio, P

    2005-01-01

    Astrocytes have been recognized as important elements in controlling inflammatory as well as immune processes in the central nervous system (CNS). Recently, glial cells have been shown to produce cysteinyl leukotrienes (CysLTs) which are known lipid mediators of inflammation and whose extracellular concentrations rise under different pathological conditions in the brain. In the same conditions also extracellular concentrations of ATP dramatically increase reaching levels able to activate P2X7 ionotropic receptors for which an emerging role in neuroinflammation and neurodegeneration has been claimed. RTPCR analysis showed that primary cultures of rat brain astrocytes express P2X7 receptors. Application of the selective P2X7 agonist benzoyl benzoly ATP (BzATP) markedly increased [Ca2+]i which was mediated by a calcium influx from the extracellular milieu. The P2X7 antagonist, oATP, suppressed the BzATP-induced calcium increase. Consistent with the evidence that increased calcium levels activate the leukotriene biosynthetic pathway, challenge of astrocytes with either the calcium ionophore A23187 or BzATP significantly increased CysLT production and the cell pre-treatment with EGTA abolished these effects. Again the P2X7 antagonist prevented the BzATP-mediated CysLT efflux, whereas the astrocyte pretreatment with MK-571, a CysLT1 receptor antagonist, was ineffective. The astrocyte pre-treatment with a cocktail of inhibitors of ATP binding cassette (ABC) proteins reduced the BzATP-mediated CysLT production confirming that ABC transporters are involved in the release of CysLTs. The astrocyte P2X7- evoked rise of CysLT efflux was abolished in the presence of MK-886, an inhibitor of 5-lipoxygenase activating protein (FLAP) whose expression, along with that of 5-lipoxygenase (5-LO) was reported by Northern Blot analysis. The stimulation of P2X7 induced an up-regulation of FLAPmRNA that was reduced by the antagonist oATP. These data suggest that in rat brain cultured

  9. HIV-1 Tat Regulates Occludin and Aβ Transfer Receptor Expression in Brain Endothelial Cells via Rho/ROCK Signaling Pathway

    Science.gov (United States)

    Chen, Yanlan; Jiang, Wenlin; Wu, Xianghong; Ye, Biao; Zhou, Xiaoting

    2016-01-01

    HIV-1 transactivator protein (Tat) has been shown to play an important role in HIV-associated neurocognitive disorders. The aim of the present study was to evaluate the relationship between occludin and amyloid-beta (Aβ) transfer receptors in human cerebral microvascular endothelial cells (hCMEC/D3) in the context of HIV-1-related pathology. The protein expressions of occludin, receptor for advanced glycation end products (RAGE), and low-density lipoprotein receptor-related protein 1 (LRP1) in hCMEC/D3 cells were examined using western blotting and immunofluorescent staining. The mRNA levels of occludin, RAGE, and LRP1 were measured using quantitative real-time polymerase chain reaction. HIV-1 Tat at 1 µg/mL and the Rho inhibitor hydroxyfasudil (HF) at 30 µmol/L, with 24 h exposure, had no significant effect on hCMEC/D3 cell viability. Treatment with HIV-1 Tat protein decreased mRNA and protein levels of occludin and LRP1 and upregulated the expression of RAGE; however, these effects were attenuated by HF. These data suggest that the Rho/ROCK signaling pathway is involved in HIV-1 Tat-mediated changes in occludin, RAGE, and LRP1 in hCMEC/D3 cells. HF may have a beneficial influence by protecting the integrity of the blood-brain barrier and the expression of Aβ transfer receptors.

  10. Short-term regulation of muscarinic acetylcholine receptors: An assessment utilizing mouse brain and mouse neuroblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Cioffi, C.L.

    1988-01-01

    The effects of muscarinic agonists and diisopropylfluorophosphate (DFP) on muscarinic receptor density and muscarinic receptor-mediated responses was assessed in mouse brain and mouse neuroblastoma cells (clone N1E-115). Utilizing the antagonist ({sup 3}H)quinuclidinyl benzilate (({sup 3}H)QNB), there was no difference in the maximal binding capacity (B{sub max}) or equilibrium dissociation constant (K{sub d}) between untreated and 24 hour DFP-treated mice. However, one administration of DFP produced a 24% and 33% decrease in B{sub max} measured by ({sup 3}H)N-methylscopolamine (({sup 3}H)NMS) after 18 and 24 hours which was rapidly reversible within 36 hours after DFP treatment. The loss of ({sup 3}H)NMS binding sites following acute DFP treatment was not accompanied by a change in a particular muscarinic receptor binding conformation. Furthermore, the magnitude of muscarinic receptor-mediated phosphoinositide hydrolysis was unchanged following short-term DFP treatment.

  11. Effects of chronic delta-9-tetrahydrocannabinol (THC) administration on neurotransmitter concentrations and receptor binding in the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Ali, S.F.; Newport, G.D.; Scallet, A.C.; Gee, K.W.; Paule, M.G.; Brown, R.M.; Slikker, W. Jr. (National Center for Toxicological Research, Jefferson, Arkansas (USA))

    THC is the major psychoactive constituent of marijuana and is also known as an hallucinogenic compound. Numerous reports have shown that large doses of THC produce significant alterations in various neurotransmitter systems. The present study was designed to determine whether chronic exposure to THC produces significant alterations in selected neurotransmitter systems (dopamine, serotonin, acetylcholine, GABAergic, benzodiazepine, and opiate) in the rat brain. In Experiment 1, male Sprague-Dawley rats were gavaged with vehicle, 10 or 20 mg THC/kg body weight daily, 5 days/week for 90 days. Animals were killed either 24 hours or two months after the last dose. Brains were dissected into different regions for neurochemical analyses. Two months after the cessation of chronic administration, there was a significant decrease in GABA receptor binding in the hippocampus of animals in the high dose group. However, no other significant changes were found in neurotransmitter receptor binding characteristics in the hippocampus or in neurotransmitter concentrations in the caudate nucleus, hypothalamus or septum after chronic THC administration. In an attempt to replicate the GABA receptor binding changes and also to determine the (35S)TBPS binding in hippocampus, we designed Experiment 2. In this experiment, we dosed the animals by gavage with 0, 5, 10 or 20 mg THC/kg daily, 5 days/week or with 20 mg THC/kg Monday through Thursday and 60 mg/kg on Friday for 90 days. Results from this experiment failed to replicate the dose-dependent effect of THC on GABA receptor binding in hippocampus. Modulation of (35S)TBPS binding by GABA or 3 alpha-OH-DHP or inhibition by cold TBPS in frontal cortex did not show any significant dose-related effects.

  12. Effects of chronic delta-9-tetrahydrocannabinol (THC) administration on neurotransmitter concentrations and receptor binding in the rat brain

    International Nuclear Information System (INIS)

    THC is the major psychoactive constituent of marijuana and is also known as an hallucinogenic compound. Numerous reports have shown that large doses of THC produce significant alterations in various neurotransmitter systems. The present study was designed to determine whether chronic exposure to THC produces significant alterations in selected neurotransmitter systems (dopamine, serotonin, acetylcholine, GABAergic, benzodiazepine, and opiate) in the rat brain. In Experiment 1, male Sprague-Dawley rats were gavaged with vehicle, 10 or 20 mg THC/kg body weight daily, 5 days/week for 90 days. Animals were killed either 24 hours or two months after the last dose. Brains were dissected into different regions for neurochemical analyses. Two months after the cessation of chronic administration, there was a significant decrease in GABA receptor binding in the hippocampus of animals in the high dose group. However, no other significant changes were found in neurotransmitter receptor binding characteristics in the hippocampus or in neurotransmitter concentrations in the caudate nucleus, hypothalamus or septum after chronic THC administration. In an attempt to replicate the GABA receptor binding changes and also to determine the [35S]TBPS binding in hippocampus, we designed Experiment 2. In this experiment, we dosed the animals by gavage with 0, 5, 10 or 20 mg THC/kg daily, 5 days/week or with 20 mg THC/kg Monday through Thursday and 60 mg/kg on Friday for 90 days. Results from this experiment failed to replicate the dose-dependent effect of THC on GABA receptor binding in hippocampus. Modulation of [35S]TBPS binding by GABA or 3 alpha-OH-DHP or inhibition by cold TBPS in frontal cortex did not show any significant dose-related effects

  13. HMGB1 Contributes to the Expression of P-Glycoprotein in Mouse Epileptic Brain through Toll-Like Receptor 4 and Receptor for Advanced Glycation End Products.

    Directory of Open Access Journals (Sweden)

    Yan Chen

    Full Text Available The objective of the present study was to investigate the role of high-mobility group box-1 (HMGB1 in the seizure-induced P-glycoprotein (P-gp overexpression and the underlying mechanism. Kainic acid (KA-induced mouse seizure model was used for in vivo experiments. Male C57BL/6 mice were divided into four groups: normal saline control (NS group, KA-induced epileptic seizure (EP group, and EP group pretreated with HMGB1 (EP+HMGB1 group or BoxA (HMGB1 antagonist, EP+BoxA group. Compared to the NS group, increased levels of HMGB1 and P-gp in the brain were observed in the EP group. Injection of HMGB1 before the induction of KA further increased the expression of P-gp while pre-treatment with BoxA abolished this up-regulation. Next, the regulatory role of HMGB1 and its potential involved signal pathways were investigated in mouse microvascular endothelial bEnd.3 cells in vitro. Cells were treated with HMGB1, HMGB1 plus lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS [toll-like receptor 4 (TLR4 antagonist], HMGB1 plus FPS-ZM1 [receptor for advanced glycation end products (RAGE inhibitor], HMGB1 plus SN50 [nuclear factor-kappa B (NF-κB inhibitor], or vehicle. Treatment with HMGB1 increased the expression levels of P-gp, TLR4, RAGE and the activation of NF-κB in bEnd.3 cells. These effects were inhibited by the pre-treatment with either LPS-RS or FPS-ZM1, and were abolished by the pre-treatment of SN50 or a combination treatment of both LPS-RS and FPS-ZM1. Luciferase reporter assays showed that exogenous expression of NF-κB p65 increased the promoter activity of multidrug resistance 1a (P-gp-encoding gene in endothelial cells. These data indicate that HMGB1 contributes to the overexpression of P-gp in mouse epileptic brain tissues via activation of TLR4/RAGE receptors and the downstream transcription factor NF-κB in brain microvascular endothelial cells.

  14. DAPK1 Interaction with NMDA Receptor NR2B Subunits Mediates Brain Damage in Stroke

    Science.gov (United States)

    Tu, Weihong; Xu, Xin; Peng, Lisheng; Zhong, Xiaofen; Zhang, Wenfeng; Soundarapandian, Mangala M.; Balel, Cherine; Wang, Manqi; Jia, Nali; Zhang, Wen; Lew, Frank; Chan, Sic Lung; Chen, Yanfang; Lu, Youming

    2010-01-01

    SUMMARY N-methyl-D-aspartate (NMDA) receptors constitute a major subtype of glutamate receptors at extra-synaptic sites that link multiple intracellular catabolic processes responsible for irreversible neuronal death. Here, we report that cerebral ischemia recruits death-associated protein kinase 1 (DAPK1) into the NMDA receptor NR2B protein complex in the cortex of adult mice. DAPK1 directly binds with the NMDA receptor NR2B C-terminal tail consisting of amino acid 1292–1304 (NR2BCT). A constitutively active DAPK1 phosphorylates NR2B subunit at Ser-1303 and in turn enhances the NR1/NR2B receptor channel conductance. Genetic deletion of DAPK1 or administration of NR2BCT that uncouples an activated DAPK1 from an NMDA receptor NR2B subunit in vivo in mice blocks injurious Ca2+ influx through NMDA receptor channels at extrasynaptic sites and protects neurons against cerebral ischemic insults. Thus, DAPK1 physically and functionally interacts with the NMDA receptor NR2B subunit at extra-synaptic sites and this interaction acts as a central mediator for stroke damage. PMID:20141836

  15. Androgen regulation of corticotropin-releasing hormone receptor 2 (CRHR2) mRNA expression and receptor binding in the rat brain

    Science.gov (United States)

    Weiser, Michael J.; Goel, Nirupa; Sandau, Ursula S.; Bale, Tracy L.; Handa, Robert J.

    2008-01-01

    Stress-induced affective disorders, such as depression and anxiety, are more prevalent in females than in males. The reduced vulnerability to these disorders in males may be due to the presence of androgens, which are known to dampen the stress response and reduce anxiety-like behaviors. However, a neurobiological mechanism for this sex difference has yet to be elucidated. Corticotropin-releasing hormone receptor 2 (CRHR2) has been implicated in regulating anxiety-type behaviors and is expressed in stress-responsive brain regions that also contain androgen receptors (AR). We hypothesized that androgen may exert its effects through actions on CRHR2 and we therefore examined the regulation of CRHR2 mRNA and receptor binding in the male rat forebrain following androgen administration. Young adult male Sprague/Dawley rats were gonadectomized (GDX) and treated with the non-aromatizable androgen, dihydrotestosterone propionate (DHTP) using hormone filled Silastic capsules. Control animals received empty capsules. Using quantitative real time RT-PCR, CRHR2 mRNA levels were determined in block dissected brain regions. DHTP treatment significantly increased CRHR2 mRNA expression in the hippocampus, hypothalamus, and lateral septum (p < 0.01) when compared to vehicle-treated controls. A similar trend was observed in amygdala (p = 0.05). Furthermore, in vitro autoradiography revealed significantly higher CRHR2 binding in the lateral septum in androgen-treated males, with the highest difference observed in the ventral lateral region. Regulation of CRHR2 mRNA by AR was also examined using an in vitro approach. Hippocampal neurons, which contain high levels of AR, were harvested from E17–18 rat fetuses, and maintained in primary culture for 14 days. Neurons were then treated with dihydrotestosterone (DHT; 1 nM), DHT plus flutamide (an androgen receptor antagonist), or vehicle for 48 hours. CRHR2 mRNA levels were measured using quantitative real time RT-PCR. Consistent with in

  16. Immunohistochemical Localization of AT1a, AT1b, and AT2 Angiotensin II Receptor Subtypes in the Rat Adrenal, Pituitary, and Brain with a Perspective Commentary

    Directory of Open Access Journals (Sweden)

    Courtney Premer

    2013-01-01

    Full Text Available Angiotensin II increases blood pressure and stimulates thirst and sodium appetite in the brain. It also stimulates secretion of aldosterone from the adrenal zona glomerulosa and epinephrine from the adrenal medulla. The rat has 3 subtypes of angiotensin II receptors: AT1a, AT1b, and AT2. mRNAs for all three subtypes occur in the adrenal and brain. To immunohistochemically differentiate these receptor subtypes, rabbits were immunized with C-terminal fragments of these subtypes to generate receptor subtype-specific antibodies. Immunofluorescence revealed AT1a and AT2 receptors in adrenal zona glomerulosa and medulla. AT1b immunofluorescence was present in the zona glomerulosa, but not the medulla. Ultrastructural immunogold labeling for the AT1a receptor in glomerulosa and medullary cells localized it to plasma membrane, endocytic vesicles, multivesicular bodies, and the nucleus. AT1b and AT2, but not AT1a, immunofluorescence was observed in the anterior pituitary. Stellate cells were AT1b positive while ovoid cells were AT2 positive. In the brain, neurons were AT1a, AT1b, and AT2 positive, but glia was only AT1b positive. Highest levels of AT1a, AT1b, and AT2 receptor immunofluorescence were in the subfornical organ, median eminence, area postrema, paraventricular nucleus, and solitary tract nucleus. These studies complement those employing different techniques to characterize Ang II receptors.

  17. Assessment of α7 nicotinic acetylcholine receptor availability in juvenile pig brain with [18F]NS10743

    International Nuclear Information System (INIS)

    To conduct a quantitative PET assessment of the specific binding sites in the brain of juvenile pigs for [18F]NS10743, a novel diazabicyclononane derivative targeting α7 nicotinic acetylcholine receptors (α7 nAChRs). Dynamic PET recordings were made in isoflurane-anaesthetized juvenile pigs during 120 min after administration of [18F]NS10743 under baseline conditions (n = 3) and after blocking of the α7 nAChR with NS6740 (3 mg.kg-1 bolus + 1 mg.kg-1.h-1 continuous infusion; n = 3). Arterial plasma samples were collected for determining the input function of the unmetabolized tracer. Kinetic analysis of regional brain time-radioactivity curves was performed, and parametric maps were calculated relative to arterial input. Plasma [18F]NS10743 passed readily into the brain, with peak uptake occurring in α7 nAChR-expressing brain regions such as the colliculi, thalamus, temporal lobe and hippocampus. The highest SUVmax was approximately 2.3, whereas the lowest uptake was in the olfactory bulb (SUVmax 1.53 ± 0.32). Administration of NS6740 significantly decreased [18F]NS10743 binding late in the emission recording throughout the brain, except in the olfactory bulb, which was therefore chosen as reference region for calculation of BPND. The baseline BPND ranged from 0.39 ± 0.08 in the cerebellum to 0.76 ± 0.07 in the temporal lobe. Pretreatment and constant infusion with NS6740 significantly reduced the BPND in regions with high [18F]NS10743 binding (temporal lobe -29%, p = 0.01; midbrain: -35%, p = 0.02), without significantly altering the BPND in low binding regions (cerebellum: -16%, p = 0.2). This study confirms the potential of [18F]NS10743 as a target-specific radiotracer for the molecular imaging of central α7 nAChRs by PET. (orig.)

  18. Muscarinic receptor plasticity in the brain of senescent rats: down-regulation after repeated administration of diisopropyl fluorophosphate

    International Nuclear Information System (INIS)

    Potential age-related differences in the response of Fischer 344 rats to subchronic treatment with diisopropylfluorophosphate (DFP) were evaluated in terms of brain cholinesterase (ChE) inhibition and muscarinic receptor sites. Male 3- and 24-month old rats were sc injected with sublethal doses of DFP for 2 weeks and killed 48 hrs after the last treatment. In the cerebral cortex, hippocampus and striatum of control rats a significant age-related reduction of ChE and of maximum number of 3H-QNB binding sites (Bmax) was observed. The administration of DFP to senescent rats resulted in more pronounced and longer lasting syndrome of cholinergic stimulation, with marked body weight loss and 60% mortality. The percentage inhibition of brain ChE induced by DFP did not differ between young and senescent rats. As expected, in young rats DFP caused a significant decrease of Bmax, which in the cerebral cortex reached about 40%. In the surviving senescent rats, the percentage decrease of Bmax due to DFP with respect to age-matched controls was very similar to that of young animals, especially in the cerebral cortex. Thus there is great variability in the response of aged rats to DFP treatment, from total failure of adaptive mechanisms resulting in death to considerable muscarinic receptor plasticity

  19. Muscarinic receptor plasticity in the brain of senescent rats: down-regulation after repeated administration of diisopropyl fluorophosphate

    Energy Technology Data Exchange (ETDEWEB)

    Pintor, A.; Fortuna, S.; Volpe, M.T.; Michalek, H.

    1988-01-01

    Potential age-related differences in the response of Fischer 344 rats to subchronic treatment with diisopropylfluorophosphate (DFP) were evaluated in terms of brain cholinesterase (ChE) inhibition and muscarinic receptor sites. Male 3- and 24-month old rats were sc injected with sublethal doses of DFP for 2 weeks and killed 48 hrs after the last treatment. In the cerebral cortex, hippocampus and striatum of control rats a significant age-related reduction of ChE and of maximum number of /sup 3/H-QNB binding sites (Bmax) was observed. The administration of DFP to senescent rats resulted in more pronounced and longer lasting syndrome of cholinergic stimulation, with marked body weight loss and 60% mortality. The percentage inhibition of brain ChE induced by DFP did not differ between young and senescent rats. As expected, in young rats DFP caused a significant decrease of Bmax, which in the cerebral cortex reached about 40%. In the surviving senescent rats, the percentage decrease of Bmax due to DFP with respect to age-matched controls was very similar to that of young animals, especially in the cerebral cortex. Thus there is great variability in the response of aged rats to DFP treatment, from total failure of adaptive mechanisms resulting in death to considerable muscarinic receptor plasticity.

  20. Identification and molecular docking studies for novel inverse agonists of SREB, super conserved receptor expressed in brain.

    Science.gov (United States)

    Yanai, Toshihiro; Kurosawa, Aya; Nikaido, Yoshiaki; Nakajima, Nozomi; Saito, Tamio; Osada, Hiroyuki; Konno, Ayumu; Hirai, Hirokazu; Takeda, Shigeki

    2016-07-01

    The identification of novel synthetic ligands for G protein-coupled receptors (GPCRs) is important not only for understanding human physiology, but also for the development of novel drugs, especially for orphan GPCRs for which endogenous ligands are unknown. One of the orphan GPCR subfamilies, Super conserved Receptor Expressed in Brain (SREB), consists of GPR27, GPR85 and GPR173 and is expressed in the central nervous system. We report herein the identification of inverse agonists for the SREB family without their agonists. We carried out an in vitro screening of 5472 chemical compounds from the RIKEN NPDepo chemical library. The binding of [(35) S]GTPγS to the GPR173-Gsα fusion protein expressed in Sf9 cells was measured and resulted in the identification of 8 novel GPR173 inverse agonists. The most potent compound showed an IC50 of approximately 8 μm. The identified compounds were also antagonists for other SREB members, GPR27 and GPR85. These results indicated that the SREB family could couple Gs-type G proteins, and SREB-Gsα fusion proteins showed significant constitutive activities. Moreover, a molecular model of GPR173 was constructed using the screening results. The combination of computational and biological methods will provide a unique approach to ligand identification for orphan GPCRs and brain research. PMID:27184081

  1. Suppression of ischaemia-induced injuries in rat brain by protease-activated receptor-1 (PAR-1) activating peptide.

    Science.gov (United States)

    Zhen, Xia; Ng, Ethel Sau Kuen; Lam, Francis Fu Yuen

    2016-09-01

    Ischaemic stroke has become one of the leading causes of death and disability worldwide. The role of protease activated receptor-1 (PAR-1) in this disease is uncertain. In the present study, the actions of a protease activated receptor-1 activating peptide (PAR-1 AP) SFLLRN-NH2 were investigated in an in vivo rat model of ischaemic stroke induced by middle cerebral artery occlusion (MCAO) and in an in vitro model induced by oxygen and glucose deprivation (OGD) in primary cultured rat embryonic cortical neurones. Rats subjected to MCAO exhibited increased brain infarct volume, oedema, and neurological deficit. Rat cortical neurones subjected to OGD showed increased lactate dehydrogenase, caspase-3 activity and TUNEL positive cells, whereas, mitochondrial membrane potential and cell viability were decreased. Furthermore, both models had elevated levels of reactive oxygen species, nitrite, and malondialdehyde, while anti-oxidant enzymes and bcl-2/bax ratio were decreased. These detrimental changes were suppressed by SFLLRN-NH2, and its protective actions were inhibited by a PAR-1 antagonist (BMS-200261). In summary, SFLLRN-NH2 was found to possess anti-oxidant and anti-apoptotic properties, and it produced marked inhibition on the detrimental effects of ischaemia in in vivo and in vitro models of ischaemic stroke. The present findings suggest PAR-1 is a promising target for development of novel treatments of ischaemic brain disease. PMID:27238976

  2. Characterization of GABA/sub A/ receptor-mediated /sup 36/chloride uptake in rat brain synaptoneurosomes

    Energy Technology Data Exchange (ETDEWEB)

    Luu, M.D.; Morrow, A.L.; Paul, S.M.; Schwartz, R.D.

    1987-09-07

    ..gamma..-Aminobutyric acid (GABA) receptor-mediated /sup 36/chloride (/sup 36/Cl/sup -/) uptake was measured in synaptoneurosomes from rat brain. GABA and GABA agonists stimulated /sup 36/Cl/sup -/ uptake in a concentration-dependent manner with the following order of potency: Muscimol>GABA>piperidine-4-sulfonic acid (P4S)>4,5,6,7-tetrahydroisoxazolo-(5,4-c)pyridin-3-ol (THIP)=3-aminopropanesulfonic acid (3APS)>>taurine. Both P4S and 3APS behaved as partial agonists, while the GABA/sub B/ agonist, baclofen, was ineffective. The response to muscimol was inhibited by bicuculline and picrotoxin in a mixed competitive/non-competitive manner. Other inhibitors of GABA receptor-opened channels or non-neuronal anion channels such as penicillin, picrate, furosemide and disulfonic acid stilbenes also inhibited the response to muscimol. A regional variation in muscimol-stimulated /sup 36/Cl/sup -/ uptake was observed; the largest responses were observed in the cerebral cortex, cerebellum and hippocampus, moderate responses were obtained in the striatum and hypothalamus and the smallest response was observed in the pons-medulla. GABA receptor-mediated /sup 36/Cl/sup -/ uptake was also dependent on the anion present in the media. The muscinol response varied in media containing the following anions: Br/sup -/>Cl/sup -/greater than or equal toNO/sub 3//sup -/>I/sup -/greater than or equal toSCN/sup -/>>C/sub 3/H/sub 5/OO/sup -/greater than or equal toClO/sub 4//sup -/>F/sup -/, consistent with the relative anion permeability through GABA receptor-gated anion channels and the enhancement of convulsant binding to the GABA receptor-gated Cl/sup -/ channel. 43 references, 4 figures, 3 tables.

  3. Two members of a distinct subfamily of 5-hydroxytryptamine receptors differentially expressed in rat brain.

    OpenAIRE

    Erlander, M G; Lovenberg, T W; Baron, B M; de Lecea, L; Danielson, P E; Racke, M; Slone, A L; Siegel, B W; Foye, P. E.; Cannon, K

    1993-01-01

    We report two serotonin (5-hydroxytryptamine, 5-HT) receptors, MR22 and REC17, that belong to the G-protein-associated receptor superfamily. MR22 and REC17 are 371 and 357 amino acids long, respectively, as deduced from nucleotide sequence and share 68% mutual amino acid identity and 30-35% identity with known catecholamine and 5-HT receptors. Saturable binding of 125I-labeled (+)-lysergic acid diethylamide to transiently expressed MR22 in COS-M6 cells was inhibited by ergotamine > methiothep...

  4. Effects of antidepressant drugs on histamine-H1 receptors in the brain

    International Nuclear Information System (INIS)

    The histamine-H1 receptor blocking properties of a number of structurally different antidepressant drugs have been evaluated using a 3H-mepyramine binding assay and a guinea-pig ileum preparation. The tricyclic antidepressants all inhibited the histamine-H1 receptor. Some newer antidepressant drugs, such as zimeldine and nomifensine were devoid of activity while others, such as iprindole and mianserin were very potent. It is concluded that antagonistic effects on the histamine-H1 receptor is not associated with the therapeutic efficacy in depression, but may contribute to the sedative effects of the antidepressant drugs

  5. Sulfonylurea Receptor 1 Contributes to the Astrocyte Swelling and Brain Edema in Acute Liver Failure

    OpenAIRE

    Jayakumar, A.R.; Valdes, V.; Tong, X. Y.; Shamaladevi, N.; W Gonzalez; Norenberg, M.D.

    2014-01-01

    Astrocyte swelling (cytotoxic brain edema) is the major neurological complication of acute liver failure (ALF), a condition in which ammonia has been strongly implicated in its etiology. Ion channels and transporters are known to be involved in cell volume regulation and a disturbance in these systems may result in cell swelling. One ion channel known to contribute to astrocyte swelling/brain edema in other neurological disorders is the ATP-dependent, non-selective cation channel (NCCa-ATP ch...

  6. Novel Humanized Recombinant T Cell Receptor Ligands Protect the Female Brain After Experimental Stroke

    OpenAIRE

    Pan, Jie; Palmateer, Julie; Schallert, Timothy; Hart, Madison; Pandya, Arushi; Vandenbark, Arthur A.; Offner, Halina; Hurn, Patricia D.

    2014-01-01

    Transmigration of peripheral leukocytes to the brain is a major contributor to cerebral ischemic cell death mechanisms. Humanized partial major histocompatibility complex class II constructs (pMHC), covalently linked to myelin peptides, are effective for treating experimental stroke in males, but new evidence suggests that some inflammatory cell death mechanisms after brain injury are sex-specific. We here demonstrate that treatment with pMHC constructs also improves outcomes in female mice w...

  7. Quantification of GABAA receptors in the rat brain with [123I]Iomazenil SPECT from factor analysis-denoised images

    International Nuclear Information System (INIS)

    Purpose: In vivo imaging of GABAA receptors is essential for the comprehension of psychiatric disorders in which the GABAergic system is implicated. Small animal SPECT provides a modality for in vivo imaging of the GABAergic system in rodents using [123I]Iomazenil, an antagonist of the GABAA receptor. The goal of this work is to describe and evaluate different quantitative reference tissue methods that enable reliable binding potential (BP) estimations in the rat brain to be obtained. Methods: Five male Sprague–Dawley rats were used for [123I]Iomazenil brain SPECT scans. Binding parameters were obtained with a one-tissue compartment model (1TC), a constrained two-tissue compartment model (2TCc), the two-step Simplified Reference Tissue Model (SRTM2), Logan graphical analysis and analysis of delayed-activity images. In addition, we employed factor analysis (FA) to deal with noise in data. Results: BPND obtained with SRTM2, Logan graphical analysis and delayed-activity analysis was highly correlated with BPF values obtained with 2TCc (r = 0.954 and 0.945 respectively, p c and SRTM2 in raw and FA-denoised images (r = 0.961 and 0.909 respectively, p ND values from raw images while scans of only 70 min are sufficient from FA-denoised images. These images are also associated with significantly lower standard errors of 2TCc and SRTM2 BP values. Conclusion: Reference tissue methods such as SRTM2 and Logan graphical analysis can provide equally reliable BPND values from rat brain [123I]Iomazenil SPECT. Acquisitions, however, can be much less time-consuming either with analysis of delayed activity obtained from a 20-minute scan 50 min after tracer injection or with FA-denoising of images

  8. Opioid receptor imaging and displacement studies with [6-O-[11C] methyl]buprenorphine in baboon brain.

    Science.gov (United States)

    Galynker, I; Schlyer, D J; Dewey, S L; Fowler, J S; Logan, J; Gatley, S J; MacGregor, R R; Ferrieri, R A; Holland, M J; Brodie, J; Simon, E; Wolf, A P

    1996-04-01

    Buprenorphine (BPN) is a mixed opiate agonist-antagonist used as an analgesic and in the treatment of opiate addiction. We have used [6-O-[11C]methyl]buprenorphine ([11C]BPN) to measure the regional distribution in baboon brain, the test-retest stability of repeated studies in the same animal, the displacement of the labeled drug by naloxone in vivo, and the tissue distribution in mice. The regional distribution of radioactivity in baboon brain determined with PET was striatum > thalamus > cingulate gyrus > frontal cortex > parietal cortex > occipital cortex > cerebellum. This distribution corresponded to opiate receptor density and to previously published data (37). The tracer uptake in adult female baboons showed no significant variation in serial scans in the same baboon with no intervention in the same scanning session. HPLC analysis of baboon plasma showed the presence of labeled metabolites with 92% +/- 2.2% and 43% +/- 14.4% of the intact tracer remaining at 5 and 30 min, respectively. Naloxone, an opiate receptor antagonist, administered 30-40 min after tracer injection at a dose of 1.0 mg/kg i.v., reduced [11C]BPN binding in thalamus, striatum, cingulate gyrus, and frontal cortex to values 0.25 to 0.60 of that with no intervention. There were minimal (Naloxone treatment significantly reduced the slope of the Patlak plot in receptor-containing regions. These results demonstrate that [11C]BPN can be displaced by naloxone in vivo, and they affirm the feasibility of using this tracer and displacement methodology for short-term kinetics studies with PET. Mouse tissue distribution data were used to estimate the radiation dosimetry to humans. The critical organ was the small intestine, with a radiation dose estimate to humans of 117 nrad/mCi. PMID:8782244

  9. Opioid receptor imaging and displacement studies with [6-O-[{sup 11}C]methyl]buprenorphine in baboon brain

    Energy Technology Data Exchange (ETDEWEB)

    Galynker, Igor; Schlyer, David J.; Dewey, Stephen L.; Fowler, Joanna S.; Logan, Jean; Gatley, S. John; MacGregor, Robert R.; Ferrieri, Richard A.; Holland, M. J.; Brodie, Jonathan; Simon, Eric; Wolf, Alfred P

    1996-04-01

    Buprenorphine (BPN) is a mixed opiate agonist-antagonist used as an analgesic and in the treatment of opiate addiction. We have used [6-O-[{sup 11}C]methyl]buprenorphine ([{sup 11}C]BPN) to measure the regional distribution in baboon brain, the test-retest stability of repeated studies in the same animal, the displacement of the labeled drug by naloxone in vivo, and the tissue distribution in mice. The regional distribution of radioactivity in baboon brain determined with PET was striatum > thalamus > cingulate gyrus > frontal cortex > parietal cortex > occipital cortex > cerebellum. This distribution corresponded to opiate receptor density and to previously published data (37). The tracer uptake in adult female baboons showed no significant variation in serial scans in the same baboon with no intervention in the same scanning session. HPLC analysis of baboon plasma showed the presence of labeled metabolites with 92% {+-} 2.2% and 43% {+-} 14.4% of the intact tracer remaining at 5 and 30 min, respectively. Naloxone, an opiate receptor antagonist, administered 30-40 min after tracer injection at a dose of 1.0 mg/kg i.v., reduced [{sup 11}C]BPN binding in thalamus, striatum, cingulate gyrus, and frontal cortex to values 0.25 to 0.60 of that with no intervention. There were minimal (< 15%) effects on cerebellum. Naloxone treatment significantly reduced the slope of the Patlak plot in receptor-containing regions. These results demonstrate that [{sup 11}C]BPN can be displaced by naloxone in vivo, and they affirm the feasibility of using this tracer and displacement methodology for short-term kinetics studies with PET. Mouse tissue distribution data were used to estimate the radiation dosimetry to humans. The critical organ was the small intestine, with a radiation dose estimate to humans of 117 nrad/mCi.

  10. Effects of Rhizoma Acori Tatarinowii extracts on gamma-aminobutyric acid type A receptor alpha 1 subunit brain expression during development in a recurrent seizure rat model

    Institute of Scientific and Technical Information of China (English)

    Liqun Liu; Ding'an Mao; Keqiang Chi; Xingfang Li; Tao Bo; Jinming Guo; Zhuwen Yi

    2011-01-01

    Extracts from Rhizoma Acori Tatarinowii (Grassleaf Sweetflag Rhizome, Shichangpu) have been shown to improve learning and memory, reduce anxiety, allay excitement, and suppress seizures. Rhizoma Acori Tatarinowii extracts interact with γ-aminobutyric acid and activate the γ-aminobutyric acid type A receptor, although few studies have addressed the precise effects of γ-aminobutyric acid type A receptor α1 subunit. In the present study, γ-aminobutyric acid type A receptor α1 subunit protein expression in the cerebral cortex and hippocampus, and pathological scores of brain injury, were significantly greater following recurrent seizures, but significantly decreased following treatment with Rhizoma Acori Tatarinowii extracts. These results indicated that Rhizoma Acori Tatarinowii extracts down-regulated γ-aminobutyric acid type A receptor α1 subunit protein expression in the cerebral cortex and hippocampus and protected seizure-induced brain injury during development.

  11. Cyclopentadienyl tricarbonyl complexes of 99mTc for the in vivo imaging of the serotonin 5-HT 1a receptor in the brain

    International Nuclear Information System (INIS)

    The present interest in the 5-HT 1a receptor is due to its implicated role in several major neuropsychiatric disorders such as depression, eating disorders and anxiety. For the diagnosis of these pathophysiological processes it is important to have radioligands in hand able to specifically bind on the 5-HT 1a receptor in order to allow brain imaging. due to the optimal radiation properties of 99mTc there is a considerable interest in the development of 99mTc radiopharmaceuticals for imaging serotonergic CNS receptors using single-photon emission tomography (SPET). Here we introduce two cyclopentadienyl technitium tricarbonyl conjugates of piperidine derivatives which show high accumulation of radioactivity in brain areas rich in 5-HT 1a receptors

  12. Mannose receptor expression specifically reveals perivascular macrophages in normal, injured, and diseased mouse brain

    OpenAIRE

    Galea, Ian; Palin, Karine; Newman, Tracey A; van Rooijen, Nico; Perry, V. Hugh; Boche, Delphine

    2005-01-01

    Perivascular macrophages are believed to have a significant role in inflammation in the central nervous system (CNS). They express a number of different receptors that point toward functions in both innate immunity, through pathogen-associated molecular pattern recognition, phagocytosis, and cytokine responsiveness, and acquired immunity, through antigen presentation and co-stimulation. We are interested in the receptors that are differentially expressed by perivascular macrophages and microg...

  13. Progesterone receptor expression in the brain of the socially monogamous and paternal male prairie vole

    OpenAIRE

    Williams, Brittany; Northcutt, Katharine V.; Rusanowsky, Rebecca D.; Mennella, Thomas A.; Lonstein, Joseph S.; Quadros-Mennella, Princy S.

    2013-01-01

    Differences in the social organization and behavior of male mammals are attributable to species differences in neurochemistry, including differential expression of steroid hormone receptors. However, the distribution of progestin receptors (PR) in a socially monogamous and spontaneously parental male rodent has never been examined. Here we determined if PR exists and is regulated by testicular hormones in forebrain sites traditionally influencing socioreproductive behaviors in male prairie vo...

  14. Minocycline Attenuates Neonatal Germinal-Matrix-Hemorrhage-Induced Neuroinflammation and Brain Edema by Activating Cannabinoid Receptor 2.

    Science.gov (United States)

    Tang, Jun; Chen, Qianwei; Guo, Jing; Yang, Liming; Tao, Yihao; Li, Lin; Miao, Hongping; Feng, Hua; Chen, Zhi; Zhu, Gang

    2016-04-01

    Germinal matrix hemorrhage (GMH) is the most common neurological disease of premature newborns leading to detrimental neurological sequelae. Minocycline has been reported to play a key role in neurological inflammatory diseases by controlling some mechanisms that involve cannabinoid receptor 2 (CB2R). The current study investigated whether minocycline reduces neuroinflammation and protects the brain from injury in a rat model of collagenase-induced GMH by regulating CB2R activity. To test this hypothesis, the effects of minocycline and a CB2R antagonist (AM630) were evaluated in male rat pups that were post-natal day 7 (P7) after GMH. We found that minocycline can lead to increased CB2R mRNA expression and protein expression in microglia. Minocycline significantly reduced GMH-induced brain edema, microglial activation, and lateral ventricular volume. Additionally, minocycline enhanced cortical thickness after injury. All of these neuroprotective effects of minocycline were prevented by AM630. A cannabinoid CB2 agonist (JWH133) was used to strengthen the hypothesis, which showed the identical neuroprotective effects of minocycline. Our study demonstrates, for the first time, that minocycline attenuates neuroinflammation and brain injury in a rat model of GMH, and activation of CBR2 was partially involved in these processes. PMID:25833102

  15. Recombinant human interleukin-1 receptor antagonist promotes M1 microglia biased cytokines and chemokines following human traumatic brain injury.

    Science.gov (United States)

    Helmy, Adel; Guilfoyle, Mathew R; Carpenter, Keri Lh; Pickard, John D; Menon, David K; Hutchinson, Peter J

    2016-08-01

    Interleukin-1 receptor antagonist (IL1ra) has demonstrated efficacy in a wide range of animal models of neuronal injury. We have previously published a randomised controlled study of IL1ra in human severe TBI, with concomitant microdialysis and plasma sampling of 42 cytokines and chemokines. In this study, we have used partial least squares discriminant analysis to model the effects of drug administration and time following injury on the cytokine milieu within the injured brain. We demonstrate that treatment with rhIL1ra causes a brain-specific modification of the cytokine and chemokine response to injury, particularly in samples from the first 48 h following injury. The magnitude of this response is dependent on the concentration of IL1ra achieved in the brain extracellular space. Chemokines related to recruitment of macrophages from the plasma compartment (MCP-1) and biasing towards a M1 microglial phenotype (GM-CSF, IL1) are increased in patient samples in the rhIL1ra-treated patients. In control patients, cytokines and chemokines biased to a M2 microglia phenotype (IL4, IL10, MDC) are relatively increased. This pattern of response suggests that a simple classification of IL1ra as an 'anti-inflammatory' cytokine may not be appropriate and highlights the importance of the microglial response to injury. PMID:26661249

  16. Hypoxia regulates Toll-like receptor-9 expression and invasive function in human brain cancer cells in vitro

    Science.gov (United States)

    SANDHOLM, JOUKO; TUOMELA, JOHANNA; KAUPPILA, JOONAS H.; HARRIS, KEVIN W.; GRAVES, DAVID; SELANDER, KATRI S.

    2014-01-01

    Toll-like receptor-9 (TLR9) is a cellular DNA sensor of the innate immune system. TLR9 is widely expressed in a number of tumors, including brain cancer; however, little is known regarding its regulation and involvement in cancer pathophysiology. The present study demonstrated that hypoxia upregulates and downregulates TLR9 expression in human brain cancer cells in vitro, in a cell-specific manner. In addition, hypoxia-induced TLR9 upregulation was associated with hypoxia-induced invasion; however, such invasion was not detected in cells where hypoxia had suppressed TLR9 expression. Furthermore, suppression of TLR9 expression through TLR9 siRNA resulted in an upregulation of matrix metalloproteinase (MMP)-2, -9 and -13 and tissue inhibitor of matrix metalloproteinases-3 (TIMP-3) mRNA, and a decreased invasion of cells in normoxia, in a cell-specific manner. In cells where hypoxia induced TLR9 expression, TLR9 expression and invasion were reduced by TLR9 siRNA. The decreased invasion observed in hypoxia was associated with the decreased expression of the MMPs and a concomitant increase in TIMP-3 expression. In conclusion, hypoxia regulates the invasion of brain cancer cells in vitro in a TLR9-dependent manner, which is considered to be associated with a complex expression pattern of TLR9-regulated mediators and inhibitors of invasion. PMID:24959259

  17. Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment.

    Science.gov (United States)

    Blank, Thomas; Detje, Claudia N; Spieß, Alena; Hagemeyer, Nora; Brendecke, Stefanie M; Wolfart, Jakob; Staszewski, Ori; Zöller, Tanja; Papageorgiou, Ismini; Schneider, Justus; Paricio-Montesinos, Ricardo; Eisel, Ulrich L M; Manahan-Vaughan, Denise; Jansen, Stephan; Lienenklaus, Stefan; Lu, Bao; Imai, Yumiko; Müller, Marcus; Goelz, Susan E; Baker, Darren P; Schwaninger, Markus; Kann, Oliver; Heikenwalder, Mathias; Kalinke, Ulrich; Prinz, Marco

    2016-04-19

    Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy. PMID:27096319

  18. Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival

    Science.gov (United States)

    Vajkoczy, Peter; Knyazev, Pjotr; Kunkel, Andrea; Capelle, Hans-Holger; Behrndt, Sandra; von Tengg-Kobligk, Hendrik; Kiessling, Fabian; Eichelsbacher, Uta; Essig, Marco; Read, Tracy-Ann; Erber, Ralf; Ullrich, Axel

    2006-01-01

    Malignant gliomas remain incurable brain tumors because of their diffuse-invasive growth. So far, the genetic and molecular events underlying gliomagenesis are poorly understood. In this study, we have identified the receptor tyrosine kinase Axl as a mediator of glioma growth and invasion. We demonstrate that Axl and its ligand Gas6 are overexpressed in human glioma cell lines and that Axl is activated under baseline conditions. Furthermore, Axl is expressed at high levels in human malignant glioma. Inhibition of Axl signaling by overexpression of a dominant-negative receptor mutant (AXL-DN) suppressed experimental gliomagenesis (growth inhibition >85%, P 72 days). A detailed analysis of the distinct hallmarks of glioma pathology, such as cell proliferation, migration, and invasion and tumor angiogenesis, revealed that inhibition of Axl signaling interfered with cell proliferation (inhibition 30% versus AXL-WT), glioma cell migration (inhibition 90% versus mock and AXL-WT, P < 0.05), and invasion (inhibition 62% and 79% versus mock and AXL-WT, respectively; P < 0.05). This study describes the identification, functional manipulation, in vitro and in vivo validation, and preclinical therapeutic inhibition of a target receptor tyrosine kinase mediating glioma growth and invasion. Our findings implicate Axl in gliomagenesis and validate it as a promising target for the development of approaches toward a therapy of these highly aggressive but, as yet, therapy-refractory, tumors. PMID:16585512

  19. Induction of nuclear receptors and drug resistance in the brain microvascular endothelial cells treated with antiepileptic drugs.

    Science.gov (United States)

    Lombardo, Laura; Pellitteri, Rosalia; Balazy, Michael; Cardile, Venera

    2008-05-01

    Our work contributes to the understanding of the mechanisms of drug resistance in epilepsis. This study aimed to investigate i) the levels of expression of P-glycoprotein (P-gp), and multidrug resistance-associated proteins (MRP)1 and 2, ii) the activation of the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), and iii) the relationship between increased P-gp and MRPs expression and PXR and CAR activation, in immortalized rat brain microvascular endothelial cell lines, GPNT and RBE4, following treatment with the antiepileptic drugs (AEDs), topiramate, phenobarbital, carbamazepine, tiagabine, levetiracetam, and phenytoin, using Western blotting and immunocytochemistry methods. Carbamazepine, phenobarbital and phenytoin induced the highest levels of P-gp and MPRs expression that was associated with increased activation of PXR and CAR receptors as compared to levetiracetam, tiagabine and topiramate. We conclude that P-gp and MRPs are differently overexpressed in GPNT and RBE4 by various AEDs and both PXR and CAR are involved in the drug-resistant epilepsy induced by carbamazepine, phenobarbital and phenytoin. PMID:18473823

  20. [18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor

    OpenAIRE

    Burns, H. Donald; Van Laere, Koen; Sanabria-Bohórquez, Sandra; Hamill, Terence G.; Bormans, Guy; Eng, Wai-si; Gibson, Ray; Ryan, Christine; Connolly, Brett; Patel, Shil; Krause, Stephen; Vanko, Amy; Van Hecken, Anne; DUPONT, Patrick; De Lepeleire, Inge

    2007-01-01

    [(18)F]MK-9470 is a selective, high-affinity, inverse agonist (human IC(50), 0.7 nM) for the cannabinoid CB1 receptor (CB1R) that has been developed for use in human brain imaging. Autoradiographic studies in rhesus monkey brain showed that [(18)F]MK-9470 binding is aligned with the reported distribution of CB1 receptors with high specific binding in the cerebral cortex, cerebellum, caudate/putamen, globus pallidus, substantia nigra, and hippocampus. Positron emission tomography (PET) imaging...

  1. Increase in brain 125I-cholecystokinin (CCK) receptor binding following chronic haloperidol treatment, intracisternal 6-hydroxydopamine or ventral tegmental lesions

    International Nuclear Information System (INIS)

    Specific 125I-CCK receptor binding was significantly increased in brain tissue taken from guinea pig or mouse following chronic (2-3 week) daily administration of haloperidol (2-3 mg/kg/day). Scatchard analysis indicated the increase in CCK binding was due to an increased receptor number (B max) with no change in affinity (Kd). In guinea pigs, the increased CCK binding was observed in the mesolimbic regions and frontal cortex, but not in striatum, hippocampus nor posterior cortex. In mice, however, the increases occurred in both pooled cerebral cortical-hippocampal tissue, and in the remainder of the brain. Enhanced CCK receptor binding was also observed in membranes prepared from whole brain of mice one month following intracisternal injection of 6-hydroxydopamine. Additionally, an increase in CCK binding was observed in mesolimbic regions and frontal cortex, but not striatum or hippocampus, of guinea pigs 3 weeks after an unilateral radiofrequency lesions of the ipsilateral ventral tegmentum. The present studies demonstrate that three different procedures which reduce dopaminergic function in the brain enhance CCK receptor binding. The data provide further support for a functional interrelationship between dopaminergic systems and CCK in some brain regions and raise the possibility that CCK may play a role in the antipsychotic action of neuroleptics

  2. Moderate exercise and chronic stress produce counteractive effects on different areas of the brain by acting through various neurotransmitter receptor subtypes: A hypothesis

    Directory of Open Access Journals (Sweden)

    Saha Asit K

    2006-09-01

    Full Text Available Abstract Background Regular, "moderate", physical exercise is an established non-pharmacological form of treatment for depressive disorders. Brain lateralization has a significant role in the progress of depression. External stimuli such as various stressors or exercise influence the higher functions of the brain (cognition and affect. These effects often do not follow a linear course. Therefore, nonlinear dynamics seem best suited for modeling many of the phenomena, and putative global pathways in the brain, attributable to such external influences. Hypothesis The general hypothesis presented here considers only the nonlinear aspects of the effects produced by "moderate" exercise and "chronic" stressors, but does not preclude the possibility of linear responses. In reality, both linear and nonlinear mechanisms may be involved in the final outcomes. The well-known neurotransmitters serotonin (5-HT, dopamine (D and norepinephrine (NE all have various receptor subtypes. The article hypothesizes that 'Stress' increases the activity/concentration of some particular subtypes of receptors (designated nts for each of the known (and unknown neurotransmitters in the right anterior (RA and left posterior (LP regions (cortical and subcortical of the brain, and has the converse effects on a different set of receptor subtypes (designated nth. In contrast, 'Exercise' increases nth activity/concentration and/or reduces nts activity/concentration in the LA and RP areas of the brain. These effects may be initiated by the activation of Brain Derived Neurotrophic Factor (BDNF (among others in exercise and its suppression in stress. Conclusion On the basis of this hypothesis, a better understanding of brain neurodynamics might be achieved by considering the oscillations caused by single neurotransmitters acting on their different receptor subtypes, and the temporal pattern of recruitment of these subtypes. Further, appropriately designed and planned experiments

  3. Toll-like receptor 4 mediates microglial activation and production of inflammatory mediators in neonatal rat brain following hypoxia: role of TLR4 in hypoxic microglia

    OpenAIRE

    Yao Linli; Kan Enci Mary; Lu Jia; Hao Aijun; Dheen S Thameem; Kaur Charanjit; Ling Eng-Ang

    2013-01-01

    Abstract Background Hypoxia induces microglial activation which causes damage to the developing brain. Microglia derived inflammatory mediators may contribute to this process. Toll-like receptor 4 (TLR4) has been reported to induce microglial activation and cytokines production in brain injuries; however, its role in hypoxic injury remains uncertain. We investigate here TLR4 expression and its roles in neuroinflammation in neonatal rats following hypoxic injury. Methods One day old Wistar rat...

  4. Brain angiogenesis inhibitor 1 (BAI1) is a pattern recognition receptor that mediates macrophage binding and engulfment of Gram-negative bacteria

    OpenAIRE

    Das, Soumita; Owen, Katherine A.; Ly, Kim T.; Park, Daeho; Black, Steven G.; Wilson, Jeffrey M.; Sifri, Costi D.; Ravichandran, Kodi S.; Ernst, Peter B.; Casanova, James E.

    2011-01-01

    Bacterial recognition by host cells is essential for initiation of infection and the host response. Bacteria interact with host cells via multiple pattern recognition receptors that recognize microbial products or pathogen-associated molecular patterns. In response to this interaction, host cell signaling cascades are activated that lead to inflammatory responses and/or phagocytic clearance of attached bacteria. Brain angiogenesis inhibitor 1 (BAI1) is a receptor that recognizes apoptotic cel...

  5. Effects of repeated treatment with fluoxetine and citalopram, 5-HT uptake inhibitors, on 5-HT1A and 5-HT2 receptors in the rat brain.

    OpenAIRE

    Klimek, V; Zak-Knapik, J; Mackowiak, M.

    1994-01-01

    Repeated treatment with fluoxetine and citalopram, which are potent 5-HT reuptake inhibitors, resulted in different regulation of 5-HT1A and 5-HT2 receptors in the rat brain. Their effects were compared with those of other antidepressants: imipramine, mianserin and levoprotiline. The density of 5-HT1A receptors, labelled with [3H]8-OH-DPAT, in the rat hippocampus was enhanced after citalopram, imipramine, mianserin and levoprotiline, but not altered after fluoxetine administration. [3H]Ketans...

  6. P2Y2 receptor up-regulation induced by guanosine or UTP in rat brain cultured astrocytes.

    Science.gov (United States)

    Ballerini, P; Di Iorio, P; Caciagli, F; Rathbone, M P; Jiang, S; Nargi, E; Buccella, S; Giuliani, P; D'Alimonte, I; Fischione, G; Masciulli, A; Romano, S; Ciccarelli, R

    2006-01-01

    Among P2 metabotropic ATP receptors, P2Y2 subtype seems to be peculiar as its upregulation triggers important biological events in different cells types. In non-stimulated cells including astrocytes, P2Y2 receptors are usually expressed at levels lower than P2Y1 sites, however the promoter region of the P2Y2 receptors has not yet been studied and little is known about the mechanisms underlying the regulation of the expression of this ATP receptor. We showed that not only UTP and ATP are the most potent and naturally occurring agonist for P2Y2 sites, but also guanosine induced an up-regulation of astrocyte P2Y2 receptor mRNA evaluated by Northern blot analysis. We also focused our attention on this nucleoside since in our previous studies it was reported to be released by cultured astrocytes and to exert different neuroprotective effects. UTP and guanosine-evoked P2Y2 receptor up-regulation in rat brain cultured astrocytes was linked to an increased P2Y2-mediated intracellular calcium response, thus suggesting an increased P2Y2 activity. Actinomycin D, a RNA polymerase inhibitor, abrogated both UTP and guanosine-mediated P2Y2 up-regulation, thus indicating that de novo transcription was required. The effect of UTP and guanosine was also evaluated in astrocytes pretreated with different inhibitors of signal transduction pathways including ERK, PKC and PKA reported to be involved in the regulation of other cell surface receptor mRNAs. The results show that ERK1-2/MAPK pathway play a key role in the P2Y2 receptor up-regulation mediated by either UTP or guanosine. Moreover, our data suggest that PKA is also involved in guanosine-induced transcriptional activation of P2Y2 mRNA and that increased intracellular calcium levels and PKC activation may also mediate P2Y2 receptor up-regulation triggered by UTP. The extracellular release of ATP under physiological and pathological conditions has been widely studied. On the contrary, little is known about the release of

  7. 1α,25-Dihydroxyvitamin D3-Liganded Vitamin D Receptor Increases Expression and Transport Activity of P-glycoprotein in Isolated Rat Brain Capillaries and Human and Rat Brain Microvessel Endothelial Cells

    OpenAIRE

    Durk, Matthew R.; Chan, Gary N.Y.; Campos, Christopher R.; Peart, John C.; Chow, Edwin C.Y.; Lee, Eason; Cannon, Ronald E.; Bendayan, Reina; Miller, David S.; Pang, K. Sandy

    2012-01-01

    MDR1/P-gp induction by the vitamin D receptor (VDR) was investigated in isolated rat brain capillaries and rat (RBE4) and human (hCMEC/D3) brain microvessel endothelial cell lines. Incubation of isolated rat brain capillaries with 10 nM of the VDR ligand, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] for 4 h increased P-gp protein expression (4-fold). Incubation with 1,25(OH)2D3 for 4 or 24 h increased P-gp transport activity (specific luminal accumulation of NBD-CSA, the fluorescent P-gp substrate...

  8. Correlations between the Memory-Related Behavior and the Level of Oxidative Stress Biomarkers in the Mice Brain, Provoked by an Acute Administration of CB Receptor Ligands

    Science.gov (United States)

    Kruk-Slomka, Marta; Boguszewska-Czubara, Anna; Slomka, Tomasz; Budzynska, Barbara; Biala, Grazyna

    2016-01-01

    The endocannabinoid system, through cannabinoid (CB) receptors, is involved in memory-related responses, as well as in processes that may affect cognition, like oxidative stress processes. The purpose of the experiments was to investigate the impact of CB1 and CB2 receptor ligands on the long-term memory stages in male Swiss mice, using the passive avoidance (PA) test, as well as the influence of these compounds on the level of oxidative stress biomarkers in the mice brain. A single injection of a selective CB1 receptor antagonist, AM 251, improved long-term memory acquisition and consolidation in the PA test in mice, while a mixed CB1/CB2 receptor agonist WIN 55,212-2 impaired both stages of cognition. Additionally, JWH 133, a selective CB2 receptor agonist, and AM 630, a competitive CB2 receptor antagonist, significantly improved memory. Additionally, an acute administration of the highest used doses of JWH 133, WIN 55,212-2, and AM 630, but not AM 251, increased total antioxidant capacity (TAC) in the brain. In turn, the processes of lipids peroxidation, expressed as the concentration of malondialdehyde (MDA), were more advanced in case of AM 251. Thus, some changes in the PA performance may be connected with the level of oxidative stress in the brain. PMID:26839719

  9. Correlations between the Memory-Related Behavior and the Level of Oxidative Stress Biomarkers in the Mice Brain, Provoked by an Acute Administration of CB Receptor Ligands

    Directory of Open Access Journals (Sweden)

    Marta Kruk-Slomka

    2016-01-01

    Full Text Available The endocannabinoid system, through cannabinoid (CB receptors, is involved in memory-related responses, as well as in processes that may affect cognition, like oxidative stress processes. The purpose of the experiments was to investigate the impact of CB1 and CB2 receptor ligands on the long-term memory stages in male Swiss mice, using the passive avoidance (PA test, as well as the influence of these compounds on the level of oxidative stress biomarkers in the mice brain. A single injection of a selective CB1 receptor antagonist, AM 251, improved long-term memory acquisition and consolidation in the PA test in mice, while a mixed CB1/CB2 receptor agonist WIN 55,212-2 impaired both stages of cognition. Additionally, JWH 133, a selective CB2 receptor agonist, and AM 630, a competitive CB2 receptor antagonist, significantly improved memory. Additionally, an acute administration of the highest used doses of JWH 133, WIN 55,212-2, and AM 630, but not AM 251, increased total antioxidant capacity (TAC in the brain. In turn, the processes of lipids peroxidation, expressed as the concentration of malondialdehyde (MDA, were more advanced in case of AM 251. Thus, some changes in the PA performance may be connected with the level of oxidative stress in the brain.

  10. "Neuro-semeiotics" and "free-energy minimization" suggest a unified perspective for integrative brain actions: focus on receptor heteromers and Roamer type of volume transmission.

    Science.gov (United States)

    Agnati, Luigi F; Guidolin, Diego; Marcoli, Manuela; Genedani, Susanna; Borroto-Escuela, Dasiel; Maura, Guido; Fuxe, Kjell

    2014-01-01

    Two far-reaching theoretical approaches, namely "Neuro-semeiotics" (NS) and "Free-energy Minimization" (FEM), have been recently proposed as frames within which to put forward heuristic hypotheses on integrative brain actions. In the present paper these two theoretical approaches are briefly discussed in the perspective of a recent model of brain architecture and information handling based on what we suggest calling Jacob's tinkering principle, whereby "to create is to recombine!". The NS and FEM theoretical approaches will be discussed from the perspective both of the Roamer-Type Volume Transmission (especially exosome-mediated) of intercellular communication and of the impact of receptor oligomers and Receptor-Receptor Interactions (RRIs) on signal recognition/decoding processes. In particular, the Bio-semeiotics concept of "adaptor" will be used to analyze RRIs as an important feature of NS. Furthermore, the concept of phenotypic plasticity of cells will be introduced in view of the demonstration of the possible transfer of receptors (i.e., adaptors) into a computational network via exosomes (see also Appendix). Thus, Jacob's tinkering principle will be proposed as a theoretical basis for some learning processes both at the network level (Turing-like type of machine) and at the molecular level as a consequence of both the plastic changes in the adaptors caused by the allosteric interactions in the receptor oligomers and the intercellular transfer of receptors. Finally, on the basis of NS and FEM theories, a unified perspective for integrative brain actions will be proposed. PMID:25175453

  11. Brain penetration of telmisartan, a unique centrally acting angiotensin II type 1 receptor blocker, studied by PET in conscious rhesus macaques

    International Nuclear Information System (INIS)

    Introduction: Telmisartan is a widely used, long-acting antihypertensive agent. Known to be a selective angiotensin II type 1 (AT1) receptor (AT1R) blocker (ARB), telmisartan acts as a partial agonist of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and inhibits centrally mediated effects of angiotensin II in rats following peripheral administration, although the brain penetration of telmisartan remains unclear. We investigated the brain concentration and localization of telmisartan using 11 C-labeled telmisartan and positron emission tomography (PET) in conscious rhesus macaques. Methods: Three male rhesus macaques were bolus intravenously administered [11 C]telmisartan either alone or as a mixture with unlabeled telmisartan (1 mg/kg). Dynamic PET images were acquired for 95 min following administration. Blood samples were collected for the analysis of plasma concentration and metabolites, and brain and plasma concentrations were calculated from detected radioactivity using the specific activity of the administered drug preparation, in which whole blood radioactivity was used for the correction of intravascular blood radioactivity in brain. Results: Telmisartan penetrated into the brain little but enough to block AT1R and showed a consistently increasing brain/plasma ratio within the PET scanning period, suggesting slow clearance of the compound from the brain compared to the plasma clearance. Brain/plasma ratios at 30, 60, and 90 min were 0.06, 0.13, and 0.18, respectively. No marked localization according to the AT1R distribution was noted over the entire brain, even on tracer alone dosing. Conclusions: Telmisartan penetrated into the brain enough to block AT1R and showed a slow clearance from the brain in conscious rhesus macaques, supporting the long-acting and central responses of telmisartan as a unique property among ARBs.

  12. Stress-responsive heme oxygenase-1 isoenzyme participates in Toll-like receptor 4-induced inflammation during brain ischemia.

    Science.gov (United States)

    Wang, Rui; Wang, Shu-Ting; Wang, Yu-Di; Wu, Gang; Du, Yan; Qian, Man-Qing; Liang, Xing-Guang; Elbatreek, Mahmoud H; Yang, Hong-Yu; Liu, Zhi-Rong; Fukunaga, Kohji; Liu, Jian-Xiang; Lu, Ying-Mei

    2016-04-13

    Toll-like receptors (TLRs) are involved in the progression of ischemic brain injury and hence vascular dementia; however, the underlying mechanisms are largely unknown. Here, we have investigated the interrelationship between stress-responsive heme oxygenase (HO)-1 isoenzyme and TLR4 during chronic brain hypoperfusion. The right unilateral common carotid artery occlusion was performed by ligation of the right common carotid artery in C57BL/6J mice. The brain cortex or hippocampus was removed for western blotting and confocal immunofluorescence analysis. The link between HO-1 and TLR4 was further examined by silencing TLR4 and pharmacological inhibition of HO-1 in primary cultured cortical neurons. Cognitive dysfunction and decrease in cerebral blood flow in mice were observed 4 weeks after the occlusion. Our data further show that common carotid artery occlusion induced an increase in TLR4 and HO-1 protein levels. Although the administration of CoPP (10 mg/kg), HO-1 agonist, improved the cognitive dysfunction in a mice model of occlusion, western blot analysis in primary cultured cortical neurons showed that HO-1 was upregulated after lipopolysaccharide treatment; this was partially abolished by the TLR4 siRNA interference. The flow cytometry analysis showed that pharmacological inhibition of HO-1 by ZnPP (100 μM) further exaggerated lipopolysaccharide-induced neuronal cell death. Hence, stress-responsive HO-1 isoenzyme participates in TLR4-induced inflammation during chronic brain ischemia. The pharmacological manipulation of TLR4 or the HO-1 antioxidant defense pathway may represent a novel treatment strategy for neuronal protection in vascular dementia. PMID:26966782

  13. Effects of atrial and brain natriuretic peptides upon cyclic GMP levels, potassium transport, and receptor binding in rat astrocytes

    Energy Technology Data Exchange (ETDEWEB)

    Beaumont, K.; Tan, P.K. (Univ. of California, San Diego, La Jolla (USA))

    1990-02-01

    The ability of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) to alter cyclic GMP levels and NaKCl cotransport in rat neocortical astrocytes was determined. At concentrations of 10(-9)-10(-6) M, rat ANP99-126 (rANF), rat ANP102-126 (auriculin B), and rat ANP103-126 (atriopeptin III) stimulated 6- to 100-fold increases in cyclic GMP levels. Porcine BNP (pBNP) and rat BNP (rBNP) were 20%-90% as effective as rANF over most of this concentration range, although 10(-6) M pBNP produced a greater effect than rANF. NaKCl cotransport as measured by bumetanide-sensitive 86Rb+ influx was not altered by exposure of astrocytes to 10(-6)M rANF, pBNP, or rBNP. Both pBNP and rBNP, as well as rat ANP103-123 (atriopeptin I) and des(gl18, ser19, gly20, leu21, gly22) ANF4-23-NH2 (C-ANF4-23) strongly competed for specific 125I-rANF binding sites in astrocyte membranes with affinities ranging from 0.03 to 0.4 nM, suggesting that virtually all binding sites measured at subnanomolar concentrations of 125I-rANF were of the ANP-C (ANF-R2) receptor subtype. These receptors are thought to serve a clearance function and may be linked to a guanylate cyclase activity that is chemically and pharmacologically distinct from that coupled to ANP-A (ANF-R1) receptors. ANP receptors on astrocytes may function in limiting the access of ANP and BNP to neurons involved in body fluid and cardiovascular regulation.

  14. In vivo binding of 125I-LSD to serotonin 5-HT2 receptors in mouse brain

    International Nuclear Information System (INIS)

    The binding of 125I-LSD (2-[125I]-lysergic acid diethylamide) was studied in various mouse brain regions following intravenous injection of the radioligand. The high specific activity of 125I-LSD enabled the injection of low mass doses (14ng/kg), which are well below the threshold for induction of any known physiological effect of the probe. The highest levels of 125I-LSD binding were found in the frontal cortex, olfactory tubercles, extra-frontal cortex and striatum while the lowest level was found in the cerebellum. Binding was saturable in the frontal cortex but increased linearly in the cerebellum with increasing doses of 125I-LSD. Serotonergic compounds potently inhibited 125I-LSD binding in cortical regions, olfactory tubercles, and hypothalamus but had no effect in the cerebellum. Dopaminergic compounds caused partial inhibition of binding in the striatum while adrenergic compounds were inactive. From these studies the authors conclude that 125I-LSD labels serotonin 5-HT2 receptor sites in cortical regions with no indication that other receptor sites are labeled. In the olfactory tubercles and hypothalamus, 125I-LSD labeling occurs predominantly or entirely at serotonic 5-HT2 sites. In the striatum, 125I-LSD labels approximately equal proportions of serotonergic and dopaminergic sites. These data indicate that 125I-LSD labels serotonin receptors in vivo and suggests that appropriate derivatives of 2I-LSD may prove useful for tomographic imaging of serotonin 5-HT2 receptors in the mammalian cortex

  15. Effects of atrial and brain natriuretic peptides upon cyclic GMP levels, potassium transport, and receptor binding in rat astrocytes

    International Nuclear Information System (INIS)

    The ability of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) to alter cyclic GMP levels and NaKCl cotransport in rat neocortical astrocytes was determined. At concentrations of 10(-9)-10(-6) M, rat ANP99-126 (rANF), rat ANP102-126 (auriculin B), and rat ANP103-126 (atriopeptin III) stimulated 6- to 100-fold increases in cyclic GMP levels. Porcine BNP (pBNP) and rat BNP (rBNP) were 20%-90% as effective as rANF over most of this concentration range, although 10(-6) M pBNP produced a greater effect than rANF. NaKCl cotransport as measured by bumetanide-sensitive 86Rb+ influx was not altered by exposure of astrocytes to 10(-6)M rANF, pBNP, or rBNP. Both pBNP and rBNP, as well as rat ANP103-123 (atriopeptin I) and des[gl18, ser19, gly20, leu21, gly22] ANF4-23-NH2 (C-ANF4-23) strongly competed for specific 125I-rANF binding sites in astrocyte membranes with affinities ranging from 0.03 to 0.4 nM, suggesting that virtually all binding sites measured at subnanomolar concentrations of 125I-rANF were of the ANP-C (ANF-R2) receptor subtype. These receptors are thought to serve a clearance function and may be linked to a guanylate cyclase activity that is chemically and pharmacologically distinct from that coupled to ANP-A (ANF-R1) receptors. ANP receptors on astrocytes may function in limiting the access of ANP and BNP to neurons involved in body fluid and cardiovascular regulation

  16. Calcium-permeable ion channels involved in glutamate receptor-independent ischemic brain injury

    Institute of Scientific and Technical Information of China (English)

    Ming-hua LI; Koichi INOUE; Hong-fang SI; Zhi-gang XIONG

    2011-01-01

    Brain ischemia is a leading cause of death and long-term disabilities worldwide. Unfortunately, current treatment is limited to thrombolysis, which has limited success and a potential side effect of intracerebral hemorrhage. Searching for new cell injury mechanisms and therapeutic interventions has become a major challenge in the field. It has been recognized for many years that intracellular Ca2+overload in neurons is essential for neuronal injury associated with brain ischemia. However, the exact pathway(s) underlying the toxic Ca2+ loading remained elusive. This review discusses the role of two Ca2+-permeable cation channels, TRPM7 and acid-sensing channels, in glutamate-independent Ca2+ toxicity associated with brain ischemia.

  17. Brain serotonin 2A receptor binding: Relations to body mass index, tobacco and alcohol use

    DEFF Research Database (Denmark)

    Erritzoe, D.; Frokjaer, V. G.; Haugbol, S.;

    2009-01-01

    to increased food and alcohol intake, and conversely, stimulation of the serotonergic system induces weight reduction and decreased food/alcohol intake as well as tobacco smoking. To investigate whether body weight, alcohol intake and tobacco smoking were related to the regulation of the cerebral serotonin 2A...... receptor (5-HT(2A)) in humans, we tested in 136 healthy human subjects if body mass index (BMI), degree of alcohol consumption and tobacco smoking was associated to the cerebral in vivo 5-HT(2A) receptor binding as measured with (18)F-altanserin PET. The subjects' BMI's ranged from 18.4 to 42.8 (25...

  18. Application of 5-hydroxytryptamine receptor imaging for study of neuropsychiatric disorders and brain functions

    International Nuclear Information System (INIS)

    In the central nervous system, the widely distributed 5-hydroxytryptamine (5-HT)receptors are involved in regulating a large number of psychological and physiological functions, including mood, sleep, endocrine and autonomic nervous system. Abnormal 5-HT transmission has been implicated in a variety of neuropsychiatric disorders, such as pain, depression and epilepsy. With the development of radioligands, non-invasive nuclear imaging technique with exquisite sensitivity and specificity has been applied for delineation of neurotransmitter function in vivo. It does great benefit for researches of these diseases and development of drugs. This review provided an overview of 5-HT receptors radioligands and recent findings. (authors)

  19. Ultrastructural localization of cholinergic muscarinic receptors in rat brain cortical capillaries

    NARCIS (Netherlands)

    Luiten, PGM; deJong, GI; VanderZee, EA; vanDijken, H; Dijken, H. van

    1996-01-01

    Cholinergic innervation of the cerebrovasculature is known to regulate vascular tone, perfusion rate and permeability of the microvascular wall. Notably the cholinergic innervation of cerebral capillaries is of interest since these capillaries form the blood-brain barrier. Although there is a genera

  20. Local oxytocin expression and oxytocin receptor binding in the male rat brain is associated with aggressiveness

    NARCIS (Netherlands)

    Calcagnoli, Federica; de Boer, Sietse F.; Beiderbeck, Daniela I.; Althaus, Monika; Koolhaas, Jaap M.; Neumann, Inga D.

    2014-01-01

    We recently demonstrated in male wild-type Groningen rats that enhancing brain oxytocin (OXT) levels acutely produces marked pro-social explorative and anti-aggressive effects. Moreover, these pharmacologically-induced changes are moderated by the individual's aggressive phenotype, suggesting an inv

  1. Toll-like receptor 2 signaling in response to brain injury: an innate bridge to neuroinflammation

    DEFF Research Database (Denmark)

    Babcock, Alicia; Wirenfeldt, Martin; Holm, Thomas;

    2006-01-01

    -mutant mice. Consistent with the fact that responses in knock-out mice had all returned to wild-type levels by 8 d, there was no evidence for effects on neuronal plasticity at 20 d. These results identify a role for TLR2 signaling in the early glial response to brain injury, acting as an innate bridge to...

  2. AGE-RELATED CHANGES IN RECEPTOR-MEDIATED PHOSPHOINOSITIDE HYDROLYSIS IN VARIOUS REGIONS OF RAT BRAIN

    Science.gov (United States)

    The effects of age on cholinergic markers and receptor-stimulated phosphoinositide hydrolysis was dined in the frontal cortex and striatum of male Fischer-344 rats. holine acetyltransferase activity was decreased 27% in the striatum of aged (24 month) rats cared to young (3 month...

  3. Flavylium salts as in vitro precursors of potent ligands to brain GABA-A receptors

    DEFF Research Database (Denmark)

    Kueny-Stotz, Marie; Chassaing, Stefan; Brouillard, Raymond;

    2008-01-01

    The synthesis of a series of derivatized flavylium cations was undertaken and the affinity to the benzodiazepine binding site of the GABA-A receptor evaluated. The observed high affinity for some derivatives (sub-muM range) was explained by an in vitro transformation of the flavylium cations into...

  4. Changes of brain neuropeptide Y and its receptors in rats with flurazepam tolerance and dependence

    Institute of Scientific and Technical Information of China (English)

    Li-ping ZHANG; Li WANG

    2005-01-01

    Aim: Anticonvulsant tolerance and dependence are two obstacles that restrict the clinical use of benzodiazepines (BDZ). In order to explore the mechanism of these two adverse reactions, changes of neuropeptide Y (NPY) and its receptors in the hippocampus of rat models, in relation to flurazepam (FZP, a member of BDZ) tolerance and dependence, were investigated. Methods: The mRNA of preproNPY and its receptors (Y1, Y2, and Y5) in the hippocampus were determined by competitive RT-PCR, and the distribution of NPY in the hippocampus was examined by immunohistochemistry. Results: A decrease of preproNPY mRNA in the hippocampus was foundin tolerant and dependent rats. The level ofpreproNPY mRNA in the hippocampus was reversely correlated with the degree of tolerance and dependence, measured by the threshold of pentylenetetrazol-induced seizures.Immunohistochemistry indicated a decrease of NPY-immunoreactive material in neurons of the CA1, CA3, and dentate gyrus regions of both tolerant and dependent rats. The mRNA of NPY receptors Y1 and Y5 decreased in tolerant rats but did not change in dependent rats. The mRNA of NPY receptor Y2 increased in tolerant rats but decreased in dependent rats. Conclusion: A decrease of NPY in the hippocampus might be involved in anticonvulsant tolerance and dependence following long-term treatment with FZP. Y1, Y2, and Y5 mRNA were also altered in FZP tolerance and dependence.

  5. Differentiation of extrastriatal dopamine D2 receptor density and affinity in the human brain using PET.

    Science.gov (United States)

    Olsson, Hans; Halldin, Christer; Farde, Lars

    2004-06-01

    Dopaminergic neurotransmission in extrastriatal regions may play a crucial role in the pathophysiology and treatment of neuropsychiatric disorders. The high-affinity radioligands [(11)C]FLB 457, [(123)I]epidepride, and [(18)F]fallypride are now used in clinical studies to measure these low-density receptor populations in vivo. However, a single determination of the regional binding potential (BP) does not differentiate receptor density (B(max)) from the apparent affinity (K(D)). In this positron emission tomography (PET) study, we measured extrastriatal dopamine D2 receptor density (B(max)) and apparent affinity (K(D)) in 10 healthy subjects using an in vivo saturation approach. Each subject participated in two to three PET measurements with different specific radioactivity of [(11)C]FLB 457. The commonly used simplified reference tissue model (SRTM) was used in a comparison of BP values with the B(max) values obtained from the saturation analysis. The calculated regional receptor density values were of the same magnitude (0.33-1.68 nM) and showed the same rank order as reported from postmortem studies, that is, in descending order thalamus, lateral temporal cortex, anterior cinguli, and frontal cortex. The affinity ranged from 0.27 to 0.43 nM, that is, approximately 10-20 times the value found in vitro (20 pM). The area under the cerebellar time activity curve (TAC) was slightly lower (11 +/- 8%, mean +/- SD, P = 0.004, n = 10) after injection of low as compared with high specific radioactivity, indicating sensitivity to the minute density of dopamine D2 receptors in the this region. The results of the present study support that dopamine D2 receptor density and affinity can be differentiated in low-density regions using a saturation approach. There was a significant (P < 0.001) correlation between the binding potential calculated with SRTM and the receptor density (B(max)), which supports the use of BP in clinical studies where differentiation of B(max) and K

  6. Influence of apolipoprotein E and its receptors on cerebral amyloid precursor protein metabolism following traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    ZHOU Shuai; SUN Xiao-chuan

    2012-01-01

    Traumatic brain injury (TBI) is the leading cause of mortality and disability among young individuals in our society,and globally the incidence of TBI is rising sharply.Mounting evidence has indicated that apolipoprotein E (apoE:protein; APOE:gene) genotype influences the outcome after TBI.The proposed mechanism by which APOE affects the clinicopathological consequences of TBI is multifactorial and includes amyloid deposition,disruption of lipid distribution,dysfunction of mitochondrial energy production,oxidative stress and increases intracellular calcium in response to injury.This paper reviews the current state of knowledge regarding the influence of apoE and its receptors on cerebral amyloid betaprotein precursor metabolism following TBI.

  7. Natriuretic peptide receptor-3 underpins the disparate regulation of endothelial and vascular smooth muscle cell proliferation by C-type natriuretic peptide

    OpenAIRE

    Khambata, Rayomand S.; Panayiotou, Catherine M; Hobbs, Adrian J

    2011-01-01

    BACKGROUND AND PURPOSE C-type natriuretic peptide (CNP) is an endothelium-derived vasorelaxant, exerting anti-atherogenic actions in the vasculature and salvaging the myocardium from ischaemic injury. The cytoprotective effects of CNP are mediated in part via the Gi-coupled natriuretic peptide receptor (NPR)3. As GPCRs are well-known to control cell proliferation, we investigated if NPR3 activation underlies effects of CNP on endothelial and vascular smooth muscle cell mitogenesis. EXPERIMENT...

  8. Effect of brain-derived neurotropic factor released from hypoxic astrocytes on gamma-aminobutyric acid type A receptor function in normal hippocampal neurons

    Institute of Scientific and Technical Information of China (English)

    Hongliang Liu; Tijun Dai

    2011-01-01

    Astrocytes can release increased levels of brain-derived neurotrophic factor during cerebral ischemia, but it is unclear whether brain-derived neurotrophic factor affects γ-aminobutyric acid type A receptor function in normal neurons. Results from this study demonstrated that γ-aminobutyric acid at 100 μmol/L concentration raised the intracellular calcium level in neurons treated with medium from cultured hypoxic astrocytes, and the rise in calcium level could be inhibited by γ-aminobutyric acid type A receptor antagonist bicuculline or brain-derived neurotrophic factor receptor antagonist k252a. Γ-aminobutyric acid type A-gated current induced by 100 μmol/L γ-aminobutyric acid was in an inward direction in physiological conditions, but shifted to the outward direction in neurons when treated with the medium from cultured hypoxic astrocytes, and this effect could be inhibited by k252a. The reverse potential was shifted leftward to -93 Mv, which could be inhibited by k252a and Na+-K+-Cl- cotransporter inhibitor bumetanide. Brain-derived neurotrophic factor was released from hypoxic astrocytes at a high level. It shifted the reverse potential of γ-aminobutyric acid type A-gated currents leftward in normal neurons by enhancing the function of Na+-K+-Cl- cotransporter, and caused γ-aminobutyric acid to exert an excitatory effect by activating γ-aminobutyric acid type A receptor.

  9. Pharmacokinetics and Brain Uptake in the Rhesus Monkey of a Fusion Protein of Arylsulfatase A and a Monoclonal Antibody Against the Human Insulin Receptor

    Science.gov (United States)

    Boado, Ruben J.; Lu, Jeff Zhiqiang; Hui, Eric K.-W.; Sumbria, Rachita K.; Pardridge, William M.

    2014-01-01

    Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder of the brain caused by mutations in the gene encoding the lysosomal sulfatase, arylsulfatase A (ASA). It is not possible to treat the brain in MLD with recombinant ASA, because the enzyme does not cross the blood-brain barrier (BBB). In the present investigation, a BBB-penetrating IgG-ASA fusion protein is engineered and expressed, where the ASA monomer is fused to the carboxyl terminus of each heavy chain of an engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb crosses the BBB via receptor-mediated transport on the endogenous BBB insulin receptor, and acts as a molecular Trojan horse to ferry the ASA into brain from blood. The HIRMAb-ASA is expressed in stably transfected Chinese hamster ovary cells grown in serum free medium, and purified by protein A affinity chromatography. The fusion protein retains high affinity binding to the HIR, EC50 = 0.34 ± 0.11 nM, and retains high ASA enzyme activity, 20 ± 1 units/mg. The HIRMAb-ASA fusion protein is endocytosed and triaged to the lysosomal compartment in MLD fibroblasts. The fusion protein was radio-labeled with the Bolton-Hunter reagent, and the [125I]-HIRMAb-ASA rapidly penetrates the brain in the Rhesus monkey following intravenous administration. Film and emulsion autoradiography of primate brain shows global distribution of the fusion protein throughout the monkey brain. These studies describe a new biological entity that is designed to treat the brain of humans with MLD following non-invasive, intravenous infusion of an IgG-ASA fusion protein. PMID:23192358

  10. Evaluation of MRI and cannabinoid type 1 receptor PET templates constructed using DARTEL for spatial normalization of rat brains

    Energy Technology Data Exchange (ETDEWEB)

    Kronfeld, Andrea; Müller-Forell, Wibke [Institute of Neuroradiology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, Mainz 55131 (Germany); Buchholz, Hans-Georg; Maus, Stephan; Reuss, Stefan; Schreckenberger, Mathias; Miederer, Isabelle, E-mail: isabelle.miederer@unimedizin-mainz.de [Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, Mainz 55131 (Germany); Lutz, Beat [Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, Mainz 55128 (Germany)

    2015-12-15

    Purpose: Image registration is one prerequisite for the analysis of brain regions in magnetic-resonance-imaging (MRI) or positron-emission-tomography (PET) studies. Diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) is a nonlinear, diffeomorphic algorithm for image registration and construction of image templates. The goal of this small animal study was (1) the evaluation of a MRI and calculation of several cannabinoid type 1 (CB1) receptor PET templates constructed using DARTEL and (2) the analysis of the image registration accuracy of MR and PET images to their DARTEL templates with reference to analytical and iterative PET reconstruction algorithms. Methods: Five male Sprague Dawley rats were investigated for template construction using MRI and [{sup 18}F]MK-9470 PET for CB1 receptor representation. PET images were reconstructed using the algorithms filtered back-projection, ordered subset expectation maximization in 2D, and maximum a posteriori in 3D. Landmarks were defined on each MR image, and templates were constructed under different settings, i.e., based on different tissue class images [gray matter (GM), white matter (WM), and GM + WM] and regularization forms (“linear elastic energy,” “membrane energy,” and “bending energy”). Registration accuracy for MRI and PET templates was evaluated by means of the distance between landmark coordinates. Results: The best MRI template was constructed based on gray and white matter images and the regularization form linear elastic energy. In this case, most distances between landmark coordinates were <1 mm. Accordingly, MRI-based spatial normalization was most accurate, but results of the PET-based spatial normalization were quite comparable. Conclusions: Image registration using DARTEL provides a standardized and automatic framework for small animal brain data analysis. The authors were able to show that this method works with high reliability and validity. Using DARTEL

  11. Opioid receptor imaging and displacement studies with [6-O-[11C]methyl]buprenorphine in baboon brain

    International Nuclear Information System (INIS)

    Buprenorphine (BPN) is a mixed opiate agonist-antagonist used as an analgesic and in the treatment of opiate addiction. We have used [6-O-[11C]methyl]buprenorphine ([11C]BPN) to measure the regional distribution in baboon brain, the test-retest stability of repeated studies in the same animal, the displacement of the labeled drug by naloxone in vivo, and the tissue distribution in mice. The regional distribution of radioactivity in baboon brain determined with PET was striatum > thalamus > cingulate gyrus > frontal cortex > parietal cortex > occipital cortex > cerebellum. This distribution corresponded to opiate receptor density and to previously published data (37). The tracer uptake in adult female baboons showed no significant variation in serial scans in the same baboon with no intervention in the same scanning session. HPLC analysis of baboon plasma showed the presence of labeled metabolites with 92% ± 2.2% and 43% ± 14.4% of the intact tracer remaining at 5 and 30 min, respectively. Naloxone, an opiate receptor antagonist, administered 30-40 min after tracer injection at a dose of 1.0 mg/kg i.v., reduced [11C]BPN binding in thalamus, striatum, cingulate gyrus, and frontal cortex to values 0.25 to 0.60 of that with no intervention. There were minimal (11C]BPN can be displaced by naloxone in vivo, and they affirm the feasibility of using this tracer and displacement methodology for short-term kinetics studies with PET. Mouse tissue distribution data were used to estimate the radiation dosimetry to humans. The critical organ was the small intestine, with a radiation dose estimate to humans of 117 nrad/mCi

  12. Evaluation of MRI and cannabinoid type 1 receptor PET templates constructed using DARTEL for spatial normalization of rat brains

    International Nuclear Information System (INIS)

    Purpose: Image registration is one prerequisite for the analysis of brain regions in magnetic-resonance-imaging (MRI) or positron-emission-tomography (PET) studies. Diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) is a nonlinear, diffeomorphic algorithm for image registration and construction of image templates. The goal of this small animal study was (1) the evaluation of a MRI and calculation of several cannabinoid type 1 (CB1) receptor PET templates constructed using DARTEL and (2) the analysis of the image registration accuracy of MR and PET images to their DARTEL templates with reference to analytical and iterative PET reconstruction algorithms. Methods: Five male Sprague Dawley rats were investigated for template construction using MRI and [18F]MK-9470 PET for CB1 receptor representation. PET images were reconstructed using the algorithms filtered back-projection, ordered subset expectation maximization in 2D, and maximum a posteriori in 3D. Landmarks were defined on each MR image, and templates were constructed under different settings, i.e., based on different tissue class images [gray matter (GM), white matter (WM), and GM + WM] and regularization forms (“linear elastic energy,” “membrane energy,” and “bending energy”). Registration accuracy for MRI and PET templates was evaluated by means of the distance between landmark coordinates. Results: The best MRI template was constructed based on gray and white matter images and the regularization form linear elastic energy. In this case, most distances between landmark coordinates were <1 mm. Accordingly, MRI-based spatial normalization was most accurate, but results of the PET-based spatial normalization were quite comparable. Conclusions: Image registration using DARTEL provides a standardized and automatic framework for small animal brain data analysis. The authors were able to show that this method works with high reliability and validity. Using DARTEL templates

  13. Mapping oxytocin receptor gene expression in the mouse brain and mammary gland using an oxytocin receptor-LacZ reporter mouse.

    Science.gov (United States)

    Gould, B R; Zingg, H H

    2003-01-01

    The hypothalamic nonapeptide oxytocin (OT) has an established role as a circulating hormone but can also act as a neurotransmitter and as a neuromodulator by interacting with its central OT receptor (OTR). To understand the role of the OTR in the mouse brain we investigated the expression of the OTR gene at the cellular level. We targeted the lacZ reporter gene to the OTR gene locus downstream of the endogenous OTR regulatory elements. Using lactating mouse mammary gland as a control for OTR promoter directed specificity of lacZ gene expression, X-gal histochemistry on tissue sections confirmed that gene expression was restricted to the myoepithelial cells. We also identified for the first time in mice the expression of the OTR gene in neighbouring adipocytes. Further, investigation in the mouse brain identified numerous nuclei containing neurons expressing the OTR gene. Whilst some of these regions had been described for rat or sheep, the OTR-LacZ reporter mouse enabled the identification of novel sites of central OTR gene expression. These regions include the accessory olfactory bulb, the medial septal nucleus, the posterolateral cortical amygdala nucleus, the posterior aspect of the basomedial amygdala nucleus, the medial part of the supramammillary nucleus, the dorsotuberomammillary nucleus, the medial and lateral entorhinal cortices, as well as specific dorsal tegmental, vestibular, spinal trigeminal, and solitary tract subnuclei. By mapping the distribution of OTR gene expression, depicted through histochemical detection of beta-galactosidase, we were able to identify single OTR gene expressing neurons and small neuron clusters that would have remained undetected by conventional approaches. These novel sites of OTR gene expression suggest additional functions of the oxytocinergic system in the mouse. These results lay the foundation for future investigation into the neural role of the OTR and provide a useful model for further study of oxytocin functions in

  14. Specific in vivo binding in the rat brain of [18F]RP 62203: A selective 5-HT2A receptor radioligand for positron emission tomography

    International Nuclear Information System (INIS)

    In vivo pharmacokinetic and brain binding characteristics of [18F]RP 62203, a selective high-affinity serotonergic 5-HT2A receptor antagonist, were assessed in the rat following intravenous injection of trace amount of the radioligand. The radioactive distribution profile observed in the brain 60 min after injection was characterized by greater than fourfold higher uptake in neocortex as compared to cerebellum (0.38 ± 0.07% injected dose/g, % ID/g and 0.08 ± 0.01 ID/g, respectively), consistent with in vivo specific binding to the 5-HT2A receptor. Furthermore, specific [18F]RP 62203 binding significantly correlated with the reported in vitro distribution of 5-HT2A receptors, but not with known concentration profiles of dopaminergic D2 or adrenergic α1 receptors. Finally, detectable specific binding was abolished by pretreatment with large doses of ritanserin, a selective 5-HT2A antagonist, which resulted in uniform uptakes across cortical, striatal and cerebellar tissues. Thus, [18F]RP 62203 appears to be a promising selective tool to visualize and quantify 5-HT2A brain receptors in vivo with positron emission tomography

  15. Assessment of {alpha}7 nicotinic acetylcholine receptor availability in juvenile pig brain with [{sup 18}F]NS10743

    Energy Technology Data Exchange (ETDEWEB)

    Deuther-Conrad, Winnie; Fischer, Steffen; Hiller, Achim; Funke, Uta; Brust, Peter [Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmacy, Leipzig (Germany); Becker, Georg; Sabri, Osama [Univ. of Leipzig, Dept. of Nuclear Medicine, Leipzig (Germany); Cumming, Paul; Xiong, Guoming [Univ. of Munich, Dept. of Nuclear Medicine, Munich (Germany); Peters, Dan [NeuroSearch A/S, Ballerup (Denmark)

    2011-08-15

    To conduct a quantitative PET assessment of the specific binding sites in the brain of juvenile pigs for [{sup 18}F]NS10743, a novel diazabicyclononane derivative targeting {alpha}7 nicotinic acetylcholine receptors ({alpha}7 nAChRs). Dynamic PET recordings were made in isoflurane-anaesthetized juvenile pigs during 120 min after administration of [{sup 18}F]NS10743 under baseline conditions (n = 3) and after blocking of the {alpha}7 nAChR with NS6740 (3 mg.kg{sup -1} bolus + 1 mg.kg{sup -1}.h{sup -1} continuous infusion; n = 3). Arterial plasma samples were collected for determining the input function of the unmetabolized tracer. Kinetic analysis of regional brain time-radioactivity curves was performed, and parametric maps were calculated relative to arterial input. Plasma [{sup 18}F]NS10743 passed readily into the brain, with peak uptake occurring in {alpha}7 nAChR-expressing brain regions such as the colliculi, thalamus, temporal lobe and hippocampus. The highest SUV{sub max} was approximately 2.3, whereas the lowest uptake was in the olfactory bulb (SUV{sub max} 1.53 {+-} 0.32). Administration of NS6740 significantly decreased [{sup 18}F]NS10743 binding late in the emission recording throughout the brain, except in the olfactory bulb, which was therefore chosen as reference region for calculation of BP{sub ND}. The baseline BP{sub ND} ranged from 0.39 {+-} 0.08 in the cerebellum to 0.76 {+-} 0.07 in the temporal lobe. Pretreatment and constant infusion with NS6740 significantly reduced the BP{sub ND} in regions with high [{sup 18}F]NS10743 binding (temporal lobe -29%, p = 0.01; midbrain: -35%, p = 0.02), without significantly altering the BP{sub ND} in low binding regions (cerebellum: -16%, p = 0.2). This study confirms the potential of [{sup 18}F]NS10743 as a target-specific radiotracer for the molecular imaging of central {alpha}7 nAChRs by PET. (orig.)

  16. Autoradiographic visualization of A 1-adenosine receptors in brain and peripheral tissues of rat and guinea pig using 125I-HPIA

    International Nuclear Information System (INIS)

    A 1-adenosine receptors were identified in sections of rat brain and guinea pig kidney with the radioiodinated agonist 125I-N6-p-hydroxyphenylisopropyladenosine (125I-HPIA) using in vitro autoradiography. The affinities of adenosine receptor ligands in competing with 125I-HPIA binding to tissue sections were in good agreement with those found in membranes and indicate that the binding site represents an A 1 pattern of [3H]N6-cyclohexyladenosine ([3H]CHA) binding sites determined previously, with highest densities in the hippocampus and dentate gyrus, the cerebellar cortex, some thalamic nuclei and certain layers of the cerebral cortex. In the guinea pig kidney 125I-HPIA labelled longitudinal structures in the medulla. This study demonstrates that 125I-HPIA allows the autoradiographic detection of A-1 adenosine receptors in the brain and peripheral organs and has the advantage of short exposure times (author)

  17. Activation of AMPA Receptors Mediates the Antidepressant Action of Deep Brain Stimulation of the Infralimbic Prefrontal Cortex.

    Science.gov (United States)

    Jiménez-Sánchez, Laura; Castañé, Anna; Pérez-Caballero, Laura; Grifoll-Escoda, Marc; López-Gil, Xavier; Campa, Leticia; Galofré, Mireia; Berrocoso, Esther; Adell, Albert

    2016-06-01

    Although deep brain stimulation (DBS) has been used with success in treatment-resistant depression, little is known about its mechanism of action. We examined the antidepressant-like activity of short (1 h) DBS applied to the infralimbic prefrontal cortex in the forced swim test (FST) and the novelty-suppressed feeding test (NSFT). We also used in vivo microdialysis to evaluate the release of glutamate, γ-aminobutyric acid, serotonin, dopamine, and noradrenaline in the prefrontal cortex and c-Fos immunohistochemistry to determine the brain regions activated by DBS. One hour of DBS of the infralimbic prefrontal cortex has antidepressant-like effects in FST and NSFT, and increases prefrontal efflux of glutamate, which would activate AMPA receptors (AMPARs). This effect is specific of the infralimbic area since it is not observed after DBS of the prelimbic subregion. The activation of prefrontal AMPARs would result in a stimulation of prefrontal output to the brainstem, thus increasing serotonin, dopamine, and noradrenaline in the prefrontal cortex. Further, the activation of prefrontal AMPARs is necessary and sufficient condition for the antidepressant response of 1 h DBS. PMID:26088969

  18. A Multi-Route Model of Nicotine-Cotinine Pharmacokinetics, Pharmacodynamics and Brain Nicotinic Acetylcholine Receptor Binding in Humans

    Energy Technology Data Exchange (ETDEWEB)

    Teeguarden, Justin G.; Housand, Conrad; Smith, Jordan N.; Hinderliter, Paul M.; Gunawan, Rudy; Timchalk, Charles

    2013-02-01

    The pharmacokinetics of nicotine, the pharmacologically active alkaloid in tobacco responsible for addiction, are well characterized in humans. We developed a physiologically based pharmacokinetic/pharmacodynamic model of nicotine pharmacokinetics, brain dosimetry and brain nicotinic acetylcholine receptor (nAChRs) occupancy. A Bayesian framework was applied to optimize model parameters against multiple human data sets. The resulting model was consistent with both calibration and test data sets, but in general underestimated variability. A pharmacodynamic model relating nicotine levels to increases in heart rate as a proxy for the pharmacological effects of nicotine accurately described the nicotine related changes in heart rate and the development and decay of tolerance to nicotine. The PBPK model was utilized to quantitatively capture the combined impact of variation in physiological and metabolic parameters, nicotine availability and smoking compensation on the change in number of cigarettes smoked and toxicant exposure in a population of 10,000 people presented with a reduced toxicant (50%), reduced nicotine (50%) cigarette Across the population, toxicant exposure is reduced in some but not all smokers. Reductions are not in proportion to reductions in toxicant yields, largely due to partial compensation in response to reduced nicotine yields. This framework can be used as a key element of a dosimetry-driven risk assessment strategy for cigarette smoke constituents.

  19. Region-specific up-regulation of oxytocin receptor binding in the brain of mice following chronic nicotine administration.

    Science.gov (United States)

    Zanos, Panos; Georgiou, Polymnia; Metaxas, Athanasios; Kitchen, Ian; Winsky-Sommerer, Raphaelle; Bailey, Alexis

    2015-07-23

    Nicotine addiction is considered to be the main preventable cause of death worldwide. While growing evidence indicates that the neurohypophysial peptide oxytocin can modulate the addictive properties of several abused drugs, the regulation of the oxytocinergic system following nicotine administration has so far received little attention. Here, we examined the effects of long-term nicotine or saline administration on the central oxytocinergic system using [(125)I]OVTA autoradiographic binding in mouse brain. Male, 7-week old C57BL6J mice were treated with either nicotine (7.8 mg/kg daily; rate of 0.5 μl per hour) or saline for a period of 14-days via osmotic minipumps. Chronic nicotine administration induced a marked region-specific upregulation of the oxytocin receptor binding in the amygdala, a brain region involved in stress and emotional regulation. These results provide direct evidence for nicotine-induced neuroadaptations in the oxytocinergic system, which may be involved in the modulation of nicotine-seeking as well as emotional consequence of chronic drug use. PMID:26037668

  20. Effect of peptides corresponding to extracellular domains of serotonin 1B/1D receptors and melanocortin 3 and 4 receptors on hormonal regulation of adenylate cyclase in rat brain.

    Science.gov (United States)

    Shpakova, E A; Derkach, K V; Shpakov, A O

    2014-03-01

    The ligand-recognizing part of G protein-coupled receptors consists of their extracellular loops and N-terminal domain. Identification of these sites is essential for receptor mapping and for the development and testing of new hormone system regulators. The peptides corresponding by their structure to extracellular loop 2 of serotonin 1B/1D receptor (peptide 1), extracellular loop 3 of melanocortin 3 receptor (peptide 2), and N-terminal domain of melanocortin 4 (peptide 3) were synthesized by the solid-phase method. In synaptosomal membranes isolated from rat brain, peptide 1 (10(-5)-10(-4) M) attenuated the effects of 5-nonyloxytryptamine (selective agonist of serotonin 1B/1D receptor) and to a lesser extent serotonin and 5-methoxy-N,N-dimethyltryptamine acting on all the subtypes of serotonin receptor 1. Peptide 2 (10(-5)-10(-4) M) significantly reduced the adenylate cyclase-stimulating effect of γ-melanocyte-stimulating hormone (agonist of melanocortin receptor 3), but had no effect on the adenylate cyclase effect of THIQ (agonist melanocortin receptor 4). Peptide 3 reduced the adenylate cyclase-stimulating effects of THIQ and α-melanocyte-stimulating hormone (non-selective agonist of melanocortin receptors 3 and 4), but did not modulate the effect of γ-melanocyte-stimulating hormone. The effect of peptide 3 was weaker: it was observed at peptide 3 concentration of 10(-4) M. Peptides 1-3 did no change the adenylate cyclase-modulating effects of hormones acting through non-homologous receptors. Thus, the synthesized peptides specifically inhibited the regulatory effects of hormones acting through homologous receptors. This suggests that the corresponding extracellular domains are involved in ligand recognition and binding and determine functional activity of the receptor. PMID:24770752

  1. A switch in G protein coupling for type 1 corticotropin-releasing factor receptors promotes excitability in epileptic brains.

    Science.gov (United States)

    Narla, Chakravarthi; Scidmore, Tanner; Jeong, Jaymin; Everest, Michelle; Chidiac, Peter; Poulter, Michael O

    2016-01-01

    Anxiety and stress increase the frequency of epileptic seizures. These behavioral states induce the secretion of corticotropin-releasing factor (CRF), a 40-amino acid neuropeptide neurotransmitter that coordinates many behavioral responses to stress in the central nervous system. In the piriform cortex, which is one of the most seizurogenic regions of the brain, CRF normally dampens excitability. By contrast, CRF increased the excitability of the piriform cortex in rats subjected to kindling, a model of temporal lobe epilepsy. In nonkindled rats, CRF activates its receptor, a G protein (heterotrimeric guanosine triphosphate-binding protein)-coupled receptor, and signals through a Gαq/11-mediated pathway. After seizure induction, CRF signaling occurred through a pathway involving Gαs This change in signaling was associated with reduced abundance of regulator of G protein signaling protein type 2 (RGS2), which has been reported to inhibit Gαs-dependent signaling. RGS2 knockout mice responded to CRF in a similar manner as epileptic rats. These observations indicate that seizures produce changes in neuronal signaling that can increase seizure occurrence by converting a beneficial stress response into an epileptic trigger. PMID:27303056

  2. Characterization of a purified nicotinic receptor from rat brain by using idiotypic and anti-idiotypic antibodies

    International Nuclear Information System (INIS)

    The availability of an anti-nicotine monoclonal antibody has made it possible to further establish the nature of the nicotine recognition proteins purified from rat brain by affinity chromatography and to provide a highly sensitive assay for determining [3H]nicotine binding to the purified material. An enantiomeric analogue of nicotine. (-)-6-hydroxymethylnicotine, was used to prepare the affinity column. In addition, with the use of an anti-idiotypic monoclonal antibody, it was confirmed that the recognition site for nicotine resides on a protein complex composed of two components with molecular masses of 62 and 57 kDa. It was also demonstrated that the same two proteins could be purified by immunoaffinity chromatography with the use of an anti-idiotypic monoclonal antibody. With the use of the anti-nicotine antibody to measure [3H]nicotine binding, the purified material was shown to bind 250 pmol/mg of protein. By utilizing a procedure in which the purified receptor protein was conjugated to membranes by disulfide bonds, a binding activity of 80 pmol/mg was obtained. With the availability of sterospecific monoclonal antibodies to (-)-nicotine as well as monoclonal anti-idiotypic antibodies derived when the anti-nicotine antibodies were used as immunogens, additional procedures became available for the further characterization of the purified nicotine receptor and examining its (-)-[3H]nicotine-binding characteristics

  3. Higher expression of monocyte chemoattractant protein 1 and its receptor in brain tissue of intractable epilepsy patients.

    Science.gov (United States)

    Wang, Chunyan; Yang, Lihua; Zhang, Jiadong; Lin, Zhiguo; Qi, Jiping; Duan, Shurong

    2016-06-01

    We aimed to explore the pathogenesis of monocyte chemoattractant protein-1 (MCP1) and CC chemokine receptor 2 (CCR2) in brain tissue of patients with intractable epilepsy (IE). Hippocampi or temporal lobe tissues were obtained from 40 patients with IE and five patients without IE who had undergone surgical decompression and debridement. The levels of MCP1 and CCR2 were evaluated using immunohistochemistry. Pearson correlation analysis was employed to evaluate the correlation between levels of MCP1 and CCR2 in IE with or without hippocampal sclerosis (HS) and the disease duration, along with age. Higher levels of MCP1 (11.68±4.68% versus 1.72±1.54%) and CCR2 (11.54±4.65% versus 1.52±1.29%; Pcorrelated with the disease duration. However, no correlation was found in IE patients without HS. There was also no correlation between levels of MCP1 and CCR2 in IE patients with age, either with HS or without HS. These results suggest that MCP1 and its receptor may play a role in the pathogenesis and progression of IE. PMID:26810469

  4. Platelet activating factor receptor blockade enhances recovery after multifocal brain ischemia

    Energy Technology Data Exchange (ETDEWEB)

    Kochanek, P.M.; Dutka, A.J.; Kumaroo, K.K.; Hallenbech, J.M.

    1987-12-14

    The authors treated four anesthetized dogs with the platelet activating factor (PAF) receptor antagonist kadsurenone prior to 60 min of multifocal ischemia induced by air embolism, and measured neuronal recovery, blood flow and autologous /sup 111/In-labeled platelet accumulation for 4 h after ischemia. Four anesthetized animals with identical ischemia served as controls. Kadsurenone administered 5 min prior to ischemia and continuously throughout ischemia and recovery significantly enhanced recovery of cortical somatosensory evoked response (CSER) amplitude when compared to controls. They estimated platelet accumulation as /sup 111/In activity (cmp/g tissue) in the injured hemisphere minus that in the non-injured hemisphere. Kadsurenone treated animals did not exhibit significantly altered /sup 111/In labeled platelet accumulation when compared to controls. Beneficial effects of PAF receptor blockade other than those on platelet accumulation may be involved. 20 references, 1 figure.

  5. Platelet activating factor receptor blockade enhances recovery after multifocal brain ischemia

    International Nuclear Information System (INIS)

    The authors treated four anesthetized dogs with the platelet activating factor (PAF) receptor antagonist kadsurenone prior to 60 min of multifocal ischemia induced by air embolism, and measured neuronal recovery, blood flow and autologous 111In-labeled platelet accumulation for 4 h after ischemia. Four anesthetized animals with identical ischemia served as controls. Kadsurenone administered 5 min prior to ischemia and continuously throughout ischemia and recovery significantly enhanced recovery of cortical somatosensory evoked response (CSER) amplitude when compared to controls. They estimated platelet accumulation as 111In activity (cmp/g tissue) in the injured hemisphere minus that in the non-injured hemisphere. Kadsurenone treated animals did not exhibit significantly altered 111In labeled platelet accumulation when compared to controls. Beneficial effects of PAF receptor blockade other than those on platelet accumulation may be involved. 20 references, 1 figure

  6. Asymmetric Synthesis of Spirocyclic 2-Benzopyrans for Positron Emission Tomography of σ1 Receptors in the Brain

    Directory of Open Access Journals (Sweden)

    Katharina Holl

    2014-01-01

    Full Text Available Sharpless asymmetric dihydroxylation of styrene derivative 6 afforded chiral triols (R-7 and (S-7, which were cyclized with tosyl chloride in the presence of Bu2SnO to provide 2-benzopyrans (R-4 and (S-4 with high regioselectivity. The additional hydroxy moiety in the 4-position was exploited for the introduction of various substituents. Williamson ether synthesis and replacement of the Boc protective group with a benzyl moiety led to potent σ1 ligands with high σ1/σ2-selectivity. With exception of the ethoxy derivative 16, the (R-configured enantiomers represent eutomers with eudismic ratios of up to 29 for the ester (R-18. The methyl ether (R-15 represents the most potent σ1 ligand of this series of compounds, with a Ki value of 1.2 nM and an eudismic ratio of 7. Tosylate (R-21 was used as precursor for the radiosynthesis of [18F]-(R-20, which was available by nucleophilic substitution with K[18F]F K222 carbonate complex. The radiochemical yield of [18F]-(R-20 was 18%–20%, the radiochemical purity greater than 97% and the specific radioactivity 175–300 GBq/µmol. Although radiometabolites were detected in plasma, urine and liver samples, radiometabolites were not found in brain samples. After 30 min, the uptake of the radiotracer in the brain was 3.4% of injected dose per gram of tissue and could be reduced by coadministration of the σ1 antagonist haloperidol. [18F]-(R-20 was able to label those regions of the brain, which were reported to have high density of σ1 receptors.

  7. Prolonged androgen deprivation may influence the autoregulation of estrogen receptors in the brain and pelvic floor muscles of male rats.

    Science.gov (United States)

    Wibowo, Erik; Calich, Hannah J; Currie, R William; Wassersug, Richard J

    2015-06-01

    Androgen deprivation in males has detrimental effects on various tissues and bodily functions, some of which can be restored by estradiol (E2) administration. We investigated how the duration of androgen deprivation affects the autoregulation of estrogen receptors (ERs) levels in core brain areas associated with sexual behavior and cognition, as well as in pelvic floor muscles (PFM). We also measured c-Fos levels in brain areas associated with sexual behavior shortly after the rats mated. Prolonged castration increases ERα levels in the preoptic area (POA) and E2 treatment reverses these effects. In the POA, c-Fos levels after mating are not affected by the duration of androgen deprivation and/or E2 treatment. ERβ levels in the POA as well as c-Fos levels in the POA and the core area of nucleus accumbens correlate with the mounting frequency for E2-treated Short-Term castrates. Additionally, ERβ levels in the medial amygdala are positively correlated with the mounting frequency of Long-Term castrates that received E2 treatment. In the hippocampus, ERs are downregulated only when E2 is administered early after castration, whereas downregulation of ERα in the prefrontal cortex only occurs with delayed E2 treatment. Early, but not delayed, E2 treatment after castration increases ERβ levels in the bulbocavernosus and ERα levels in the levator ani of male rats. Our data suggest that the duration of androgen deprivation may influence the autoregulation of ERs by E2 treatment in select brain areas and pelvic floor muscles of male rats. PMID:25746452

  8. Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity.

    Science.gov (United States)

    Hammer, C; Stepniak, B; Schneider, A; Papiol, S; Tantra, M; Begemann, M; Sirén, A-L; Pardo, L A; Sperling, S; Mohd Jofrry, S; Gurvich, A; Jensen, N; Ostmeier, K; Lühder, F; Probst, C; Martens, H; Gillis, M; Saher, G; Assogna, F; Spalletta, G; Stöcker, W; Schulz, T F; Nave, K-A; Ehrenreich, H

    2014-10-01

    In 2007, a multifaceted syndrome, associated with anti-NMDA receptor autoantibodies (NMDAR-AB) of immunoglobulin-G isotype, has been described, which variably consists of psychosis, epilepsy, cognitive decline and extrapyramidal symptoms. Prevalence and significance of NMDAR-AB in complex neuropsychiatric disease versus health, however, have remained unclear. We tested sera of 2817 subjects (1325 healthy, 1081 schizophrenic, 263 Parkinson and 148 affective-disorder subjects) for presence of NMDAR-AB, conducted a genome-wide genetic association study, comparing AB carriers versus non-carriers, and assessed their influenza AB status. For mechanistic insight and documentation of AB functionality, in vivo experiments involving mice with deficient blood-brain barrier (ApoE(-/-)) and in vitro endocytosis assays in primary cortical neurons were performed. In 10.5% of subjects, NMDAR-AB (NR1 subunit) of any immunoglobulin isotype were detected, with no difference in seroprevalence, titer or in vitro functionality between patients and healthy controls. Administration of extracted human serum to mice influenced basal and MK-801-induced activity in the open field only in ApoE(-/-) mice injected with NMDAR-AB-positive serum but not in respective controls. Seropositive schizophrenic patients with a history of neurotrauma or birth complications, indicating an at least temporarily compromised blood-brain barrier, had more neurological abnormalities than seronegative patients with comparable history. A common genetic variant (rs524991, P=6.15E-08) as well as past influenza A (P=0.024) or B (P=0.006) infection were identified as predisposing factors for NMDAR-AB seropositivity. The >10% overall seroprevalence of NMDAR-AB of both healthy individuals and patients is unexpectedly high. Clinical significance, however, apparently depends on association with past or present perturbations of blood-brain barrier function. PMID:23999527

  9. Neuropsychological, Metabolic, and GABAA Receptor Studies in Subjects with Repetitive Traumatic Brain Injury.

    Science.gov (United States)

    Bang, Seong Ae; Song, Yoo Sung; Moon, Byung Seok; Lee, Byung Chul; Lee, Ho-Young; Kim, Jong-Min; Kim, Sang Eun

    2016-06-01

    Repetitive traumatic brain injury (rTBI) occurs as a result of mild and accumulative brain damage. A prototype of rTBI is chronic traumatic encephalopathy (CTE), which is a degenerative disease that occurs in patients with histories of multiple concussions or head injuries. Boxers have been the most commonly studied patient group because they may experience thousands of subconcussive hits over the course of a career. This study examined the consequences of rTBI with structural brain imaging and biomolecular imaging and investigated whether the neuropsychological features of rTBI were related to the findings of the imaging studies. Five retired professional boxers (mean age, 46.8 ± 3.19 years) and four age-matched controls (mean age, 48.5 ± 3.32 years) were studied. Cognitive-motor related functional impairment was assessed, and all subjects underwent neuropsychological evaluation and behavioral tasks, as well as structural brain imaging and functional-molecular imaging. In neuropsychological tests, boxers showed deficits in delayed retrieval of visuospatial memory and motor coordination, which had a meaningful relationship with biomolecular imaging results indicative of neuronal injury. Morphometric abnormalities were not found in professional boxers by structural magnetic resonance imaging (MRI). Glucose metabolism was impaired in frontal areas associated with cognitive dysfunction, similar to findings in Alzheimer's disease. Low binding potential (BP) of (18)F-flumazenil (FMZ) was found in the angular gyrus and temporal cortical regions, revealing neuronal deficits. These results suggested that cognitive impairment and motor dysfunction reflect chronic damage to neurons in professional boxers with rTBI. PMID:26414498

  10. A previously uncharacterized role for estrogen receptor β: Defeminization of male brain and behavior

    OpenAIRE

    Kudwa, Andrea E.; Bodo, Cristian; Gustafsson, Jan-Åke; Rissman, Emilie F.

    2005-01-01

    Sex differences in brain and behavior are ubiquitous in sexually reproducing species. One cause of sexual dimorphisms is developmental differences in circulating concentrations of gonadal steroids. Neonatal testes produce androgens; thus, males are exposed to both testosterone and estradiol, whereas females are not exposed to high concentrations of either hormone until puberty. Classically, the development of neural sex differences is initiated by estradiol, which activates two processes in m...

  11. Electrophysiological and autoradiographical evidence of V1 vasopressin receptors in the lateral septum of the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Raggenbass, M.; Tribollet, E.; Dreifuss, J.J.

    1987-11-01

    Extracellular recordings were obtained from single neurons located in the lateral septum, an area known to receive a vasopressinergic innervation in the rat brain. Approximately half of the neurons tested responded to 8-L-arginine vasopressin (AVP) by a marked increase in firing rate at concentrations greater than 1 nM. The effect of vasopressin was blocked by synthetic structural analogues possessing antagonistic properties on peripheral vasopressin and oxytocin receptors. Oxytocin was much less potent than vasopressin in firing septal neurons, and a selective oxytocic agonist was totally ineffective. The action of vasopressin on neuronal firing was mimicked by the vasopressor agonist (2-phenylalanine,8-ornithine)vasotocin but not by the selective antidiuretic agonist 1-deamino(8-D-arginine)vasopressin. In a parallel study, sites that bind (/sup 3/H)AVP at low concentration (1.5 nM) were found by in vitro autoradiography in the lateral septum. Adjacent sections were also incubated with 1.5 mM (/sup 3/H)AVP and, in addition, with 100 nM (2-phenylalanine,8-ornithine)vasotocin or 1-deamino(8-D-arginine)vasopressin--i.e., the same compounds as those used for the electrophysiological study. Results showed that the vasopressor agonist, but not the antidiuretic agonist, displaced (/sup 3/H)AVP, thus indicating that the vasopressin binding sites detected by autoradiography in the septum were V1 (vasopressor type) rather than V2 (antidiuretic type) receptors. Based on the electrophysiological evidence, we conclude that these receptors, when occupied, lead to increased firing of lateral septal neurons.

  12. GABAB receptor modulation of adenylate cyclase activity in rat brain slices.

    OpenAIRE

    Hill, D R

    1985-01-01

    An investigation of the effects of gamma-aminobutyric acid (GABA) and the selective GABAB receptor agonist, baclofen, on basal and stimulated adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels in slices of rat cerebral cortex has been carried out. Neither GABA nor baclofen produced any significant change in basal cyclic AMP levels. By contrast noradrenaline and forskolin both produced dose-dependent increases in cellular cyclic AMP accumulation. GABA (in the presence of nipecotic acid) ...

  13. The Nuclear Receptor PPARγ as a Therapeutic Target for Cerebrovascular and Brain Dysfunction in Alzheimer's Disease

    OpenAIRE

    Nektaria Nicolakakis

    2010-01-01

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that regulate peripheral lipid and glucose metabolism. Three subtypes make up the PPAR family (α, γ, β/δ), and synthetic ligands for PPARα (fibrates) and PPARγ (Thiazolidinediones, TZDs) are currently prescribed for the respective management of dyslipidemia and type 2 diabetes. In contrast to the well characterized action of PPARs in the periphery, little w...

  14. Elevated Brain Cannabinoid CB1 Receptor Availability in Posttraumatic Stress Disorder: A Positron Emission Tomography Study

    OpenAIRE

    Neumeister, Alexander; Normandin, Marc D.; Pietrzak, Robert H.; Piomelli, Daniele; Zheng, Ming-Qiang; Gujarro-Anton, Ana; Potenza, Marc N.; Bailey, Christopher R.; Lin, Shu-fei; Najafzadeh, Soheila; Ropchan, Jim; Henry, Shannan; Corsi-Travali, Stefani; Carson, Richard E; Huang, Yiyun

    2013-01-01

    Endocannabinoids and their attending cannabinoid type 1 receptor (CB1) have been implicated in animal models of posttraumatic stress disorder (PTSD). However, their specific role has not been studied in people with PTSD. Herein, we present an in vivo imaging study using positron emission tomography (PET) and the CB1-selective radioligand [11C]OMAR in individuals with PTSD, and healthy controls with lifetime histories of trauma (trauma controls [TC]) and those without such histories (healthy c...

  15. Age-related changes in receptor-mediated phosphoinositide hydrolysis in various regions of rat brain

    International Nuclear Information System (INIS)

    The effects of age on cholinergic markers and receptor-stimulated phosphoinositide hydrolysis was examined in the frontal cortex and striatum of male Fischer-344 rats. Choline acetyltransferase activity was decreased 27% in the striatum of aged rats compared to young controls. Muscarinic receptor density as measured by [3H]-quinuclidinyl benzilate binding showed a similar 26% decrease in the striatum of aged rats. Phosphoinositide hydrolysis was measured by the release of inositol phosphate (IP) from tissue slices prelabeled with [3H]myoinositol in response to carbachol, norepinephrine, and quisqualate. In the cortex, stimulated IP release was significantly greater in slices from aged rats compared to young rats for all three agonists. In contrast, stimulated IP release was significantly decreased in striatal slices from aged rats compared to young for all three agonists. These data indicate a differential effect of age on agonist-stimulated phosphoinositide hydrolysis in the cortex and striatum. The decreased responsiveness in the latter area may result from the age-related loss of postsynaptic receptors

  16. Binding of receptor-recognized forms of alpha2-macroglobulin to the alpha2-macroglobulin signaling receptor activates phosphatidylinositol 3-kinase.

    Science.gov (United States)

    Misra, U K; Pizzo, S V

    1998-05-29

    Ligation of the alpha2-macroglobulin (alpha2M) signaling receptor by receptor-recognized forms of alpha2M (alpha2M*) initiates mitogenesis secondary to increased intracellular Ca2+. We report here that ligation of the alpha2M signaling receptor also causes a 1. 5-2.5-fold increase in wortmannin-sensitive phosphatidylinositol 3-kinase (PI3K) activity as measured by the quantitation of phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 formation was alpha2M* concentration-dependent with a maximal response at approximately 50 pM ligand concentration. The peak formation of PIP3 occurred at 10 min of incubation. The alpha2M receptor binding fragment mutant K1370R which binds to the alpha2M signaling receptor activating the signaling cascade, increased PIP3 formation by 2-fold. The mutant K1374A, which binds very poorly to the alpha2M signaling receptor, did not cause any increase in PIP3 formation. alpha2M*-induced DNA synthesis was inhibited by wortmannin. 1, 2Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acetoxymethylester a chelator of intracellular Ca2+, drastically reduced alpha2M*-induced increases in PIP3 formation. We conclude that PI3K is involved in alpha2M*-induced mitogenesis in macrophages and intracellular Ca2+ plays a role in PI3K activation. PMID:9593670

  17. Preclinical evaluation and quantification of [18F]MK-9470 as a radioligand for PET imaging of the type 1 cannabinoid receptor in rat brain

    International Nuclear Information System (INIS)

    [18F]MK-9470 is an inverse agonist for the type 1 cannabinoid (CB1) receptor allowing its use in PET imaging. We characterized the kinetics of [18F]MK-9470 and evaluated its ability to quantify CB1 receptor availability in the rat brain. Dynamic small-animal PET scans with [18F]MK-9470 were performed in Wistar rats on a FOCUS-220 system for up to 10 h. Both plasma and perfused brain homogenates were analysed using HPLC to quantify radiometabolites. Displacement and blocking experiments were done using cold MK-9470 and another inverse agonist, SR141716A. The distribution volume (VT) of [18F]MK-9470 was used as a quantitative measure and compared to the use of brain uptake, expressed as SUV, a simplified method of quantification. The percentage of intact [18F]MK-9470 in arterial plasma samples was 80 ± 23 % at 10 min, 38 ± 30 % at 40 min and 13 ± 14 % at 210 min. A polar radiometabolite fraction was detected in plasma and brain tissue. The brain radiometabolite concentration was uniform across the whole brain. Displacement and pretreatment studies showed that 56 % of the tracer binding was specific and reversible. VT values obtained with a one-tissue compartment model plus constrained radiometabolite input had good identifiability (≤10 %). Ignoring the radiometabolite contribution using a one-tissue compartment model alone, i.e. without constrained radiometabolite input, overestimated the [18F]MK-9470 VT, but was correlated. A correlation between [18F]MK-9470 VT and SUV in the brain was also found (R 2 = 0.26-0.33; p ≤ 0.03). While the presence of a brain-penetrating radiometabolite fraction complicates the quantification of [18F]MK-9470 in the rat brain, its tracer kinetics can be modelled using a one-tissue compartment model with and without constrained radiometabolite input. (orig.)

  18. Radiotherapy for asymptomatic brain metastasis in epidermal growth factor receptor mutant non-small cell lung cancer without prior tyrosine kinase inhibitors treatment: a retrospective clinical study

    International Nuclear Information System (INIS)

    Non-small cell lung cancer (NSCLC) with brain metastasis (BM) harboring an epidermal growth factor receptor (EGFR) mutation shows good response to tyrosine kinase inhibitors (TKIs). This study is to assess the appropriate timing of brain radiotherapy (RT) for asymptomatic BM in EGFR mutant NSCLC patients. There were 628 patients diagnosed with EGFR mutant NSCLC between October 2005 and December 2011. Treatment outcomes had been retrospectively evaluated in 96 patients with asymptomatic BM without prior TKI treatment. 39 patients received first-line brain RT, 23 patients received delayed brain RT, and 34 patients did not receive brain RT. With a median follow-up of 26 months, the 2-year OS was 40.6 %. Univariate analyses revealed that ECOG performance status (p = 0.006), other distant metastases (p = 0.002) and first line systemic treatment (p = 0.032) were significantly associated with overall survival (OS). Multivariate analyses revealed that other sites of distant metastases (p = 0.030) were prognostic factor. The timing of brain RT was not significantly related to OS (p = 0.246). The 2-year BM progression-free survival (PFS) was 26.9 %. Brain RT as first-line therapy failed to demonstrate a significant association with BM PFS (p = 0.643). First-line brain RT failed to improve long-term survival in TKI-naïve EGFR mutant NSCLC patients with asymptomatic BM. Prospective studies are needed to validate these clinical findings

  19. Interleukin-1 interaction with neuroregulatory systems: selective enhancement by recombinant human and mouse interleukin-1 of in vitro opioid peptide receptor binding in rat brain

    International Nuclear Information System (INIS)

    Interleukin-1 (IL-1) exerts a wide variety of biological effects on various cell types and may be regarded as a pleiotropic peptide hormone. Biological evidence suggests that IL-1 participates in the modulation of central nervous system physiology and behavior in a fashion characteristic of neuroendocrine hormones. In this investigation, recombinant (r) human (h) IL-1 and r mouse (m) IL-1 were examined for their modulation of opioid peptide receptor binding in vitro. Experiments were performed on frozen sections of rat brain. Receptor binding of radiolabeled substance P and of radiolabeled neurotensin were not significantly affected by the presence of rIL-1s. Recombinant IL-1s, however, significantly enhanced specific binding of 125I-beta-endorphin (125I-beta-END) and of D-ala2-(tyrosyl-3,5-3H)enkephalin-(5-D-leucine) (3H-D-ALA), equipotently and in a concentration-dependent manner with maximal activity occurring at a concentration of 10 LAF units/ml. The increased binding of 125I-beta-END and 3H-D-ALA was blocked steroselectively by (-)-naloxone and by etorphine, suggesting detection of opiate receptors. In addition, brain distribution patterns of receptors labeled in the presence of rIL-1s corresponded to patterns previously published for opiate receptors. Autoradiographic visualization of receptors revealed that rIL-1s in the different areas of the brain exert their effect on opioid binding with comparable potencies. The data suggest that certain central nervous system effects of IL-1s may be mediated by their selective interaction with opiatergic systems at the receptor level

  20. Interleukin-1 interaction with neuroregulatory systems: selective enhancement by recombinant human and mouse interleukin-1 of in vitro opioid peptide receptor binding in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Wiedermann, C.J.

    1989-02-01

    Interleukin-1 (IL-1) exerts a wide variety of biological effects on various cell types and may be regarded as a pleiotropic peptide hormone. Biological evidence suggests that IL-1 participates in the modulation of central nervous system physiology and behavior in a fashion characteristic of neuroendocrine hormones. In this investigation, recombinant (r) human (h) IL-1 and r mouse (m) IL-1 were examined for their modulation of opioid peptide receptor binding in vitro. Experiments were performed on frozen sections of rat brain. Receptor binding of radiolabeled substance P and of radiolabeled neurotensin were not significantly affected by the presence of rIL-1s. Recombinant IL-1s, however, significantly enhanced specific binding of 125I-beta-endorphin (125I-beta-END) and of D-ala2-(tyrosyl-3,5-3H)enkephalin-(5-D-leucine) (3H-D-ALA), equipotently and in a concentration-dependent manner with maximal activity occurring at a concentration of 10 LAF units/ml. The increased binding of 125I-beta-END and 3H-D-ALA was blocked steroselectively by (-)-naloxone and by etorphine, suggesting detection of opiate receptors. In addition, brain distribution patterns of receptors labeled in the presence of rIL-1s corresponded to patterns previously published for opiate receptors. Autoradiographic visualization of receptors revealed that rIL-1s in the different areas of the brain exert their effect on opioid binding with comparable potencies. The data suggest that certain central nervous system effects of IL-1s may be mediated by their selective interaction with opiatergic systems at the receptor level.

  1. Brain mapping

    Directory of Open Access Journals (Sweden)

    Blaž Koritnik

    2004-08-01

    Full Text Available Cartography of the brain ("brain mapping" aims to represent the complexities of the working brain in an understandable and usable way. There are four crucial steps in brain mapping: (1 acquiring data about brain structure and function, (2 transformation of data into a common reference, (3 visualization and interpretation of results, and (4 databasing and archiving. Electrophysiological and functional imaging methods provide information about function of the human brain. A prerequisite for multisubject, multidimensional and multimodal mapping is transformation of individual images to match a standard brain template. To produce brain maps, color, contours, and other visual cues are used to differentiate metabolic rates, electrical field potentials, receptor densities, and other attributes of structure or function. Databases are used to organize and archive data records. By relating the maps to cognitive functions and psychological models, brain mapping offers a prerequisite for the understanding of organizational principles of the human brain.

  2. 3D Reconstructed Cyto-, Muscarinic M2 Receptor, and Fiber Architecture of the Rat Brain Registered to the Waxholm Space Atlas

    Science.gov (United States)

    Schubert, Nicole; Axer, Markus; Schober, Martin; Huynh, Anh-Minh; Huysegoms, Marcel; Palomero-Gallagher, Nicola; Bjaalie, Jan G.; Leergaard, Trygve B.; Kirlangic, Mehmet E.; Amunts, Katrin; Zilles, Karl

    2016-01-01

    High-resolution multiscale and multimodal 3D models of the brain are essential tools to understand its complex structural and functional organization. Neuroimaging techniques addressing different aspects of brain organization should be integrated in a reference space to enable topographically correct alignment and subsequent analysis of the various datasets and their modalities. The Waxholm Space (http://software.incf.org/software/waxholm-space) is a publicly available 3D coordinate-based standard reference space for the mapping and registration of neuroanatomical data in rodent brains. This paper provides a newly developed pipeline combining imaging and reconstruction steps with a novel registration strategy to integrate new neuroimaging modalities into the Waxholm Space atlas. As a proof of principle, we incorporated large scale high-resolution cyto-, muscarinic M2 receptor, and fiber architectonic images of rat brains into the 3D digital MRI based atlas of the Sprague Dawley rat in Waxholm Space. We describe the whole workflow, from image acquisition to reconstruction and registration of these three modalities into the Waxholm Space rat atlas. The registration of the brain sections into the atlas is performed by using both linear and non-linear transformations. The validity of the procedure is qualitatively demonstrated by visual inspection, and a quantitative evaluation is performed by measurement of the concordance between representative atlas-delineated regions and the same regions based on receptor or fiber architectonic data. This novel approach enables for the first time the generation of 3D reconstructed volumes of nerve fibers and fiber tracts, or of muscarinic M2 receptor density distributions, in an entire rat brain. Additionally, our pipeline facilitates the inclusion of further neuroimaging datasets, e.g., 3D reconstructed volumes of histochemical stainings or of the regional distributions of multiple other receptor types, into the Waxholm Space

  3. Sigma{sub 1} and dopamine D{sub 2} receptor occupancy in the mouse brain after a single administration of haloperidol and two dopamine D{sub 2}-like receptor ligands

    Energy Technology Data Exchange (ETDEWEB)

    Ishiwata, Kiichi E-mail: ishiwata@pet.tmig.or.jp; Kawamura, Kazunori; Kobayashi, Tadayuki; Matsuno, Kiyoshi

    2003-05-01

    We investigated sigma{sub 1} and dopamine D{sub 2} receptor occupancy in mouse brain after a single injection of haloperidol, nemonapride, or spiperone using [{sup 11}C]SA4503 and [{sup 11}C]raclopride, respectively. Co-injection of the three compounds significantly blocked the uptake of each radioligand. Six hours later, only haloperidol blocked [{sup 11}C]SA4503 uptake, while all three reduced [{sup 11}C]raclopride uptake. Sigma{sub 1} receptor occupancy by haloperidol was reduced to 19% at day 2 when D{sub 2} receptor occupancy disappeared. [{sup 11}C]SA4503 would be applicable to the investigation of sigma{sub 1} receptor occupancy of antispychotic drugs using PET.

  4. Brain serotonin 4 receptor binding is associated with the cortisol awakening response

    DEFF Research Database (Denmark)

    Jakobsen, Gustav R; Fisher, Patrick M; Dyssegaard, Agnete;

    2016-01-01

    Serotonin signalling is considered critical for an appropriate and dynamic adaptation to stress. Previously, we have shown that prefrontal serotonin transporter (SERT) binding is positively associated with the cortisol awakening response (CAR) (Frokjaer et al., 2013), which is an index of...... hypothalamic-pituitary-adrenal (HPA)-axis output dynamics. Here, we investigated in healthy individuals if cerebral serotonin 4 receptor (5-HT4r) binding, reported to be a proxy for serotonin levels, is associated with CAR. Thirty healthy volunteers (25 males, age range 20-56 years) underwent 5-HT4r PET...

  5. Pentobarbitone modulation of NMDA receptors in neurones isolated from the rat olfactory brain.

    OpenAIRE

    Charlesworth, P; Jacobson, I; Richards, C. D.

    1995-01-01

    1. The action of pentobarbitone on the N-methyl-D-aspartate (NMDA) receptors of neurones freshly dissociated from the olfactory bulb and olfactory tubercle has been studied using patch-clamp techniques. 2. Pentobarbitone produced a concentration-dependent depression of the currents evoked by NMDA with an IC50 value of c. 250 microM. 3. Analysis of the NMDA-evoked noise produced power spectra that could be fitted by the sum of two Lorentzians with corner frequencies of 17 and 82 Hz. Pentobarbi...

  6. Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors.

    Science.gov (United States)

    Wang, Lei; de Kloet, Annette D; Pati, Dipanwita; Hiller, Helmut; Smith, Justin A; Pioquinto, David J; Ludin, Jacob A; Oh, S Paul; Katovich, Michael J; Frazier, Charles J; Raizada, Mohan K; Krause, Eric G

    2016-06-01

    Over-activation of the brain renin-angiotensin system (RAS) has been implicated in the etiology of anxiety disorders. Angiotensin converting enzyme 2 (ACE2) inhibits RAS activity by converting angiotensin-II, the effector peptide of RAS, to angiotensin-(1-7), which activates the Mas receptor (MasR). Whether increasing brain ACE2 activity reduces anxiety by stimulating central MasR is unknown. To test the hypothesis that increasing brain ACE2 activity reduces anxiety-like behavior via central MasR stimulation, we generated male mice overexpressing ACE2 (ACE2 KI mice) and wild type littermate controls (WT). ACE2 KI mice explored the open arms of the elevated plus maze (EPM) significantly more than WT, suggesting increasing ACE2 activity is anxiolytic. Central delivery of diminazene aceturate, an ACE2 activator, to C57BL/6 mice also reduced anxiety-like behavior in the EPM, but centrally administering ACE2 KI mice A-779, a MasR antagonist, abolished their anxiolytic phenotype, suggesting that ACE2 reduces anxiety-like behavior by activating central MasR. To identify the brain circuits mediating these effects, we measured Fos, a marker of neuronal activation, subsequent to EPM exposure and found that ACE2 KI mice had decreased Fos in the bed nucleus of stria terminalis but had increased Fos in the basolateral amygdala (BLA). Within the BLA, we determined that ∼62% of GABAergic neurons contained MasR mRNA and expression of MasR mRNA was upregulated by ACE2 overexpression, suggesting that ACE2 may influence GABA neurotransmission within the BLA via MasR activation. Indeed, ACE2 overexpression was associated with increased frequency of spontaneous inhibitory postsynaptic currents (indicative of presynaptic release of GABA) onto BLA pyramidal neurons and central infusion of A-779 eliminated this effect. Collectively, these results suggest that ACE2 may reduce anxiety-like behavior by activating central MasR that facilitate GABA release onto pyramidal neurons within the

  7. Tyrosine kinase signalling in breast cancer: Epidermal growth factor receptor and c-Src interactions in breast cancer

    International Nuclear Information System (INIS)

    Both the non-receptor tyrosine kinase, c-Src, and members of the epidermal growth factor (EGF) receptor family are overexpressed in high percentages of human breast cancers. Because these molecules are plasma membrane-associated and involved in mitogenesis, it has been speculated that they function in concert with one another to promote breast cancer development and progression. Evidence to date supports a model wherein c-Src potentiates the survival, proliferation and tumorigenesis of EGF receptor family members, in part by associating with them. Phosphorylation of the EGF receptor by c-SRC is also critical for mitogenic signaling initiated by the EGF receptor itself, as well as by several G-protein coupled receptors (GPCRs), a cytokine receptor, and the estrogen receptor. Thus, c-Src appears to have pleiotropic effects on cancer cells by modulating the action of multiple growth-promoting receptors

  8. Metabolism of [{sup 123}I]epidepride may affect brain dopamine D{sub 2} receptor imaging with single-photon emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Bergstroem, K.A.; Yu, M.; Kuikka, J.T.; Aakerman, K.K. [Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio (Finland); Hiltunen, J. [MAP Medical Technologies Oy, Tikkakoski (Finland); Lehtonen, J. [Department of Psychiatry, University of Kuopio (Finland); Halldin, C. [Karolinska Institute, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, Stockholm (Sweden); Tiihonen, J. [Department of Forensic Psychiatry, University of Kuopio, Niuvanniemi Hospital, Kuopio (Finland)

    2000-02-01

    Iodine-123 labelled epidepride is a novel radiopharmaceutical for the study of cerebral dopamine D{sub 2} receptors using single-photon emission tomography (SPET). A lipophilic labelled metabolite of [{sup 123}I]epidepride which may enter the brain and hamper the quantitation of receptors has been observed in human plasma. In the present study, gradient high-performance liquid chromatography (HPLC) was used to investigate the plasma concentration of the lipophilic labelled metabolite and its correlation to SPET imaging of striatal dopamine D{sub 2} receptors. A linear regression fit showed a negative correlation between the amount of the lipophilic labelled metabolite and the striatum to cerebellum ratio (n=16, R=-0.58, P<0.02), suggesting that plasma metabolite analysis is essential when imaging dopamine D{sub 2} receptors with SPET using [{sup 123}I]epidepride. (orig.)

  9. Monocrotophos induced oxidative stress and alterations in brain dopamine and serotonin receptors in young rats.

    Science.gov (United States)

    Sankhwar, Madhu L; Yadav, Rajesh S; Shukla, Rajendra K; Singh, Dhirendra; Ansari, Reyaz W; Pant, Aditya B; Parmar, Devendra; Khanna, Vinay K

    2016-03-01

    Human exposure to monocrotophos, an organophosphate pesticide, could occur due to its high use in agriculture to protect crops. Recently, we found that postlactational exposure to monocrotophos impaired cholinergic mechanisms in young rats and such changes persisted even after withdrawal of monocrotophos exposure. In continuation to this, the effect of monocrotophos on noncholinergic targets and role of oxidative stress in its neurotoxicity has been studied. Exposure of rats from postnatal day (PD)22 to PD49 to monocrotophos (0.50 or 1.0 mg kg(-1) body weight, perorally) significantly impaired motor activity and motor coordination on PD50 as compared to controls. A significant decrease in the binding of (3)H-spiperone to striatal membrane (26%, p 0.05; 37%, p < 0.05) in those exposed at a higher dose, respectively, was observed on PD50 compared with the controls. Alterations in the binding persisted even after withdrawal of monocrotophos exposure on PD65. Increased oxidative stress in brain regions following exposure of rats to monocrotophos was also observed on PD50 that persisted 15 days after withdrawal of exposure on PD65. The results suggest that monocrotophos exerts its neurobehavioral toxicity by affecting noncholinergic functions involving dopaminergic and serotonergic systems associated with enhanced oxidative stress. The results also exhibit vulnerability of developing brain to monocrotophos as most of the changes persisted even after withdrawal of its exposure. PMID:24105069

  10. Dopamine D1 receptor imaging in the rodent and primate brain using the isoquinoline (+)-[{sup 11}C]A-69024 and positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Besret, L.; Herard, A.S.; Guillermier, M.; Hantraye, P. [CNRS, URA 2210, F-91406 Orsay (France); Dolle, F.; Demphel, S.; Hinnen, F.; Coulon, C.; Ottaviani, M.; Bottlaender, M. [CEA, DSV, I2BM, SHFJ, Lab Imagerie Mol Expt, F-91406 Orsay (France); Herard, A.S.; Guillermier, M.; Hantraye, P. [CEA, DSV, I2BM, Mol Imaging Res Ctr, F-92265 Fontenay Aux Roses (France); Kassiou, M. [Univ Sydney, Discipline Med Radiat Sci, Sydney, NSW 2006 (Australia); Kassiou, M. [Univ Sydney, Brain and Mind Res Inst, Sydney, NSW 2050 (Australia); Kassiou, M. [Univ Sydney, Sch Chem, Sydney, NSW 2006 (Australia)

    2008-07-01

    In vivo pharmacokinetic and brain binding characteristics of (+)-[{sup 11}C]A-69024, a high-affinity-D1-selective dopamine receptor antagonist, were assessed with micro-PET and {beta}-microprobes in the rat and PET in the baboon. The biodistribution of (+)-[{sup 11}C]A-69024 in rats and baboons showed a rapid brain uptake (reaching a maximal value at 5 and 15 min postinjection in rats and baboons, respectively), followed by a slow wash out. The region/cerebellum concentration ratio was characterized by a fourfold higher uptake in striatum and a twofold higher uptake in cortical regions, consistent with in vivo specific binding of the radiotracer in these cerebral regions. Furthermore, this specific (+)-[{sup 11}C]A-69024 binding significantly correlated with the reported in vitro distribution of dopamine D1-receptors. Finally, the specific uptake of the tracer in the striatum and cortical regions was completely prevented by either a pretreatment with large doses of nonradioactive {+-}A-69024 or of the D1-selective antagonist SCH23390, resulting in a similar uptake in the reference region (cerebellum) and in other brain regions. Thus, (+)-[{sup 11}C]A-69024 appears to be a specific and enantioselective radioligand to visualize and quantify brain dopamine D1 receptors in vivo using positron emission tomography. (authors)

  11. Radioligands for the study of brain 5-HT1A receptors in vivo-development of some new analogues of way

    International Nuclear Information System (INIS)

    [Carbonyl-11C]WAY-100635 (WAY) has proved to be a very useful radioligand for the imaging of brain 5-HT1A receptors in human brain in vivo with positron emission tomography (PET). WAY is now being applied widely for clinical research and drug development. However, WAY is rapidly cleared from plasma and is also rapidly metabolised. A comparable radioligand, with a higher and more sustained delivery to brain, is desirable since these properties might lead to better biomathematical modelling of acquired PET data. There are also needs for other types of 5-HT1A receptor radioligands, for example, ligands sensitive to elevated serotonin levels, ligands labelled with longer-lived fluorine-18 for distribution to 'satellite' PET centres, and ligands labelled with iodine-123 for single photon emission computerised tomography (SPECT) imaging. Here we describe our progress toward these aims through the exploration of WAY analogues, including the development of [carbonyl-11C]desmethyl-WAY (DWAY) as a promising, more brain-penetrant radioligand for PET imaging of human 5-HT1A receptors, and (pyridinyl-6-halo)-analogues as promising leads for the development of radiohalogenated ligands

  12. Felbamate antagonizes isoniazid- and FG 7142-induced reduction of GABAA receptor function in mouse brain.

    Science.gov (United States)

    Serra, M; Ghiani, C A; Spano, S; Biggio, G

    1994-11-24

    Injection of the antiepileptic drug, felbamate (2-phenyl-1,3-propanediol dicarbamate), into mice reduced in a dose-dependent manner (150-300 mg/kg i.p.) the isoniazid (200 mg/kg s.c.)-induced increase in ex vivo binding of t-[35S]butylbicyclophosphorothionate ([35S]TBPS) to cerebral cortical and hippocampal membranes. The same doses of felbamate reduced significantly the number of mice exhibiting isoniazid-induced seizures. A dose of felbamate (50 mg/kg) ineffective in isoniazid-treated mice completely antagonized the increase of [35S]TBPS binding elicited by FG 7142 (N-methyl-beta-carboline-3-carboxamide), a benzodiazepine receptor inverse agonist. The above effects of felbamate resembled those of diazepam. Accordingly, the combination of ineffective doses of felbamate (50 mg/kg) and diazepam (0.2 mg/kg) elicited a marked decrease of [35S]TBPS binding. The results indicate that facilitation of gamma-aminobutyric acid type A (GABAA) receptor function may play a role in the anticonvulsant action of felbamate. PMID:7875235

  13. STRATEGIES FOR QUANTIFYING PET IMAGING DATA FROM TRACER STUDIES OF BRAIN RECEPTORS AND ENZYMES.

    Energy Technology Data Exchange (ETDEWEB)

    Logan, J.

    2001-04-02

    A description of some of the methods used in neuroreceptor imaging to distinguish changes in receptor availability has been presented in this chapter. It is necessary to look beyond regional uptake of the tracer since uptake generally is affected by factors other than the number of receptors for which the tracer has affinity. An exception is the infusion method producing an equilibrium state. The techniques vary in complexity some requiring arterial blood measurements of unmetabolized tracer and multiple time uptake data. Others require only a few plasma and uptake measurements and those based on a reference region require no plasma measurements. We have outlined some of the limitations of the different methods. Laruelle (1999) has pointed out that test/retest studies to which various methods can be applied are crucial in determining the optimal method for a particular study. The choice of method will also depend upon the application. In a clinical setting, methods not involving arterial blood sampling are generally preferred. In the future techniques for externally measuring arterial plasma radioactivity with only a few blood samples for metabolite correction will extend the modeling options of clinical PET. Also since parametric images can provide information beyond that of ROI analysis, improved techniques for generating such images will be important, particularly for ligands requiring more than a one-compartment model. Techniques such as the wavelet transform proposed by Turkheimer et al. (2000) may prove to be important in reducing noise and improving quantitation.

  14. Neurokinin-1 Receptor (NK1-R) Expression in the Brains of SIV-Infected Rhesus Macaques

    Science.gov (United States)

    Vinet-Oliphant, Heather; Alvarez, Xavier; Buza, Elizabeth; Borda, Juan T.; Mohan, Mahesh; Aye, Pyone P.; Tuluc, Florin; Douglas, Steven D.; Lackner, Andrew A.

    2010-01-01

    Recent studies suggest a link between neuropsychiatric disorders and HIV/SIV infection. Most evidence indicates that monocytes/macrophages are the primary cell type infected within the CNS and that they contribute to CNS inflammation and neurological disease. Substance P (SP), a pleotropic neuropeptide implicated in inflammation, depression, and immune modulation via interaction with its cognate receptor, the neurokinin 1 receptor (NK1-R), is produced by monocyte/macrophages. While the presence of NK1-R on neurons is well known, its role on cells of the immune system such as monocyte/macrophages is just beginning to emerge. Therefore, we have examined the expression of SP and NK1-R and their relationship to SIV/HIV encephalitis (SIVE/HIVE) lesions and SIV-infected cells. These studies demonstrated intense expression of SP and NK1-R in SIVE lesions, with macrophages being the principal cell expressing NK1-R. Interestingly, all of the SIV-infected macrophages expressed NK1-R. Additionally, we examined the functional role of SP as a proinflammatory mediator of monocyte activation and chemotaxis. These studies demonstrated that treatment of monocytes with SP elicited changes in cell-surface expression for CCR5 and NK1-R in a dose-dependent manner. Moreover, pretreatment with SP enhanced both SP- and CCL5-mediated chemotaxis. All of these findings suggest that SP and NK1-R are important in SIV infection of macrophages and the development of SIVE lesions. PMID:20671267

  15. Action of ZDY101 on passive avoidance test and brain M-receptor density after intracranial co-injection of Aβ plus ibotenic acid

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The aim of this study was to establish a model by single injection of Aβ1-40+IA into rat brain basal ganglion and examine the effect of ZDY101, an active component of a Yin tonic from Chinese traditional medicinal herb. The results showed that the amnestic effect of co-injection of Aβ and IA lasted for at least 2 months. At same time, the total M-receptor density in model brain was significantly lower than blank control, indicating the change is profound enough for long term pathological studies or drug screening. It can be clearly seen that the decreased brain M-receptor density caused by Aβ was significantly increased by ZDY101. Such an elevation effect was significantly correlated with dose of ZDY101 when the dose was examined in a certain reasonable range. It can also be clearly seen that such an elevation of M-cholinergic receptor density was significantly correlated with the improvement of memory which indicated that the increase of M-cholinergic receptor density was animportant factor in improving the memory of such animal model.

  16. Action of ZDY101 on passive avoidance test and brain M-receptor density after intracranial co-injection of Aβ plus ibotenic acid

    International Nuclear Information System (INIS)

    The aim of the study was to establish a model by single injection of Aβ1-40 + IA into rat brain basal ganglion and examine the effect of ZDY101, an active component of a Yin tonic from Chinese traditional medicinal herb. The results showed that the amnestic effect of co-injection of Aβ and IA lasted for at least 2 months. At same time, the total M-receptor density in model brain was significantly lower than blank control, indicating the change is profound enough for long term pathological studies or drug screening. It can be clearly seen that the decreased brain M-receptor density caused by Aβ was significantly increased by ZDY101. Such an elevation effect was significantly correlated with dose of ZDY101 when the dose was examined in a certain reasonable range. It can also be clearly seen that such an elevation of M-cholinergic receptor density was significantly correlated with the improvement of memory which indicated that the increase of M-cholinergic receptor density was an important factor in improving the memory of such animal model

  17. Regional distribution of the opioid receptor agonist N-(methyl- sup 11 C)pethidine in the brain of the rhesus monkey studied with positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Hartvig, P. (Hospital Pharmacy, University Hospital, Uppsala (Sweden)); Eckernaes, S.Aa. (Departments of Neurology, University Hospital, Uppsala (Sweden)); Lindberg, B.S. (Department of Obstetrics and Gynaelogy, University Hospital, Uppsala (Sweden)); Lundqvist, H. (Centre for Radiation Sciences, University of Uppsala (Sweden)); Antoni, G.; Rimland, A.; Laangstroem, B. (Department of Organic Chemistry, University of Uppsala (Sweden))

    1990-01-01

    The regional distribution and kinetics in the brain of Rhesus monkeys of N-(methyl-{sup 11}C)-pethidine have been studied by positron emission tomography, PET. {sup 11}C-Pethidine reached the brain with peak radioactivities appearing within 6-10 min. after administration. Highest radioactivities were measured in areas corresponding to the thalamus, the striatal area and also the lowest transection of the temporal lobes, with an uptake of 2.7-3.1 times the homogenous dilution of the radioactive dose. Low radioactivities were seen in the cerebellum and the occipital lobes. This distribution corresponds to the regional density of opioid receptors using in vitro binding techniques. The {sup 11}C-pethidine derived radioactivity left the brain with an initial half-life of 40--60 minutes, followed by an elimination which paralleled the plasma elimination of unlabelled pethidine. After pretreatment of the monkey with a small dose of naloxone, the radioactivities decreased about 40% in areas corresponding to the thalamus, striatum and lowest section of the temporal lobes, indicating competition for the same binding sties. By the use of a three-compartment model, it was possible to get an estimate of {sup 11}C-pethidine receptor binding characteristics in the brain. The ratio of Kon/Koff, equal to Bmax.Kd, was 0.06-0.1. This indicates that pethidine is bound with low affinity to the opioid receptors and is a poor ligand for studies of opioid receptor function with PET. Brain kinetics of {sup 11}C-pethidine is mainly determined by its blood kinetics. (author).

  18. Regional distribution of the opioid receptor agonist N-(methyl-11C)pethidine in the brain of the rhesus monkey studied with positron emission tomography

    International Nuclear Information System (INIS)

    The regional distribution and kinetics in the brain of Rhesus monkeys of N-(methyl-11C)-pethidine have been studied by positron emission tomography, PET. 11C-Pethidine reached the brain with peak radioactivities appearing within 6-10 min. after administration. Highest radioactivities were measured in areas corresponding to the thalamus, the striatal area and also the lowest transection of the temporal lobes, with an uptake of 2.7-3.1 times the homogenous dilution of the radioactive dose. Low radioactivities were seen in the cerebellum and the occipital lobes. This distribution corresponds to the regional density of opioid receptors using in vitro binding techniques. The 11C-pethidine derived radioactivity left the brain with an initial half-life of 40-60 min., followed by an elimination which paralleled the plasma elimination of unlabelled pethidine. After pretreatment of the monkey with a small dose of naloxone, the radioactivities decreased about 40% in areas corresponding to the thalamus, striatum and lowest section of the temporal lobes, indicating competition for the same binding sties. By the use of a three-compartment model, it was possible to get an estimate of 11C-pethidine receptor binding characteristics in the brain. The ratio of Kon/Koff, equal to Bmax.(Kd, was 0.06-0.1. This indicates that pethidine is bound with low affinity to the opioid receptors and is a poor ligand for studies of opioid receptor function with PET. Brain kinetics of 11C-pethidine is mainly determined by its blood kinetics. (author)

  19. Role of histamine H1-receptor on behavioral states and wake maintenance during deficiency of a brain activating system: A study using a knockout mouse model.

    Science.gov (United States)

    Parmentier, Régis; Zhao, Yan; Perier, Magali; Akaoka, Hideo; Lintunen, Minnamaija; Hou, Yiping; Panula, Pertti; Watanabe, Takeshi; Franco, Patricia; Lin, Jian-Sheng

    2016-07-01

    Using knockout (KO) mice lacking the histamine (HA)-synthesizing enzyme (histidine decarboxylase, HDC), we have previously shown the importance of histaminergic neurons in maintaining wakefulness (W) under behavioral challenges. Since the central actions of HA are mediated by several receptor subtypes, it remains to be determined which one(s) could be responsible for such a role. We have therefore compared the cortical-EEG, sleep and W under baseline conditions or behavioral/pharmacological stimuli in littermate wild-type (WT) and H1-receptor KO (H1-/-) mice. We found that H1-/- mice shared several characteristics with HDC KO mice, i.e. 1) a decrease in W after lights-off despite its normal baseline daily amount; 2) a decreased EEG slow wave sleep (SWS)/W power ratio; 3) inability to maintain W in response to behavioral challenges demonstrated by a decreased sleep latency when facing various stimuli. These effects were mediated by central H1-receptors. Indeed, in WT mice, injection of triprolidine, a brain-penetrating H1-receptor antagonist increased SWS, whereas ciproxifan (H3-receptor antagonist/inverse agonist) elicited W; all these injections had no effect in H1-/- mice. Finally, H1-/- mice showed markedly greater changes in EEG power (notably in the 0.8-5 Hz band) and sleep-wake cycle than in WT mice after application of a cholinergic antagonist or an indirect agonist, i.e., scopolamine or physostigmine. Hence, the role of HA in wake-promotion is largely ensured by H1-receptors. An upregulated cholinergic system may account for a quasi-normal daily amount of W in HDC or H1-receptor KO mice and likely constitutes a major compensatory mechanism when the brain is facing deficiency of an activating system. This article is part of the Special Issue entitled 'Histamine Receptors'. PMID:26723880

  20. Metabolically stable bradykinin B2 receptor agonists enhance transvascular drug delivery into malignant brain tumors by increasing drug half-life

    Directory of Open Access Journals (Sweden)

    Glen Daniel

    2009-05-01

    Full Text Available Abstract Background The intravenous co-infusion of labradimil, a metabolically stable bradykinin B2 receptor agonist, has been shown to temporarily enhance the transvascular delivery of small chemotherapy drugs, such as carboplatin, across the blood-brain tumor barrier. It has been thought that the primary mechanism by which labradimil does so is by acting selectively on tumor microvasculature to increase the local transvascular flow rate across the blood-brain tumor barrier. This mechanism of action does not explain why, in the clinical setting, carboplatin dosing based on patient renal function over-estimates the carboplatin dose required for target carboplatin exposure. In this study we investigated the systemic actions of labradimil, as well as other bradykinin B2 receptor agonists with a range of metabolic stabilities, in context of the local actions of the respective B2 receptor agonists on the blood-brain tumor barrier of rodent malignant gliomas. Methods Using dynamic contrast-enhanced MRI, the pharmacokinetics of gadolinium-diethyltriaminepentaacetic acid (Gd-DTPA, a small MRI contrast agent, were imaged in rodents bearing orthotopic RG-2 malignant gliomas. Baseline blood and brain tumor tissue pharmacokinetics were imaged with the 1st bolus of Gd-DTPA over the first hour, and then re-imaged with a 2nd bolus of Gd-DTPA over the second hour, during which normal saline or a bradykinin B2 receptor agonist was infused intravenously for 15 minutes. Changes in mean arterial blood pressure were recorded. Imaging data was analyzed using both qualitative and quantitative methods. Results The decrease in systemic blood pressure correlated with the known metabolic stability of the bradykinin B2 receptor agonist infused. Metabolically stable bradykinin B2 agonists, methionine-lysine-bradykinin and labradimil, had differential effects on the transvascular flow rate of Gd-DTPA across the blood-brain tumor barrier. Both methionine

  1. Inhibition of β2-adrenergic receptor reduces triple-negative breast cancer brain metastases: The potential benefit of perioperative β-blockade.

    Science.gov (United States)

    Choy, Cecilia; Raytis, John L; Smith, David D; Duenas, Matthew; Neman, Josh; Jandial, Rahul; Lew, Michael W

    2016-06-01

    In response to recent studies, we investigated an association between perioperative β-blockade and breast cancer metastases. First, a retrospective study examining perioperative β-blocker use and cancer recurrence and metastases was conducted on 1,029 patients who underwent breast cancer surgery at the City of Hope Cancer Center between 2000 and 2010. We followed the clinical study and examined proliferation, migration, and invasion in vitro of primary and brain-metastatic breast cancer cells in response to β2-activation and inhibition. We also investigated in vivo the metastatic potential of propranolol-treated metastatic cells. For stage II breast cancer patients, perioperative β-blockade was associated with decreased cancer recurrence using Cox regression analysis (hazard's ratio =0.51; 95% CI: 0.23-0.97; p=0.041). Triple-negative (TN) brain-metastatic cells were found to have increased β2-adrenergic receptor mRNA and protein expression relative to TN primary cells. In response to β2-adrenergic receptor activation, TN brain-metastatic cells also exhibited increased cell proliferation and migration relative to the control. These effects were abrogated by propranolol. Propranolol decreased β2-adrenergic receptor-activated invasion. In vivo, propranolol treatment of TN brain-metastatic cells decreased establishment of brain metastases. Our results suggest that stress and corresponding β2-activation may promote the establishment of brain metastases of TN breast cancer cells. In addition, our data suggest a benefit to perioperative β-blockade during surgery-induced stress with respect to breast cancer recurrence and metastases. PMID:27035124

  2. Binding of [3H]ethyl-β-carboline-3-carboxylate to brain benzodiazepine receptors

    International Nuclear Information System (INIS)

    It is reported that in contrast to the changes in affinity of [3H]benzodiazepines elicited by halide ions, barbiturates, and pyrazolopyridines, the apparent affinity of β-[3H]CCE (ethyl-β-carboline-3-carboxylate) is unaffected by these agents. Furthermore, Scatchard analysis of β-[3H]CCE binding to cerebral cortical and cerebellar membranes revealed a significantly greater number of binding sites than was observed with either [3H]diazepam or [3H]flunitazepam, suggesting that at low concentrations benzodiazepines selectively label a subpopulation of the receptors labelled with β-[3H]CCE. Alternatively, β-[3H]CCE may bind to sites that are distinct from those labelled with [3H]-benzodiazepines. (Auth.)

  3. Triazolam-induced modulation of muscarinic acetylcholine receptor in living brain slices as revealed by a new positron-based imaging technique

    International Nuclear Information System (INIS)

    The effect of triazolam, a potent benzodiazepine (BZ) agonist, on muscarinic acetylcholinergic receptor (mAChR) binding was investigated in living brain slices by use of a novel positron-based imaging technique. Fresh rat brain slices were incubated with [11C]N-methyl-4-piperidylbenzilate ([11C]NMPB), a mAChR antagonist, in oxygenated Krebs-Ringer solution at 37 degree C. During incubation, time-resolved imaging of [11C]NMPB binding in the slices was constructed on the storage phosphor screens. Addition of triazolam (1 μM) plus muscimol (30 μM), a GABAA receptor agonist, to the incubation mixture decreased the specific binding of [11C]NMPB. Ro15-1788, a BZ receptor antagonist, prevented this effect, indicating that the effect was exerted through the GABAA/BZ receptor complex. These results demonstrated that stimulation of the GABAA/BZ receptor lowers the affinity of the mAChR for its ligand, which may underlie the BZ-induced amnesia, a serious clinical side effect of BZ. No such effect in the P2-fraction instead implies that the integrity of the neuronal cells and/or their environment is prerequisite for the modulation of mAChR by GABAA/BZ stimulation. (author)

  4. Changes in dopamine D2 and GluR-1 glutamate receptor mRNAs in the rat brain after treatment with phencyclidine.

    Directory of Open Access Journals (Sweden)

    Tomita,Hiroaki

    1995-04-01

    Full Text Available In situ hybridization of slide-mounted brain sections from rats subjected to acute and chronic phencyclidine treatment was carried out using synthetic oligonucleotides complementary to dopamine D2-receptor and non-N-methyl-D-aspartate (NMDA glutamate-receptor-subunit (GluR-1 mRNAs. There was no significant difference in either the D2-receptor or the GluR-1 mRNA levels in any brain region of the acute phencyclidine (10 mg/kg-treated and control groups. However, chronic administration of phencyclidine (10 mg/kg/day, 14 days significantly decreased the dopamine D2-receptor mRNA level in the caudate-putamen (by 27%, P < 0.01 and significantly increased the GluR-1 mRNA level in the prefrontal cortex (by 29%, P < 0.001. These results suggest that the chronic pharmaco-behavioral effects of phencyclidine may involve expression of both dopamine- and non-NMDA glutamate-receptor mRNAs.

  5. Detection and photoaffinity labeling of the Ca2+-activated K+ channel-associated apamin receptor in cultured astrocytes from rat brain.

    Science.gov (United States)

    Seagar, M J; Deprez, P; Martin-Moutot, N; Couraud, F

    1987-05-19

    Apamin, an 18-amino acid bee venom peptide, is a specific blocker of a class of Ca2+ activated K+ channels. Mono 125I-iodoapamin was used to detect the K+ channel-associated receptor site in cultured astrocytes from rat brain. Specific high-affinity binding to intact glial cells with a Kd of about 90 pM at 1 degree C and pH 7.5 was demonstrated by equilibrium and kinetic methods. The average receptor capacity was 3 fmol/mg cell protein which is 2 to 3-fold lower than in primary cultured neurons. Binding was stimulated by K+ ions, but to a lesser extent than with neuronal receptors. Photoaffinity labeling of receptor/ion channel components using an arylazide derivative of 125I-monoiodoapamin revealed the presence of the 86- and 33-kDa polypeptides, previously detected in neurones. However a 59-kDa peptide which is present in synaptic membrane preparations from adult rat brain, but not in cultured neurons, was also clearly labeled in intact astrocytes. This indicates that the 59-kDa polypeptide is not a proteolytic fragment of the 86-kDa chain but an associated subunit which is only accessible to photolabeling in certain apamin receptor preparations. Apamin-sensitive Ca2+-activated K+ channels in astrocytes may be one of the pathways by which glial cells redistribute K+ in the central nervous system (CNS). PMID:2440516

  6. Brain receptor single-photon emission computer tomography with 123I Datscan in Parkinson's disease

    International Nuclear Information System (INIS)

    Clinical aspects of Parkinson's disease are not enough for the early diagnosis of the disease. Positron emission tomography and the receptor single - photon emission tomography can be used for imaging functional integrity of nigrostriatal dopaminergic structures. 24 patient (17 men and 7 women) were investigated. 20 of them are with Parkinson's disease and 4 are with essential tremor. The radiopharmaceutical - 123I-Datscan (ioflupane, bind with 123I) represent a cocaine analogue with selective affinity to dopamine transporters, located in the dopaminergic nigrostriatal terminals in the striatum. Single - photon emission computer tomography was performed with SPECT gamma camera (ADAC, SH Epic detector). The scintigraphic study was made 3 to 6 hours after intravenous injection of the radiopharmaceutical - 123I- Datscan in dose 185 MBq. 120 frames are registered with duration of each one 22 seconds and gamma camera rotation 360. After generation of transversal slices we generated two composites pictures. The first composite picture image the striatum, the second - the occipital region. Two ratios were calculated representing the uptake of the radiopharmaceutical in the left and right striatum. Qualitative and quantitative criteria were elaborated for evaluating the scintigraphic patterns. Decreased, nonhomogeneous and asymmetric uptake of the radiopharmaceutical coupled with low quantitative parameters in range from 1.44 to 2.87 represents the characteristic scintigraphic pattern for Parkinson's disease with clear clinical picture. Homogenous with high intensity and symmetric uptake of the radiopharmaceutical in the striatum coupled with his clear frontier and with quantitative parameters up to 4.40 represent the scintigraphic pattern in two patients with essential tremor. Receptor single - photon emission computer tomography with 123I - Datscan represents an accurate nuclear-medicine method for precise diagnosis of Parkinson's disease and for its differentiation from

  7. Role of astrocytic leptin receptor subtypes on leptin permeation across hCMEC/D3 human brain endothelial cells.

    Science.gov (United States)

    Hsuchou, Hung; Kastin, Abba J; Tu, Hong; Joan Abbott, N; Couraud, Pierre-Olivier; Pan, Weihong

    2010-12-01

    Astrocytic leptin receptors (ObR) can be up-regulated in conditions such as adult-onset obesity. To determine whether the levels and subtypes of astrocytic ObR modulate leptin transport, we co-cultured hCMEC/D3 human brain endothelial cells and C6 astrocytoma cells in the Transwell system, and tested leptin permeation from apical to basolateral chambers. In comparison with hCMEC alone, co-culture of C6 cells reduced the permeability of paracellular markers and leptin. Unexpectedly, ObRb over-expression in C6 cells increased leptin permeation whereas ObRa over-expression showed no effect when compared with the control group of pcDNA-transfected C6 cells. By contrast, the paracellular permeability to the sodium fluorescein control was unchanged by over-expression of ObR subtypes. Leptin remained intact after crossing the monolayer as shown by HPLC and acid precipitation, and this was not affected by C6 cell co-culture or the over-expression of different ObR subtypes. Thus, increased expression of ObRb (and to a lesser extent ObRe) in C6 cells specifically increased the permeation of leptin across the hCMEC monolayer. Consistent with the evidence that the most apparent regulatory changes of ObR during obesity and inflammation occur in astrocytes, the results indicate that astrocytes actively regulate leptin transport across the blood-brain barrier, a mechanism independent of reduction of paracellular permeability. PMID:20977476

  8. Dopamine D(2) receptor quantification in extrastriatal brain regions using [(123)I]epidepride with bolus/infusion.

    Science.gov (United States)

    Pinborg, L H; Videbaek, C; Knudsen, G M; Swahn, C G; Halldin, C; Friberg, L; Paulson, O B; Lassen, N A

    2000-06-15

    The iodinated benzamide epidepride, which shows a picomolar affinity binding to dopamine D(2) receptors, has been designed for in vivo studies using SPECT. The aim of the present study was to apply a steady-state condition by the bolus/infusion approach with [(123)I]epidepride for the quantification of striatal and extrastriatal dopamine D(2) receptors in humans. In this way the distribution volume of the tracer can be determined from a single SPECT image and one blood sample. Based on bolus experiments, an algorithm using conventional convolution arguments for prediction of the outcome of a bolus/infusion (B/I) experiment was applied. It was predicted that a B/I protocol with infusion of one-third of the initial bolus per hour would be appropriate. Steady-state conditions were attained in extrastriatal regions within 3-4 h but the infusion continued up to 7 h in order to minimize the significance of individual differences in plasma clearance and binding parameters. A steady-state condition, however, could not be attained in striatal brain regions using a B/I protocol of 20 h, even after 11 h. Under near steady-state conditions a striatal:cerebellar ratio of 23 was demonstrated. Epidepride has a unique signal-to-noise ratio compared to [(123)I]IBZM but present difficulties for steady-state measurements of striatal regions. The bolus/infusion approach is particularly feasible for quantification of the binding potential in extrastriatal regions. PMID:10819910

  9. Expression of receptor for advanced glycation endproducts and nuclear factor κB in brain hippocampus of rat with chronic fluorosis

    Institute of Scientific and Technical Information of China (English)

    张凯琳

    2014-01-01

    Objective To investigate the expressions of receptor for advanced glycation endproducts(RAGE)and nuclear factorκB(NF-κB)in brain hippocampus of rat with chronic fluorosis,and to reveal the mechanism of brain damage resulted from chronic fluorosis.Methods Sixty clean grade SD rats were randomly divided to three groups(20 rats in each group,10 female and 10 male)fed with different contents of fluoride,control group with normal tap-water(<0.5 mg/L fluoride),

  10. Correlations between the Memory-Related Behavior and the Level of Oxidative Stress Biomarkers in the Mice Brain, Provoked by an Acute Administration of CB Receptor Ligands

    OpenAIRE

    Marta Kruk-Slomka; Anna Boguszewska-Czubara; Tomasz Slomka; Barbara Budzynska; Grazyna Biala

    2015-01-01

    The endocannabinoid system, through cannabinoid (CB) receptors, is involved in memory-related responses, as well as in processes that may affect cognition, like oxidative stress processes. The purpose of the experiments was to investigate the impact of CB1 and CB2 receptor ligands on the long-term memory stages in male Swiss mice, using the passive avoidance (PA) test, as well as the influence of these compounds on the level of oxidative stress biomarkers in the mice brain. A single injection...

  11. Characterization of Aromatase Expression in the Adult Male and Female Mouse Brain. I. Coexistence with Oestrogen Receptors α and β, and Androgen Receptors

    OpenAIRE

    Davor Stanić; Sydney Dubois; Hui Kheng Chua; Bruce Tonge; Nicole Rinehart; Malcolm K Horne; Wah Chin Boon

    2014-01-01

    Aromatase catalyses the last step of oestrogen synthesis. There is growing evidence that local oestrogens influence many brain regions to modulate brain development and behaviour. We examined, by immunohistochemistry, the expression of aromatase in the adult male and female mouse brain, using mice in which enhanced green fluorescent protein (EGFP) is transcribed following the physiological activation of the Cyp19A1 gene. EGFP-immunoreactive processes were distributed in many brain regions, in...

  12. Sigma-1 Receptor Imaging in the Brain: Cerebral sigma-1 receptors and cognition: Small-animal PET studies using 11C-SA4503

    OpenAIRE

    Kuzhuppilly Ramakrishnan, Nisha

    2014-01-01

    The sigma-1 receptor is a unique orphan receptor, strongly expressed in neurons and glia. Sigma-1 receptors are involved in several central nervous system (CNS) disorders like depression, anxiety, psychosis, schizophrenia, Parkinson’s disease, Alzheimer’s disease, addiction and neuropathic pain. Several CNS drugs like haloperidol, donepezil, rimcazole, fluvoxamine, sertraline and clorgyline have moderate to high sigma-1 receptor affinity. Pharmaceutical companies currently involved in R&D and...

  13. Sigma-1 Receptor Imaging in the Brain : Cerebral sigma-1 receptors and cognition: Small-animal PET studies using 11C-SA4503

    NARCIS (Netherlands)

    Kuzhuppilly Ramakrishnan, Nisha

    2014-01-01

    The sigma-1 receptor is a unique orphan receptor, strongly expressed in neurons and glia. Sigma-1 receptors are involved in several central nervous system (CNS) disorders like depression, anxiety, psychosis, schizophrenia, Parkinson’s disease, Alzheimer’s disease, addiction and neuropathic pain. Sev

  14. Postnatal Development of Brain-Derived Neurotrophic Factor (BDNF) and Tyrosine Protein Kinase B (TrkB) Receptor Immunoreactivity in Multiple Brain Stem Respiratory-Related Nuclei of the Rat

    OpenAIRE

    LIU, QIULI; Wong-Riley, Margaret T.T.

    2013-01-01

    Previously, we found a transient imbalance between suppressed excitation and enhanced inhibition in the respiratory network of the rat around postnatal days (P) 12–13, a critical period when the hypoxic ventilatory response is at its weakest. The mechanism underlying the imbalance is poorly understood. Brain-derived neurotrophic factor (BDNF) and its tyrosine protein kinase B (TrkB) receptors are known to potentiate glutamatergic and attenuate gamma-aminobutyric acid (GABA)ergic neurotransmis...

  15. The protective effect of heat acclimation from hypoxic damage in the brain involves changes in the expression of glutamate receptors

    Science.gov (United States)

    Yacobi, Assaf; Stern Bach, Yael; Horowitz, Michal

    2014-01-01

    Long-term heat acclimation (34 °C, 30d) alters the physiological responses and the metabolic state of organisms. It also improves ability to cope with hypoxic stress via a cross-tolerance mechanism. Within the brain, the hippocampal and frontal cortex neurons are the most sensitive to hypoxia and cell death is mainly caused by calcium influx via glutamate-gated ion channels, specifically NMDA and AMPA receptors. GluN1 subunit levels of NMDA-R correspond to NMDA-R levels. GluN2B/GluN2A subunit ratio is a qualitative index of channel activity; a higher ratio implies lower calcium permeability. The GluA2 subunit of AMPA-R controls channel permeability by inhibiting calcium penetration. Here, in rats model we (i)used behavioral-assessment tests to evaluate heat acclimation mediated hypoxic (15’ 4.5 ± 0.5% O2) neuroprotection, (ii) measured protein and transcript levels of NMDA-R and AMPA-R subunits before and after hypoxia in the hippocampus and the frontal cortex, to evaluate the role of Ca2+ in neuro-protection/cross-tolerance. Behavioral tests confirmed hypoxic tolerance in long-term (30d) but not in short-term (2d) heat acclimated rats. Hypoxic tolerance in the long-term acclimated phenotype was accompanied by a significant decrease in basal NMDA receptor GluN1 protein and an increase in its mRNA. The long-term acclimated rats also showed post ischemic increases in the GluN2B/GluN2A subunit ratio and GluA2 subunit of the AMPA receptor, supporting the hypothesis that reduced calcium permeability contributes to heat acclimation mediated hypoxia cross-tolerance. Abrupt post ischemic change in GluN2B/GluN2A subunit ratio with no change in NMDA-R subunits transcript levels implies that post-translational processes are inseparable acclimatory cross-tolerance mechanism.

  16. Distribution of the 5-HT1A receptor antagonist [18F]FPWAY in blood and brain of the rat with and without isoflurane anesthesia

    International Nuclear Information System (INIS)

    To determine whether brain and plasma equilibrium of a proposed PET tracer for 5-HT1A, [18F]FPWAY, can be achieved in a sufficiently short time for practical use of the brain to plasma equilibrium distribution ratio (DR) to monitor receptor availability with and without isoflurane anesthesia. Awake (n=4) and isoflurane-anesthetized (n=4) rats were administered a continuous 60 min intravenous infusion of [18F]FPWAY with timed arterial blood sampling. Brains of the isoflurane-anesthetized rats were scanned with the ATLAS small animal PET scanner; awake rats were not. All rats were killed at 60 min and scanned postmortem for 15 min, followed by brain slicing for autoradiography. Several regions of interest (ROIs) were defined in the PET images as well as in the autoradiographic images. Regional DRs were calculated as total activity in the brain ROI divided by plasma [18F]FPWAY activity. DRs in the anesthetized animals were constant between 30 and 60 min, indicating that near equilibrium between brain and plasma had been achieved by ∝30 min. DRs determined from postmortem PET data were higher in the isoflurane-anesthetized rats by 24% (not significant) and 33% (p=0.065) in whole brain and hippocampus, respectively. DRs determined from autoradiographic data were greater in isoflurane-anesthetized rats in medial hippocampus, lateral hippocampus, and cerebellum by 33% (p=0.054), 63% (p18F]FPWAY could be an appropriate ligand for monitoring changes in receptor availability in the serotonergic system using a bolus/infusion paradigm. One possible explanation for higher DRs in anesthetized rats may be a reduction in endogenous 5-HT secretion under isoflurane anesthesia. (orig.)

  17. Insulin: its binding to specific receptors and its stimulation of DNA synthesis and 2',3'-cyclic nucleotide phosphohydrolase in embryonic mouse brain cell cultures

    International Nuclear Information System (INIS)

    Previously, the authors demonstrated that ornithine decarboxylase was stimulated by insulin in cultures of embryonic mouse brain cells. In the present work, they have investigated the presence and specificity of insulin receptors in these cultures. A time study showed that maximum binding of 125[I] labelled insulin was around 75 min. Other studies measured the influence of concentration and age on insulin binding. A displacement study using increasing concentrations of cold insulin, glucagon or growth hormone demonstrated that the specificity of the receptors for insulin was rather high. It was also found that insulin displayed a clear dose-dependent stimulation of thymidine incorporation into the brain cells. Insulin also stimulated the glial enzyme 2':3'-cyclic nucleotide phosphohydrolase (CNP-ase). The results suggest a dual role for insulin; it regulates both cell proliferation as well as differentiation

  18. Development of radioactive agent for image diagnosis of brain dopamine receptor

    Energy Technology Data Exchange (ETDEWEB)

    Fujita, Motoi; Kitamura, Hideaki; Nakajima, Takashi [Saigata National Hospital, Niigata (Japan)

    2000-02-01

    Recently, MRI is often used to examine pathological degeneration of intracerebellar neurons of patients with Parkinson's disease, Huntington's chorea, spinocerebellar degeneration, etc. However, the efficacy of MRI is still unsatisfactory at present. In this project, the efficacy of SPECT was examined to evaluate the cerebellar functions in the previous year and it was found that the benzodiazepin receptor in CNS was detectable using SPECT with {sup 125}I iomazenil. In this year, ocular movements as one of cerebellar functions was attempted using functional MRI and patients' ocular movements were analyzed on the basis of the saccade during functional MRI imaging by Ober2 (Permobil Sweden). Image of an activated region in the frontal eye field (FEF), supplementary eye field (SEF), parietal eye field (PEF), posterior lobe or cerebellum was obtainable by Ober2-attached functional MRI. Especially, vermis 5, 6 and 7 lobules in the cerebellum were activated and random saccade was much stronger than regular saccade in the cerebellum. These results indicated that functional MRI was usable for clinical evaluation of patients with central nervous degeneration. (M.N.)

  19. Development of radioactive agent for image diagnosis of brain dopamine receptor

    International Nuclear Information System (INIS)

    Recently, MRI is often used to examine pathological degeneration of intracerebellar neurons of patients with Parkinson's disease, Huntington's chorea, spinocerebellar degeneration, etc. However, the efficacy of MRI is still unsatisfactory at present. In this project, the efficacy of SPECT was examined to evaluate the cerebellar functions in the previous year and it was found that the benzodiazepin receptor in CNS was detectable using SPECT with 125I iomazenil. In this year, ocular movements as one of cerebellar functions was attempted using functional MRI and patients' ocular movements were analyzed on the basis of the saccade during functional MRI imaging by Ober2 (Permobil Sweden). Image of an activated region in the frontal eye field (FEF), supplementary eye field (SEF), parietal eye field (PEF), posterior lobe or cerebellum was obtainable by Ober2-attached functional MRI. Especially, vermis 5, 6 and 7 lobules in the cerebellum were activated and random saccade was much stronger than regular saccade in the cerebellum. These results indicated that functional MRI was usable for clinical evaluation of patients with central nervous degeneration. (M.N.)

  20. [3H] glycogen hydrolysis in brain slices: responses to meurotransmitters and modulation of noradrenaline receptors

    International Nuclear Information System (INIS)

    Different agents have been investigated for their effects on [3H] glycogen synthesized in mouse cortical slices. Of these noradrenaline, serotonin and histamine induced clear concentration-dependent glycogenesis. [3H] glycogen hydrolysis induced by noradrenaline appears to be mediated by beta-adrenergic receptors because it is completely prevented by timolol, while phentolamine is ineffective. It seems to involve cyclic AMP because it is potentiated in the presence of isobutylmethylxanthine; in addition dibutyryl cyclic AMP (but not dibutyryl cyclic GMP) promotes glycogenolysis. Lower concentrations of noradrenaline were necessary for [3H] glycogen hydrolysis (ECsub(50) 0.5μM) than for stimulation of cyclic AMP accumulation (ECsub(50) = 8μM). After subchronic reserpine treatment the concentration-response curve to noradrenaline was significantly shifted to the left (ECsub(50) = 0.09 +- 0.02 μM as compared with 0.49 +- 0.08μM in saline-pretreated mice) without modifications of either the basal [3H] glycogen level, maximal glycogenolytic effect, or the dibutyryl cAMP-induced glycogenolytic response. In addition to noradrenaline, clear concentration-dependent [3H] glycogen hydrolysis was observed in the presence of histamine or serotonin. In contrast to the partial [3H] glycogen hydrolysis elicited by these biogenic amines, depolarization of the slices by 50 mM K+ provoked a nearly total [3H] glycogen hydrolysis. (author)

  1. Increase in serotonin 5-HT1A receptors in prefrontal and temporal cortices of brains from patients with chronic schizophrenia

    International Nuclear Information System (INIS)

    Binding studies with [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT), a specific serotonin1A (5-HT1A) receptor agonist, were done on the autopsied brains from control subjects and from patients with chronic schizophrenia. In the controls, representative Scatchard plots for the specific [3H]8-OH-DPAT bindings in the prefrontal cortex and hippocampus revealed a single component of high affinity binding site. The [3H]8-OH-DPAT bindings to the prefrontal cortex and hippocampus were potently inhibited by serotonin and 5-HT1A agonists, while other neurotransmitters, 5-HT2 and 5-HT3 related compounds did not inhibit the binding. The bindings were decreased in the presence of 0.1mM GTP and 0.1mM GppNHp but not in the presence of 0.1mM GMP. In the prefrontal and temporal cortices of schizophrenics, there was a significant increase in the specific [3H]8-OH-DPAT binding, by 40% and 60%, respectively, with no change in the hippocampus, amygdala, cingulum, motor cortex, parietal or occipital cortex, as compared to findings in the controls

  2. Sexually dimorphic effects of NMDA receptor antagonism on brain-pituitary-gonad axis development in the platyfish

    Science.gov (United States)

    Flynn, Katherine M.; Miller, Shelly A.; Sower, Stacia A.; Schreibman, Martin P.

    2002-01-01

    The N-methyl-D-aspartate glutamate receptor (NMDAR) is found in hypothalamic nuclei involved in the regulation of reproduction in several species of mammals and fishes. NMDAR is believed to affect reproductive development and function by regulating gonadotropin releasing hormone (GnRH)-producing cells. These pathways are likely to be sexually dimorphic, as are several other neurotransmitter systems involved in reproductive function. In this report, male and female platyfish received intraperitoneal injections of 0, 5, 10, 20, 40 or 60 microg/g body wt. of the non-competitive NMDAR antagonist MK-801. Injections began at 6 weeks of age and continued thrice weekly until control animals reached puberty, as evidenced by anal fin maturation. The percent of pubescent animals was significantly affected by sex and treatment, with fewer MK-801-injected females in puberty than control females at each dose (Pbrain-pituitary-gonad (BPG) axis was limited to GnRH-containing brain cells in all animals; however, NMDAR1 distribution was in an immature pattern in treated females and a mature pattern in all others. Neural concentrations of GnRH were unaffected by MK-801 treatment in both sexes. These data suggest that in the platyfish, NMDAR influence on reproductive development is sexually dimorphic and occurs at, or above, the level of GnRH-containing cells of the BPG axis.

  3. Discordance of Mutation Statuses of Epidermal Growth Factor Receptor and K-ras between Primary Adenocarcinoma of Lung and Brain Metastasis

    OpenAIRE

    Kun-Ming Rau; Han-Ku Chen; Li-Yen Shiu; Tsai-Ling Chao; Yi-Ping Lo; Chin-Chou Wang; Meng-Chih Lin; Chao-Cheng Huang

    2016-01-01

    Mutations on epidermal growth factor receptor (EGFR) of adenocarcinomas of lung have been found to be associated with increased sensitivity to EGFR tyrosine kinase inhibitors and K-ras mutations may correlate with primary resistance. We aimed to explore the discordant mutation statuses of EGFR and K-ras between primary tumors and matched brain metastases in adenocarcinomas of lung. We used a sensitive Scorpion ARMS method to analyze EGFR mutation, and Sanger sequencing followed by allele-spec...

  4. Polychlorinated biphenyls (PCBs) exert thyroid hormone-like effects in the fetal rat brain but do not bind to thyroid hormone receptors.

    OpenAIRE

    Gauger, Kelly J; Kato, Yoshihisa; Haraguchi, Koichi; Lehmler, Hans-Joachim; Robertson, Larry W.; Bansal, Ruby; Zoeller, R. Thomas

    2004-01-01

    Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants routinely found in human and animal tissues. Developmental exposure to PCBs is associated with neuropsychologic deficits, which may be related to effects on thyroid hormone (TH) signaling in the developing brain. However, PCBs may interfere with TH signaling solely by reducing circulating levels of TH, or they may exert direct effects on TH receptors (TRs). Therefore, we tested whether maternal exposure to a commercial...

  5. Overlapping patterns of brain activation to food and cocaine cues in cocaine abusers: association to striatal D2/D3 receptors

    OpenAIRE

    Tomasi, Dardo; Wang, Gene-Jack; Wang, Ruiliang; Caparelli, Elisabeth C.; Logan, Jean; Volkow, Nora D.

    2014-01-01

    Cocaine, through its activation of dopamine (DA) signaling, usurps pathways that process natural rewards. However, the extent to which there is overlap between the networks that process natural and drug rewards and whether DA signaling associated with cocaine abuse influences these networks have not been investigated in humans. We measured brain activation responses to food and cocaine cues with fMRI, and D2/D3 receptors in the striatum with [11C]raclopride and PET in 20 active cocaine abuser...

  6. Complete remission through icotinib treatment in Non-small cell lung cancer epidermal growth factor receptor mutation patient with brain metastasis: A case report

    OpenAIRE

    Wang Tao; Wang Ruimin; Dong Zhouhuan; Liang Naichao; Chang Ping

    2016-01-01

    Brain metastasis (BM) has been universally recognized as a poor prognostic factor in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown efficacy in treating BM with an EGFR mutation. This paper reports a case of BM patient with EGFR-mutated NSCLC. According to the findings, a complete remission (CR) of the BM was achieved by icotinib treatment without conducting a radiotherapy, which was followed by a resection of the prima...

  7. Modulation of memory consolidation by the basolateral amygdala or nucleus accumbens shell requires concurrent dopamine receptor activation in both brain regions

    OpenAIRE

    LaLumiere, Ryan T; Nawar, Erene M.; McGaugh, James L.

    2005-01-01

    Previous findings indicate that the basolateral amygdala (BLA) and the nucleus accumbens (NAc) interact in influencing memory consolidation. The current study investigated whether this interaction requires concurrent dopamine (DA) receptor activation in both brain regions. Unilateral, right-side cannulae were implanted into the BLA and the ipsilateral NAc shell or core in male Sprague-Dawley rats (∼300 g). One week later, the rats were trained on an inhibitory avoidance (IA) task and, 48 h la...

  8. Inter-sexual variation in social interactions and distribution of estrogen receptor alpha in the brain of mandarin voles Microtus mandarinus

    OpenAIRE

    ZHAI Pei-Yuan,; TAI Fa-Dao; Xue, Hui; Jia Rui

    2008-01-01

    To explore the effects of estrogen receptor alpha (ERα) on social behaviors of mandarin voles (Microtus mandarinus), same-sex social interaction tests in mandarin voles were conducted and the distribution of ERα immunoreactivity(IR) cells were examined in the brains of male and female mandarin voles by immunocytochemistry. The results showed that female mandarin voles displayed significantly less affiliation and more defense (P

  9. Brain activation by short-term nicotine exposure in anesthetized wild-type and beta2-nicotinic receptors knockout mice: a BOLD fMRI study

    Energy Technology Data Exchange (ETDEWEB)

    Suarez, S.V.; Changeux, J.P.; Granon, S. [Unite de Neurobiologie Integrative du Systeme Cholinergique, URA CNRS 2182, Institut Pasteur, Departement de Neuroscience, 25 rue du Dr Roux, 75015 Paris (France); Amadon, A.; Giacomini, E.; Le Bihan, D. [Service Hospitalier Frederic Joliot, 4 place du general Leclerc, 91400 Orsay (France); Wiklund, A. [Section of Anaesthesiology and Intensive Care Medicine, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm (Sweden)

    2009-07-01

    Rationale: The behavioral effects of nicotine and the role of the beta2-containing nicotinic receptors in these behaviors are well documented. However, the behaviors altered by nicotine rely on the functioning on multiple brain circuits where the high-affinity {beta}2-containing nicotinic receptors ({beta}2*nAChRs) are located. Objectives We intend to see which brain circuits are activated when nicotine is given in animals naive for nicotine and whether the {beta}2*nAChRs are needed for its activation of the blood oxygen level dependent (BOLD) signal in all brain areas. Materials and methods: We used functional magnetic resonance imaging (fMRI) to measure the brain activation evoked by nicotine (1 mg/kg delivered at a slow rate for 45 min) in anesthetized C57BL/6J mice and {beta}2 knockout (KO) mice. Results: Acute nicotine injection results in a significant increased activation in anterior frontal, motor, and somatosensory cortices and in the ventral tegmental area and the substantia nigra. Anesthetized mice receiving no nicotine injection exhibited a major decreased activation in all cortical and subcortical structures, likely due to prolonged anesthesia. At a global level, {beta}2 KO mice were not rescued from the globally declining BOLD signal. However, nicotine still activated regions of a meso-cortico-limbic circuit likely via {alpha}7 nicotinic receptors. Conclusions: Acute nicotine exposure compensates for the drop in brain activation due to anesthesia through the meso-cortico-limbic network via the action of nicotine on {beta}2*nAChRs. The developed fMRI method is suitable for comparing responses in wild-type and mutant mice. (authors)

  10. Brain activation by short-term nicotine exposure in anesthetized wild-type and beta2-nicotinic receptors knockout mice: a BOLD fMRI study

    International Nuclear Information System (INIS)

    Rationale: The behavioral effects of nicotine and the role of the beta2-containing nicotinic receptors in these behaviors are well documented. However, the behaviors altered by nicotine rely on the functioning on multiple brain circuits where the high-affinity β2-containing nicotinic receptors (β2*nAChRs) are located. Objectives We intend to see which brain circuits are activated when nicotine is given in animals naive for nicotine and whether the β2*nAChRs are needed for its activation of the blood oxygen level dependent (BOLD) signal in all brain areas. Materials and methods: We used functional magnetic resonance imaging (fMRI) to measure the brain activation evoked by nicotine (1 mg/kg delivered at a slow rate for 45 min) in anesthetized C57BL/6J mice and β2 knockout (KO) mice. Results: Acute nicotine injection results in a significant increased activation in anterior frontal, motor, and somatosensory cortices and in the ventral tegmental area and the substantia nigra. Anesthetized mice receiving no nicotine injection exhibited a major decreased activation in all cortical and subcortical structures, likely due to prolonged anesthesia. At a global level, β2 KO mice were not rescued from the globally declining BOLD signal. However, nicotine still activated regions of a meso-cortico-limbic circuit likely via α7 nicotinic receptors. Conclusions: Acute nicotine exposure compensates for the drop in brain activation due to anesthesia through the meso-cortico-limbic network via the action of nicotine on β2*nAChRs. The developed fMRI method is suitable for comparing responses in wild-type and mutant mice. (authors)

  11. CRF receptor 1 antagonism and brain distribution of active components contribute to the ameliorative effect of rikkunshito on stress-induced anorexia.

    Science.gov (United States)

    Mogami, Sachiko; Sadakane, Chiharu; Nahata, Miwa; Mizuhara, Yasuharu; Yamada, Chihiro; Hattori, Tomohisa; Takeda, Hiroshi

    2016-01-01

    Rikkunshito (RKT), a Kampo medicine, has been reported to show an ameliorative effect on sustained hypophagia after novelty stress exposure in aged mice through serotonin 2C receptor (5-HT2CR) antagonism. We aimed to determine (1) whether the activation of anorexigenic neurons, corticotropin-releasing factor (CRF), and pro-opiomelanocortin (POMC) neurons, is involved in the initiation of hypophagia induced by novelty stress in aged mice; (2) whether the ameliorative effect of RKT is associated with CRF and POMC neurons and downstream signal transduction; and (3) the plasma and brain distribution of the active components of RKT. The administration of RKT or 5-HT2CR, CRF receptor 1 (CRFR1), and melanocortin-4 receptor antagonists significantly restored the decreased food intake observed in aged male C57BL/6 mice in the early stage after novelty stress exposure. Seven components of RKT exhibited antagonistic activity against CRFR1. Hesperetin and isoliquiritigenin, which showed antagonistic effects against both CRFR1 and 5-HT2CR, were distributed in the plasma and brain of male Sprague-Dawley rats after a single oral administration of RKT. In conclusion, the ameliorative effect of RKT in this model is assumed to be at least partly due to brain-distributed active components possessing 5-HT2CR and CRFR1 antagonistic activities. PMID:27273195

  12. Insulin signaling, lifespan and stress resistance are modulated by metabotropic GABA receptors on insulin producing cells in the brain of Drosophila.

    Science.gov (United States)

    Enell, Lina E; Kapan, Neval; Söderberg, Jeannette A E; Kahsai, Lily; Nässel, Dick R

    2010-01-01

    Insulin-like peptides (ILPs) regulate growth, reproduction, metabolic homeostasis, life span and stress resistance in worms, flies and mammals. A set of insulin producing cells (IPCs) in the Drosophila brain that express three ILPs (DILP2, 3 and 5) have been the main focus of interest in hormonal DILP signaling. Little is, however, known about factors that regulate DILP production and release by these IPCs. Here we show that the IPCs express the metabotropic GABA(B) receptor (GBR), but not the ionotropic GABA(A) receptor subunit RDL. Diminishing the GBR expression on these cells by targeted RNA interference abbreviates life span, decreases metabolic stress resistance and alters carbohydrate and lipid metabolism at stress, but not growth in Drosophila. A direct effect of diminishing GBR on IPCs is an increase in DILP immunofluorescence in these cells, an effect that is accentuated at starvation. Knockdown of irk3, possibly part of a G protein-activated inwardly rectifying K(+) channel that may link to GBRs, phenocopies GBR knockdown in starvation experiments. Our experiments suggest that the GBR is involved in inhibitory control of DILP production and release in adult flies at metabolic stress and that this receptor mediates a GABA signal from brain interneurons that may convey nutritional signals. This is the first demonstration of a neurotransmitter that inhibits insulin signaling in its regulation of metabolism, stress and life span in an invertebrate brain. PMID:21209905

  13. CRF receptor 1 antagonism and brain distribution of active components contribute to the ameliorative effect of rikkunshito on stress-induced anorexia

    Science.gov (United States)

    Mogami, Sachiko; Sadakane, Chiharu; Nahata, Miwa; Mizuhara, Yasuharu; Yamada, Chihiro; Hattori, Tomohisa; Takeda, Hiroshi

    2016-01-01

    Rikkunshito (RKT), a Kampo medicine, has been reported to show an ameliorative effect on sustained hypophagia after novelty stress exposure in aged mice through serotonin 2C receptor (5-HT2CR) antagonism. We aimed to determine (1) whether the activation of anorexigenic neurons, corticotropin-releasing factor (CRF), and pro-opiomelanocortin (POMC) neurons, is involved in the initiation of hypophagia induced by novelty stress in aged mice; (2) whether the ameliorative effect of RKT is associated with CRF and POMC neurons and downstream signal transduction; and (3) the plasma and brain distribution of the active components of RKT. The administration of RKT or 5-HT2CR, CRF receptor 1 (CRFR1), and melanocortin-4 receptor antagonists significantly restored the decreased food intake observed in aged male C57BL/6 mice in the early stage after novelty stress exposure. Seven components of RKT exhibited antagonistic activity against CRFR1. Hesperetin and isoliquiritigenin, which showed antagonistic effects against both CRFR1 and 5-HT2CR, were distributed in the plasma and brain of male Sprague-Dawley rats after a single oral administration of RKT. In conclusion, the ameliorative effect of RKT in this model is assumed to be at least partly due to brain-distributed active components possessing 5-HT2CR and CRFR1 antagonistic activities. PMID:27273195

  14. Novel G Protein-Coupled Oestrogen Receptor GPR30 Shows Changes in mRNA Expression in the Rat Brain over the Oestrous Cycle

    Directory of Open Access Journals (Sweden)

    Emma J. Spary

    2012-02-01

    Full Text Available Oestrogen influences autonomic function via actions at classical nuclear oestrogen receptors α and β in the brain, and recent evidence suggests the orphan G protein-coupled receptor GPR30 may also function as a cytoplasmic oestrogen receptor. We investigated the expression of GPR30 in female rat brains throughout the oestrous cycle and after ovariectomy to determine whether GPR30 expression in central autonomic nuclei is correlated with circulating oestrogen levels. In the nucleus of the solitary tract (NTS, ventrolateral medulla (VLM and periaqueductal gray (PAG GPR30 mRNA, quantified by real-time PCR, was increased in proestrus and oestrus. In ovariectomised (OVX rats, expression in NTS and VLM appeared increased compared to metoestrus, but in the hypothalamic paraventricular nucleus and PAG lower mRNA levels were seen in OVX. GPR30-like immunoreactivity (GPR30-LI colocalised with Golgi in neurones in many brain areas associated with autonomic pathways, and analysis of numbers of immunoreactive neurones showed differences consistent with the PCR data. GPR30-LI was found in a variety of transmitter phenotypes, including cholinergic, serotonergic, catecholaminergic and nitrergic neurones in different neuronal groups. These observations support the view that GPR30 could act as a rapid transducer responding to oestrogen levels and thus modulate the activity of central autonomic pathways.

  15. Spatiotemporal expression of repulsive guidance molecules (RGMs and their receptor neogenin in the mouse brain.

    Directory of Open Access Journals (Sweden)

    Dianne M A van den Heuvel

    Full Text Available Neogenin has been implicated in a variety of developmental processes such as neurogenesis, neuronal differentiation, apoptosis, migration and axon guidance. Binding of repulsive guidance molecules (RGMs to Neogenin inhibits axon outgrowth of different neuronal populations. This effect requires Neogenin to interact with co-receptors of the uncoordinated locomotion-5 (Unc5 family to activate downstream Rho signaling. Although previous studies have reported RGM, Neogenin, and/or Unc5 expression, a systematic comparison of RGM and Neogenin expression in the developing nervous system is lacking, especially at later developmental stages. Furthermore, information on RGM and Neogenin expression at the protein level is limited. To fill this void and to gain further insight into the role of RGM-Neogenin signaling during mouse neural development, we studied the expression of RGMa, RGMb, Neogenin and Unc5A-D using in situ hybridization, immunohistochemistry and RGMa section binding. Expression patterns in the primary olfactory system, cortex, hippocampus, habenula, and cerebellum were studied in more detail. Characteristic cell layer-specific expression patterns were detected for RGMa, RGMb, Neogenin and Unc5A-D. Furthermore, strong expression of RGMa, RGMb and Neogenin protein was found on several major axon tracts such as the primary olfactory projections, anterior commissure and fasciculus retroflexus. These data not only hint at a role for RGM-Neogenin signaling during the development of different neuronal systems, but also suggest that Neogenin partners with different Unc5 family members in different systems. Overall, the results presented here will serve as a framework for further dissection of the role of RGM-Neogenin signaling during neural development.

  16. Depressive behavior and alterations in receptors for dopamine and 5-hydroxytryptamine in the brain of the senescence accelerated mouse (SAM)-P10.

    Science.gov (United States)

    Onodera, T; Watanabe, R; Tha, K K; Hayashi, Y; Murayama, T; Okuma, Y; Ono, C; Oketani, Y; Hosokawa, M; Nomura, Y

    2000-08-01

    The senescence accelerated mouse (SAM) is known as a murine model of aging. SAM consists of senescence accelerated-prone mouse (SAMP) and senescence accelerated-resistant mouse (SAMR). Previous studies reported that SAMP10 exhibits age-related learning impairments and behavioral depression in a tail suspension test after 7 months. We investigated the changes in emotional behavior in a forced swimming test and in receptors for dopamine and 5-hydroxytryptamine (5-HT) in SAMP10. SAMP10 at 8 months showed an increase of immobility in the test compared with SAMR1. Treatment with desipramine (25 mg/kg, i.p., 3 days) in SAMP10 caused a decrease in immobility. In the cortex from SAMP10, [3H]quinpirole binding to D2/D3 dopamine receptors increased significantly compared with control SAMR1. In the hippocampus from SAMP10, [3H]8-hydroxy DPAT binding to 5-HT1A receptor increased. In midbrains from SAMP10, bindings of [3H]quinpirole and [3H]8-hydroxy DPAT increased. [3H]SCH23390 binding to D1/D5 receptors and [3H]ketanserin binding to 5-HT2 receptor in brain regions examined in SAMP10 were similar to those in SAMR1. The present findings represent the first neurochemical evidence of an increase of D2/D3 and 5-HT1A receptors in SAMP10. SAMP10 may be a useful model of aging associated depressive behavior. PMID:11001177

  17. Preparation and biodistribution in mice of ( sup 11 C)carfentanil; A radiopharmaceutical for studying brain. mu. -opioid receptors by positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Saji, Hideo; Tsutsumi, Daisuke; Iida, Yasuhiko; Yokoyama, Akira (Kyoto Univ. (Japan). Faculty of Pharmaceutical Science); Magata, Yasuhiro; Konishi, Junji

    1992-02-01

    A potent {mu}-opioid agonist, ({sup 11}C)carfentanil, was prepared by the methylation of carfentanil carboxylic acid with ({sup 11}C)methyl iodide in order to study brain {mu}-opioid receptors by positron emission tomography. Synthesis (including purification) was completed within 25 min and the radiochemical yield was approximately 40%. The radiochemical purity of the product was more than 99% and its specific activity was 3.7-7.4 GBq/{mu}mol. Biodistribution studies performed in mice after intravenous injection showed a high brain uptake and rapid blood clearance, so a high brain/blood ratio of 1.5-1.8 was found from 5 to 30 min. Regional cerebral distribution studies in the mouse showed a significantly higher uptake of ({sup 11}C)carfentanil by the thalamus and striatum than by the cerebellum, with the radioactivity in the striatum disappearing more rapidly than that in the thalamus. Treatment with naloxone significantly reduced the uptake of ({sup 11}C)carfentanil by the thalamus and striatum. These results indicate that ({sup 11}C)carfentanil binds specifically to brain {mu}-opioid receptors. (author).

  18. Melatonin Inhibits GnRH-1, GnRH-3 and GnRH Receptor Expression in the Brain of the European Sea Bass, Dicentrarchus labrax

    Directory of Open Access Journals (Sweden)

    José Antonio Muñoz-Cueto

    2013-04-01

    Full Text Available Several evidences supported the existence of melatonin effects on reproductive system in fish. In order to investigate whether melatonin is involved in the modulation of GnRH systems in the European sea bass, we have injected melatonin (0.5 µg/g body mass in male specimens. The brain mRNA transcript levels of the three GnRH forms and the five GnRH receptors present in this species were determined by real time quantitative PCR. Our findings revealed day–night variations in the brain expression of GnRH-1, GnRH-3 and several GnRH receptors (dlGnRHR-II-1c, -2a, which exhibited higher transcript levels at mid-light compared to mid-dark phase of the photocycle. Moreover, an inhibitory effect of melatonin on the nocturnal expression of GnRH-1, GnRH-3, and GnRH receptors subtypes 1c, 2a and 2b was also demonstrated. Interestingly, the inhibitory effect of melatonin affected the expression of hypophysiotrophic GnRH forms and GnRH receptors that exhibit day–night fluctuations, suggesting that exogenous melatonin reinforce physiological mechanisms already established. These interactions between melatoninergic and GnRH systems could be mediating photoperiod effects on reproductive and other rhythmic physiological events in the European sea bass.

  19. Dopamine D2-receptor imaging with [sup 123]I-iodobenzamide SPECT in migraine patients abusing ergotamine: does ergotamine cross the blood brain barrier

    Energy Technology Data Exchange (ETDEWEB)

    Verhoeff, N.P.; Visser, W.H.; Ferrari, M.D.; Saxena, P.R.; Royen, E.A. van (Erasmus Univ., Rotterdam (Netherlands))

    1993-10-01

    Two migraine patients were studied by in vivo SPECT using the dopamine D2-receptor specific radioligand [sup 123]I-3-iodo-6-methoxybenzamide ([sup 123]I-IBZM) during ergotamine abuse and after withdrawal. Results were compared with 15 healthy controls. Striatum/cerebellum and striatum/occipital cortex ratios of count rate density were calculated as a semiquantitative measurement for striatal dopamine D2-receptor binding potential. No differences were found in striatal uptake of [sup 123]I-IBZM between healthy controls and the patients when on or off ergotamine. Preliminary evidence suggests that ergotamine may not occupy striatal dopamine D2-receptors to a large extent and thus may not cross the blood brain barrier in large quantities. 23 refs., 3 figs.

  20. Dopamine D2-receptor imaging with 123I-iodobenzamide SPECT in migraine patients abusing ergotamine: does ergotamine cross the blood brain barrier?

    International Nuclear Information System (INIS)

    Two migraine patients were studied by in vivo SPECT using the dopamine D2-receptor specific radioligand 123I-3-iodo-6-methoxybenzamide (123I-IBZM) during ergotamine abuse and after withdrawal. Results were compared with 15 healthy controls. Striatum/cerebellum and striatum/occipital cortex ratios of count rate density were calculated as a semiquantitative measurement for striatal dopamine D2-receptor binding potential. No differences were found in striatal uptake of 123I-IBZM between healthy controls and the patients when on or off ergotamine. Preliminary evidence suggests that ergotamine may not occupy striatal dopamine D2-receptors to a large extent and thus may not cross the blood brain barrier in large quantities. 23 refs., 3 figs

  1. In vitro assessment of the agonist properties of the novel 5-HT{sub 1A} receptor ligand, CUMI-101 (MMP), in rat brain tissue

    Energy Technology Data Exchange (ETDEWEB)

    Hendry, Nicola; Christie, Isabel [Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, CM19 5AW Essex (United Kingdom); Rabiner, Eugenii Alfredovich, E-mail: eugenii_a_rabiner@gsk.co [GSK Clinical Imaging Centre, London Hammersmith Hospital-IC, W12 0NN London (United Kingdom); Laruelle, Marc; Watson, Jeannette [Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, CM19 5AW Essex (United Kingdom)

    2011-02-15

    Introduction: Development of agonist positron emission tomography (PET) radioligands for the 5-HT neurotransmitter system is an important target to enable the understanding of human 5-HT function in vivo. [{sup 11}C]CUMI-101, proposed as the first 5-HT{sub 1A} receptor agonist PET ligand, has been reported to behave as a potent 5-HT{sub 1A} agonist in a cellular system stably expressing human recombinant 5-HT{sub 1A} receptors. In this study, we investigate the agonist properties of CUMI-101 in rat brain tissue. Methods: [{sup 35}S]-GTP{gamma}S binding studies were used to determine receptor function in HEK (human embryonic kidney) 293 cells transfected with human recombinant 5-HT{sub 1A} receptors and in rat cortex and rat hippocampal tissue, following administration of CUMI-101 and standard 5-HT1A antagonists (5-HT, 5-CT and 8-OH-DPAT). Results: CUMI-101 behaved as an agonist at human recombinant 5-HT{sub 1A} receptors (pEC{sub 50} 9.2). However, CUMI-101 did not show agonist activity in either rat cortex or hippocampus at concentrations up to 10 {mu}M. In these tissues, CUMI-behaved as an antagonist with pK{sub B}s of 9.2 and 9.3, respectively. Conclusions: Our studies demonstrate that as opposed to its behavior in human recombinant system, in rat brain tissue CUMI-101 behaves as a potent 5-HT{sub 1A} receptor antagonist.

  2. receptores

    Directory of Open Access Journals (Sweden)

    Salete Regina Daronco Benetti

    2006-01-01

    Full Text Available Se trata de un estudio etnográfico, que tuvo lo objetivo de interpretar el sistema de conocimiento y del significado atribuidos a la sangre referente a la transfusión sanguínea por los donadores y receptores de un banco de sangre. Para la colecta de las informaciones se observaron los participantes y la entrevista etnográfica se realizó el análisis de dominio, taxonómicos y temáticos. Los dominios culturales fueron: la sangre es vida: fuente de vida y alimento valioso; creencias religiosas: fuentes simbólicas de apoyos; donación sanguínea: un gesto colaborador que exige cuidarse, gratifica y trae felicidad; donación sanguínea: fuente simbólica de inseguridad; estar enfermo es una condición para realizar transfusión sanguínea; transfusión sanguínea: esperanza de vida; Creencias populares: transfusión sanguínea como riesgo para la salud; donadores de sangre: personas benditas; donar y recibir sangre: como significado de felicidad. Temática: “líquido precioso que origina, sostiene, modifica la vida, provoca miedo e inseguridad”.

  3. Incidence, symptoms, treatment, and prognosis in 113 patients with brain/meningeal metastasis from breast cancer. Screening in accordance with hormone receptor and HER2/neu

    International Nuclear Information System (INIS)

    In 113 of 422 patients with metastatic/recurrent breast cancer (MBC who were treated in our hospital after 2001, brain/meningeal metastasis was detected. In 240 patients who died, the overall incidence of brain/meningeal metastasis was 36.3% (n=87). With respect to hormone receptor (HR) and HER2 presence, metastasis was detected in 32 (58.2%) of 55 patients showing HR(-) and HER2(+), 17 (39.5%) of 43 patients showing HR(-) and HER2(-), 19 (31.5%) of 54 patients showing HR(+) and HER2(+), and 17 (20%) of 85 patients showing HR(+) and HER2(-) (brain metastasis was detected in 2 of 3 patients in whom HR or HER2 was unclear); the incidence was significantly higher in HR(-) or HER2(+) patients. Of our series including surviving patients, asymptomatic brain metastasis was detected using contrast-enhanced MRI in 24 HER2(+) patients. In the above 113 patients, the median survival time (MST) after diagnosis was 10 months. However, it was 17 months in 24 patients who underwent screening. For treatment, whole brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) mainly with a gamma knife was performed. During a follow-up of more than 12 months, 1 to 4 sessions of treatment (mean: 2.39, median: 2) were required. In 50% of the patients, both WBRT and SRS were performed. There were no HR- or HER2- related differences in survival after brain metastasis. However, the MST was 34 months in 7 patients in whom the 1st relapse site involved the brain. In the future, the usefulness of early treatment via brain metastasis screening should be reviewed in HR(-) and HER2(+) patients. (author)

  4. P2X4 receptor in the dorsal horn partially contributes to brain-derived neurotrophic factor oversecretion and toll-like receptor-4 receptor activation associated with bone cancer pain.

    Science.gov (United States)

    Jin, Xiao-Hong; Wang, Li-Na; Zuo, Jian-Ling; Yang, Jian-Ping; Liu, Si-Lan

    2014-12-01

    Previous studies have suggested that the microglial P2X7 purinoceptor is involved in the release of tumor necrosis factor-α (TNFα) following activation of toll-like receptor-4 (TLR4), which is associated with nociceptive behavior. In addition, this progress is evoked by the activation of the P2X4 purinoceptor (P2X4R). Although P2X4R is also localized within spinal microglia in the dorsal horn, little is known about its role in cancer-induced bone pain (CIBP), which is in some ways unique. With the present rat model of CIBP, we demonstrate a critical role of the microglial P2X4R in the enhanced nociceptive transmission, which is associated with TLR4 activation and secretion of brain-derived neurotrophic factor (BDNF) and TNFα in the dorsal horn. We assessed mechanical threshold and spontaneous pain of CIBP rats. Moreover, P2X4R small interfering RNA (siRNA) was administered intrathecally, and real-time PCR, Western blots, immunofluorescence histochemistry, and ELISA were used to detect the expression of P2X4R, TLR4, OX-42, phosphorylated-p38 MAPK (p-p38), BDNF, and TNFα. Compared with controls, intrathecal injection of P2X4R siRNA could prevent nociceptive behavior induced by ATP plus lipopolysaccharide and CIBP and reduce the expression of P2X4R, TLR4, p-p38, BDNF, and TNFα. In addition, the increase of BDNF protein in rat microglial cells depended on P2X4 receptor signaling, which is partially associated with TLR4 activation. The ability of microglial P2X4R to activate TLR4 in spinal cord leading to behavioral hypersensitivity and oversecretion of BDNF could provide an opportunity for the prevention and treatment of CIBP. PMID:24984884

  5. (18)F-FCWAY, a serotonin 1A receptor radioligand, is a substrate for efflux transport at the human blood-brain barrier.

    Science.gov (United States)

    Liow, Jeih-San; Zoghbi, Sami S; Hu, Shuo; Hall, Matthew D; Hines, Christina S; Shetty, H Umesha; Araneta, Maria D; Page, Emily M; Pike, Victor W; Kreisl, William C; Herscovitch, Peter; Gottesman, Michael M; Theodore, William H; Innis, Robert B

    2016-09-01

    Efflux transporters at the blood-brain barrier can decrease the entry of drugs and increase the removal of those molecules able to bypass the transporter. We previously hypothesized that (18)F-FCWAY, a radioligand for the serotonin 5-HT1A receptor, is a weak substrate for permeability glycoprotein (P-gp) based on its very early peak and rapid washout from human brain. To determine whether (18)F-FCWAY is a substrate for P-gp, breast cancer resistance protein (BCRP), and multidrug resistance protein (MRP1) - the three most prevalent efflux transporters at the blood-brain barrier - we performed three sets of experiments. In vitro, we conducted fluorescence-activated cell sorting (FACS) flow cytometry studies in cells over-expressing P-gp, BCRP, and MRP1 treated with inhibitors specific to each transporter and with FCWAY. Ex vivo, we measured (18)F-FCWAY concentration in plasma and brain homogenate of transporter knockout mice using γ-counter and radio-HPLC. In vivo, we conducted positron emission tomography (PET) studies to assess changes in humans who received (18)F-FCWAY during an infusion of tariquidar (2-4mg/kg iv), a potent and selective P-gp inhibitor. In vitro studies showed that FCWAY allowed fluorescent substrates to get into the cell by competitive inhibition of all three transporters at the cell membrane. Ex vivo measurements in knockout mice indicate that (18)F-FCWAY is a substrate only for P-gp and not BCRP. In vivo, tariquidar increased (18)F-FCWAY brain uptake in seven of eight subjects by 60-100% compared to each person's baseline. Tariquidar did not increase brain uptake via some peripheral mechanism, given that it did not significantly alter concentrations in plasma of the parent radioligand (18)F-FCWAY or its brain-penetrant radiometabolite (18)F-FC. These results show that (18)F-FCWAY is a weak substrate for efflux transport at the blood-brain barrier; some radioligand can enter brain, but its removal is hastened by P-gp. Although (18)F-FCWAY is

  6. Blockade of cannabinoid CB receptor function protects against in vivo disseminating brain damage following NMDA-induced excitotoxicity

    DEFF Research Database (Denmark)

    Hansen, H.H.; Ramos, J.A.; Fernández-Ruiz, J.; Azcoitia, I.; Hansen, Harald S.; Pons, S.; García-Segura, L.M.; Romero, J.

    2002-01-01

    The ability of cannabinoid CB, receptors to influence glutamatergic excitatory neurotransmission has fueled interest in how these receptors and their endogenous ligands may interact in conditions of excitotoxic insults. The present study characterized the impact of stimulated and inhibited CB...

  7. Measurement of dopamine D{sub 2} receptors in living human brain using [{sup 11}C]raclopride with ultra-high specific radioactivity

    Energy Technology Data Exchange (ETDEWEB)

    Fujimura, Yota [Molecular Neuroimaging Group, Molecular Imaging Center, National Institutes of Radiological Sciences, Inage-ku, Chiba, 263-8555 (Japan); Department of Psychiatry, School of Medicine, Teikyo University, Itabashi-Ku, Tokyo, 173-8605 (Japan); Ito, Hiroshi, E-mail: hito@nirs.go.j [Molecular Neuroimaging Group, Molecular Imaging Center, National Institutes of Radiological Sciences, Inage-ku, Chiba, 263-8555 (Japan); Takahashi, Hidehiko; Yasuno, Fumihiko; Ikoma, Yoko [Molecular Neuroimaging Group, Molecular Imaging Center, National Institutes of Radiological Sciences, Inage-ku, Chiba, 263-8555 (Japan); Zhang, Ming-Rong [Molecular Probe Group, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba, 263-8555 (Japan); Nanko, Shinichiro [Department of Psychiatry, School of Medicine, Teikyo University, Itabashi-Ku, Tokyo, 173-8605 (Japan); Suzuki, Kazutoshi [Molecular Probe Group, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba, 263-8555 (Japan); Suhara, Tetsuya [Molecular Neuroimaging Group, Molecular Imaging Center, National Institutes of Radiological Sciences, Inage-ku, Chiba, 263-8555 (Japan)

    2010-10-15

    Introduction: High specific radioactivity is preferable in the measurement of neuroreceptor bindings with positron emission tomography (PET) because receptor occupancy by mixed cold ligand hampers the accurate estimation of receptor binding. Recently, we succeeded in synthesizing [{sup 11}C]raclopride, a dopamine D{sub 2} receptor ligand, with ultra-high specific radioactivity, i.e., several thousand GBq/{mu}mol. In the present study, we compared the [{sup 11}C]raclopride bindings to dopamine D{sub 2} receptors between radioligands with ultra-high specific radioactivity and ordinary high specific radioactivity in healthy human subjects. Methods: Two PET studies using [{sup 11}C]raclopride with ultra-high specific radioactivity (4302-7222 GBq/{mu}mol) or ordinary high specific radioactivity (133-280 GBq/{mu}mol) were performed on different days in 14 healthy men. Binding potential (BP) was calculated by the simplified reference tissue method, peak equilibrium method, and area-under-the-curve method for each region-of-interest using time-activity data in the cerebellum as a reference brain region. Results: BP values for radioligands with ultra-high specific radioactivity and ordinary high specific radioactivity calculated by the simplified reference tissue method were 4.06{+-}0.29 and 4.10{+-}0.25 in the putamen, 0.44{+-}0.07 and 0.47{+-}0.07 in the thalamus and 0.37{+-}0.06 and 0.38{+-}0.06 in the temporal cortex, respectively (mean{+-}S.D.). No significant difference in BP was observed between ultra-high specific radioactivity and ordinary high specific radioactivity in any of the brain regions. Conclusion: BP values of [{sup 11}C]raclopride with ultra-high specific radioactivity did not differ from those with ordinary high specific radioactivity in the measured brain regions, including striatal and extrastriatal regions.

  8. κ-Opioid Receptor Is Colocalized in GnRH and KNDy Cells in the Female Ovine and Rat Brain.

    Science.gov (United States)

    Weems, Peyton W; Witty, Christine F; Amstalden, Marcel; Coolen, Lique M; Goodman, Robert L; Lehman, Michael N

    2016-06-01

    Kisspeptin-neurokinin B-dynorphin (KNDy) cells of the hypothalamus are a key component in the neuroendocrine regulation of GnRH secretion. Evidence in sheep and other species suggests that dynorphin released by KNDy cells inhibits pulsatile GnRH secretion by acting upon κ-opioid receptors (KOR). However, the precise anatomical location and neurochemical phenotype of KOR-expressing cells in sheep remain unknown. To this end, we determined the distribution of KOR mRNA and protein in the brains of luteal phase ewes, using an ovine specific KOR mRNA probe for in situ hybridization and an antibody whose specificity we confirmed by Western blot analyses and blocking peptide controls. KOR cells were observed in a number of regions, including the preoptic area (POA); anterior hypothalamic area; supraoptic and paraventricular nuclei; ventromedial, dorsomedial, and lateral hypothalamus; and arcuate nucleus. Next, we determined whether KOR is colocalized in KNDy and/or GnRH cells. Dual-label immunofluorescence and confocal analysis of the KNDy population showed a high degree of colocalization, with greater than 90% of these neurons containing KOR. Surprisingly, GnRH cells also showed high levels of colocalization in sheep, ranging from 74.4% to 95.4% for GnRH cells in the POA and medial basal hypothalamus, respectively. Similarly, 97.4% of GnRH neurons in the POA of ovariectomized, steroid-primed female rats also contained immunoreactive KOR protein. These findings suggest that the inhibitory effects of dynorphin on pulsatile GnRH secretion may occur either indirectly by actions upon KOR within the KNDy population and/or directly via the activation of KOR on GnRH cells. PMID:27064940

  9. Maternal epileptic seizure induced by Pentylenetetrazol: Apoptotic neurodegeneration and decreased GABAB1 receptor expression in prenatal rat brain

    Directory of Open Access Journals (Sweden)

    Naseer Muhammad

    2009-06-01

    Full Text Available Abstract Epilepsy is a prominent sign of neurological dysfunction in children with various fetal and maternal deficiencies. However, the detailed mechanism and influences underlying epileptic disorders are still unrevealed. The hippocampal neurons are vulnerable to epilepsy-induced pathologic changes and often manifests as neuronal death. The present study was designed to investigate the effect of maternal epileptic seizure on apoptotic neuronal death, modulation of GABAB1 receptor (R, and protein kinase A-α (PKA in prenatal rat hippocampal neurons at gestational days (GD 17.5. Seizure was induced in pregnant rat using intraperitoneal injection of pentylenetetrazol (PTZ (40 mg/kg for 15 days. To confirm the seizure electroencephalography (EEG data was obtained by the Laxtha EEG-monitoring device in the EEG recording room and EEG were monitored 5 min and 15 min after PTZ injection. The RT-PCR and Western blot results showed significant increased expression of cytochrome-c and caspases-3, while decreased levels of GABAB1R, and PKA protein expression upon ethanol, PTZ and ethanol plus PTZ exposure in primary neuronal cells cultured from PTZ-induced seizure model as compare to non-PTZ treated maternal group. Apoptotic neurodegeneration was further confirmed with Fluoro-Jade B and propidium iodide staining, where neurons were scattered and shrunken, with markedly condensed nuclei in PTZ treated group compared with control. This study for the first time indicate that PTZ-induced seizures triggered activation of caspases-3 to induce widespread apoptotic neuronal death and decreased GABAB1R expression in hippocampal neurons, providing a possible mechanistic link between maternal epilepsy induced neurodegeneration alteration of GABAB1R and PKA expression level during prenatal brain development. This revealed new aspects of PTZ and ethanol's modulation on GABAB1R, learning and memory. Further, explain the possibility that children delivered by epileptic

  10. Sleep Deprivation-Induced Blood-Brain Barrier Breakdown and Brain Dysfunction are Exacerbated by Size-Related Exposure to Ag and Cu Nanoparticles. Neuroprotective Effects of a 5-HT3 Receptor Antagonist Ondansetron.

    Science.gov (United States)

    Sharma, Aruna; Muresanu, Dafin F; Lafuente, José V; Patnaik, Ranjana; Tian, Z Ryan; Buzoianu, Anca D; Sharma, Hari S

    2015-10-01

    Military personnel are often subjected to sleep deprivation (SD) during combat operations. Since SD is a severe stress and alters neurochemical metabolism in the brain, a possibility exists that acute or long-term SD will influence blood-brain barrier (BBB) function and brain pathology. This hypothesis was examined in young adult rats (age 12 to 14 weeks) using an inverted flowerpot model. Rats were placed over an inverted flowerpot platform (6.5 cm diameter) in a water pool where the water levels are just 3 cm below the surface. In this model, animals can go to sleep for brief periods but cannot achieve deep sleep as they would fall into water and thus experience sleep interruption. These animals showed leakage of Evans blue in the cerebellum, hippocampus, caudate nucleus, parietal, temporal, occipital, cingulate cerebral cortices, and brain stem. The ventricular walls of the lateral and fourth ventricles were also stained blue, indicating disruption of the BBB and the blood-cerebrospinal fluid barrier (BCSFB). Breakdown of the BBB or the BCSFB fluid barrier was progressive in nature from 12 to 48 h but no apparent differences in BBB leakage were seen between 48 and 72 h of SD. Interestingly, rats treated with metal nanoparticles, e.g., Cu or Ag, showed profound exacerbation of BBB disruption by 1.5- to 4-fold, depending on the duration of SD. Measurement of plasma and brain serotonin showed a close correlation between BBB disruption and the amine level. Repeated treatment with the serotonin 5-HT3 receptor antagonist ondansetron (1 mg/kg, s.c.) 4 and 8 h after SD markedly reduced BBB disruption and brain pathology after 12 to 24 h SD but not following 48 or 72 h after SD. However, TiO2-nanowired ondansetron (1 mg/kg, s.c) in an identical manner induced neuroprotection in rats following 48 or 72 h SD. However, plasma and serotonin levels were not affected by ondansetron treatment. Taken together, our observations are the first to show that (i) SD could induce BBB

  11. An in vivo study of the dopaminergic receptors in the brain of man using 11C-pimozide and positron emission tomography

    International Nuclear Information System (INIS)

    Positron emission tomography was used to establish the regional cerebral pharmacokinetics of a carbon 11-labelled neuroleptic, pimozide, in an attempt to observe its specific bonding to dopaminergic receptors in vivo. The 11C-pimozide kinetics were compared in two brain structures at the two ends of the dopaminergic receptor density scale: the striatum and cerebellum, very rich in and devoid of these receptors respectively. In 8 patients a significant radioactivity uptake was observed in the striatum as compared with the cerebellum, in agreement with in vivo studies on animals using tritiated pimozide. In 5 patients pre-treated by a therapeutic dose of a cold neuroleptic (haloperidol) this difference in kinetics no longer existed. Moreover no kinetic difference is observed, either before or after haloperidol administration, between the frontal cortex (relatively low in dopaminergic receptors) and cerebellum. These results strongly suggest that pharmacokinetic phenomena directly related to the specific bonding of 11C-pimozide on the striatal dopaminergic receptors are observable on man in vivo. This specific bonding however remains quantitatively weak as compared with the strong non-specific bonding

  12. Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium

    OpenAIRE

    Cooke, P S; Buchanan, D. L.; Young, P.; Setiawan, T.; Brody, J.; Korach, K S; Taylor, J; Lubahn, D.B.; Cunha, G R

    1997-01-01

    Estradiol-17β (E2) acts through the estrogen receptor (ER) to regulate uterine growth and functional differentiation. To determine whether E2 elicits epithelial mitogenesis through epithelial ER versus indirectly via ER-positive stromal cells, uteri from adult ER-deficient ER knockout (ko) mice and neonatal ER-positive wild-type (wt) BALB/c mice were used to produce the following tissue recombinants containing ER in epithelium (E) and/or stroma (S), or lacking ER altogether: wt-S + wt-E, wt-S...

  13. Partially silencing brain toll-like receptor 4 prevents in part left ventricular remodeling with sympathoinhibition in rats with myocardial infarction-induced heart failure.

    Directory of Open Access Journals (Sweden)

    Kiyohiro Ogawa

    Full Text Available BACKGROUND: Left ventricular (LV remodeling and activation of sympathetic nervous system (SNS are cardinal features of heart failure. We previously demonstrated that enhanced central sympathetic outflow is associated with brain toll-like receptor 4 (TLR4 probably mediated by brain angiotensin II type 1 receptor in mice with myocardial infarction (MI-induced heart failure. The purpose of the present study was to examine whether silencing brain TLR4 could prevent LV remodeling with sympathoinhibition in MI-induced heart failure. METHODOLOGY/PRINCIPAL FINDINGS: MI-induced heart failure model rats were created by ligation of left coronary artery. The expression level of TLR4 in brainstem was significantly higher in MI-induced heart failure treated with intracerebroventricular (ICV injection of hGAPDH-SiRNA than in sham. TLR4 in brainstem was significantly lower in MI-induced heart failure treated with ICV injection of TLR4-SiRNA than in that treated with ICV injection of hGAPDH-SiRNA. Lung weight, urinary norepinephrine excretion, and LV end-diastolic pressure were significantly lower and LV dimension was significantly smaller in MI-induced heart failure treated with TLR4-SiRNA than in that treated with hGAPDH-SiRNA for 2 weeks. CONCLUSIONS: Partially silencing brain TLR4 by ICV injection of TLR4-SiRNA for 2 weeks could in part prevent LV remodeling with sympathoinhibition in rats with MI-induced heart failure. Brain TLR4 has a potential to be a target of the treatment for MI-induced heart failure.

  14. Possible involvement of brain prostaglandin E2 and prostanoid EP3 receptors in prostaglandin E2 glycerol ester-induced activation of central sympathetic outflow in the rat.

    Science.gov (United States)

    Shimizu, Takahiro; Tanaka, Kenjiro; Nakamura, Kumiko; Taniuchi, Keisuke; Yawata, Toshio; Higashi, Youichirou; Ueba, Tetsuya; Dimitriadis, Fotios; Shimizu, Shogo; Yokotani, Kunihiko; Saito, Motoaki

    2014-07-01

    We recently reported that intracerebroventricularly administered 2-arachidonoylglycerol elevated plasma noradrenaline and adrenaline by brain monoacylglycerol lipase- (MGL) and cyclooxygenase-mediated mechanisms in the rat. These results suggest that 2-arachidonoylglycerol is hydrolyzed by MGL to free arachidonic acid, which is further metabolized to prostaglandins (PGs) by cyclooxygenase in the brain, thereby elevating plasma noradrenaline and adrenaline. On the other hand, 2-arachidonoylglycerol can be also metabolized by cyclooxygenase to PG glycerol esters (PG-Gs), which seems to be hydrolyzed by MGL to free PGs. Here, we examined the involvement of brain PG-Gs in the elevation of plasma noradrenaline and adrenaline regarding PGE2-G and prostanoid EP receptors using anesthetized male Wistar rats. Intracerebroventricularly administered PGE2-G (1.5 and 3 nmol/animal) dose-dependently elevated plasma noradrenaline but not adrenaline. PGE2-G also elevated systolic, mean and diastolic blood pressure and heart rate. The PGE2-G-induced elevation of plasma noradrenaline was attenuated by JZL184 (MGL inhibitor). Intracerebroventricularly administered PGE2 (0.3 and 1.5 nmol/animal) and sulprostone (0.1 and 0.3 nmol/animal) (EP1/EP3 agonist) also elevated plasma noradrenaline but not adrenaline in a dose-dependent manner. The sulprostone-induced elevation was attenuated by L-798,106 (EP3 antagonist), but not by SC-51322 (EP1 antagonist). L-798,106 also attenuated the PGE2-G- and PGE2-induced elevation of plasma noradrenaline, while PF-04418948 (EP2 antagonist) and L-161,982 (EP4 antagonist) had no effect on the PGE2-G-induced response. These results suggest a possibility that brain PGE2-G produced from 2-arachidonoylglycerol can be hydrolyzed to free PGE2, thereby activating central sympathetic outflow by brain prostanoid EP3 receptor-mediated mechanisms in the rat. PMID:24657150

  15. Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate

    Energy Technology Data Exchange (ETDEWEB)

    Michaelides, M.; Wang, G.; Michaelides, M.; Pascau, J.; Gispert, J.-D.; Delis, F.; Grandy, D.K.; Wang, G.-J.; Desco, M.; Rubinstein, M.; Volkow, N.D.; Thanos, P.K.

    2010-07-16

    Methylphenidate (MP) is widely used to treat attention deficit hyperactivity disorder (ADHD). Variable number of tandem repeats polymorphisms in the dopamine D4 receptor (D{sub 4}) gene have been implicated in vulnerability to ADHD and the response to MP. Here we examined the contribution of dopamine D4 receptors (D4Rs) to baseline brain glucose metabolism and to the regional metabolic responses to MP. We compared brain glucose metabolism (measured with micro-positron emission tomography and [{sup 18}F]2-fluoro-2-deoxy-D-glucose) at baseline and after MP (10 mg/kg, i.p.) administration in mice with genetic deletion of the D{sub 4}. Images were analyzed using a novel automated image registration procedure. Baseline D{sub 4}{sup -/-} mice had lower metabolism in the prefrontal cortex (PFC) and greater metabolism in the cerebellar vermis (CBV) than D{sub 4}{sup +/+} and D{sub 4}{sup +/-} mice; when given MP, D{sub 4}{sup -/-} mice increased metabolism in the PFC and decreased it in the CBV, whereas in D{sub 4}{sup +/+} and D{sub 4}{sup +/-} mice, MP decreased metabolism in the PFC and increased it in the CBV. These findings provide evidence that D4Rs modulate not only the PFC, which may reflect the activation by dopamine of D4Rs located in this region, but also the CBV, which may reflect an indirect modulation as D4Rs are minimally expressed in this region. As individuals with ADHD show structural and/or functional abnormalities in these brain regions, the association of ADHD with D4Rs may reflect its modulation of these brain regions. The differential response to MP as a function of genotype could explain differences in brain functional responses to MP between patients with ADHD and healthy controls and between patients with ADHD with different D{sub 4} polymorphisms.

  16. Insulin Receptor Antibody-α-N-Acetylglucosaminidase Fusion Protein Penetrates the Primate Blood-Brain Barrier and Reduces Glycosoaminoglycans in Sanfilippo Type B Fibroblasts.

    Science.gov (United States)

    Boado, Ruben J; Lu, Jeff Zhiqiang; Hui, Eric Ka-Wai; Lin, Huilan; Pardridge, William M

    2016-04-01

    Mucopolysaccharidosis Type IIIB (MPSIIIB) is caused by mutations in the gene encoding the lysosomal enzyme, α-N-acetylglucosaminidase (NAGLU). MPSIIIB presents with severe disease of the central nervous system, but intravenous NAGLU enzyme replacement therapy has not been developed because the NAGLU enzyme does not cross the blood-brain barrier (BBB). A BBB-penetrating form of the enzyme was produced by re-engineering NAGLU as an IgG-enzyme fusion protein, where the IgG domain is a monoclonal antibody (mAb) against the human insulin receptor (HIR). The HIRMAb traverses the BBB via transport on the endogenous insulin receptor and acts as a molecular Trojan horse to ferry the fused NAGLU across the BBB from blood. The NAGLU was fused to the carboxyl terminus of each heavy chain of the HIRMAb via an extended 31-amino acid linker, and the fusion protein is designated HIRMAb-LL-NAGLU. The fusion protein retains high affinity binding to the HIR, and on a molar basis has an enzyme activity equal to that of recombinant human NAGLU. Treatment of MPSIIIB fibroblasts with the fusion protein normalizes intracellular NAGLU enzyme activity and reduces sulfate incorporation into intracellular glycosoaminoglycan. The fusion protein is targeted to the lysosomal compartment of the cells as shown by confocal microscopy. The fusion protein was radiolabeled with the [(125)I]-Bolton-Hunter reagent and injected intravenously in the adult Rhesus monkey. The fusion protein was rapidly cleared from plasma by all major peripheral organs. The high brain uptake of the fusion protein, 1% injected dose/brain, enables normalization of brain NAGLU enzyme activity with a therapeutic dose of 1 mg/kg. The HIRMAb-LL-NAGLU fusion protein is a new treatment of the brain in MPSIIIB, which can be administered by noninvasive intravenous infusion. PMID:26910785

  17. Preclinical evaluation of [{sup 11}C]SA4503. Radiation dosimetry, in vivo selectivity and PET imaging of sigma{sub 1} receptors in the cat brain

    Energy Technology Data Exchange (ETDEWEB)

    Kawamura, Kazunori; Ishiwata, Kiichi; Shimada, Yuhei; Kimura, Yuichi; Senda, Michio [Tokyo Metropolitan Inst. of Gerontology (Japan). Positron Medical Center; Kobayashi, Tadayuki; Matsuno, Kiyoshi; Homma, Yoshio

    2000-08-01

    Our previous in vivo study with rats has demonstrated that {sup 11}C-labeled 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine ([{sup 11}C]SA4503) is a potential radioligand for mapping central nervous system (CNS) sigma{sub 1} receptors by positron emission tomography (PET). In the present study, we further characterized this ligand. The radiation absorbed-dose of [{sup 11}C]SA4503 in humans estimated with the tissue distribution in mice, was higher in the liver, kidney and pancreas than in other organs studied, but was low enough for clinical use. The brain uptake of [{sup 11}C]SA4503 in mice was reduced to approximately 60-70% by co-injection of carrier SA4503 and haloperidol, but not by co-injection of any of six ligands for sigma{sub 2} or other receptors, for which SA4503 showed in vitro >100 times weaker affinity than for sigma{sub 1} receptor. In the cat brain, the uptake in the cortex was higher than that in the cerebellum. The radioactivity in the cortex and cerebellum accumulated for the first 10 min and then gradually decreased until 81.5 min in the baseline measurement, but rapidly decreased in the carrier-loading condition. The receptor-mediated uptake was estimated to be approximately 60-65% of the total radioactivity in the cortex and cerebellum at 76 min after tracer injection. We have concluded that [{sup 11}C]SA4503 has the potential for mapping sigma{sub 1} receptor by PET. (author)

  18. Isolation of an additional member of the fibroblast growth factor receptor family, FGFR-3

    International Nuclear Information System (INIS)

    The fibroblast growth factors are a family of polypeptide growth factors involved in a variety of activities including mitogenesis, angiogenesis, and wound healing. Fibroblast growth factor receptors (FGFRs) have previously been identified in chicken, mouse, and human and have been shown to contain an extracellular domain with either two or three immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tyrosine kinase domain. The authors have isolated a human cDNA for another tyrosine kinase receptor that is highly homologous to the previously described FGFR. Expression of this receptor cDNA in COS cells directs the expression of a 125-kDa glycoprotein. They demonstrate that this cDNA encodes a biologically active receptor by showing that human acidic and basic fibroblast growth factors activate this receptor as measured by 45Ca2+ efflux assays. These data establish the existence of an additional member of the FGFR family that they have named FGFR-3

  19. Glutamate and glycine modulation of 3H-MK801 binding to the NMDA receptor-ion channel complex in the vitamin B-6 deficient neonatal rat brain

    International Nuclear Information System (INIS)

    The authors have previously shown that the concentrations of the neuroactive amino acids glutamate (GLU) and glycine (GLY) are significantly altered in the seizure-prone vitamin B-6 deficient neonatal rat brain. Recently, it has been shown that GLU and GLY modulate the binding of 3H-MK801 to the ion channel associated with the N-methyl-D-aspartate (NMDA)-glutamate receptor subtype. The present investigation was undertaken to determine if GLU or GLY modulation of 3H-MK801 binding was altered in B-6 deficient neonatal rat brain. Preparation of cortical membranes from control and deficient 14 day old rats and 3H-MK801 binding assay were done as described by Ransom and Stec. The results show a significant reduction in the potency and efficacy of GLU modulation of 3H-MK801 binding, as well as a reduction in the efficacy of GLY, in membrane preparations from deficient rats compared to controls. These results indicate a reduced ability of GLU and GLY to potentiate the binding of 3H-MK801 to the NMDA receptor-ion channel in the B-6 deficient neonatal rat brain

  20. Effect of MgSO4 on NMDA receptor in brain tissue and serum NSE in rats with radiation-induced acute brain injury

    International Nuclear Information System (INIS)

    Objective: To explore the protection of magnesium sulfate (MgSO4) on radiation-induced acute brain injury. Methods Thirty six mature Sprague-Dawley rats were randomly divided into 3 groups: the blank control group, experimental control group and experimental therapy group. The whole brain of SD rats in the experimental control group and experimental therapy group were irradiated with a dose of 20 Gy using 6 MeV electron beam. Magnesium sulfate was injected intraperitoneally into the rats in the experimental therapy group before and after irradiation for seven times. The blood and the brain tissue were taken on the 1st, 3rd and 14th day after irradiation. ELISA was used to measure the level of serum NSE. Western blot technique was used to detect the expression of NR1 and NR2B subunit protein in brain tissue. Results: Compared with the blank control group, the level of serum NSE in the experimental control group increased significantly (P4 used in early stage can inhibit the level of serum NSE and the expression of NR1 and NR2B after radiation-induced acute brain injury. It shows a protective effect on radiation-induced acute brain injury. (authors)

  1. Gz mediates the long-lasting desensitization of brain CB1 receptors and is essential for cross-tolerance with morphine

    Directory of Open Access Journals (Sweden)

    Rodríguez-Muñoz María

    2009-03-01

    Full Text Available Abstract Background Although the systemic administration of cannabinoids produces antinociception, their chronic use leads to analgesic tolerance as well as cross-tolerance to morphine. These effects are mediated by cannabinoids binding to peripheral, spinal and supraspinal CB1 and CB2 receptors, making it difficult to determine the relevance of each receptor type to these phenomena. However, in the brain, the CB1 receptors (CB1Rs are expressed at high levels in neurons, whereas the expression of CB2Rs is marginal. Thus, CB1Rs mediate the effects of smoked cannabis and are also implicated in emotional behaviors. We have analyzed the production of supraspinal analgesia and the development of tolerance at CB1Rs by the direct injection of a series of cannabinoids into the brain. The influence of the activation of CB1Rs on supraspinal analgesia evoked by morphine was also evaluated. Results Intracerebroventricular (icv administration of cannabinoid receptor agonists, WIN55,212-2, ACEA or methanandamide, generated a dose-dependent analgesia. Notably, a single administration of these compounds brought about profound analgesic tolerance that lasted for more than 14 days. This decrease in the effect of cannabinoid receptor agonists was not mediated by depletion of CB1Rs or the loss of regulated G proteins, but, nevertheless, it was accompanied by reduced morphine analgesia. On the other hand, acute morphine administration produced tolerance that lasted only 3 days and did not affect the CB1R. We found that both neural mu-opioid receptors (MORs and CB1Rs interact with the HINT1-RGSZ module, thereby regulating pertussis toxin-insensitive Gz proteins. In mice with reduced levels of these Gz proteins, the CB1R agonists produced no such desensitization or morphine cross-tolerance. On the other hand, experimental enhancement of Gz signaling enabled an acute icv administration of morphine to produce a long-lasting tolerance at MORs that persisted for more than

  2. Solubilization of high affinity corticotropin-releasing factor receptors from rat brain: Characterization of an active digitonin-solubilized receptor complex

    International Nuclear Information System (INIS)

    The binding characteristics of CRF receptors in rat frontal cerebral cortex membranes solubilized in 1% digitonin were determined. The binding of [125I]Tyro-ovine CRF ([125I]oCRF) to solubilized membrane proteins was dependent on incubation time, temperature, and protein concentration, was saturable and of high affinity, and was absent in boiled tissue. The solubilized receptors retained their high affinity for [125I] oCRF in the solubilized state, exhibiting a dissociation constant (KD) of approximately 200 pM, as determined by direct binding saturation isotherms. Solubilized CRF receptors maintained the rank order of potencies for various related and unrelated CRF peptides characteristic of the membrane CRF receptor: rat/human CRF congruent to ovine CRF congruent to Nle21,38-rat CRF greater than alpha-helical oCRF-(9-41) greater than oCRF-(7-41) much greater than vasoactive intestinal peptide, arginine vasopressin, or the substance-P antagonist. Furthermore, the absolute potencies (Ki values) for the various CRF-related peptides in solubilized receptors were almost identical to those observed in the membrane preparations, indicating that the CRF receptor retained its high affinity binding capacity in the digitonin-solubilized state. Chemical affinity cross-linking of digitonin-solubilized rat cortical membrane proteins revealed a specifically labeled protein with an apparent mol wt of 58,000 which was similar to the labeled protein in native membrane homogenates. Although solubilized CRF receptors retained their high affinity for agonists, their sensitivity for guanine nucleotide was lost. Size exclusion chromatography substantiated these results, demonstrating that in the presence or absence of guanine nucleotides, [125I]oCRF labeled the same size receptor complex

  3. In situ detection of H1-receptor mRNA and absence of apoptosis in the transient histamine system of the embryonic rat brain.

    Science.gov (United States)

    Kinnunen, A; Lintunen, M; Karlstedt, K; Fukui, H; Panula, P

    1998-04-27

    In the developing brain, histamine is one of the first neurotransmitters to appear. The concentration of histamine in the prenatal brain is fivefold that of adult levels. During the prenatal development a large transiently histamine-immunoreactive cell population distinct from the adult histaminergic system can be found within a subpopulation of the developing serotonergic raphe nuclei neurons. Also histamine-immunoreactive nerve fibers are widely distributed already during the prenatal development extending to the diencephalon, the thalamus, the cortex, and the spinal cord. Large numbers of histamine-containing mast cells also migrate into the brain during the late prenatal life. The wide distribution and high prenatal concentrations imply important functions for the histaminergic system during intrauterine development. However, little is known about the actual functions of histamine during development, and which of the histamine receptors are present in the prenatal rat brain is currently unknown. In the present study, we used in situ hybridization to study the distribution of H1-receptor (H1R) mRNA in the embryonic rat brain and spinal cord. H1R mRNA could be detected in rat brain and in spinal cord on embryonic day (E) 14, and the expression pattern seemed to partially localize in areas containing histamine-immunoreactive nerve fibers through E14-E20. H1R mRNA was also detected by reverse transcriptase polymerase chain reaction from embryonic brain samples and by Northern hybridization. The possible involvement of apoptosis in the disappearance of the developing transiently histaminergic system was studied by using apoptosis detection based on the terminal dUTP nick end labeling (TUNEL) technique and with c-Fos immunostaining. Although histamine immunoreactivity disappears dramatically from the developing raphe nuclei after E18, only occasional apoptotic nuclei could be seen in the histamine-immunoreactive cell bodies. The presence of H1R mRNA during the

  4. Oxytocin receptor ligand binding in embryonic tissue and postnatal brain development of the C57BL/6J mouse

    OpenAIRE

    Elizabeth eHammock; Pat eLevitt

    2013-01-01

    Oxytocin (OXT) has drawn increasing attention as a developmentally relevant neuropeptide given its role in the brain regulation of social behavior. It has been suggested that OXT plays an important role in the infant brain during caregiver attachment in nurturing familial contexts, but there is incomplete experimental evidence. Mouse models of OXT system genes have been particularly informative for the role of the OXT system in social behavior, however, the developing brain areas that could r...

  5. The effect of heart-and kidney-Benefiting Chinese Herbal Medicine on the function of cholinergic M-and Gamma amino-butyric acid (GABA) receptor in brain tissues of analogue dementia rats

    International Nuclear Information System (INIS)

    3H-QNB and 3H-GABA were used as radioactive ligand for M-and GABA receptors respectively. M-and GABA receptors were assayed by radioligand binding assay (RBA) in cerebral cortex, hippocampus and cerebellum of analogue dementia rats. It was found that Rt of M receptor was decreased in cerebral cortex and hippocampus and Rt of GABA receptor was decreased in cerebellum of analogue dementia rats. The dissociation constant (KD) of M-receptor was decreased significantly in cerebral cortex and KD value of (GABA) receptor was decreased in cerebellum of analogue dementia rats. The decreased Rt of M-and GABA receptor in brain tissue of analogue dementia rats was raised by Heart- and Kidney-Benefiting Chinese Herbs as well as hydergin

  6. A Promising PET Tracer for Imaging of α7 Nicotinic Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based Radioligand

    Directory of Open Access Journals (Sweden)

    Rodrigo Teodoro

    2015-10-01

    Full Text Available Changes in the expression of α7 nicotinic acetylcholine receptors (α7 nAChRs in the human brain are widely assumed to be associated with neurological and neurooncological processes. Investigation of these receptors in vivo depends on the availability of imaging agents such as radioactively labelled ligands applicable in positron emission tomography (PET. We report on a series of new ligands for α7 nAChRs designed by the combination of dibenzothiophene dioxide as a novel hydrogen bond acceptor functionality with diazabicyclononane as an established cationic center. To assess the structure-activity relationship (SAR of this new basic structure, we further modified the cationic center systematically by introduction of three different piperazine-based scaffolds. Based on in vitro binding affinity and selectivity, assessed by radioligand displacement studies at different rat and human nAChR subtypes and at the structurally related human 5-HT3 receptor, we selected the compound 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl-2-fluorodibenzo-[b,d]thiophene 5,5-dioxide (10a for radiolabeling and further evaluation in vivo. Radiosynthesis of [18F]10a was optimized and transferred to an automated module. Dynamic PET imaging studies with [18F]10a in piglets and a monkey demonstrated high uptake of radioactivity in the brain, followed by washout and target-region specific accumulation under baseline conditions. Kinetic analysis of [18F]10a in pig was performed using a two-tissue compartment model with arterial-derived input function. Our initial evaluation revealed that the dibenzothiophene-based PET radioligand [18F]10a ([18F]DBT-10 has high potential to provide clinically relevant information about the expression and availability of α7 nAChR in the brain.

  7. α7 Nicotinic acetylcholine receptor-specific antibody induces inflammation and amyloid β42 accumulation in the mouse brain to impair memory.

    Directory of Open Access Journals (Sweden)

    Olena Lykhmus

    Full Text Available Nicotinic acetylcholine receptors (nAChRs expressed in the brain are involved in regulating cognitive functions, as well as inflammatory reactions. Their density is decreased upon Alzheimer disease accompanied by accumulation of β-amyloid (Aβ42, memory deficit and neuroinflammation. Previously we found that α7 nAChR-specific antibody induced pro-inflammatory interleukin-6 production in U373 glioblastoma cells and that such antibodies were present in the blood of humans. We raised a hypothesis that α7 nAChR-specific antibody can cause neuroinflammation when penetrating the brain. To test this, C57Bl/6 mice were either immunized with extracellular domain of α7 nAChR subunit α7(1-208 or injected with bacterial lipopolysaccharide (LPS for 5 months. We studied their behavior and the presence of α3, α4, α7, β2 and β4 nAChR subunits, Aβ40 and Aβ42 and activated astrocytes in the brain by sandwich ELISA and confocal microscopy. It was found that either LPS injections or immunizations with α7(1-208 resulted in region-specific decrease of α7 and α4β2 and increase of α3β4 nAChRs, accumulation of Aβ42 and activated astrocytes in the brain of mice and worsening of their episodic memory. Intravenously transferred α7 nAChR-specific-antibodies penetrated the brain parenchyma of mice pre-injected with LPS. Our data demonstrate that (1 neuroinflammation is sufficient to provoke the decrease of α7 and α4β2 nAChRs, Aβ42 accumulation and memory impairment in mice and (2 α7(1-208 nAChR-specific antibodies can cause inflammation within the brain resulting in the symptoms typical for Alzheimer disease.

  8. Vitamin D prevents hypoxia/reoxygenation-induced blood-brain barrier disruption via vitamin D receptor-mediated NF-kB signaling pathways.

    Science.gov (United States)

    Won, Soonmi; Sayeed, Iqbal; Peterson, Bethany L; Wali, Bushra; Kahn, Jared S; Stein, Donald G

    2015-01-01

    Maintaining blood-