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Sample records for brain cannabinoid type-1

  1. Rising stars: modulation of brain functions by astroglial type-1 cannabinoid receptors.

    Science.gov (United States)

    Metna-Laurent, Mathilde; Marsicano, Giovanni

    2015-03-01

    The type-1-cannabinoid (CB1 ) receptor is amongst the most widely expressed G protein-coupled receptors in the brain. In few decades, CB1 receptors have been shown to regulate a large array of functions from brain cell development and survival to complex cognitive processes. Understanding the cellular mechanisms underlying these functions of CB1 is complex due to the heterogeneity of the brain cell types on which the receptor is expressed. Although the large majority of CB1 receptors act on neurons, early studies pointed to a direct control of CB1 receptors over astroglial functions including brain energy supply and neuroprotection. In line with the growing concept of the tripartite synapse highlighting astrocytes as direct players in synaptic plasticity, astroglial CB1 receptor signaling recently emerged as the mediator of several forms of synaptic plasticity associated to important cognitive functions. Here, we shortly review the current knowledge on CB1 receptor-mediated astroglial functions. This functional spectrum is large and most of the mechanisms by which CB1 receptors control astrocytes, as well as their consequences in vivo, are still unknown, requiring innovative approaches to improve this new cannabinoid research field. © 2014 Wiley Periodicals, Inc.

  2. Evaluation of MRI and cannabinoid type 1 receptor PET templates constructed using DARTEL for spatial normalization of rat brains

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    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

  3. Cannabinoids on the Brain

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    Andrew J. Irving

    2002-01-01

    Full Text Available Cannabis has a long history of consumption both for recreational and medicinal uses. Recently there have been significant advances in our understanding of how cannabis and related compounds (cannabinoids affect the brain and this review addresses the current state of knowledge of these effects. Cannabinoids act primarily via two types of receptor, CB1 and CB2, with CB1 receptors mediating most of the central actions of cannabinoids. The presence of a new type of brain cannabinoid receptor is also indicated. Important advances have been made in our understanding of cannabinoid receptor signaling pathways, their modulation of synaptic transmission and plasticity, the cellular targets of cannabinoids in different central nervous system (CNS regions and, in particular, the role of the endogenous brain cannabinoid (endocannabinoid system. Cannabinoids have widespread actions in the brain: in the hippocampus they influence learning and memory; in the basal ganglia they modulate locomotor activity and reward pathways; in the hypothalamus they have a role in the control of appetite. Cannabinoids may also be protective against neurodegeneration and brain damage and exhibit anticonvulsant activity. Some of the analgesic effects of cannabinoids also appear to involve sites within the brain. These advances in our understanding of the actions of cannabinoids and the brain endocannabinoid system have led to important new insights into neuronal function which are likely to result in the development of new therapeutic strategies for the treatment of a number of key CNS disorders.

  4. Cannabinoids on the brain.

    Science.gov (United States)

    Irving, Andrew J; Rae, Mark G; Coutts, Angela A

    2002-03-09

    Cannabis has a long history of consumption both for recreational and medicinal uses. Recently there have been significant advances in our understanding of how cannabis and related compounds (cannabinoids) affect the brain and this review addresses the current state of knowledge of these effects. Cannabinoids act primarily via two types of receptor, CB1 and CB2, with CB1 receptors mediating most of the central actions of cannabinoids. The presence of a new type of brain cannabinoid receptor is also indicated. Important advances have been made in our understanding of cannabinoid receptor signaling pathways, their modulation of synaptic transmission and plasticity, the cellular targets of cannabinoids in different central nervous system (CNS) regions and, in particular, the role of the endogenous brain cannabinoid (endocannabinoid) system. Cannabinoids have widespread actions in the brain: in the hippocampus they influence learning and memory; in the basal ganglia they modulate locomotor activity and reward pathways; in the hypothalamus they have a role in the control of appetite. Cannabinoids may also be protective against neurodegeneration and brain damage and exhibit anticonvulsant activity. Some of the analgesic effects of cannabinoids also appear to involve sites within the brain. These advances in our understanding of the actions of cannabinoids and the brain endocannabinoid system have led to important new insights into neuronal function which are likely to result in the development of new therapeutic strategies for the treatment of a number of key CNS disorders.

  5. Preclinical evaluation and quantification of [{sup 18}F]MK-9470 as a radioligand for PET imaging of the type 1 cannabinoid receptor in rat brain

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    Casteels, Cindy [K.U. Leuven, University Hospital Leuven, Division of Nuclear Medicine, Leuven (Belgium); K.U. Leuven, MoSAIC, Molecular Small Animal Imaging Center, Leuven (Belgium); University Hospital Gasthuisberg, Division of Nuclear Medicine, Leuven (Belgium); Koole, Michel; Laere, Koen van [K.U. Leuven, University Hospital Leuven, Division of Nuclear Medicine, Leuven (Belgium); K.U. Leuven, MoSAIC, Molecular Small Animal Imaging Center, Leuven (Belgium); Celen, Sofie; Bormans, Guy [K.U. Leuven, MoSAIC, Molecular Small Animal Imaging Center, Leuven (Belgium); K.U. Leuven, Laboratory for Radiopharmacy, Leuven (Belgium)

    2012-09-15

    [{sup 18}F]MK-9470 is an inverse agonist for the type 1 cannabinoid (CB1) receptor allowing its use in PET imaging. We characterized the kinetics of [{sup 18}F]MK-9470 and evaluated its ability to quantify CB1 receptor availability in the rat brain. Dynamic small-animal PET scans with [{sup 18}F]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 (V{sub T}) of [{sup 18}F]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 [{sup 18}F]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. V{sub T} 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 [{sup 18}F]MK-9470 V{sub T}, but was correlated. A correlation between [{sup 18}F]MK-9470 V{sub T} and SUV in the brain was also found (R {sup 2} = 0.26-0.33; p {<=} 0.03). While the presence of a brain-penetrating radiometabolite fraction complicates the quantification of [{sup 18}F]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.)

  6. Multiple sleep alterations in mice lacking cannabinoid type 1 receptors.

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    Alessandro Silvani

    Full Text Available Cannabinoid type 1 (CB1 receptors are highly expressed in the brain and play a role in behavior control. Endogenous cannabinoid signaling is modulated by high-fat diet (HFD. We investigated the consequences of congenital lack of CB1 receptors on sleep in mice fed standard diet (SD and HFD. CB1 cannabinoid receptor knock-out (KO and wild-type (WT mice were fed SD or HFD for 4 months (n = 9-10 per group. Mice were instrumented with electroencephalographic (EEG and electromyographic electrodes. Recordings were performed during baseline (48 hours, sleep deprivation (gentle handling, 6 hours, sleep recovery (18 hours, and after cage switch (insomnia model paradigm, 6 hours. We found multiple significant effects of genotype on sleep. In particular, KO spent more time awake and less time in non-rapid-eye-movement sleep (NREMS and rapid-eye-movement sleep (REMS than WT during the dark (active period but not during the light (rest period, enhancing the day-night variation of wake-sleep amounts. KO had slower EEG theta rhythm during REMS. REMS homeostasis after sleep deprivation was less effective in KO than in WT. Finally, KO habituated more rapidly to the arousing effect of the cage-switch test than WT. We did not find any significant effects of diet or of diet x genotype interaction on sleep. The occurrence of multiple sleep alterations in KO indicates important roles of CB1 cannabinoid receptors in limiting arousal during the active period of the day, in sleep regulation, and in sleep EEG in mice.

  7. Multiple sleep alterations in mice lacking cannabinoid type 1 receptors.

    Science.gov (United States)

    Silvani, Alessandro; Berteotti, Chiara; Bastianini, Stefano; Lo Martire, Viviana; Mazza, Roberta; Pagotto, Uberto; Quarta, Carmelo; Zoccoli, Giovanna

    2014-01-01

    Cannabinoid type 1 (CB1) receptors are highly expressed in the brain and play a role in behavior control. Endogenous cannabinoid signaling is modulated by high-fat diet (HFD). We investigated the consequences of congenital lack of CB1 receptors on sleep in mice fed standard diet (SD) and HFD. CB1 cannabinoid receptor knock-out (KO) and wild-type (WT) mice were fed SD or HFD for 4 months (n = 9-10 per group). Mice were instrumented with electroencephalographic (EEG) and electromyographic electrodes. Recordings were performed during baseline (48 hours), sleep deprivation (gentle handling, 6 hours), sleep recovery (18 hours), and after cage switch (insomnia model paradigm, 6 hours). We found multiple significant effects of genotype on sleep. In particular, KO spent more time awake and less time in non-rapid-eye-movement sleep (NREMS) and rapid-eye-movement sleep (REMS) than WT during the dark (active) period but not during the light (rest) period, enhancing the day-night variation of wake-sleep amounts. KO had slower EEG theta rhythm during REMS. REMS homeostasis after sleep deprivation was less effective in KO than in WT. Finally, KO habituated more rapidly to the arousing effect of the cage-switch test than WT. We did not find any significant effects of diet or of diet x genotype interaction on sleep. The occurrence of multiple sleep alterations in KO indicates important roles of CB1 cannabinoid receptors in limiting arousal during the active period of the day, in sleep regulation, and in sleep EEG in mice.

  8. The effect of anaesthesia on [{sup 18}F]MK-9470 binding to the type 1 cannabinoid receptor in the rat brain

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    Casteels, Cindy; Van Laere, Koen [KU Leuven and University Hospital Gasthuisberg, Division of Nuclear Medicine, Leuven (Belgium); KU Leuven, MoSAIC, Molecular Small Animal Imaging Center, Leuven (Belgium); Bormans, Guy [KU Leuven, MoSAIC, Molecular Small Animal Imaging Center, Leuven (Belgium); KU Leuven, Laboratory for Radiopharmacy, Leuven (Belgium)

    2010-06-15

    Small animal PET can be applied to study molecular processes in animal models of a variety of human diseases. In order to keep the animals in a restricted position during imaging, anaesthesia is in many instances inevitable. Using small animal PET and ex vivo autoradiography, we examined the influence of pentobarbital and isoflurane anaesthesia on the rat brain uptake of [{sup 18}F]MK-9470, a radioligand for the type 1 cannabinoid receptor. PET imaging was performed on adult Wistar rats under pentobarbital (n=6) and isoflurane anaesthesia (n=7), and under control conditions (free moving during tracer uptake, n=8). Parametric PET images were generated, anatomically standardized and analysed by voxel-based Statistical Parametric Mapping and a predefined volume of interest approach. Immediately after in vivo PET, brains were processed for ex vivo autoradiography using manually placed regions of interest. An extra group (n=6) was included ex vivo, in which animals were intravenously injected without the use of anaesthetics. Using in vivo and ex vivo molecular imaging techniques, no significant changes in absolute [{sup 18}F]MK-9470 uptake were present in the brain of pentobarbital and isoflurane rats as compared to control conditions. Relative [{sup 18}F]MK-9470 uptake PET values obtained applying global scaling were, however, decreased in the cortex under both anaesthetics (pentobarbital: -13.3{+-}1.4%; isoflurane -8.7 {+-} 3.1%), while an increase was seen in the cerebellum by 13.5 {+-} 4.0% and 13.9 {+-} 4.1% under pentobarbital and isoflurane, respectively. Ex vivo results were in agreement with in vivo findings. These findings suggest a similar, regionally specific interference of pentobarbital and isoflurane anaesthesia with in vivo CB1 receptor imaging using [{sup 18}F]MK-9470. (orig.)

  9. Cannabinoid receptor localization in brain

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    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.

  10. Cannabinoid receptor type-1: breaking the dogmas [version 1; referees: 3 approved

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    Arnau Busquets Garcia

    2016-05-01

    Full Text Available The endocannabinoid system (ECS is abundantly expressed in the brain. This system regulates a plethora of physiological functions and is composed of cannabinoid receptors, their endogenous ligands (endocannabinoids, and the enzymes involved in the metabolism of endocannabinoids. In this review, we highlight the new advances in cannabinoid signaling, focusing on a key component of the ECS, the type-1 cannabinoid receptor (CB1. In recent years, the development of new imaging and molecular tools has demonstrated that this receptor can be distributed in many cell types (e.g., neuronal or glial cells and intracellular compartments (e.g., mitochondria. Interestingly, cellular and molecular effects are differentially mediated by CB1 receptors according to their specific localization (e.g., glutamatergic or GABAergic neurons. Moreover, this receptor is expressed in the periphery, where it can modulate periphery-brain connections. Finally, the better understanding of the CB1 receptor structure led researchers to propose interesting and new allosteric modulators. Thus, the advances and the new directions of the CB1 receptor field will provide new insights and better approaches to profit from its interesting therapeutic profile.

  11. Cannabinoid type-1 receptors in the paraventricular nucleus of the hypothalamus inhibit stimulated food intake.

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    Soria-Gómez, E; Massa, F; Bellocchio, L; Rueda-Orozco, P E; Ciofi, P; Cota, D; Oliet, S H R; Prospéro-García, O; Marsicano, G

    2014-03-28

    Cannabinoid receptor type 1 (CB1)-dependent signaling in the brain is known to modulate food intake. Recent evidence has actually shown that CB1 can both inhibit and stimulate food intake in fasting/refeeding conditions, depending on the specific neuronal circuits involved. However, the exact brain sites where this bimodal control is exerted and the underlying neurobiological mechanisms are not fully understood yet. Using pharmacological and electrophysiological approaches, we show that local CB1 blockade in the paraventricular nucleus of the hypothalamus (PVN) increases fasting-induced hyperphagia in rats. Furthermore, local CB1 blockade in the PVN also increases the orexigenic effect of the gut hormone ghrelin in animals fed ad libitum. At the electrophysiological level, CB1 blockade in slices containing the PVN potentiates the decrease of the activity of PVN neurons induced by long-term application of ghrelin. Hence, the PVN is (one of) the site(s) where signals associated with the body's energy status determine the direction of the effects of endocannabinoid signaling on food intake. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  12. Role of the Cannabinoid Receptor Type 1 (CB1) in Synaptic Plasticity, Memory and Emotionality

    OpenAIRE

    Jacob, Wolfgang

    2007-01-01

    The present work focused on the role of the cannabinoid receptor type 1 (CB1) in synaptic plasticity, memory and emotionality in mice. CB1 is abundantly expressed in the central nervous system and is mainly (if not exclusively) located on GABAergic and glutamatergic nerve cells. CB1 is a G-protein coupled receptor which is essentially inhibiting transmitter release from presynaptic GABAergic or glutamatergic nerve terminals. To differentiate between the physiological signifi...

  13. The Cannabinoid Type-1 Receptor Carboxyl-Terminus, More Than Just a Tail

    OpenAIRE

    Stadel, Rebecca; Ahn, Kwang H.; Kendall, Debra A.

    2011-01-01

    The cannabinoid type-1 (CB1) receptor is a G protein-coupled receptor (GPCR) that binds the main active ingredient of marijuana, Δ9-tetrahydrocannabinol, and has been implicated in several disease states, including drug addiction, anxiety, depression, obesity, and chronic pain. In the two decades since the discovery of CB1, studies at the molecular level have centered on the transmembrane core. This interest has now expanded as we discover that other regions of CB1, including the CB1 carboxyl...

  14. The dynamic nature of type 1 cannabinoid receptor (CB1) gene transcription

    Science.gov (United States)

    Laprairie, RB; Kelly, MEM; Denovan-Wright, EM

    2012-01-01

    The type 1 cannabinoid receptor (CB1) is an integral component of the endocannabinoid system that modulates several functions in the CNS and periphery. The majority of our knowledge of the endocannabinoid system involves ligand–receptor binding, mechanisms of signal transduction, and protein–protein interactions. In contrast, comparatively little is known about regulation of CB1 gene expression. The levels and anatomical distribution of CB1 mRNA and protein are developmental stage-specific and are dysregulated in several pathological conditions. Moreover, exposure to a variety of drugs, including cannabinoids themselves, alters CB1 gene expression and mRNA levels. As such, alterations in CB1 gene expression are likely to affect the optimal response to cannabinoid-based therapies, which are being developed to treat a growing number of conditions. Here, we will examine the regulation of CB1 mRNA levels and the therapeutic potential inherent in manipulating expression of this gene. Linked Articles This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8 PMID:22924606

  15. Neurofibromatosis type 1: brain stem tumours

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    Bilaniuk, L.T. [Department of Radiology, The Children`s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA (United States); Molloy, P.T. [Division of Neurology, Children`s Hospital of Philadelphia, PA (United States); Zimmerman, R.A. [Department of Radiology, The Children`s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA (United States); Phillips, P.C. [Division of Neurology, Children`s Hospital of Philadelphia, PA (United States); Vaughan, S.N. [Division of Neurology, Children`s Hospital of Philadelphia, PA (United States); Liu, G.T. [Division of Neuro-Ophthalmology, Children`s Hospital of Philadelphia, PA (United States); Sutton, L.N. [Division of Neurosurgery, Children`s Hospital of Philadelphia, PA (United States); Needle, M. [Division of Oncology, The Children`s Hospital of Philadelphia. PA (United States)

    1997-09-01

    We describe the clinical and imaging findings of brain stem tumours in patients with neurofibromatosis type 1 (NF1). The NF1 patients imaged between January 1984 and January 1996 were reviewed and 25 patients were identified with a brain stem tumour. Clinical, radiographical and pathological results were obtained by review of records and images. Brain stem tumour identification occurred much later than the clinical diagnosis of NF1. Medullary enlargement was most frequent (68 %), followed by pontine (52 %) and midbrain enlargement (44 %). Patients were further subdivided into those with diffuse (12 patients) and those with focal (13 patients) tumours. Treatment for hydrocephalus was required in 67 % of the first group and only 15 % of the second group. Surgery was performed in four patients and revealed fibrillary astrocytomas, one of which progressed to an anaplastic astrocytoma. In 40 % of patients both brain stem and optic pathway tumours were present. The biological behaviour of brain stem tumours in NF1 is unknown. Diffuse tumours in the patients with NF1 appear to have a much more favourable prognosis than patients with similar tumours without neurofibromatosis type 1. (orig.). With 7 figs., 3 tabs.

  16. Type 1 cannabinoid receptor mapping with [{sup 18}F]MK-9470 PET in the rat brain after quinolinic acid lesion: a comparison to dopamine receptors and glucose metabolism

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    Casteels, Cindy [KU Leuven and University Hospital Leuven, Division of Nuclear Medicine, Leuven (Belgium); KU Leuven, MoSAIC, Molecular Small Animal Imaging Center, Leuven (Belgium); University Hospital Gasthuisberg, Division of Nuclear Medicine, Leuven (Belgium); Martinez, Emili; Camon, Lluisa; Vera, Nuria de; Planas, Anna M. [IDIBAPS, Institute for Biomedical Research (IIBB-CSIC), Barcelona (Spain); Bormans, Guy [KU Leuven, MoSAIC, Molecular Small Animal Imaging Center, Leuven (Belgium); KU Leuven, Laboratory for Radiopharmacy, Leuven (Belgium); Baekelandt, Veerle [KU Leuven, Laboratory for Neurobiology and Gene Therapy, Leuven (Belgium); Laere, Koen van [KU Leuven and University Hospital Leuven, Division of Nuclear Medicine, Leuven (Belgium); KU Leuven, MoSAIC, Molecular Small Animal Imaging Center, Leuven (Belgium)

    2010-12-15

    Several lines of evidence imply early alterations in metabolic, dopaminergic and endocannabinoid neurotransmission in Huntington's disease (HD). Using [{sup 18}F]MK-9470 and small animal PET, we investigated cerebral changes in type 1 cannabinoid (CB{sub 1}) receptor binding in the quinolinic acid (QA) rat model of HD in relation to glucose metabolism, dopamine D{sub 2} receptor availability and amphetamine-induced turning behaviour. Twenty-one Wistar rats (11 QA and 10 shams) were investigated. Small animal PET acquisitions were conducted on a Focus 220 with approximately 18 MBq of [{sup 18}F]MK-9470, [{sup 18}F]FDG and [{sup 11}C]raclopride. Relative glucose metabolism and parametric CB{sub 1} receptor and D{sub 2} binding images were anatomically standardized to Paxinos space and analysed voxel-wise using Statistical Parametric Mapping (SPM2). In the QA model, [{sup 18}F]MK-9470 uptake, glucose metabolism and D{sub 2} receptor binding were reduced in the ipsilateral caudate-putamen by 7, 35 and 77%, respectively (all p < 2.10{sup -5}), while an increase for these markers was observed on the contralateral side (>5%, all p < 7.10{sup -4}). [{sup 18}F]MK-9470 binding was also increased in the cerebellum (p = 2.10{sup -5}), where it was inversely correlated to the number of ipsiversive turnings (p = 7.10{sup -6}), suggesting that CB{sub 1} receptor upregulation in the cerebellum is related to a better functional outcome. Additionally, glucose metabolism was relatively increased in the contralateral hippocampus, thalamus and sensorimotor cortex (p = 1.10{sup -6}). These data point to in vivo changes in endocannabinoid transmission, specifically for CB{sub 1} receptors in the QA model, with involvement of the caudate-putamen, but also distant regions of the motor circuitry, including the cerebellum. These data also indicate the occurrence of functional plasticity on metabolism, D{sub 2} and CB{sub 1} neurotransmission in the contralateral hemisphere. (orig.)

  17. Upregulation of Cannabinoid Type 1 Receptors in Dopamine D2 Receptor Knockout Mice Is Reversed by Chronic Forced Ethanol Consumption

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    Thanos, P.K.; Wang, G.; Thanos, P.K.; Gopez, V.; Delis, F.; Michaelides, M.; Grand, D.K.; Wang, G.-J.; Kunos, G.; Volkow, N.D.

    2011-01-01

    The anatomical proximity of the cannabinoid type 1 (CNR1/CB1R) and the dopamine D2 receptors (DRD2), their ability to form CB1R-DRD2 heteromers, their opposing roles in locomotion, and their involvement in ethanol's reinforcing and addictive properties prompted us to study the levels and distribution of CB1R after chronic ethanol intake, in the presence and absence of DRD2. We monitored the drinking patterns and locomotor activity of Drd2+/+ and Drd2-/- mice consuming either water or a 20% (v/v) ethanol solution (forced ethanol intake) for 6 months and used the selective CB1 receptor antagonist [{sup 3}H]SR141716A to quantify CB1R levels in different brain regions with in vitro receptor autoradiography. We found that the lack of DRD2 leads to a marked upregulation (approximately 2-fold increase) of CB1R in the cerebral cortex, the caudate-putamen, and the nucleus accumbens, which was reversed by chronic ethanol intake. The results suggest that DRD2-mediated dopaminergic neurotransmission and chronic ethanol intake exert an inhibitory effect on cannabinoid receptor expression in cortical and striatal regions implicated in the reinforcing and addictive properties of ethanol.

  18. Interaction between Cannabinoid Type 1 and Type 2 Receptors in the Modulation of Subventricular Zone and Dentate Gyrus Neurogenesis

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    Rui S. Rodrigues

    2017-08-01

    Full Text Available Neurogenesis in the adult mammalian brain occurs mainly in two neurogenic niches, the subventricular zone (SVZ and the subgranular zone (SGZ of the dentate gyrus (DG. Cannabinoid type 1 and 2 receptors (CB1R and CB2R have been shown to differently modulate neurogenesis. However, low attention has been given to the interaction between CB1R and CB2R in modulating postnatal neurogenesis (proliferation, neuronal differentiation and maturation. We focused on a putative crosstalk between CB1R and CB2R to modulate neurogenesis and cultured SVZ and DG stem/progenitor cells from early postnatal (P1-3 Sprague-Dawley rats. Data showed that the non-selective cannabinoid receptor agonist WIN55,212-2 promotes DG cell proliferation (measured by BrdU staining, an effect blocked by either CB1R or CB2R selective antagonists. Experiments with selective agonists showed that facilitation of DG cell proliferation requires co-activation of both CB1R and CB2R. Cell proliferation in the SVZ was not affected by the non-selective receptor agonist, but it was enhanced by CB1R selective activation. However, either CB1R or CB2R selective antagonists abolished the effect of the CB1R agonist in SVZ cell proliferation. Neuronal differentiation (measured by immunocytochemistry against neuronal markers of different stages and calcium imaging was facilitated by WIN55,212-2 at both SVZ and DG. This effect was mimicked by either CB1R or CB2R selective agonists and blocked by either CB1R or CB2R selective antagonists, cross-antagonism being evident. In summary, our findings indicate a tight interaction between CB1R and CB2R to modulate neurogenesis in the two major neurogenic niches, thus contributing to further unraveling the mechanisms behind the action of endocannabinoids in the brain.

  19. Exercise reduces adipose tissue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor-delta

    DEFF Research Database (Denmark)

    Yan, Zhen Cheng; Liu, Dao Yan; Zhang, Li Li

    2007-01-01

    Obesity is one major cardiovascular risk factor. We tested effects of endurance exercise on cannabinoid receptor type 1 (CB1) and peroxisome proliferator-activated receptor-delta (PPAR-delta)-dependent pathways in adipose tissue. Male Wistar rats were randomly assigned to standard laboratory chow...

  20. Type 1 Cannabinoid Receptor Ligands Display Functional Selectivity in a Cell Culture Model of Striatal Medium Spiny Projection Neurons*

    Science.gov (United States)

    Laprairie, Robert B.; Bagher, Amina M.; Kelly, Melanie E. M.; Dupré, Denis J.; Denovan-Wright, Eileen M.

    2014-01-01

    Modulation of type 1 cannabinoid receptor (CB1) activity has been touted as a potential means of treating addiction, anxiety, depression, and neurodegeneration. Different agonists of CB1 are known to evoke varied responses in vivo. Functional selectivity is the ligand-specific activation of certain signal transduction pathways at a receptor that can signal through multiple pathways. To understand cannabinoid-specific functional selectivity, different groups have examined the effect of individual cannabinoids on various signaling pathways in heterologous expression systems. In the current study, we compared the functional selectivity of six cannabinoids, including two endocannabinoids (2-arachidonyl glycerol (2-AG) and anandamide (AEA)), two synthetic cannabinoids (WIN55,212-2 and CP55,940), and two phytocannabinoids (cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC)) on arrestin2-, Gαi/o-, Gβγ-, Gαs-, and Gαq-mediated intracellular signaling in the mouse STHdhQ7/Q7 cell culture model of striatal medium spiny projection neurons that endogenously express CB1. In this system, 2-AG, THC, and CP55,940 were more potent mediators of arrestin2 recruitment than other cannabinoids tested. 2-AG, AEA, and WIN55,212-2, enhanced Gαi/o and Gβγ signaling, with 2-AG and AEA treatment leading to increased total CB1 levels. 2-AG, AEA, THC, and WIN55,212-2 also activated Gαq-dependent pathways. CP55,940 and CBD both signaled through Gαs. CP55,940, but not CBD, activated downstream Gαs pathways via CB1 targets. THC and CP55,940 promoted CB1 internalization and decreased CB1 protein levels over an 18-h period. These data demonstrate that individual cannabinoids display functional selectivity at CB1 leading to activation of distinct signaling pathways. To effectively match cannabinoids with therapeutic goals, these compounds must be screened for their signaling bias. PMID:25037227

  1. The cerebral type 1 cannabinoid receptor as modulator in dopaminergic transmission disorders: addiction and psychosis:De cerebrale type 1 cannabinoid receptor als modulator bij stoornissen in de dopaminerge neurotransmissie: verslaving en psychose

    OpenAIRE

    Ceccarini, Jenny

    2012-01-01

    SUMMARY : The endocannabinoid system (ECS) is a widespread neuromodulatory system in the brain. The ECS consists mainly of cannabinoid receptors, their endogenous ligands (endocannabinoids) of which anandamide and 2-arachidonoylglycerol (2-AG) are the best characterized examples, and transport and degradation proteins. Endocannabinoids are lipids synthesized and released ‘on-demand’ in dendrites subjected to membrane depolarization. In contrast to classic neurotransmitters, endocannabinoid...

  2. The Cannabinoid Type-1 Receptor Carboxyl-Terminus, More Than Just a Tail

    Science.gov (United States)

    Stadel, Rebecca; Ahn, Kwang H.; Kendall, Debra A.

    2011-01-01

    The cannabinoid type-1 (CB1) receptor is a G protein-coupled receptor (GPCR) that binds the main active ingredient of marijuana, Δ9-tetrahydrocannabinol, and has been implicated in several disease states, including drug addiction, anxiety, depression, obesity, and chronic pain. In the two decades since the discovery of CB1, studies at the molecular level have centered on the transmembrane core. This interest has now expanded as we discover that other regions of CB1, including the CB1 carboxyl-terminus, have critical structures that are important for CB1 activity and regulation. Following the recent description of the three dimensional structure of the full-length CB1 carboxyl-terminal tail (Ahn et al., Biopolymers (2009) 91: 565–573), several residues and structural motifs including two α-helices (termed H8 and H9) have been postulated to interact with common GPCR accessory proteins, such as G-proteins and β-arrestins. This discourse will focus on the CB1 carboxyl-terminus; our current understanding of the structural features of this region, evidence for its interaction with proteins, and the impact of structure on the binding and regulatory function of CB1 accessory proteins. The involvement of the carboxyl-terminus in the receptor life cycle including activation, desensitization, and internalization will be highlighted. PMID:21244428

  3. Altered Expression of Type-1 and Type-2 Cannabinoid Receptors in Celiac Disease

    Science.gov (United States)

    Di Tommaso, Monia; Biancheri, Paolo; Rapino, Cinzia; Giuffrida, Paolo; Papadia, Cinzia; Montana, Chiara; Pasini, Alessandra; Vanoli, Alessandro; Lanzarotto, Francesco; Villanacci, Vincenzo

    2013-01-01

    Anandamide (AEA) is the prominent member of the endocannabinoid family and its biological action is mediated through the binding to both type-1 (CB1) and type-2 (CB2) cannabinoid receptors (CBR). The presence of AEA and CBR in the gastrointestinal tract highlighted their pathophysiological role in several gut diseases, including celiac disease. Here, we aimed to investigate the expression of CBR at transcriptional and translational levels in the duodenal mucosa of untreated celiac patients, celiac patients on a gluten-free diet for at least 12 months and control subjects. Also biopsies from treated celiac patients cultured ex vivo with peptic-tryptic digest of gliadin were investigated. Our data show higher levels of both CB1 and CB2 receptors during active disease and normal CBR levels in treated celiac patients. In conclusion, we demonstrate an up-regulation of CB1 and CB2 mRNA and protein expression, that points to the therapeutic potential of targeting CBR in patients with celiac disease. PMID:23620805

  4. Association between a genetic variant of type-1 cannabinoid receptor and inflammatory neurodegeneration in multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Silvia Rossi

    Full Text Available Genetic ablation of type-1 cannabinoid receptors (CB1Rs exacerbates the neurodegenerative damage of experimental autoimmune encephalomyelitis, the rodent model of multiple sclerosis (MS. To address the role on CB1Rs in the pathophysiology of human MS, we first investigated the impact of AAT trinucleotide short tandem repeat polymorphism of CNR1 gene on CB1R cell expression, and secondly on the inflammatory neurodegeneration process responsible for irreversible disability in MS patients. We found that MS patients with long AAT repeats within the CNR1 gene (≥12 in both alleles had more pronounced neuronal degeneration in response to inflammatory white matter damage both in the optic nerve and in the cortex. Optical Coherence Tomography (OCT, in fact, showed more severe alterations of the retinal nerve fiber layer (RNFL thickness and of the macular volume (MV after an episode of optic neuritis in MS patients carrying the long AAT genotype of CNR1. MS patients with long AAT repeats also had magnetic resonance imaging (MRI evidence of increased gray matter damage in response to inflammatory lesions of the white matter, especially in areas with a major role in cognition. In parallel, visual abilities evaluated at the low contrast acuity test, and cognitive performances were negatively influenced by the long AAT CNR1 genotype in our sample of MS patients. Our results demonstrate the biological relevance of the (AATn CNR1 repeats in the inflammatory neurodegenerative damage of MS.

  5. Association between a genetic variant of type-1 cannabinoid receptor and inflammatory neurodegeneration in multiple sclerosis.

    Science.gov (United States)

    Rossi, Silvia; Bozzali, Marco; Bari, Monica; Mori, Francesco; Studer, Valeria; Motta, Caterina; Buttari, Fabio; Cercignani, Mara; Gravina, Paolo; Mastrangelo, Nicolina; Castelli, Maura; Mancino, Raffaele; Nucci, Carlo; Sottile, Fabrizio; Bernardini, Sergio; Maccarrone, Mauro; Centonze, Diego

    2013-01-01

    Genetic ablation of type-1 cannabinoid receptors (CB1Rs) exacerbates the neurodegenerative damage of experimental autoimmune encephalomyelitis, the rodent model of multiple sclerosis (MS). To address the role on CB1Rs in the pathophysiology of human MS, we first investigated the impact of AAT trinucleotide short tandem repeat polymorphism of CNR1 gene on CB1R cell expression, and secondly on the inflammatory neurodegeneration process responsible for irreversible disability in MS patients. We found that MS patients with long AAT repeats within the CNR1 gene (≥12 in both alleles) had more pronounced neuronal degeneration in response to inflammatory white matter damage both in the optic nerve and in the cortex. Optical Coherence Tomography (OCT), in fact, showed more severe alterations of the retinal nerve fiber layer (RNFL) thickness and of the macular volume (MV) after an episode of optic neuritis in MS patients carrying the long AAT genotype of CNR1. MS patients with long AAT repeats also had magnetic resonance imaging (MRI) evidence of increased gray matter damage in response to inflammatory lesions of the white matter, especially in areas with a major role in cognition. In parallel, visual abilities evaluated at the low contrast acuity test, and cognitive performances were negatively influenced by the long AAT CNR1 genotype in our sample of MS patients. Our results demonstrate the biological relevance of the (AAT)n CNR1 repeats in the inflammatory neurodegenerative damage of MS.

  6. Activation of type-1 cannabinoid receptor shifts the balance between excitation and inhibition towards excitation in layer II/III pyramidal neurons of the rat prelimbic cortex.

    Science.gov (United States)

    den Boon, Femke S; Werkman, Taco R; Schaafsma-Zhao, Qiluan; Houthuijs, Kas; Vitalis, Tania; Kruse, Chris G; Wadman, Wytse J; Chameau, Pascal

    2015-07-01

    Activation of the endocannabinoid (eCB) system by exogenous cannabinoids (drug abuse) can alter the physiology of the brain circuits involved in higher-order cognitive functions such as the medial prefrontal cortex (mPFC). A proper balance between excitation and inhibition (E/I balance) is critical for neuronal network oscillations underlying cognitive functions. Since type-1 cannabinoid receptors (CB1Rs), expressed in many brain areas including the mPFC, can modulate excitatory and inhibitory neurotransmission, we aimed to determine whether CB1R activation results in modifications of the E/I balance. We first confirm the presence of functional presynaptic CB1Rs that can modulate both excitatory and inhibitory inputs to layer II/III pyramidal neurons of the prelimbic (PL) area of the mPFC. By decomposing the synaptic response evoked by layer I stimulation into its excitatory and inhibitory components, we show that in vitro CB1R activation with the cannabinoid receptor agonists WIN55,212-2 (WIN) and CP-55940 (CP) modulates the balance between excitation and inhibition (E/I balance) of layer II/III pyramidal neurons. This treatment caused a significant shift of the E/I balance towards excitation, from 18/82 % to 25/75 % (WIN) and from 17/83 to 30/70 % (CP). Finally, when animals were injected with a cannabinoid receptor agonist, we observed a shift of the E/I balance (measured in vitro) towards excitation 1 h after WIN (24/76 %) or after CP injection (30/70 %) when compared to vehicle-injected animals (18/82 %). This modulation of the E/I balance by CB1Rs may thus be fundamental in the regulation of local PL cortical network excitability and could be the mechanism through which excessive CB1R activation (cannabis abuse) affects cognitive functions.

  7. Reduced Brain Cannabinoid Receptor Availability in Schizophrenia.

    Science.gov (United States)

    Ranganathan, Mohini; Cortes-Briones, Jose; Radhakrishnan, Rajiv; Thurnauer, Halle; Planeta, Beata; Skosnik, Patrick; Gao, Hong; Labaree, David; Neumeister, Alexander; Pittman, Brian; Surti, Toral; Huang, Yiyun; Carson, Richard E; D'Souza, Deepak Cyril

    2016-06-15

    Several lines of evidence suggest the presence of abnormalities in the endocannabinoid (eCB) system in schizophrenia (SCZ). However, there are limited in vivo measures of the eCB system in SCZ. Twenty five male SCZ subjects (SCZs) (18 antipsychotic treated and 7 antipsychotic free) were compared with 18 age-matched male healthy control subjects (HCs). Subjects underwent one positron emission tomography scan each with the cannabinoid receptor-1 (CB1R) selective radiotracer [(11)C]OMAR on the high resolution research tomography scanner. Regional volume of distribution (VT) values were determined using kinetic modeling of positron emission tomography data as a measure of CB1R availability. Group differences in mean composite [(11)C]OMAR VT values were compared between SCZs and HCs. Exploratory comparisons of CB1R availability within 15 brain regions were also conducted. All analyses were covaried for age and body mass index. SCZs showed significantly (p = .02) lower composite [(11)C]OMAR VT relative to HCs (~12% difference, effect size d = .73). [(11)C]OMAR VT was significantly (all ps antipsychotic treated SZCs > antipsychotic free SZCs. Furthermore, composite [(11)C]OMAR VT was greater in HCs than SCZ smokers (n = 11) and SCZ nonsmokers (n = 14). CB1R availability is lower in male SCZ subjects compared with HCs. Furthermore, antipsychotics and tobacco use may increase CB1R availability in this population. The findings of the study provide further evidence supporting the hypothesis that alterations in the eCB system might contribute to the pathophysiology of SCZ. Published by Elsevier Inc.

  8. Genetic dissection of the role of cannabinoid type-1 receptors in the emotional consequences of repeated social stress in mice.

    Science.gov (United States)

    Dubreucq, Sarah; Matias, Isabelle; Cardinal, Pierre; Häring, Martin; Lutz, Beat; Marsicano, Giovanni; Chaouloff, Francis

    2012-07-01

    The endocannabinoid system (ECS) tightly controls emotional responses to acute aversive stimuli. Repeated stress alters ECS activity but the role played by the ECS in the emotional consequences of repeated stress has not been investigated in detail. This study used social defeat stress, together with pharmacology and genetics to examine the role of cannabinoid type-1 (CB(1)) receptors on repeated stress-induced emotional alterations. Seven daily social defeat sessions increased water (but not food) intake, sucrose preference, anxiety, cued fear expression, and adrenal weight in C57BL/6N mice. The first and the last social stress sessions triggered immediate brain region-dependent changes in the concentrations of the principal endocannabinoids anandamide and 2-arachidonoylglycerol. Pretreatment before each of the seven stress sessions with the CB(1) receptor antagonist rimonabant prolonged freezing responses of stressed mice during cued fear recall tests. Repeated social stress abolished the increased fear expression displayed by constitutive CB(1) receptor-deficient mice. The use of mutant mice lacking CB(1) receptors from cortical glutamatergic neurons or from GABAergic neurons indicated that it is the absence of the former CB(1) receptor population that is responsible for the fear responses in socially stressed CB(1) mutant mice. In addition, stress-induced hypolocomotor reactivity was amplified by the absence of CB(1) receptors from GABAergic neurons. Mutant mice lacking CB(1) receptors from serotonergic neurons displayed a higher anxiety but decreased cued fear expression than their wild-type controls. These mutant mice failed to show social stress-elicited increased sucrose preference. This study shows that (i) release of endocannabinoids during stress exposure impedes stress-elicited amplification of cued fear behavior, (ii) social stress opposes the increased fear expression and delayed between-session extinction because of the absence of CB(1) receptors

  9. Studies of the brain cannabinoid system using positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Gatley, S.J.; Volkow, N.D.

    1995-10-01

    Studies using radiolabeled psychoactive drugs in conjunction with positron emission tomography (PET) have permitted the imaging of binding sites in the human brain. Similar studies of marijuana have been hampered by the unsuitability of radiolabeled THC for PET studies, and the current unavailability of other in vivo imaging agents for cannabinoid receptors. Recent developments in medicinal chemistry suggest that a PET radiotracer for cannabinoid receptors will soon become available. This chapter briefly reviews these developments, together with the results of PET studies of the effects of marijuana and other abused drugs on brain metabolism. It also reviews PET studies of cocaine binding sites, to demonstrate the kind of investigations that will be possible when a cannabinoid receptor PET radioligand becomes available.

  10. Cannabinoid Type-1 Receptor Gene Polymorphisms Are Associated with Central Obesity in a Southern Brazilian Population

    Directory of Open Access Journals (Sweden)

    Janaína P. Jaeger

    2008-01-01

    Full Text Available The CB1 cannabinoid receptor and its endogenous ligands, the endocannabinoids, are involved in energy balance control, stimulating appetite and increasing body weight in wasting syndromes. Different studies have investigated the relationship between polymorphisms of the cannabinoid receptor 1 (CNR1 gene and obesity with conflicting results. In the present study, we investigated the 1359G/A (rs1049353, 3813A/G (rs12720071 and 4895A/G (rs806368 polymorphisms in the CNR1 gene in a Brazilian population of European descent. To verify the association between these variants and obesity-related traits in this population, 756 individuals were genotyped by PCR-RFLP methods. The 4895G allele was associated with waist to hip ratio (WHR (P = 0.014; P = 0.042 after Bonferroni correction. An additive effect with the GAA haplotype was associated with WHR (P = 0.028, although this statistical significance disappeared after Bonferroni correction (P = 0.084. No significant association was observed between the genotypes of the 1359G/A and 3813A/G polymorphisms and any of the quantitative variables investigated. Our findings suggest that CNR1 gene polymorphism is associated with central obesity in this Brazilian population of European ancestry.

  11. Brain imaging in myotonic dystrophy type 1: A systematic review

    NARCIS (Netherlands)

    Okkersen, K.; Monckton, D.G.; Le, N.; Tuladhar, A.M.; Raaphorst, J.; Engelen, B.G.M. van

    2017-01-01

    OBJECTIVE: To systematically review brain imaging studies in myotonic dystrophy type 1 (DM1). METHODS: We searched Embase (index period 1974-2016) and MEDLINE (index period 1946-2016) for studies in patients with DM1 using MRI, magnetic resonance spectroscopy (MRS), functional MRI (fMRI), CT,

  12. Opposing roles for cannabinoid receptor type-1 (CB₁) and transient receptor potential vanilloid type-1 channel (TRPV1) on the modulation of panic-like responses in rats.

    Science.gov (United States)

    Casarotto, Plínio C; Terzian, Ana Luisa B; Aguiar, Daniele C; Zangrossi, Hélio; Guimarães, Francisco S; Wotjak, Carsten T; Moreira, Fabrício A

    2012-01-01

    The midbrain dorsal periaqueductal gray (dPAG) has an important role in orchestrating anxiety- and panic-related responses. Given the cellular and behavioral evidence suggesting opposite functions for cannabinoid type 1 receptor (CB₁) and transient receptor potential vanilloid type-1 channel (TRPV1), we hypothesized that they could differentially influence panic-like reactions induced by electrical stimulation of the dPAG. Drugs were injected locally and the expression of CB₁ and TRPV1 in this structure was assessed by immunofluorescence and confocal microscopy. The CB₁-selective agonist, ACEA (0.01, 0.05 and 0.5 pmol) increased the threshold for the induction of panic-like responses solely at the intermediary dose, an effect prevented by the CB₁-selective antagonist, AM251 (75 pmol). Panicolytic-like effects of ACEA at the higher dose were unmasked by pre-treatment with the TRPV1 antagonist capsazepine (0.1 nmol). Similarly to ACEA, capsazepine (1 and 10 nmol) raised the threshold for triggering panic-like reactions, an effect mimicked by another TRPV1 antagonist, SB366791 (1 nmol). Remarkably, the effects of both capsazepine and SB366791 were prevented by AM251 (75 pmol). These pharmacological data suggest that a common endogenous agonist may have opposite functions at a given synapse. Supporting this view, we observed that several neurons in the dPAG co-expressed CB₁ and TRPV1. Thus, the present work provides evidence that an endogenous substance, possibly anandamide, may exert both panicolytic and panicogenic effects via its actions at CB₁ receptors and TRPV1 channels, respectively. This tripartite set-point system might be exploited for the pharmacotherapy of panic attacks and anxiety-related disorders.

  13. Modulation of Type-1 and Type-2 Cannabinoid Receptors by Saffron in a Rat Model of Retinal Neurodegeneration

    Science.gov (United States)

    Maccarone, Rita; Rapino, Cinzia; Zerti, Darin; di Tommaso, Monia; Battista, Natalia; Di Marco, Stefano; Bisti, Silvia; Maccarrone, Mauro

    2016-01-01

    Experimental studies demonstrated that saffron (Crocus sativus) given as a dietary supplement counteracts the effects of bright continuous light (BCL) exposure in the albino rat retina, preserving both morphology and function and probably acting as a regulator of programmed cell death [1]. The purpose of this study was to ascertain whether the neuroprotective effect of saffron on rat retina exposed to BCL is associated with a modulation of the endocannabinoid system (ECS). To this aim, we used eight experimental groups of Sprague-Dawley rats, of which six were exposed to BCL for 24 hours. Following retinal function evaluation, retinas were quickly removed for biochemical and morphological analyses. Rats were either saffron-prefed or intravitreally injected with selective type-1 (CB1) or type-2 (CB2) cannabinoid receptor antagonists before BCL. Prefeeding and intravitreally injections were combined in two experimental groups before BCL. BCL exposure led to enhanced gene and protein expression of retinal CB1 and CB2 without affecting the other ECS elements. This effect of BCL on CB1 and CB2 was reversed by saffron treatment. Selective CB1 and CB2 antagonists reduced photoreceptor death, preserved morphology and visual function of retina, and mitigated the outer nuclear layer (ONL) damage due to BCL. Of interest, CB2-dependent neuroprotection was more pronounced than that conferred by CB1. These data suggest that BCL modulates only distinct ECS elements like CB1 and CB2, and that saffron and cannabinoid receptors could share the same mechanism in order to afford retinal protection. PMID:27861558

  14. Type-1 Cannabinoid Receptors Reduce Membrane Fluidity of Capacitated Boar Sperm by Impairing Their Activation by Bicarbonate

    Science.gov (United States)

    Barboni, Barbara; Bernabò, Nicola; Palestini, Paola; Botto, Laura; Pistilli, Maria Gabriella; Charini, Marco; Tettamanti, Enzo; Battista, Natalia

    2011-01-01

    Background Mammalian spermatozoa acquire their full fertilizing ability (so called capacitation) within the female genital tract, where they are progressively exposed to inverse gradients of inhibiting and stimulating molecules. Methodology/Principal Findings In the present research, the effect on this process of anandamide, an endocannabinoid that can either activate or inhibit cannabinoid receptors depending on its concentration, and bicarbonate, an oviductal activatory molecule, was assessed, in order to study the role exerted by the type 1 cannabinoid receptor (CB1R) in the process of lipid membrane remodeling crucial to complete capacitation. To this aim, boar sperm were incubated in vitro under capacitating conditions (stimulated by bicarbonate) in the presence or in the absence of methanandamide (Met-AEA), a non-hydrolysable analogue of anandamide. The CB1R involvement was studied by using the specific inhibitor (SR141716) or mimicking its activation by adding a permeable cAMP analogue (8Br-cAMP). By an immunocytochemistry approach it was shown that the Met-AEA inhibits the bicarbonate-dependent translocation of CB1R from the post-equatorial to equatorial region of sperm head. In addition it was found that Met-AEA is able to prevent the bicarbonate-induced increase in membrane disorder and the cholesterol extraction, both preliminary to capacitation, acting through a CB1R-cAMP mediated pathway, as indicated by MC540 and filipin staining, EPR spectroscopy and biochemical analysis on whole membranes (CB1R activity) and on membrane enriched fraction (C/P content and anisotropy). Conclusions/Significance Altogether, these data demonstrate that the endocannabinoid system strongly inhibits the process of sperm capacitation, acting as membrane stabilizing agent, thus increasing the basic knowledge on capacitation-related signaling and potentially opening new perspectives in diagnostics and therapeutics of male infertility. PMID:21829686

  15. Modulation of Type-1 and Type-2 Cannabinoid Receptors by Saffron in a Rat Model of Retinal Neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Rita Maccarone

    Full Text Available Experimental studies demonstrated that saffron (Crocus sativus given as a dietary supplement counteracts the effects of bright continuous light (BCL exposure in the albino rat retina, preserving both morphology and function and probably acting as a regulator of programmed cell death [1]. The purpose of this study was to ascertain whether the neuroprotective effect of saffron on rat retina exposed to BCL is associated with a modulation of the endocannabinoid system (ECS. To this aim, we used eight experimental groups of Sprague-Dawley rats, of which six were exposed to BCL for 24 hours. Following retinal function evaluation, retinas were quickly removed for biochemical and morphological analyses. Rats were either saffron-prefed or intravitreally injected with selective type-1 (CB1 or type-2 (CB2 cannabinoid receptor antagonists before BCL. Prefeeding and intravitreally injections were combined in two experimental groups before BCL. BCL exposure led to enhanced gene and protein expression of retinal CB1 and CB2 without affecting the other ECS elements. This effect of BCL on CB1 and CB2 was reversed by saffron treatment. Selective CB1 and CB2 antagonists reduced photoreceptor death, preserved morphology and visual function of retina, and mitigated the outer nuclear layer (ONL damage due to BCL. Of interest, CB2-dependent neuroprotection was more pronounced than that conferred by CB1. These data suggest that BCL modulates only distinct ECS elements like CB1 and CB2, and that saffron and cannabinoid receptors could share the same mechanism in order to afford retinal protection.

  16. Type-1 cannabinoid receptors reduce membrane fluidity of capacitated boar sperm by impairing their activation by bicarbonate.

    Directory of Open Access Journals (Sweden)

    Barbara Barboni

    Full Text Available BACKGROUND: Mammalian spermatozoa acquire their full fertilizing ability (so called capacitation within the female genital tract, where they are progressively exposed to inverse gradients of inhibiting and stimulating molecules. METHODOLOGY/PRINCIPAL FINDINGS: In the present research, the effect on this process of anandamide, an endocannabinoid that can either activate or inhibit cannabinoid receptors depending on its concentration, and bicarbonate, an oviductal activatory molecule, was assessed, in order to study the role exerted by the type 1 cannabinoid receptor (CB1R in the process of lipid membrane remodeling crucial to complete capacitation. To this aim, boar sperm were incubated in vitro under capacitating conditions (stimulated by bicarbonate in the presence or in the absence of methanandamide (Met-AEA, a non-hydrolysable analogue of anandamide. The CB1R involvement was studied by using the specific inhibitor (SR141716 or mimicking its activation by adding a permeable cAMP analogue (8Br-cAMP. By an immunocytochemistry approach it was shown that the Met-AEA inhibits the bicarbonate-dependent translocation of CB1R from the post-equatorial to equatorial region of sperm head. In addition it was found that Met-AEA is able to prevent the bicarbonate-induced increase in membrane disorder and the cholesterol extraction, both preliminary to capacitation, acting through a CB1R-cAMP mediated pathway, as indicated by MC540 and filipin staining, EPR spectroscopy and biochemical analysis on whole membranes (CB1R activity and on membrane enriched fraction (C/P content and anisotropy. CONCLUSIONS/SIGNIFICANCE: Altogether, these data demonstrate that the endocannabinoid system strongly inhibits the process of sperm capacitation, acting as membrane stabilizing agent, thus increasing the basic knowledge on capacitation-related signaling and potentially opening new perspectives in diagnostics and therapeutics of male infertility.

  17. Pharmacokinetic/pharmaco-dynamic modelling and simulation of the effects of different cannabinoid receptor type 1 antagonists on (9)-tetrahydrocannabinol challenge tests

    NARCIS (Netherlands)

    Guan, Zheng; Klumpers, Linda E.; Oyetayo, Olubukayo-Opeyemi; Heuberger, Jules; van Gerven, Joop M. A.; Stevens, Jasper

    Aim: The severe psychiatric side effects of cannabinoid receptor type 1 (CB1) antagonists hampered their wide development but this might be overcome by careful management of drug development with pharmacokinetic/pharmacodynamic (PK/PD) analyses. PK/PD models suitable for direct comparison of

  18. Possible Therapeutic Doses of Cannabinoid Type 1 Receptor Antagonist Reverses Key Alterations in Fragile X Syndrome Mouse Model

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    Maria Gomis-González

    2016-08-01

    Full Text Available Fragile X syndrome (FXS is the most common monogenetic cause of intellectual disability. The cognitive deficits in the mouse model for this disorder, the Fragile X Mental Retardation 1 (Fmr1 knockout (KO mouse, have been restored by different pharmacological approaches, among those the blockade of cannabinoid type 1 (CB1 receptor. In this regard, our previous study showed that the CB1 receptor antagonist/inverse agonist rimonabant normalized a number of core features in the Fmr1 knockout mouse. Rimonabant was commercialized at high doses for its anti-obesity properties, and withdrawn from the market on the bases of mood-related adverse effects. In this study we show, by using electrophysiological approaches, that low dosages of rimonabant (0.1 mg/kg manage to normalize metabotropic glutamate receptor dependent long-term depression (mGluR-LTD. In addition, low doses of rimonabant (from 0.01 mg/kg equally normalized the cognitive deficit in the mouse model of FXS. These doses of rimonabant were from 30 to 300 times lower than those required to reduce body weight in rodents and to presumably produce adverse effects in humans. Furthermore, NESS0327, a CB1 receptor neutral antagonist, was also effective in preventing the novel object-recognition memory deficit in Fmr1 KO mice. These data further support targeting CB1 receptors as a relevant therapy for FXS.

  19. Diffusion Tensor Imaging Of the Brain in Type 1 Diabetes

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    Jo Ann V. Antenor-Dorsey

    2014-10-01

    Full Text Available Individuals with Type 1 diabetes mellitus (T1DM are required to carefully manage their insulin dosing, dietary intake, and activity levels in order to maintain optimal blood sugar levels. Over time, exposure to hyperglycaemia is known to cause significant damage to the peripheral nervous system, but its impact on the central nervous system has been less well studied. Researchers have begun to explore the cumulative impact of commonly experienced blood glucose fluctuations on brain structure and function in patient populations. To date, these studies have typically used magnetic resonance imaging to measure regional grey and white matter volumes across the brain. However, newer methods, such as diffusion tensor imaging (DTI can measure the microstructural properties of white matter, which can be more sensitive to neurological effects than standard volumetric measures. Studies are beginning to use DTI to understand the impact of T1DM on white matter structure in the human brain. This work, its implications, future directions, and important caveats, are the focus of this review.

  20. Activation of type-1 cannabinoid receptor shifts the balance between excitation and inhibition towards excitation in layer II/III pyramidal neurons of the rat prelimbic cortex

    NARCIS (Netherlands)

    den Boon, F.S.; Werkman, T.R.; Schaafsma-Zhao, Q.; Houthuijs, K.; Vitalis, T.; Kruse, C.G.; Wadman, W.J.; Chameau, P.

    2015-01-01

    Activation of the endocannabinoid (eCB) system by exogenous cannabinoids (drug abuse) can alter the physiology of the brain circuits involved in higher-order cognitive functions such as the medial prefrontal cortex (mPFC). A proper balance between excitation and inhibition (E/I balance) is critical

  1. Spatial distribution of cannabinoid receptor type 1 (CB1) in normal canine central and peripheral nervous system

    Science.gov (United States)

    Baumgärtner, Wolfgang; Tipold, Andrea

    2017-01-01

    The endocannabinoid system is a regulatory pathway consisting of two main types of cannabinoid receptors (CB1 and CB2) and their endogenous ligands, the endocannabinoids. The CB1 receptor is highly expressed in the central and peripheral nervous systems (PNS) in mammalians and is involved in neuromodulatory functions. Since endocannabinoids were shown to be elevated in cerebrospinal fluid of epileptic dogs, knowledge about the species specific CB receptor expression in the nervous system is required. Therefore, we assessed the spatial distribution of CB1 receptors in the normal canine CNS and PNS. Immunohistochemistry of several regions of the brain, spinal cord and peripheral nerves from a healthy four-week-old puppy, three six-month-old dogs, and one ten-year-old dog revealed strong dot-like immunoreactivity in the neuropil of the cerebral cortex, Cornu Ammonis (CA) and dentate gyrus of the hippocampus, midbrain, cerebellum, medulla oblongata and grey matter of the spinal cord. Dense CB1 expression was found in fibres of the globus pallidus and substantia nigra surrounding immunonegative neurons. Astrocytes were constantly positive in all examined regions. CB1 labelled neurons and satellite cells of the dorsal root ganglia, and myelinating Schwann cells in the PNS. These results demonstrate for the first time the spatial distribution of CB1 receptors in the healthy canine CNS and PNS. These results can be used as a basis for further studies aiming to elucidate the physiological consequences of this particular anatomical and cellular distribution. PMID:28700706

  2. Small-animal PET imaging of the type 1 and type 2 cannabinoid receptors in a photothrombotic stroke model

    Energy Technology Data Exchange (ETDEWEB)

    Vandeputte, Caroline; Casteels, Cindy; Koole, Michel; Gerits, Anneleen [KU Leuven, Division of Nuclear Medicine, Leuven (Belgium); KU Leuven, Molecular Small Animal Imaging Center, MoSAIC, Leuven (Belgium); Struys, Tom [Hasselt University, Laboratory of Histology, Biomedical Research Institute, Hasselt (Belgium); KU Leuven, Biomedical NMR Unit, Leuven (Belgium); Veghel, Daisy van; Evens, Nele; Bormans, Guy [KU Leuven, Molecular Small Animal Imaging Center, MoSAIC, Leuven (Belgium); KU Leuven, Laboratory of Radiopharmacy, Leuven (Belgium); Dresselaers, Tom; Himmelreich, Uwe [KU Leuven, Molecular Small Animal Imaging Center, MoSAIC, Leuven (Belgium); KU Leuven, Biomedical NMR Unit, Leuven (Belgium); Lambrichts, Ivo [Hasselt University, Laboratory of Histology, Biomedical Research Institute, Hasselt (Belgium); Laere, Koen van [KU Leuven, Division of Nuclear Medicine, Leuven (Belgium); KU Leuven, Molecular Small Animal Imaging Center, MoSAIC, Leuven (Belgium); UZ Leuven, Division of Nuclear Medicine, Leuven (Belgium)

    2012-11-15

    Recent ex vivo and pharmacological evidence suggests involvement of the endocannabinoid system in the pathophysiology of stroke, but conflicting roles for type 1 and 2 cannabinoid receptors (CB{sub 1} and CB{sub 2}) have been suggested. The purpose of this study was to evaluate CB{sub 1} and CB{sub 2} receptor binding over time in vivo in a rat photothrombotic stroke model using PET. CB{sub 1} and CB{sub 2} microPET imaging was performed at regular time-points up to 2 weeks after stroke using [{sup 18}F]MK-9470 and [{sup 11}C]NE40. Stroke size was measured using MRI at 9.4 T. Ex vivo validation was performed via immunostaining for CB{sub 1} and CB{sub 2}. Immunofluorescent double stainings were also performed with markers for astrocytes (GFAP) and macrophages/microglia (CD68). [{sup 18}F]MK-9470 PET showed a strong increase in CB{sub 1} binding 24 h and 72 h after stroke in the cortex surrounding the lesion, extending to the insular cortex 24 h after surgery. These alterations were consistently confirmed by CB{sub 1} immunohistochemical staining. [{sup 11}C]NE40 did not show any significant differences between stroke and sham-operated animals, although staining for CB{sub 2} revealed minor immunoreactivity at 1 and 2 weeks after stroke in this model. Both CB{sub 1} {sup +} and CB{sub 2} {sup +} cells showed minor immunoreactivity for CD68. Time-dependent and regionally strongly increased CB{sub 1}, but not CB{sub 2}, binding are early consequences of photothrombotic stroke. Pharmacological interventions should primarily aim at CB{sub 1} signalling as the role of CB{sub 2} seems minor in the acute and subacute phases of stroke. (orig.)

  3. Activation of type 1 cannabinoid receptor (CB1R promotes neurogenesis in murine subventricular zone cell cultures.

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    Sara Xapelli

    Full Text Available The endocannabinoid system has been implicated in the modulation of adult neurogenesis. Here, we describe the effect of type 1 cannabinoid receptor (CB1R activation on self-renewal, proliferation and neuronal differentiation in mouse neonatal subventricular zone (SVZ stem/progenitor cell cultures. Expression of CB1R was detected in SVZ-derived immature cells (Nestin-positive, neurons and astrocytes. Stimulation of the CB1R by (R-(+-Methanandamide (R-m-AEA increased self-renewal of SVZ cells, as assessed by counting the number of secondary neurospheres and the number of Sox2+/+ cell pairs, an effect blocked by Notch pathway inhibition. Moreover, R-m-AEA treatment for 48 h, increased proliferation as assessed by BrdU incorporation assay, an effect mediated by activation of MAPK-ERK and AKT pathways. Surprisingly, stimulation of CB1R by R-m-AEA also promoted neuronal differentiation (without affecting glial differentiation, at 7 days, as shown by counting the number of NeuN-positive neurons in the cultures. Moreover, by monitoring intracellular calcium concentrations ([Ca(2+]i in single cells following KCl and histamine stimuli, a method that allows the functional evaluation of neuronal differentiation, we observed an increase in neuronal-like cells. This proneurogenic effect was blocked when SVZ cells were co-incubated with R-m-AEA and the CB1R antagonist AM 251, for 7 days, thus indicating that this effect involves CB1R activation. In accordance with an effect on neuronal differentiation and maturation, R-m-AEA also increased neurite growth, as evaluated by quantifying and measuring the number of MAP2-positive processes. Taken together, these results demonstrate that CB1R activation induces proliferation, self-renewal and neuronal differentiation from mouse neonatal SVZ cell cultures.

  4. Cannabinoid type 1 receptor-containing axons innervate NPY/AgRP neurons in the mouse arcuate nucleus

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    Yury M. Morozov

    2017-04-01

    Conclusions: Our immunohistochemical and ultrastructural study demonstrates the morphological substrate for cannabinoid-conducted feeding behavior via retrograde dis-inhibition of hunger-promoting AgRP/NPY neurons.

  5. Positron Emission Tomographic Imaging of the Cannabinoid Type 1 Receptor System with [11C]OMAR ([11C]JHU75528: Improvements in Image Quantification Using Wild-Type and Knockout Mice

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    Raúl Herance

    2011-11-01

    Full Text Available In this study, we assessed the feasibility of using positron emission tomography (PET and the tracer [11C]OMAR ([11C]JHU75528, an analogue of rimonabant, to study the brain cannabinoid type 1 (CB1 receptor system. Wild-type (WT andCB1 knockout (KO animals were imaged at baseline and after pretreatment with blocking doses of rimonabant. Brain uptake in WT animals was higher (50% than in KO animals in baseline conditions. After pretreatment with rimonabant, WT uptake lowered to the level of KO animals. The results of this study support the feasibility of using PET with the radiotracer [11C]JHU75528 to image the brain CB1 receptor system in mice. In addition, this methodology can be used to assess the effect of new drugs in preclinical studies using genetically manipulated animals.

  6. Cannabinoid control of brain bioenergetics: Exploring the subcellular localization of the CB1 receptor

    Science.gov (United States)

    Hebert-Chatelain, Etienne; Reguero, Leire; Puente, Nagore; Lutz, Beat; Chaouloff, Francis; Rossignol, Rodrigue; Piazza, Pier-Vincenzo; Benard, Giovanni; Grandes, Pedro; Marsicano, Giovanni

    2014-01-01

    Brain mitochondrial activity is centrally involved in the central control of energy balance. When studying mitochondrial functions in the brain, however, discrepant results might be obtained, depending on the experimental approaches. For instance, immunostaining experiments and biochemical isolation of organelles expose investigators to risks of false positive and/or false negative results. As an example, the functional presence of cannabinoid type 1 (CB1) receptors on brain mitochondrial membranes (mtCB1) was recently reported and rapidly challenged, claiming that the original observation was likely due to artifact results. Here, we addressed this issue by directly comparing the procedures used in the two studies. Our results show that the use of appropriate controls and quantifications allows detecting mtCB1 receptor with CB1 receptor antibodies, and that, if mitochondrial fractions are enriched and purified, CB1 receptor agonists reliably decrease respiration in brain mitochondria. These data further underline the importance of adapted experimental procedures to study brain mitochondrial functions. PMID:24944910

  7. The presence and distribution of cannabinoid type 1 and 2 receptors in the mandibular gland: The influence of different physical forms of diets on their expression in piglets.

    Science.gov (United States)

    Pirino, C; Cappai, M G; Maranesi, M; Tomassoni, D; Giontella, A; Pinna, W; Boiti, C; Kamphues, J; Dall'Aglio, C

    2017-12-07

    We explored the expression and cell type distribution of cannabinoid receptors type 1 (CB1) and cannabinoid receptors type 2 (CB2) in the mandibular glands of pigs in relation to different physical forms of the diet. Thirty-two crossbred growing pigs (ages 5-6 weeks) were randomly allotted to four experimental groups (eight pigs/group) and fed four different physical types of the same diet for 4 weeks: finely ground pellet (FP), coarsely ground meal (CM), coarsely ground pellet (CP) and coarsely ground extruded (CE) with dMEAN of 0.46, 0.88, 0.84 and 0.66 mm respectively. At the end of the feeding trial, the pigs were euthanized and the mandibular gland was collected after dissection. By immunohistochemistry, positive signals for CB1 were found in the cytoplasm of duct epithelial cells of pigs fed CP, FP and CE diets and in the serous cells of mixed acini in pigs fed the coarser CM diet. Positive signals for CB2 were detected in duct epithelial cells and in neurons of ganglia close to major secretory ducts of all pigs. The differential expression and localization of these receptors in response to variable chewing activity due to the type of diet suggest that endocannabinoids may influence the functional activity of the mandibular gland by modifying qualitative and/or quantitative aspects of salivary secretion. Journal of Animal Physiology and Animal Nutrition © 2017 Blackwell Verlag GmbH.

  8. Cannabinoid Signaling and Neuroinflammatory Diseases: A Melting pot for the Regulation of Brain Immune Responses.

    Science.gov (United States)

    Chiurchiù, Valerio; Leuti, Alessandro; Maccarrone, Mauro

    2015-06-01

    The concept of the central nervous system (CNS) as an immune-privileged site, essentially due to the presence of the blood brain barrier, appears to be overly simplistic. Indeed, within healthy CNS immune activities are permitted and are required for neuronal function and host defense, not only due to the presence of the resident innate immune cells of the brain, but also by virtue of a complex cross-talk of the CNS with peripheral immune cells. Nonetheless, long-standing and persisting neuroinflammatory responses are most often detrimental and characterize several neuroinflammatory diseases, including multiple sclerosis, Alzheimer's disease and amyotrophic lateral sclerosis. A growing body of evidence suggests that Cannabis sativa-derived phytocannabinoids, as well as synthetic cannabinoids, are endowed with significant immunoregulatory and anti-inflammatory properties, both in peripheral tissues and in the CNS, through the activation of cannabinoid receptors. In this review, the immunomodulatory effects of cannabinoid signaling on the most relevant brain immune cells will be discussed. In addition, the impact of cannabinoid regulation on the overall integration of the manifold brain immune responses will also be highlighted, along with the implication of these compounds as potential agents for the management of neuroinflammatory disorders.

  9. Early decrease of type 1 cannabinoid receptor binding and phosphodiesterase 10A activity in vivo in R6/2 Huntington mice.

    Science.gov (United States)

    Ooms, Maarten; Rietjens, Roma; Rangarajan, Janaki Raman; Vunckx, Kathleen; Valdeolivas, Sara; Maes, Frederik; Himmelreich, Uwe; Fernandez-Ruiz, Javier; Bormans, Guy; Van Laere, Koen; Casteels, Cindy

    2014-12-01

    Several lines of evidence imply early alterations in endocannabinoid and phosphodiesterase 10A (PDE10A) signaling in Huntington disease (HD). Using [(18)F]MK-9470 and [(18)F]JNJ42259152 small-animal positron emission tomography (PET), we investigated for the first time cerebral changes in type 1 cannabinoid (CB1) receptor binding and PDE10A levels in vivo in presymptomatic, early symptomatic, and late symptomatic HD (R6/2) mice, in relation to glucose metabolism ([(18)F]FDG PET), brain morphology (magnetic resonance imaging) and motor function. Ten R6/2 and 16 wild-type (WT) mice were investigated at 3 different time points between the age of 4 and 13 weeks. Parametric CB1 receptor and PDE10A images were anatomically standardized to Paxinos space and analyzed voxelwise. Volumetric microMRI imaging was performed to assess HD pathology. In R6/2 mice, CB1 receptor binding was decreased in comparison with WT in a cluster comprising the bilateral caudate-putamen, globus pallidus, and thalamic nucleus at week 5 (-8.1% ± 2.6%, p = 1.7 × 10(-5)). Longitudinal follow-up showed further progressive decline compared with controls in a cluster comprising the bilateral hippocampus, caudate-putamen, globus pallidus, superior colliculus, thalamic nucleus, and cerebellum (late vs. presymptomatic age: -13.7% ± 3.1% for R6/2 and +1.5% ± 4.0% for WT, p = 1.9 × 10(-5)). In R6/2 mice, PDE10A binding potential also decreased over time to reach significance at early and late symptomatic HD (late vs. presymptomatic age: -79.1% ± 1.9% for R6/2 and +2.1% ± 2.7% for WT, p = 1.5 × 10(-4)). The observed changes in CB1 receptor and PDE10A binding were correlated to anomalies exhibited by R6/2 animals in motor function, whereas no correlation was found with magnetic resonance imaging-based striatal volume. Our findings point to early regional dysfunctions in endocannabinoid and PDE10A signaling, involving the caudate-putamen and lateral globus pallidus, which may play a role

  10. Enzymatic synthesis of anandamide, an endogenous ligand for the cannabinoid receptor, by brain membranes.

    OpenAIRE

    Devane, W A; Axelrod, J

    1994-01-01

    Anandamide, an endogenous eicosanoid derivative (arachidonoylethanolamide), binds to the cannabinoid receptor, a member of the G protein-coupled superfamily. It also inhibits both adenylate cyclase and N-type calcium channel opening. The enzymatic synthesis of anandamide in bovine brain tissue was examined by incubating brain membranes with [14C]ethanolamine and arachidonic acid. Following incubation and extraction into toluene, a radioactive product was identified which had the same Rf value...

  11. BIASED AGONISM OF THREE DIFFERENT CANNABINOID RECEPTOR AGONISTS IN MOUSE BRAIN CORTEX

    Directory of Open Access Journals (Sweden)

    Rebeca Diez-Alarcia

    2016-11-01

    Full Text Available Cannabinoid receptors are able to couple to different families of G-proteins when activated by an agonist drug. It has been suggested that different intracellular responses may be activated depending on the ligand. The goal of the present study was to characterize the pattern of G protein subunit stimulation triggered by three different cannabinoid ligands, THC, WIN55212-2 and ACEA in mouse brain cortex.Stimulation of the [35S]GTPS binding coupled to specific immunoprecipitation with antibodies against different subtypes of G proteins (Gαi1, Gαi2, Gαi3, Gαo, Gαz, Gαs, Gαq/11, and Gα12/13, in the presence of Δ9-THC, WIN55212-2 and ACEA (submaximal concentration 10 µM was determined by Scintillation Proximity Assay (SPA technique in mouse cortex of wild type, CB1 knock-out, CB2 knock-out and CB1/CB2 double knock-out mice. Results show that, in mouse brain cortex, cannabinoid agonists are able to significantly stimulate not only the classical inhibitory Gαi/o subunits but also other G subunits like Gαz, Gαq/11, and Gα12/13. Moreover, the specific pattern of G protein subunit activation is different depending on the ligand. In conclusion, our results demonstrate that, in mice brain native tissue, different exogenous cannabinoid ligands are able to selectively activate different inhibitory and non-inhibitory Gα protein subtypes, through the activation of CB1 and/or CB2 receptors. Results of the present study may help to understand the specific molecular pathways involved in the pharmacological effects of cannabinoid-derived drugs.

  12. Cannabinoid-induced alterations in brain disposition of drugs of abuse.

    Science.gov (United States)

    Reid, M J; Bornheim, L M

    2001-06-01

    Marijuana contains a complex mixture of compounds including tetrahydrocannabinol (THC), the major psychoactive constituent, and cannabidiol (CBD), a nonpsychoactive constituent. We have shown previously that CBD pretreatment of mice increases brain levels of THC and have now further characterized this effect and determined whether the brain pharmacokinetics of other drugs are also affected. CBD pretreatment of mice (30-60 min) increased brain levels of THC nearly 3-fold, whereas CBD co-administration did not. Because marijuana is often consumed with other drugs, the influence of cannabinoids on the brain levels of several other drugs of abuse was also determined. CBD pretreatment of mice increased brain levels (2- to 4-fold) of subsequently administered cocaine as well as phencyclidine (PCP). Although CBD pretreatment increased blood and brain levels of cocaine comparably, blood levels of PCP were only modestly elevated (up to 50%). Behavioral tests indicated that the CBD-mediated increases in the brain levels of THC, cocaine, and PCP correlated with increased pharmacological responses. Pretreatment with THC instead of CBD could similarly increase brain levels of cocaine, PCP, and CBD, although with a lower potency than CBD. On the other hand, pretreatment of mice with CBD had no effect on the brain levels of several other drugs of abuse including morphine, methadone, or methylenedioxyphenyl-methamphetamine. These findings demonstrate that cannabinoids can increase the brain concentrations and pharmacological actions of several other drugs of abuse, thereby providing a biochemical basis for the common practice of using marijuana concurrently with such drugs.

  13. Diabetes and the brain: Cognitive performance in type 1 and type 2 diabetes mellitus

    NARCIS (Netherlands)

    Brands, A.M.A.

    2007-01-01

    Both type 1 and type 2 diabetes mellitus are associated with altered brain function, a complication referred to as diabetic encephalopathy. The issues surrounding the cognitive and emotional status in chronic, older diabetic patients remain complex. The literature shows contrasting findings and

  14. Ablation of Type-1 IFN Signaling in Hematopoietic Cells Confers Protection Following Traumatic Brain Injury.

    Science.gov (United States)

    Karve, Ila P; Zhang, Moses; Habgood, Mark; Frugier, Tony; Brody, Kate M; Sashindranath, Maithili; Ek, C Joakim; Chappaz, Stephane; Kile, Ben T; Wright, David; Wang, Hong; Johnston, Leigh; Daglas, Maria; Ates, Robert C; Medcalf, Robert L; Taylor, Juliet M; Crack, Peter J

    2016-01-01

    Type-1 interferons (IFNs) are pleiotropic cytokines that signal through the type-1 IFN receptor (IFNAR1). Recent literature has implicated the type-1 IFNs in disorders of the CNS. In this study, we have investigated the role of type-1 IFNs in neuroinflammation following traumatic brain injury (TBI). Using a controlled cortical impact model, TBI was induced in 8- to 10-week-old male C57BL/6J WT and IFNAR1(-/-) mice and brains were excised to study infarct volume, inflammatory mediator release via quantitative PCR analysis and immune cell profile via immunohistochemistry. IFNAR1(-/-) mice displayed smaller infarcts compared with WT mice after TBI. IFNAR1(-/-) mice exhibited an altered anti-inflammatory environment compared with WT mice, with significantly reduced levels of the proinflammatory mediators TNFα, IL-1β and IL-6, an up-regulation of the anti-inflammatory mediator IL-10 and an increased activation of resident and peripheral immune cells after TBI. WT mice injected intravenously with an anti-IFNAR1 blocking monoclonal antibody (MAR1) 1 h before, 30 min after or 30 min and 2 d after TBI displayed significantly improved histological and behavioral outcome. Bone marrow chimeras demonstrated that the hematopoietic cells are a peripheral source of type-1 IFNs that drives neuroinflammation and a worsened TBI outcome. Type-1 IFN mRNA levels were confirmed to be significantly altered in human postmortem TBI brains. Together, these data demonstrate that type-1 IFN signaling is a critical pathway in the progression of neuroinflammation and presents a viable therapeutic target for the treatment of TBI.

  15. Ablation of Type-1 IFN Signaling in Hematopoietic Cells Confers Protection Following Traumatic Brain Injury123

    Science.gov (United States)

    Karve, Ila P.; Zhang, Moses; Habgood, Mark; Frugier, Tony; Brody, Kate M.; Sashindranath, Maithili; Ek, C. Joakim; Kile, Ben T.; Wright, David; Wang, Hong; Johnston, Leigh; Daglas, Maria; Ates, Robert C.; Medcalf, Robert L.; Taylor, Juliet M.

    2016-01-01

    Abstract Type-1 interferons (IFNs) are pleiotropic cytokines that signal through the type-1 IFN receptor (IFNAR1). Recent literature has implicated the type-1 IFNs in disorders of the CNS. In this study, we have investigated the role of type-1 IFNs in neuroinflammation following traumatic brain injury (TBI). Using a controlled cortical impact model, TBI was induced in 8- to 10-week-old male C57BL/6J WT and IFNAR1−/− mice and brains were excised to study infarct volume, inflammatory mediator release via quantitative PCR analysis and immune cell profile via immunohistochemistry. IFNAR1−/− mice displayed smaller infarcts compared with WT mice after TBI. IFNAR1−/− mice exhibited an altered anti-inflammatory environment compared with WT mice, with significantly reduced levels of the proinflammatory mediators TNFα, IL-1β and IL-6, an up-regulation of the anti-inflammatory mediator IL-10 and an increased activation of resident and peripheral immune cells after TBI. WT mice injected intravenously with an anti-IFNAR1 blocking monoclonal antibody (MAR1) 1 h before, 30 min after or 30 min and 2 d after TBI displayed significantly improved histological and behavioral outcome. Bone marrow chimeras demonstrated that the hematopoietic cells are a peripheral source of type-1 IFNs that drives neuroinflammation and a worsened TBI outcome. Type-1 IFN mRNA levels were confirmed to be significantly altered in human postmortem TBI brains. Together, these data demonstrate that type-1 IFN signaling is a critical pathway in the progression of neuroinflammation and presents a viable therapeutic target for the treatment of TBI. PMID:27022620

  16. Pharmacokinetic/pharmaco-dynamic modelling and simulation of the effects of different cannabinoid receptor type 1 antagonists on Δ(9)-tetrahydrocannabinol challenge tests.

    Science.gov (United States)

    Guan, Zheng; Klumpers, Linda E; Oyetayo, Olubukayo-Opeyemi; Heuberger, Jules; van Gerven, Joop M A; Stevens, Jasper

    2016-04-01

    The severe psychiatric side effects of cannabinoid receptor type 1 (CB1 ) antagonists hampered their wide development but this might be overcome by careful management of drug development with pharmacokinetic/pharmacodynamic (PK/PD) analyses. PK/PD models suitable for direct comparison of different CB1 antagonists in Δ(9) -tetrahydrocannabinol (THC) challenge tests in healthy volunteer were constructed. The pharmacokinetic models of THC and four CB1 antagonists were built separately. THC-induced effects on heart rate and the visual analogue scale of feeling high in healthy volunteers and inhibitive effects of CB1 antagonists on THC-induced effects were modelled in PD models linked to the PK models. Simulations were then applied to evaluate the reduction rate of each antagonist on the reversal of the THC-induced effect in a unified simulation scenario. The final PK model of THC and antagonists was a two compartment model. An Emax model and logistic regression model were used for effect measures and the antagonist effect was added in these models in a competitive binding manner. t1/2ke0 ranged from 0.00462 to 63.7 h for heart rate and from 0.964 to 150 h for VAS. IC50 ranged from 6.42 to 202 ng ml(-1) for heart rate and from 12.1 to 376 ng ml(-1) for VAS. Benchmark simulation showed different dose-efficacy profiles of two efficacy measures for each CB1 antagonist. PK/PD modelling and simulation approach was suitable for describing and predicting heart rate and feeling high for CB1 antagonists in THC challenge tests. Direct comparison of four antagonists based on simulated efficacy profiles might be of benefit to guide future studies. © 2015 The British Pharmacological Society.

  17. Augmented inhibition from cannabinoid sensitive interneurons diminishes CA1 output after traumatic brain injury

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    Brian Neal Johnson

    2014-12-01

    Full Text Available The neurological impairments associated with traumatic brain injury include learning and memory deficits and increased risk of seizures. The hippocampus is critically involved in both of these phenomena and highly susceptible to damage by traumatic brain injury. To examine network activity in the hippocampal CA1 region after lateral fluid percussion injury, we used a combination of voltage sensitive dye, field potential and patch clamp recording in mouse hippocampal brain slices. When the stratum radiatum was stimulated in slices from injured mice we found decreased depolarization in stratum radiatum and increased hyperpolarization in stratum oriens, together with a decrease in the percentage of pyramidal neurons firing stimulus-evoked action potentials. Increased hyperpolarization in stratum oriens persisted when glutamatergic transmission was blocked. However, we found no changes in stratum oriens responses when the alveus was stimulated to directly activate stratum oriens. These results suggest that the increased stratum oriens hyperpolarization evoked by stratum radiatum stimulation was mediated by interneurons that have cell bodies and/or axons in stratum radiatum, and form synapses in stratum pyramidale and stratum oriens. A low concentration (100 nM of the synthetic cannabinoid WIN55,212-2,restored CA1 output in slices from injured animals. These findings support the hypothesis that increased GABAergic signaling by cannabinoid sensitive interneurons contributes to the reduced CA1 output following traumatic brain injury.

  18. Brain Connectomics' Modification to Clarify Motor and Nonmotor Features of Myotonic Dystrophy Type 1.

    Science.gov (United States)

    Serra, Laura; Mancini, Matteo; Silvestri, Gabriella; Petrucci, Antonio; Masciullo, Marcella; Spanò, Barbara; Torso, Mario; Mastropasqua, Chiara; Giacanelli, Manlio; Caltagirone, Carlo; Cercignani, Mara; Meola, Giovanni; Bozzali, Marco

    2016-01-01

    The adult form of myotonic dystrophy type 1 (DM1) presents with paradoxical inconsistencies between severity of brain damage, relative preservation of cognition, and failure in everyday life. This study, based on the assessment of brain connectivity and mechanisms of plasticity, aimed at reconciling these conflicting issues. Resting-state functional MRI and graph theoretical methods of analysis were used to assess brain topological features in a large cohort of patients with DM1. Patients, compared to controls, revealed reduced connectivity in a large frontoparietal network that correlated with their isolated impairment in visuospatial reasoning. Despite a global preservation of the topological properties, peculiar patterns of frontal disconnection and increased parietal-cerebellar connectivity were also identified in patients' brains. The balance between loss of connectivity and compensatory mechanisms in different brain networks might explain the paradoxical mismatch between structural brain damage and minimal cognitive deficits observed in these patients. This study provides a comprehensive assessment of brain abnormalities that fit well with both motor and nonmotor clinical features experienced by patients in their everyday life. The current findings suggest that measures of functional connectivity may offer the possibility of characterizing individual patients with the potential to become a clinical tool.

  19. Brain Connectomics’ Modification to Clarify Motor and Nonmotor Features of Myotonic Dystrophy Type 1

    Directory of Open Access Journals (Sweden)

    Laura Serra

    2016-01-01

    Full Text Available The adult form of myotonic dystrophy type 1 (DM1 presents with paradoxical inconsistencies between severity of brain damage, relative preservation of cognition, and failure in everyday life. This study, based on the assessment of brain connectivity and mechanisms of plasticity, aimed at reconciling these conflicting issues. Resting-state functional MRI and graph theoretical methods of analysis were used to assess brain topological features in a large cohort of patients with DM1. Patients, compared to controls, revealed reduced connectivity in a large frontoparietal network that correlated with their isolated impairment in visuospatial reasoning. Despite a global preservation of the topological properties, peculiar patterns of frontal disconnection and increased parietal-cerebellar connectivity were also identified in patients’ brains. The balance between loss of connectivity and compensatory mechanisms in different brain networks might explain the paradoxical mismatch between structural brain damage and minimal cognitive deficits observed in these patients. This study provides a comprehensive assessment of brain abnormalities that fit well with both motor and nonmotor clinical features experienced by patients in their everyday life. The current findings suggest that measures of functional connectivity may offer the possibility of characterizing individual patients with the potential to become a clinical tool.

  20. Lovastatin regulates brain spontaneous low-frequency brain activity in Neurofibromatosis type 1

    NARCIS (Netherlands)

    Chabernaud, C.; Mennes, M.J.J.; Kardel, P.G.; Gaillard, W.D.; Kalbfleisch, M.L.; Vanmeter, J.W.; Packer, R.J.; Milham, M.P.; Castellanos, F.X.; Acosta, M.T.

    2012-01-01

    In the Neurofibromatosis type 1 (NF1) mouse model, lovastatin, used clinically for hypercholesterolemia, improves cognitive dysfunction. While such impairment has been studied in NF1, the neural substrates remain unclear. The aim of this imaging add-on to a Phase 1 open-label trial was to examine

  1. 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.

  2. Novel brain arteriovenous malformation mouse models for type 1 hereditary hemorrhagic telangiectasia.

    Directory of Open Access Journals (Sweden)

    Eun-Jung Choi

    Full Text Available Endoglin (ENG is a causative gene of type 1 hereditary hemorrhagic telangiectasia (HHT1. HHT1 patients have a higher prevalence of brain arteriovenous malformation (AVM than the general population and patients with other HHT subtypes. The pathogenesis of brain AVM in HHT1 patients is currently unknown and no specific medical therapy is available to treat patients. Proper animal models are crucial for identifying the underlying mechanisms for brain AVM development and for testing new therapies. However, creating HHT1 brain AVM models has been quite challenging because of difficulties related to deleting Eng-floxed sequence in Eng(2fl/2fl mice. To create an HHT1 brain AVM mouse model, we used several Cre transgenic mouse lines to delete Eng in different cell-types in Eng(2fl/2fl mice: R26CreER (all cell types after tamoxifen treatment, SM22α-Cre (smooth muscle and endothelial cell and LysM-Cre (lysozyme M-positive macrophage. An adeno-associated viral vector expressing vascular endothelial growth factor (AAV-VEGF was injected into the brain to induce focal angiogenesis. We found that SM22α-Cre-mediated Eng deletion in the embryo caused AVMs in the postnatal brain, spinal cord, and intestines. Induction of Eng deletion in adult mice using R26CreER plus local VEGF stimulation induced the brain AVM phenotype. In both models, Eng-null endothelial cells were detected in the brain AVM lesions, and formed mosaicism with wildtype endothelial cells. However, LysM-Cre-mediated Eng deletion in the embryo did not cause AVM in the postnatal brain even after VEGF stimulation. In this study, we report two novel HHT1 brain AVM models that mimic many phenotypes of human brain AVM and can thus be used for studying brain AVM pathogenesis and testing new therapies. Further, our data indicate that macrophage Eng deletion is insufficient and that endothelial Eng homozygous deletion is required for HHT1 brain AVM development.

  3. Antiaversive Effects of Cannabinoids: Is the Periaqueductal Gray Involved?

    OpenAIRE

    F. S. Guimarães; L. B. Resstel; A. L. Terzian; S. F. Lisboa; A. C. Campos; D. C. Aguiar; F. A. Moreira

    2008-01-01

    Cannabinoids play an important role in activity-dependent changes in synaptic activity and can interfere in several brain functions, including responses to aversive stimuli. The regions responsible for their effects, however, are still unclear. Cannabinoid type 1 (CB1) receptors are widely distributed in the central nervous system and are present in the periaqueductal gray (PAG), a midbrain structure closely involved in responses related to aversive states. Accordingly, exposure to stressful ...

  4. How genetics affects the brain to produce higher-level dysfunctions in myotonic dystrophy type 1.

    Science.gov (United States)

    Serra, Laura; Petrucci, Antonio; Spanò, Barbara; Torso, Mario; Olivito, Giusy; Lispi, Ludovico; Costanzi-Porrini, Sandro; Giulietti, Giovanni; Koch, Giacomo; Giacanelli, Manlio; Caltagirone, Carlo; Cercignani, Mara; Bozzali, Marco

    2015-01-01

    Myotonic dystrophy type 1 (DM1) is a multisystemic disorder dominated by muscular impairment and brain dysfunctions. Although brain damage has previously been demonstrated in DM1, its associations with the genetics and clinical/neuropsychological features of the disease are controversial. This study assessed the differential role of gray matter (GM) and white matter (WM) damage in determining higher-level dysfunctions in DM1. Ten patients with genetically confirmed DM1 and 16 healthy How genetics affects the brain to produce higher-level dysfunctions in myotonic dystrophy type 1 matched controls entered the study. The patients underwent a neuropsychological assessment and quantification of CTG triplet expansion. All the subjects underwent MR scanning at 3T, with studies including T1-weighted volumes and diffusion-weighted images. Voxel-based morphometry and tractbased spatial statistics were used for unbiased quantification of regional GM atrophy and WM integrity. The DM1 patients showed widespread involvement of both tissues. The extent of the damage correlated with CTG triplet expansion and cognition. This study supports the idea that genetic abnormalities in DM1mainly target the WM, but GM involvement is also crucial in determining the clinical characteristics of DM1.

  5. Diffusion tensor MR imaging in neurofibromatosis type 1: expanding the knowledge of microstructural brain abnormalities

    Energy Technology Data Exchange (ETDEWEB)

    Ferraz-Filho, Jose R.L.; Muniz, Marcos P.; Souza, Antonio S. [Medical School in Sao Jose do Rio Preto (FAMERP), Radiology Department, Sao Paulo (Brazil); Rocha, Antonio J. da [School Medical Sciences of the Santa Casa de Sao Paulo, Radiology Department, Sao Paulo (Brazil); Goloni-Bertollo, Eny M.; Pavarino-Bertelli, Erika C. [Center of Research and attendace in Neurofibromatosis (CEPAN) of Medical School in Sao Jose do Rio Preto (FAMERP), Sao Paulo (Brazil)

    2012-04-15

    Neurofibromatosis type 1 (NF1) is a hereditary disease with a dominant autosomal pattern. In children and adolescents, it is frequently associated with the appearance of T2-weighted hyperintensities in the brain's white matter. MRI with diffusion tensor imaging (DTI) is used to detect white matter abnormalities by measuring fractional anisotropy (FA). This study employed DTI to evaluate the relationship between FA patterns and the findings of T2 sequences, with the aim of improving our understanding of anatomical changes and microstructural brain abnormalities in individuals with NF1. Forty-four individuals with NF1 and 20 control subjects were evaluated. The comparative analysis of FA between NF1 and control groups was based on four predetermined anatomical regions of the brain hemispheres (basal ganglia, cerebellum, pons, thalamus) and related the presence or absence of T2-weighted hyperintensities in the brain, which are called unidentified bright objects (UBOs). The FA values between the groups demonstrated statistically significant differences (P {<=} 0.05) for the cerebellum and thalamus in patients with NF1, independent of the occurrence of UBOs. Diffusion tensor MR imaging confirms the influence of UBOs in the decrease of FA values in this series of patients with NF1. Additionally, this technique allows the characterization of microstructural abnormalities even in some brain regions that appear normal in conventional MR sequences. (orig.)

  6. Detection of cannabinoid receptors CB1 and CB2 within basal ganglia output neurons in macaques: changes following experimental parkinsonism

    OpenAIRE

    S. Sierra; Luquin, N. (Natasha); Rico, A.J. (Alberto J.); Gomez-Bautista, V. (V.); Roda, E; Dopeso-Reyes, I G; Vazquez, A.; Martinez-Pinilla, E. (Eva); Labandeira-Garcia, J.L. (José L.); Franco, R.; J.L. Lanciego

    2014-01-01

    Abstract Although type 1 cannabinoid receptors (CB1- Rs) are expressed abundantly throughout the brain, the presence of type 2 cannabinoid receptors (CB2Rs) in neurons is still somewhat controversial. Taking advantage of newly designed CB1R and CB2R mRNA riboprobes, we demonstrate by PCR and in situ hybridization that transcripts for both cannabinoid receptors are present within labeled pallidothalamic-projecting neurons of control and MPTP-treated macaques, whereas th...

  7. Atypical focal non-neoplastic brain changes in neurofibromatosis type 1: mass effect and contrast enhancement

    Energy Technology Data Exchange (ETDEWEB)

    Raininko, R. [Dept. of Oncology, Radiology and Clinical Immunology, Section of Radiology, Uppsala University (Sweden); Thelin, L. [Dept. of Pediatrics, Gaevle County Hospital (Sweden); Eeg-Olofsson, O. [Dept. of Women' s and Children' s Health, Section of Pediatrics, Uppsala University (Sweden)

    2001-07-01

    Abstract Children and young adults with neurofibromatosis type 1 often have small high-signal foci on T2-weighted images of the brain. We describe follow-up of two patients in whom one of the foci had atypical features, commonly regarded as signs of a neoplasm. In the first, one lesion showed temporary contrast enhancement and decreasing mass effect. The second developed an expanding lesion that increased minimally in size over 4.5 year's follow-up. The borderline between neoplastic and non-neoplastic lesions seems to be indistinct. (orig.)

  8. Cannabinoid Receptors CB1 and CB2 Form Functional Heteromers in Brain*

    Science.gov (United States)

    Callén, Lucía; Moreno, Estefanía; Barroso-Chinea, Pedro; Moreno-Delgado, David; Cortés, Antoni; Mallol, Josefa; Casadó, Vicent; Lanciego, José Luis; Franco, Rafael; Lluis, Carmen; Canela, Enric I.; McCormick, Peter J.

    2012-01-01

    Exploring the role of cannabinoid CB2 receptors in the brain, we present evidence of CB2 receptor molecular and functional interaction with cannabinoid CB1 receptors. Using biophysical and biochemical approaches, we discovered that CB2 receptors can form heteromers with CB1 receptors in transfected neuronal cells and in rat brain pineal gland, nucleus accumbens, and globus pallidus. Within CB1-CB2 receptor heteromers expressed in a neuronal cell model, agonist co-activation of CB1 and CB2 receptors resulted in a negative cross-talk in Akt phosphorylation and neurite outgrowth. Moreover, one specific characteristic of CB1-CB2 receptor heteromers consists of both the ability of CB1 receptor antagonists to block the effect of CB2 receptor agonists and, conversely, the ability of CB2 receptor antagonists to block the effect of CB1 receptor agonists, showing a bidirectional cross-antagonism phenomenon. Taken together, these data illuminate the mechanism by which CB2 receptors can negatively modulate CB1 receptor function. PMID:22532560

  9. The anabolic steroid nandrolone alters cannabinoid self-administration and brain CB1 receptor density and function.

    Science.gov (United States)

    Struik, Dicky; Fadda, Paola; Zara, Tamara; Zamberletti, Erica; Rubino, Tiziana; Parolaro, Daniela; Fratta, Walter; Fattore, Liana

    2017-01-01

    Clinical and pre-clinical observations indicate that anabolic-androgenic steroids can induce neurobiological changes that alter the rewarding effects of drugs of abuse. In this study, we investigated the effect of the anabolic steroid nandrolone on the rewarding properties of the cannabinoid CB1 receptor agonist WIN55,212-2 (WIN) in rats. Lister Hooded male rats were treated intramuscularly with nandrolone (15mg/kg) or vehicle for 14 consecutive days, and then allowed to self-administer WIN (12.5μg/kg/infusion) intravenously. After reaching stable drug intake, self-administration behavior was extinguished to examine drug- and cue-induced reinstatement of cannabinoid-seeking behavior. Other behavioral parameters presumed to influence drug-taking and drug-seeking behaviors were examined to gain more insight into the behavioral specificity of nandrolone treatment. Finally, animals were sacrificed for analysis of CB1 receptor density and function in selected brain areas. We found that nandrolone-treated rats self-administered up to 2 times more cannabinoid than vehicle-treated rats, but behaved similarly to control rats when tested for drug- and cue-induced reinstatement of cannabinoid-seeking behavior. Enhanced cannabinoid intake by nandrolone-treated rats was not accompanied by changes in locomotor activity, sensorimotor gating, or memory function. However, our molecular data show that after chronic WIN self-administration nandrolone-treated rats display altered CB1 receptor density and function in selected brain areas. We hypothesize that increased cannabinoid self-administration in nandrolone-treated rats results from a nandrolone-induced decrease in reward function, which rats seem to compensate by voluntarily increasing their cannabinoid intake. Altogether, our findings corroborate the hypothesis that chronic exposure to anabolic-androgenic steroids induces dysfunction of the reward pathway in rats and might represent a potential risk factor for abuse of

  10. Macrostructural brain changes in patients with longstanding type 1 diabetes mellitus - a cortical thickness analysis study

    DEFF Research Database (Denmark)

    Frøkjær, J B; Brock, C; Søfteland, E

    2013-01-01

    Longstanding diabetes mellitus (DM) is associated with the risk of complications affecting the central nervous system. The aims were to study brain volume and cortical thickness in regional brain areas in DM patients and to correlate the findings with relevant clinical data.15 patients...... with longstanding (average 24.6 years) type 1 DM and 20 healthy controls were studied in a 3T magnetic resonance scanner. Using an automated surface based cortical segmentation method, cortical thickness was assessed in anatomical regions including total and lobe-wise grey and white matter volumes. Also...... morphological changes were evaluated.No differences between patients and controls were found in regard to number of white matter lesions (P=0.50), grey and white matter volumes (P=0.25) and overall cortical thickness (P=0.64). Subanalysis revealed exclusively reduced cortical thickness of the postcentral (P=0...

  11. A cannabinoid link between mitochondria and memory.

    Science.gov (United States)

    Hebert-Chatelain, Etienne; Desprez, Tifany; Serrat, Román; Bellocchio, Luigi; Soria-Gomez, Edgar; Busquets-Garcia, Arnau; Pagano Zottola, Antonio Christian; Delamarre, Anna; Cannich, Astrid; Vincent, Peggy; Varilh, Marjorie; Robin, Laurie M; Terral, Geoffrey; García-Fernández, M Dolores; Colavita, Michelangelo; Mazier, Wilfrid; Drago, Filippo; Puente, Nagore; Reguero, Leire; Elezgarai, Izaskun; Dupuy, Jean-William; Cota, Daniela; Lopez-Rodriguez, Maria-Luz; Barreda-Gómez, Gabriel; Massa, Federico; Grandes, Pedro; Bénard, Giovanni; Marsicano, Giovanni

    2016-11-24

    Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP. Acute cannabinoid intoxication induces amnesia in humans and animals, and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB 1 ) can directly alter mitochondrial energetic activity. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established, the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB 1 receptors. Genetic exclusion of CB 1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB 1 receptors signal through intra-mitochondrial Gα i protein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects of cannabinoids. Thus, the G protein-coupled mtCB 1 receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.

  12. Lovastatin regulates brain spontaneous low-frequency brain activity in Neurofibromatosis type 1

    Science.gov (United States)

    Chabernaud, Camille; Mennes, Maarten; Kardel, Peter G.; Gaillard, William D.; Kalbfleisch, M. Layne; VanMeter, John W.; Packer, Roger J.; Milham, Michael P.; Castellanos, Francisco X.; Acosta, Maria T.

    2012-01-01

    In the Neurofibromatosis type 1 (NF1) mouse model, lovastatin, used clinically for hypercholesterolemia, improves cognitive dysfunction. While such impairment has been studied in NF1, the neural substrates remain unclear. The aim of this imaging add-on to a phase-1 open-label trial was to examine the effect of lovastatin on Default Network (DN) resting state functional connectivity (RSFC). Seven children with NF1 (aged 11.9±2.2; 1 female) were treated with lovastatin once daily for 12 weeks. A 7-minute 3-Tesla echo-planar-imaging scan was collected one day before beginning treatment (off-drug) and the last day of treatment (on-drug) while performing a Flanker task. After regressing-out task-associated variance, we used the residual time series as “continuous resting-state data” for RSFC analyses using 11 DN regions of interest. For qualitative comparisons, we included a group of 19 typically developing children (TDC) collected elsewhere. In the on-drug condition, lovastatin increased long-range positive RSFC within DN core regions (i.e., anterior medial prefrontal cortex and posterior cingulate cortex, PCC). In addition, lovastatin produced less diffuse local RSFC in the dorsomedial prefrontal cortex and PCC. The pattern of RSFC observed in the NF1 participants when on-drug closely resembled the RSFC patterns exhibited by the TDC. Lovastatin administration in this open trial regulated anterior-posterior long-range and local RSFC within the DN. These preliminary results are consistent with a role for lovastatin in normalization of developmental processes and with apparent benefits in a mouse NF1 model. PMID:22433254

  13. Brain Abnormalities in Congenital Fibrosis of the Extraocular Muscles Type 1: A Multimodal MRI Imaging Study.

    Science.gov (United States)

    Miao, Wen; Man, Fengyuan; Wu, Shaoqin; Lv, Bin; Wang, Zhenchang; Xian, Junfang; Sabel, Bernhard A; He, Huiguang; Jiao, Yonghong

    2015-01-01

    To explore the possible brain structural and functional alterations in congenital fibrosis of extraocular muscles type 1 (CFEOM1) patients using multimodal MRI imaging. T1-weighted, diffusion tensor images and functional MRI data were obtained from 9 KIF21A positive patients and 19 age- and gender-matched healthy controls. Voxel based morphometry and tract based spatial statistics were applied to the T1-weighted and diffusion tensor images, respectively. Amplitude of low frequency fluctuations and regional homogeneity were used to process the functional MRI data. We then compared these multimodal characteristics between CFEOM1 patients and healthy controls. Compared with healthy controls, CFEOM1 patients demonstrated increased grey matter volume in bilateral frontal orbital cortex and in the right temporal pole. No diffusion indices changes were detected, indicating unaffected white matter microstructure. In addition, from resting state functional MRI data, trend of amplitude of low-frequency fluctuations increases were noted in the right inferior parietal lobe and in the right frontal cortex, and a trend of ReHo increase (pabnormality of extraocular muscles and their innervating nerves. Future studies should consider the possible correlations between brain morphological/functional findings and clinical data, especially pertaining to eye movements, to obtain more precise answers about the role of brain area changes and their functional consequence in CFEOM1.

  14. Characterization of CB1 cannabinoid receptor immunoreactivity in postmortem human brain homogenates.

    Science.gov (United States)

    De Jesús, M López; Sallés, J; Meana, J J; Callado, L F

    2006-06-30

    The CB1 cannabinoid receptor (CB1) is the predominant type of cannabinoid receptor in the CNS, in which it displays a unique anatomical distribution and is present at higher densities than most other known seven transmembrane domain receptors. Nevertheless, as with almost all seven transmembrane domain receptors, the tertiary and quaternary structure of this receptor is still unknown. Studies of CB1 in rat cerebral tissue are scarce, and even less is known regarding the expression of CB1 in the human brain. Thus, the aim of the present work was to characterize CB1 expression in membranes from postmortem human brain using specific antisera raised against this protein. Western blot analysis of P1 and P2 fractions, and crude plasma membrane preparations from the prefrontal cortex showed that CB1 migrated as a 60 kDa monomer under reducing conditions. These data were confirmed by blotting experiments carried out with human U373MG astrocytoma cells as a positive control for CB1 expression and wild-type CHO cells as negative control. In addition, when proteins were solubilized in the absence of dithiothreitol, the anti-human CB1 antiserum detected a new band migrating at around 120 kDa corresponding in size to a putative CB1 dimer. This band was sensitive to reducing agents (50 mM dithiothreitol) and showed sodium dodecylsulphate stability, suggesting the existence of disulfide-linked CB1 dimers in the membrane preparations. Important differences in the anatomical distribution of CB1 were observed with regard to that described previously in monkey and rat; in the human brain, CB1 levels were higher in cortex and caudate than in the cerebellum.

  15. Cognitive performance, psychological well-being, and brain magnetic resonance imaging in older patients with type 1 diabetes.

    NARCIS (Netherlands)

    Brands, A.M.; Kessels, R.P.C.; Hoogma, R.P.L.M.; Henselmans, J.M.L.; Beek-Boter, J.W. van der; Kappelle, L.J.; Haan, E.H.F. de; Biessels, G.J.

    2006-01-01

    Modest cognitive impairment has been reported in young-adult patients with type 1 diabetes. In older patients with type 2 diabetes, cognitive impairments are more pronounced, which might be due to age but also to differential effects of type 1 diabetes and type 2 diabetes on the brain. This study

  16. Abnormal functional brain connectivity and personality traits in myotonic dystrophy type 1.

    Science.gov (United States)

    Serra, Laura; Silvestri, Gabriella; Petrucci, Antonio; Basile, Barbara; Masciullo, Marcella; Makovac, Elena; Torso, Mario; Spanò, Barbara; Mastropasqua, Chiara; Harrison, Neil A; Bianchi, Maria L E; Giacanelli, Manlio; Caltagirone, Carlo; Cercignani, Mara; Bozzali, Marco

    2014-05-01

    Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy observed in adults, is a genetic multisystem disorder affecting several other organs besides skeletal muscle, including the brain. Cognitive and personality abnormalities have been reported; however, no studies have investigated brain functional networks and their relationship with personality traits/disorders in patients with DM1. To use resting-state functional magnetic resonance imaging to assess the potential relationship between personality traits/disorders and changes to functional connectivity within the default mode network (DMN) in patients with DM1. We enrolled 27 patients with genetically confirmed DM1 and 16 matched healthy control individuals. Patients underwent personality assessment using clinical interview and Minnesota Multiphasic Personality Inventory-2 administration; all participants underwent resting-state functional magnetic resonance imaging. Investigations were conducted at the Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Catholic University of Sacred Heart, and Azienda Ospedaliera San Camillo Forlanini. Resting-state functional magnetic resonance imaging. Measures of personality traits in patients and changes in functional connectivity within the DMN in patients and controls. Changes in functional connectivity and atypical personality traits in patients were correlated. We combined results obtained from the Minnesota Multiphasic Personality Inventory-2 and clinical interview to identify a continuum of atypical personality profiles ranging from schizotypal personality traits to paranoid personality disorder within our DM1 patients. We also demonstrated an increase in functional connectivity in the bilateral posterior cingulate and left parietal DMN nodes in DM1 patients compared with controls. Moreover, patients with DM1 showed strong associations between DMN functional connectivity and schizotypal-paranoid traits. Our findings provide novel

  17. Prereproductive stress to female rats alters corticotropin releasing factor type 1 expression in ova and behavior and brain corticotropin releasing factor type 1 expression in offspring.

    Science.gov (United States)

    Zaidan, Hiba; Leshem, Micah; Gaisler-Salomon, Inna

    2013-11-01

    Human and animal studies indicate that vulnerability to stress may be heritable and that changes in germline may mediate some transgenerational effects. Corticotropin releasing factor type 1 (CRF1) is a key component in the stress response. We investigated changes in CRF1 expression in brain and ova of stressed female rats and in the brain of their neonate and adult offspring. Behavioral changes in adulthood were also assessed. Adult female rats underwent chronic unpredictable stress. We extracted mature oocytes and brain regions from a subset of rats and mated the rest 2 weeks following the stress procedure. CRF1 expression was assessed using quantitative reverse-transcription polymerase chain reaction. Tests of anxiety and aversive learning were used to examine behavior of offspring in adulthood. We show that chronic unpredictable stress leads to an increase in CRF1 messenger RNA expression in frontal cortex and mature oocytes. Neonatal offspring of stressed female rats show an increase in brain CRF1 expression. In adulthood, offspring of stressed female rats show sex differences in both CRF1 messenger RNA expression and behavior. Moreover, CRF1 expression patterns in frontal cortex of female offspring depend upon both maternal and individual adverse experience. Our findings demonstrate that stress affects CRF1 expression in brain but also in ova, pointing to a possible mechanism of transgenerational transmission. In offspring, stress-induced changes are evident at birth and are thus unlikely to result from altered maternal nurturance. Finally, brain CRF1 expression in offspring depends upon gender and upon maternal and individual exposure to adverse environment. © 2013 Society of Biological Psychiatry.

  18. Type 1 Diabetes Modifies Brain Activation in Young Patients While Performing Visuospatial Working Memory Tasks

    Directory of Open Access Journals (Sweden)

    Geisa B. Gallardo-Moreno

    2015-01-01

    Full Text Available In recent years, increasing attention has been paid to the effects of Type 1 Diabetes (T1D on cognitive functions. T1D onset usually occurs during childhood, so it is possible that the brain could be affected during neurodevelopment. We selected young patients of normal intelligence with T1D onset during neurodevelopment, no complications from diabetes, and adequate glycemic control. The purpose of this study was to compare the neural BOLD activation pattern in a group of patients with T1D versus healthy control subjects while performing a visuospatial working memory task. Sixteen patients and 16 matched healthy control subjects participated. There was no significant statistical difference in behavioral performance between the groups, but, in accordance with our hypothesis, results showed distinct brain activation patterns. Control subjects presented the expected activations related to the task, whereas the patients had greater activation in the prefrontal inferior cortex, basal ganglia, posterior cerebellum, and substantia nigra. These different patterns could be due to compensation mechanisms that allow them to maintain a behavioral performance similar to that of control subjects.

  19. Unidentified bright objects on brain MRI in children as a diagnostic criterion for neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Lopes Ferraz Filho, Jose R.; Pontes Munis, Marcos; Soares Souza, Antonio; Sanches, Rafael A. [Medical School in Sao Jose do Rio Preto, Imaging Department, Sao Jose do Rio Preto, Sao Paulo (Brazil); Goloni-Bertollo, Eni M.; Pavarino-Bertelli, Erika C. [Center of Research and Attendance in Neurofibromatosis, Sao Paulo (Brazil)

    2008-03-15

    Lesions of the brain denominated as unidentified bright objects (UBOs), which are not included in the diagnostic criteria for neurofibromatosis type 1 (NF1) established by the National Institutes of Health (NIH), have been detected by MRI. The purpose of this study was to investigate the possibility of including the presence of UBOs as a diagnostic criterion for NF1 in children. The study included 88 children between the ages of 2 and 18 years. The case group consisted of 40 children diagnosed with sporadic or familial NF1 according to the criteria established by the NIH. A control group consisted of 48 individuals referred for routine MRI of the brain for other complaints not related to NF1. UBOs were identified in 70% of the NF1 patients and in none of the control group. The sensitivity of the presence of UBOs for the diagnosis of NF1 was 70% (CI 53-83%), with a false-negative rate of 30% (CI 27-47%), a specificity of 100% (CI 86-100%) and a false-positive rate of 0% (CI 0-14%). Faced with the difficulties in diagnosing NF1 in children and the high frequency and specificity of the presence UBOs identified by MRI in our series, we recommend the inclusion of the presence UBOs as a diagnostic criterion for NF1 in children. (orig.)

  20. Brain-derived neurotrophic factor controls cannabinoid CB1 receptor function in the striatum.

    Science.gov (United States)

    De Chiara, Valentina; Angelucci, Francesco; Rossi, Silvia; Musella, Alessandra; Cavasinni, Francesca; Cantarella, Cristina; Mataluni, Giorgia; Sacchetti, Lucia; Napolitano, Francesco; Castelli, Maura; Caltagirone, Carlo; Bernardi, Giorgio; Maccarrone, Mauro; Usiello, Alessandro; Centonze, Diego

    2010-06-16

    The role of brain-derived neurotrophic factor (BDNF) in emotional processes suggests an interaction with the endocannabinoid system. Here, we addressed the functional interplay between BDNF and cannabinoid CB(1) receptors (CB(1)Rs) in the striatum, a brain area in which both BDNF and CB(1)s play a role in the emotional consequences of stress and of rewarding experiences. BDNF potently inhibited CB(1)R function in the striatum, through a mechanism mediated by altered cholesterol metabolism and membrane lipid raft function. The effect of BDNF was restricted to CB(1)Rs controlling GABA-mediated IPSCs (CB(1)R(GABA)), whereas CB(1)Rs modulating glutamate transmission and GABA(B) receptors were not affected. The action of BDNF on CB(1)R(GABA) function was tyrosine kinase dependent and was complete even after receptor sensitization with cocaine or environmental manipulations activating the dopamine (DA)-dependent reward system. In mice lacking one copy of the BDNF gene (BDNF(+/-)), CB(1)R(GABA) responses were potentiated and were preserved from the action of haloperidol, a DA D(2) receptor (D(2)R) antagonist able to fully abolish CB(1)R(GABA) function in rewarded animals. Haloperidol also enhanced BDNF levels in the striatum, suggesting that this neurotrophin may act as a downstream effector of D(2)Rs in the modulation of cannabinoid signaling. Accordingly, 5 d cocaine exposure both reduced striatal BDNF levels and increased CB(1)R(GABA) activity, through a mechanism dependent on D(2)Rs. The present study identifies a novel mechanism of CB(1)R regulation mediated by BDNF and cholesterol metabolism and provides some evidence that DA D(2)R-dependent modulation of striatal CB(1)R activity is mediated by this neurotrophin.

  1. Cannabinoid CB2 Receptors and Fatty Acid Amide Hydrolase Are Selectively Overexpressed in Neuritic Plaque-Associated Glia in Alzheimer's Disease Brains

    National Research Council Canada - National Science Library

    Benito, Cristina; Nunez, Estefania; Tolon, Rosa M; Carrier, Erica J; Rabano, Alberto; Hillard, Cecilia J; Romero, Julian

    2003-01-01

    .... We have studied the status of some of the components of the endocannabinoid system, fatty acid amide hydrolase and cannabinoid CB1 and CB2 receptors, in postmortem brains from patients with Alzheimer's disease...

  2. Magnetization transfer ratio and volumetric analysis of the brain in macrocephalic patients with neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Margariti, Persefoni N.; Katzioti, Frosso G.; Zikou, Anastasia K.; Argyropoulou, Maria I. [University of Ioannina, Department of Radiology, Medical School, Ioannina (Greece); Blekas, Konstantinos [University of Ioannina, Department of Computer Science, Ioannina (Greece); Tzoufi, Meropi [University of Ioannina, Child Health Department, Medical School, Ioannina (Greece)

    2007-02-15

    The purpose of the study was to evaluate brain myelination by measuring the magnetization transfer ratio (MTR) and to measure grey (GMV) and white matter volume (WMV) in macrocephalic children with neurofibromatosis type 1 (NF1). Seven NF1 patients (aged 0.65-16.67 years) and seven age- and gender-matched controls were studied. A three-dimensional (3D) gradient echo sequence with and without magnetization transfer (MT) prepulse was used for MTR assessment. Volume measurements of GM and WM were performed by applying segmentation techniques on T2-weighted turbo spin echo images (T2WI). MTR of unidentified bright objects (UBOs) on T2WI in cerebellar white matter (52.8{+-}3.3), cerebral peduncles (48.5{+-}1.5), hippocampus (52.6{+-}1.1), internal capsule (55.7{+-}0.3), globus pallidus (52.7{+-}3.9), and periventricular white matter (52.6{+-}1.2) was lower than in the corresponding areas of controls (64.6{+-}2.5, 60.8{+-}1.3, 56.4{+-}0.9, 64.7{+-}1.9, 59.2{+-}2.3, 63.6{+-}1.7, respectively; p<0.05). MTR of normal-appearing brain tissue in patients was not significantly different than in controls. Surface area (mm{sup 2}) of the corpus callosum (809.1{+-}62.8), GMV (cm{sup 3}) (850.7{+-}42.9), and white matter volume (WMV) (cm{sup 3}) (785.1{+-}85.2) were greater in patients than in controls (652.5{+-}52.6 mm{sup 2}, 611.2{+-}92.1 cm{sup 3}, 622.5{+-}108.7 cm{sup 3}, respectively; p<0.05). To conclude, macrocephaly in NF1 patients is related to increased GMV and WMV and corpus callosum enlargement. MTR of UBOs is lower than that of normal brain tissue. (orig.)

  3. Kinetic analysis of the cannabinoid-1 receptor PET tracer [{sup 18}F]MK-9470 in human brain

    Energy Technology Data Exchange (ETDEWEB)

    Sanabria-Bohorquez, Sandra Marina; Hamill, Terence G.; Burns, H.D. [Merck Research Laboratories, Imaging, West Point, PA (United States); Goffin, Karolien; Laere, Koen van [University Hospital and K.U. Leuven, Division of Nuclear Medicine, Leuven (Belgium); Lepeleire, Inge de [Merck Research Laboratories, Brussels (Belgium); Bormans, Guy [K.U. Leuven, Laboratory of Radiopharmacy, Leuven (Belgium)

    2010-05-15

    Quantitative imaging of the type 1 cannabinoid receptor (CB1R) opens perspectives for many neurological and psychiatric disorders. We characterized the kinetics and reproducibility of the CB1R tracer [{sup 18}F]MK-9470 in human brain. [{sup 18}F]MK-9470 data were analysed using reversible models and the distribution volume V{sub T} and V{sub ND} k{sub 3} (V{sub ND} k{sub 3} = K{sub 1} k{sub 2}) were estimated. Tracer binding was also evaluated using irreversible kinetics and the irreversible uptake constant K{sub i} and fractional uptake rate (FUR) were estimated. The effect of blood flow on these parameters was evaluated. Additionally, the possibility of determining the tracer plasma kinetics using a reduced number of blood samples was also examined. A reversible two-tissue compartment model using a global k{sub 4} value was necessary to describe brain kinetics. Both V{sub T} and V{sub ND} k{sub 3} were estimated satisfactorily and their test-retest variability was between 10% and 30%. Irreversible methods adequately described brain kinetics and FUR values were equivalent to K{sub i}. The linear relationship between K{sub i} and V{sub ND} k{sub 3} demonstrated that K{sub i} or FUR and thus the simple measure of tracer brain uptake provide CB1R availability information. The test-retest variability of K{sub i} and FUR was <10% and estimates were independent of blood flow. Brain uptake can be used as a receptor availability index, albeit at the expense of potential bias due to between-subject differences in tracer plasma kinetics. [{sup 18}F]MK-9470 specific binding can be accurately determined using FUR values requiring a short scan 90 to 120 min after tracer administration. Our results suggest that [{sup 18}F]MK-9470 plasma kinetics can be assessed using a few venous samples. (orig.)

  4. Cognitive profile and disorders affecting higher brain functions in paediatric patients with neurofibromatosis type 1.

    Science.gov (United States)

    Vaucheret Paz, E; López Ballent, A; Puga, C; García Basalo, M J; Baliarda, F; Ekonen, C; Ilari, R; Agosta, G

    2017-04-18

    Neurofibromatosis type 1 (NF1) is a common neurocutaneous syndrome often associated with specific cognitive deficits that are rarely monitored during follow-up of these patients. The purpose of our study is two-fold. First, we aimed to describe the cognitive profile of patients with NF1 and detect disorders in higher brain functions associated with the disease. Second, we identified the reasons for consultation associated with school performance in these patients. We conducted a descriptive cross-sectional study of 24 paediatric patients (ages 5 to 16) with NF1 who underwent neuropsychological assessment. The most frequent reasons for consultation were attention deficits (58.33%), learning disorders (25%), poor motor coordination (25%), and language impairment (0.8%). Although 96% of the patients displayed impairments in at least one of the assessed areas, only 83.34% of the parents had reported such impairments. Attention-deficit/hyperactivity disorder was present in 58.33% of the patients, whereas 33.33% had nonverbal learning disabilities, 20.83% had expressive language disorder, 8.33% had borderline intellectual functioning, 4.16% had mental retardation, and only 4.16% showed no cognitive impairment. Higher brain functions are frequently impaired in paediatric patients with NF1. Although many parents report such disorders, they can go undetected in some cases. Neuropsychological assessment is recommended for all paediatric patients with NF1 to detect cognitive impairment and provide early, effective rehabilitation treatment. Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  5. Brain positron emission tomography in patients with myotonic dystrophy type 1 and type 2.

    Science.gov (United States)

    Peric, Stojan; Brajkovic, Leposava; Belanovic, Bozidar; Ilic, Vera; Salak-Djokic, Biljana; Basta, Ivana; Rakocevic Stojanovic, Vidosava

    2017-07-15

    To determine regions of reduced brain metabolism in patients with myotonic dystrophy type 1 (DM1) and type 2 (DM2) using 18F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET), and to analyse their potential association with cognitive deficit. Study included 29 patients (16 DM1 and 13 DM2). FDG-PET and detailed neuropsychological testing were performed in both groups. The most common cognitive findings were executive, visuospatial, and naming dysfunction in DM1, and executive and naming dysfunction in DM2. FDG-PET showed the most prominent glucose hypometabolism in prefrontal, temporal, and pericentral regions in both DM1 and DM2 patients, with additional affection of insula and subcortical grey matter in DM2. In DM1 patients, we found association between right frontotemporal hypometabolism and executive dysfunction (pDM2 patients attention deficit was in association with prefrontal, insular, and striatal hypometabolism, as well as right frontotemporal hypometabolism (pDM2 was more common in patients with prefrontal and insular hypometabolism, right parietotemporal and frontotemporal hypometabolism, as well as left striatal hypometabolism (pDM2, but this hypothesis will have to be more strongly supported by larger studies. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Beyond THC: The New Generation of Cannabinoid Designer Drugs

    National Research Council Canada - National Science Library

    Fattore, Liana; Fratta, Walter

    2011-01-01

    Synthetic cannabinoids are functionally similar to delta9-tetrahydrocannabinol (THC), the psychoactive principle of cannabis, and bind to the same cannabinoid receptors in the brain and peripheral organs...

  7. Adolescent brain maturation, the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia.

    Science.gov (United States)

    Bossong, Matthijs G; Niesink, Raymond J M

    2010-11-01

    Cannabis use during adolescence increases the risk of developing psychotic disorders later in life. However, the neurobiological processes underlying this relationship are unknown. This review reports the results of a literature search comprising various neurobiological disciplines, ultimately converging into a model that might explain the neurobiology of cannabis-induced schizophrenia. The article briefly reviews current insights into brain development during adolescence. In particular, the role of the excitatory neurotransmitter glutamate in experience-dependent maturation of specific cortical circuitries is examined. The review also covers recent hypotheses regarding disturbances in strengthening and pruning of synaptic connections in the prefrontal cortex, and the link with latent psychotic disorders. In the present model, cannabis-induced schizophrenia is considered to be a distortion of normal late postnatal brain maturation. Distortion of glutamatergic transmission during critical periods may disturb prefrontal neurocircuitry in specific brain areas. Our model postulates that adolescent exposure to Δ9-tetrahydrocannabinol (THC), the primary psychoactive substance in cannabis, transiently disturbs physiological control of the endogenous cannabinoid system over glutamate and GABA release. As a result, THC may adversely affect adolescent experience-dependent maturation of neural circuitries within prefrontal cortical areas. Depending on dose, exact time window and duration of exposure, this may ultimately lead to the development of psychosis or schizophrenia. The proposed model provides testable hypotheses which can be addressed in future studies, including animal experiments, reanalysis of existing epidemiological data, and prospective epidemiological studies in which the role of the dose-time-effect relationship should be central. Copyright © 2010 Elsevier Ltd. All rights reserved.

  8. Pharmacological and therapeutic secrets of plant and brain (endo)cannabinoids.

    Science.gov (United States)

    Hanus, Lumír Ondrej

    2009-03-01

    Research on the chemistry and pharmacology of cannabinoids and endocannabinoids has reached enormous proportions, with approximately 15,000 articles on Cannabis sativa L. and cannabinoids and over 2,000 articles on endocannabinoids. The present review deals with the history of the Cannabis sativa L. plant, its uses, constituent compounds and their biogeneses, and similarity to compounds from Radula spp. In addition, details of the pharmacology of natural cannabinoids, as well as synthetic agonists and antagonists are presented. Finally, details regarding the pioneering isolation of the endocannabinoid anandamide, as well as the pharmacology and potential therapeutic uses of endocannabinoid congeners are presented. (c) 2008 Wiley Periodicals, Inc.

  9. Ligands that target cannabinoid receptors in the brain: from THC to anandamide and beyond.

    Science.gov (United States)

    Pertwee, Roger G

    2008-06-01

    A major finding--that (-)-trans-Delta(9)-tetrahydrocannabinol (Delta(9)-THC) is largely responsible for the psychotropic effects of cannabis--prompted research in the 1970s and 1980s that led to the discovery that this plant cannabinoid acts through at least two types of cannabinoid receptor, CB(1) and CB(2), and that Delta(9)-THC and other compounds that target either or both of these receptors as agonists or antagonists have important therapeutic applications. It also led to the discovery that mammalian tissues can themselves synthesize and release agonists for cannabinoid receptors, the first of these to be discovered being arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol. These 'endocannabinoids' are released onto their receptors in a manner that appears to maintain homeostasis within the central nervous system and sometimes either to oppose or to mediate or exacerbate the unwanted effects of certain disorders. This review provides an overview of the pharmacology of cannabinoid receptors and their ligands. It also describes actual and potential clinical uses both for cannabinoid receptor agonists and antagonists and for compounds that affect the activation of cannabinoid receptors less directly, for example by inhibiting the enzymatic hydrolysis of endocannabinoids following their release.

  10. Human Immunodeficiency Virus-Type 1 (HIV-1) and the Brain.

    Science.gov (United States)

    Grant, Igor; Heaton, Robert K.

    1990-01-01

    Provides update on what is currently known about neurobehavioral correlates of infection with human immunodeficiency virus-Type 1 (HIV-1), causative agent of acquired immunodeficiency syndrome. Discusses methodological and theoretical issues complicating interpretation of existing data and suggests strategies for future research in this area. (NB)

  11. Cannabinoid receptor binding and messenger RNA expression in human brain: an in vitro receptor autoradiography and in situ hybridization histochemistry study of normal aged and Alzheimer's brains.

    Science.gov (United States)

    Westlake, T M; Howlett, A C; Bonner, T I; Matsuda, L A; Herkenham, M

    1994-12-01

    The distribution and density of cannabinoid receptor binding and messenger RNA expression in aged human brain were examined in several forebrain and basal ganglia structures. In vitro binding of [3H]CP-55,940, a synthetic cannabinoid, was examined by autoradiography in fresh frozen brain sections from normal aged humans (n = 3), patients who died with Alzheimer's disease (n = 5) and patients who died with other forms of cortical pathology (n = 5). In the structures examined--hippocampal formation, neocortex, basal ganglia and parts of the brainstem--receptor binding showed a characteristic pattern of high densities in the dentate gyrus molecular layer, globus pallidus and substantia nigra pars reticulata, moderate densities in the hippocampus, neocortex, amygdala and striatum, and low densities in the white matter and brainstem. In situ hybridization histochemistry of human cannabinoid receptor, a ribonucleotide probe for the human cannabinoid receptor messenger RNA, showed a pattern of extremely dense transcript levels in subpopulations of cells in the hippocampus and cortex, moderate levels in hippocampal pyramidal neurons and neurons of the striatum, amygdala and hypothalamus, and no signal over dentate gyrus granule cells and most of the cells of the thalamus and upper brainstem, including the substantia nigra. In Alzheimer's brains, compared to normal brains, [3H]CP-55,940 binding was reduced by 37-45% in all of the subfields of the hippocampal formation and by 49% in the caudate. Lesser reductions (20-24%) occurred in the substantia nigra and globus pallidus, internal segment. Other neocortical and basal ganglia structures were not different from control levels. Levels of messenger RNA expression did not differ between Alzheimer's and control brains, but there were regionally discrete statistically significant losses of the intensely expressing cells in the hippocampus. The reductions in binding did not correlate with or localize to areas showing

  12. Cannabinoid modulation of fear extinction brain circuits: a novel target to advance anxiety treatment.

    Science.gov (United States)

    Rabinak, Christine A; Phan, K Luan

    2014-01-01

    Anxiety disorders, such as post-traumatic stress (PTSD), panic, and phobic disorders, can be conceptualized as a failure to inhibit inappropriate fear responses. A common, effective treatment strategy involves repeated presentations to the feared cue without any danger (extinction). However, extinction learning has a number of important limitations, and enhancing its effects, generalizability and durability via cognitive enhancers may improve its therapeutic impact. In this review we focus specifically on the role of the cannabinoid system in fear extinction learning and its retention. We address the following questions: What are the neural circuits mediating fear extinction?; Can we make fear extinction more effective?; Can cannabinoids facilitate fear extinction in humans?; How might the cannabinoid system effect fear extinction? Collectively, translational evidence suggest that enhancing cannabinoid transmission may facilitate extinction learning and its recall, and that the cannabinoid system is a potential pharmacological target for improving the active learning that occurs during exposure-based behavioral treatments prompting future research in terms of mechanisms research, novel treatment approaches ('cognitive enhancers'), and pharmacotherapeutic drug discovery.

  13. {sup 1}H MR spectroscopy evidence for the varied nature of asymptomatic focal brain lesions in neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Jones, A.P. [North Western Medical Physics, Royal Preston Hospital (United Kingdom); Gunawardena, W.J.; Coutinho, C.M.A. [Dept. of Clinical Radiology, Royal Preston Hospital (United Kingdom)

    2001-01-01

    We present the MRI and {sup 1}H MR spectroscopy findings in six patients with neurofibromatosis type 1 (NF1) and asymptomatic focal brain lesions. Variations in imaging appearances were seen, including regression of a previously identified lesion. MR spectra for the lesions and corresponding areas of normal brain show significant differences. The lesions could be separated into two groups, one demonstrating only slight metabolite ratio changes relative to normal brain and the other group showing significant increase in choline and decrease in N-acetyl aspartate. The lesion which regressed fell into the second group. These findings are not in agreement with those previously reported and provide evidence for the varied and possibly transient nature of these asymptomatic lesions. The spectroscopy findings suggest that metabolite changes may be present without visible changes on MRI. (orig.)

  14. Presumptive brain influx of large neutral amino acids and the effect of phenylalanine supplementation in patients with Tyrosinemia type 1.

    Science.gov (United States)

    van Ginkel, Willem G; van Vliet, Danique; Burgerhof, Johannes G M; de Blaauw, Pim; Rubio Gozalbo, M Estela; Heiner-Fokkema, M Rebecca; van Spronsen, Francjan J

    2017-01-01

    Hereditary Tyrosinemia type 1 (HT1) is a rare metabolic disease caused by a defect in the tyrosine degradation pathway. Current treatment consists of 2-(2-nitro-4-trifluoromethylbenoyl)-1,3-cyclohexanedione (NTBC) and a tyrosine and phenylalanine restricted diet. Recently, neuropsychological deficits have been seen in HT1 patients. These deficits are possibly associated with low blood phenylalanine concentrations and/or high blood tyrosine concentrations. Therefore, the aim of the present study was threefold. Firstly, we aimed to calculate how the plasma amino acid profile in HT1 patients may influence the presumptive brain influx of all large neutral amino acids (LNAA). Secondly, we aimed to investigate the effect of phenylalanine supplementation on presumptive brain phenylalanine and tyrosine influx. Thirdly, we aimed to theoretically determine minimal target plasma phenylalanine concentrations in HT1 patient to ensure adequate presumptive brain phenylalanine influx. Data of plasma LNAA concentrations were obtained. In total, 239 samples of 9 HT1 children, treated with NTBC, diet, and partly with phenylalanine supplementation were collected together with 596 samples of independent control children. Presumptive brain influx of all LNAA was calculated, using Michaelis-Menten parameters (Km) and Vmax-values obtained from earlier articles. In HT1 patients, plasma concentrations and presumptive brain influx of tyrosine were higher. However, plasma and especially brain influx of phenylalanine were lower in HT1 patients. Phenylalanine supplementation did not only tend to increase plasma phenylalanine concentrations, but also presumptive brain phenylalanine influx, despite increased plasma tyrosine concentrations. However, to ensure sufficient brain phenylalanine influx in HT1 patients, minimal plasma phenylalanine concentrations may need to be higher than considered thus far. This study clearly suggests a role for disturbed brain LNAA biochemistry, which is not well

  15. Glycosphingolipid studies of visceral tissues and brain from type 1 Gaucher disease variants.

    Science.gov (United States)

    Nilsson, O; Grabowski, G A; Ludman, M D; Desnick, R J; Svennerholm, L

    1985-05-01

    Glucosylceramide and glucosylsphingosine isolated from spleen, liver and brain were quantitated and characterized in two unrelated patients with Gaucher disease, neither of whom had clinical or neuropathologic evidence of neuronal involvement. Visceral glucosylceramide accumulation did not differ in the two patients. Hepatic glucosylsphingosine content was 2-fold greater in a young severely affected 3-year-old American Black patient compared to that in a 56-year-old Ashkenazi Jewish patient. In contrast, significant differences in glycosphingolipid content and composition were observed in the brains of these two cases. Cerebral and cerebellar cortical glucosylceramide accumulated to a greater extent (3-fold) in the severely affected 3-year-old patient compared to that in the older case. The compositions of the acyl and sphingosyl base residues of glucosylceramide in the cerebral and cerebellar cortices from the Ashkenazi Jewish patient were similar to those in normal individuals. In comparison, the gray matter glucosylceramide in the severely affected patient had increased percentages of stearic acid (18:0) and eicosasphingenine (d20:1), suggesting that the accumulated substrate was derived from the brain ganglioside pool. Glucosylsphingosine was found in large amounts only in cerebral and cerebellar cortices from the severely affected patient. The glycolipid content and composition in this patient was similar to that found in the Norrbottnian (Type 3) form of Gaucher disease. The differences in glucosylceramide acyl and sphingosyl base composition in gray matter from the severely affected patient and that in the Ashkenazi Jewish patient suggested that the accumulated substrates were metabolized differently by the residual enzymes in each case.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. THE STUDY OF THE BRAIN IN A PATIENT WITH TYPE 1 DIABETES MELLITUS USING TECHNIQUES OF MAGNETIC RESONANCE IMAGING

    Directory of Open Access Journals (Sweden)

    Yu. G. Samoylova

    2015-01-01

    Full Text Available Type 1 diabetes mellitus (T1DM is now widely distributed worldwide and in theRussian Federation, it is an important medical and social problem in connection with the development of serious, disabling complications. Some of these complications could make changes in the brain which are accompanied by cognitive impairments that decrease quality of life and worsening disease compensation. The diagnosis of these disorders to date, possible by using modern methods of magnetic resonance imaging, which describe not only the morphological changes of the brain, but also the metabolism of nervous tissue. The study of the brain, namely structural and metabolic manifestations of diabetes, is one of the priority problem of modern medical science.The aim of the study was to evaluate dynamics in the different techniques of magnetic resonance imaging in the diagnosis of brain changes in patients with T1DM.Research methods included physical examination, in accordance with the diagnostic algorithm of patients with T1DM, a neurologist consultation, an assessment of cognitive function, analysis of brain changes using standard magnetic resonance imaging and spectroscopy. Statistical processing was performed using software package R-system. This publication presents a clinical case of a patient with T1DM and severe cognitive impairments are associated with changes in the brain, diagnosed using standard magnetic resonance imaging and spectroscopy. The study shows the positive role of correction of carbohydrate metabolism in improving cognitive function in a patient with T1DM.In addition, the process analysis revealed the absence of dynamic changes in the brain of a patient with T1DM according to standard magnetic resonance imaging. This required the use of additional techniques – magnetic resonance spectroscopy, which revealed changes of metabolism in the thalamus N-acetyl aspartate, choline and creatinine.

  17. The Cannabinoid System in the Retrosplenial Cortex Modulates Fear Memory Consolidation, Reconsolidation, and Extinction

    Science.gov (United States)

    Sachser, Ricardo Marcelo; Crestani, Ana Paula; Quillfeldt, Jorge Alberto; e Souza, Tadeu Mello; de Oliveira Alvares, Lucas

    2015-01-01

    Despite the fact that the cannabinoid receptor type 1 (CB1R) plays a pivotal role in emotional memory processing in different regions of the brain, its function in the retrosplenial cortex (RSC) remains unknown. Here, using contextual fear conditioning in rats, we showed that a post-training intra-RSC infusion of the CB1R antagonist AM251…

  18. Time course of opioid and cannabinoid gene transcription alterations induced by repeated administration with fluoxetine in the rat brain.

    Science.gov (United States)

    Oliva, José M; Urigüen, Leyre; Pérez-Rial, Sandra; Manzanares, Jorge

    2005-10-01

    This study examined the time course effects (8, 16 and 31 days) of fluoxetine administration (1 mg/kg, p.o./day) on serotonin transporter (5-HTT), opioid, tyrosine hydroxylase (TH) and cannabinoid CB1 receptor gene expressions in selected regions of the rat brain. Treatment with fluoxetine progressively decreased (35-55%) 5-HTT gene expression in dorsal raphe nucleus at 8, 16 and 31 days. The results revealed that fluoxetine administration decreased (30%) proenkephalin gene expression in nucleus accumbens shell (AcbS) and caudate-putamen (CPu) (31 days) but was without effect in nucleus accumbens core AcbC. A pronounced and time related decrease (25-65%) in prodynorphin gene expression was detected in AcbC, AcbS, CPu, hypothalamic supraoptic and paraventricular nuclei at all time points as well as in proopiomelanocortin gene expression (20-30%) in the arcuate nucleus (ARC) of the hypothalamus. On days 16 and 31, tyrosine hydroxylase gene expression in ventral tegmental area and substantia nigra and cannabinoid CB1 receptor gene expression in the CPu decreased (approximately 45-50% from vehicle). In conclusion, fluoxetine by inhibiting the reuptake of serotonin produced pronounced and time related alterations in genes involved in the regulation of emotional behaviour, suggesting that these neuroplastic changes may be involved, at least in part, in the clinical efficacy of this drug in neuropsychiatric disorders.

  19. Changes in nociceptin/orphanin FQ levels in rat brain regions after acute and chronic cannabinoid treatment in conjunction with the development of antinociceptive tolerance.

    Science.gov (United States)

    Ulugol, Ahmet; Topuz, Ruhan D; Gunduz, Ozgur; Kizilay, Gulnur; Karadag, Hakan C

    2016-12-01

    It has been indicated that acute and chronic morphine administrations enhance nociceptin/orphanin FQ (N/OFQ) levels in the brain, which might play role in the development of tolerance to the antinociceptive effect of morphine. Accordingly, N/OFQ receptor (NOP) antagonists have been shown to prevent the development of antinociceptive tolerance to morphine. Our aim is to observe whether cannabinoids, similarly to opioids, enhance N/OFQ levels in pain-related brain regions and whether antagonism of NOP receptors attenuates the development of tolerance to the antinociceptive effect of cannabinoids. Hot plate and Tail flick tests are used to assess the antinociceptive response in Sprague-Dawley rats. N/OFQ levels are measured in cortex, amygdala, hypothalamus, periaqueductal gray, nucleus raphe magnus and locus coeruleus of rat brains using Western blotting and immunohistochemistry. Within 9 days, animals became completely tolerant to the antinociceptive effect of the cannabinoid agonist WIN 55,212-2 (2, 4, 6 mg/kg, i.p.). Chronic administration of JTC-801, a NOP receptor antagonist, at a dose that exerted no effect on its own (1 mg/kg, i.p.), attenuated development of tolerance to the antinociceptive effect of WIN 55,212-2 (4 mg/kg, i.p.). Western blotting and immunohistochemistry results showed that N/OFQ levels significantly increased in amygdala, periaqueductal gray, nucleus raphe magnus and locus coeruleus of rat brains when WIN 55,212-2 was combined with JTC-801. We hypothesize that, similar to opioids, chronic cannabinoid + NOP antagonist administration may enhance N/OFQ levels and NOP receptor antagonism prevents development of tolerance to cannabinoid antinociception. © 2016 Société Française de Pharmacologie et de Thérapeutique.

  20. Reduced artefacts and improved assessment of hyperintense brain lesions with BLADE MR imaging in patients with neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Kalle, Thekla von; Fabig-Moritz, Claudia; Mueller-Abt, Peter; Zieger, Michael; Winkler, Peter [Department of Paediatric Radiology, Stuttgart (Germany); Blank, Bernd [Haematology and Immunology, Department of Paediatric Oncology, Stuttgart (Germany); Wohlfarth, Katrin [Siemens Healthcare Sector, Erlangen (Germany)

    2009-11-15

    Assessment of small brain lesions in children is often compromised by pulsation, flow or movement artefacts. MRI with a rotating blade-like k-space covering (BLADE, PROPELLER) can compensate for these artefacts. We compared T2-weighted FLAIR images that were acquired with different k-space trajectories (conventional Cartesian and BLADE) to evaluate the impact of BLADE technique on the delineation of small or low-contrast brain lesions. The subject group comprised 26 children with neurofibromatosis type 1 (NF 1), who had been routinely scanned at 1.5 T for optic pathway gliomas with both techniques and who had the typical hyperintense brain lesions seen in NF 1. Four experienced radiologists retrospectively compared unlabelled 4-mm axial images with respect to the presence of artefacts, visibility of lesions, quality of contour and contrast. Both techniques were comparable in depicting hyperintense lesions as small as 2 mm independent of contrast and edge definition. Pulsation and movement artefacts were significantly less common with BLADE k-space trajectory. In 7 of 26 patients (27%), lesions and artefacts were rated as indistinguishable in conventional FLAIR, but not in BLADE FLAIR images. BLADE imaging significantly improved the depiction of lesions in T2-W FLAIR images due to artefact reduction especially in the posterior fossa. (orig.)

  1. Brain metabolite changes on proton magnetic resonance spectroscopy in children with poorly controlled type 1 diabetes mellitus

    Energy Technology Data Exchange (ETDEWEB)

    Sarac, K.; Alkan, A.; Baysal, T. [Inonu University School of Medicine, Department of Radiology, Malatya (Turkey); Akinci, A.; Aslan, M. [Inonu University School of Medicine, Department of Paediatric Endocrinology, Malatya (Turkey); Oezcan, C. [Inonu University School of Medicine, Department of Neurology, Malatya (Turkey)

    2005-07-01

    The metabolite changes in the brains of children with poorly controlled type 1 diabetes mellitus (DM) were investigated by proton magnetic resonance spectroscopy (MRS). A total of 30 subjects and 14 age-matched healthy volunteers underwent single-voxel MRS (TE: 136). The duration of disease, medication, presence of hypoglycaemia episodes and the level of haemoglobin A1C (HbA1C) in the patients were noted. Voxels were placed in the pons, left basal ganglion (LBG) and left posterior parietal white matter (PPWM). N-acetylaspartate (NAA)/creatinine (Cr) and choline (Cho)/Cr ratios were calculated. The average HbA1c level was 11.9{+-}3.4 (8.2-19.4). The average number of keto-acidosis episodes was 1.9{+-}2.2 (0-9) and the average number of daily insulin injections was 2.8{+-}0.97 (2-4). MRS revealed lower NAA/Cr and Cho/Cr ratios in the pons and lower NAA/Cr ratio in the PPWM of patients with DM than in control subjects. No significant correlation was observed between the number of hypoglycaemia episodes and metabolite ratios. Metabolic abnormalities have been observed by MRS in the brain of poorly controlled type 1 DM children. These metabolic changes, in particular in the pons region, include a decrease in NAA, indicating neuronal loss or functional impairment, and likely explanations for a decrease in Cho may be dynamic changes in membrane lipids and/or decreased membrane turnover. (orig.)

  2. Brain and behaviour phenotyping of a mouse model of neurofibromatosis type-1: an MRI/DTI study on social cognition.

    Science.gov (United States)

    Petrella, L I; Cai, Y; Sereno, J V; Gonçalves, S I; Silva, A J; Castelo-Branco, M

    2016-09-01

    Neurofibromatosis type-1 (NF1) is a common neurogenetic disorder and an important cause of intellectual disability. Brain-behaviour associations can be examined in vivo using morphometric magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to study brain structure. Here, we studied structural and behavioural phenotypes in heterozygous Nf1 mice (Nf1(+/-) ) using T2-weighted imaging MRI and DTI, with a focus on social recognition deficits. We found that Nf1(+/-) mice have larger volumes than wild-type (WT) mice in regions of interest involved in social cognition, the prefrontal cortex (PFC) and the caudate-putamen (CPu). Higher diffusivity was found across a distributed network of cortical and subcortical brain regions, within and beyond these regions. Significant differences were observed for the social recognition test. Most importantly, significant structure-function correlations were identified concerning social recognition performance and PFC volumes in Nf1(+/-) mice. Analyses of spatial learning corroborated the previously known deficits in the mutant mice, as corroborated by platform crossings, training quadrant time and average proximity measures. Moreover, linear discriminant analysis of spatial performance identified 2 separate sub-groups in Nf1(+/-) mice. A significant correlation between quadrant time and CPu volumes was found specifically for the sub-group of Nf1(+/-) mice with lower spatial learning performance, suggesting additional evidence for reorganization of this region. We found strong evidence that social and spatial cognition deficits can be associated with PFC/CPu structural changes and reorganization in NF1. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  3. Effect of cannabinoids on the binding of /sup 3/H-(3-MeHis/sup 2/)TRH to rat brain membranes

    Energy Technology Data Exchange (ETDEWEB)

    Matwyshyn, G.A.; Das, S.; Bhargava, H.N.

    1986-03-05

    Cannabinoids, particularly ..delta../sup 9/-THC is known to affect thyroid function. The effect of naturally occurring and synthetic cannabinoids on brain TRH receptors labeled with /sup 3/H-(3-MeHis/sup 2/)TRH(MeTRH) was determined. /sup 3/H-MeTRH bound to brain membranes at a single high affinity binding sites with a B/sub max/ of 48 +/- 2 fmol/mg protein and K/sub d/ of 4.2 +/- 0.4 nM. At 2 nM concentration the amount of /sup 3/H-MeTRH bound specifically was 10.9 +/- 0.6 fmol/mg protein. ..delta.. /sup 9/-THC (10/sup -7/ to 10/sup -3/ M) stimulated the binding of /sup 3/H-MeTRH with maximal stimulation of 60% at 10/sup -4/M concentration. Cannabinol (10/sup -6/-/sup -4/M) also enhanced the binding of /sup 3/H-MeTRH with maximal (58%) stimulation occurring at 10/sup -5/M concentration. Cannabidiol, on the other hand, had no effect on the binding of /sup 3/H-MeTRH up to 10/sup -5/M concentration. However, at 10/sup -4/M concentration of cannabidiol, the binding of /sup 3/H-MeTRH was decreased by 65%. The water soluble synthetic cannabinoids, naboctate, menabitan and SP 111 A inhibited the binding of /sup 3/H-MeTRH only at 10/sup -4/ or 10/sup -3/M concentration. These results suggest differential interaction of cannabinoids with brain TRH receptors.

  4. The decrease of dopamine D2/D3 receptor densities in the putamen and nucleus caudatus goes parallel with maintained levels of CB1 cannabinoid receptors in Parkinson's disease: a preliminary autoradiographic study with the selective dopamine D2/D3 antagonist [3H]raclopride and the novel CB1 inverse agonist [125I]SD7015

    OpenAIRE

    Farkas Szabolcs (1983-) (orvos); Nagy Katalin; Jia, Zhisheng; Harkány Tibor; Palkovits Miklós; Donohue, Sean; Pike, Victor; Halldin, Christer; Máthé Domokos; Csiba László (1952-) (neurológus, pszichiáter); Gulyás Balázs

    2012-01-01

    Cannabinoid type-1 receptors (CB1Rs) modulate synaptic neurotransmission by participating in retrograde signaling in the adult brain. Increasing evidence suggests that cannabinoids through CB1Rs play an important role in the regulation of motor activities in the striatum. In the present study, we used human brain samples to examine the relationship between CB1R and dopamine receptor density in case of Parkinson’s disease (PD).

  5. Delta FosB and AP-1-mediated transcription modulate cannabinoid CB₁ receptor signaling and desensitization in striatal and limbic brain regions.

    Science.gov (United States)

    Lazenka, Matthew F; David, Bethany G; Lichtman, Aron H; Nestler, Eric J; Selley, Dana E; Sim-Selley, Laura J

    2014-10-01

    Repeated Δ(9)-tetrahydrocannabinol (THC) administration produces cannabinoid type 1 receptor (CB₁R) desensitization and downregulation, as well as tolerance to its in vivo pharmacological effects. However, the magnitude of CB₁R desensitization varies by brain region, with CB₁Rs in the striatum and its output nuclei undergoing less desensitization than other regions. A growing body of data indicates that regional differences in CB₁R desensitization are produced, in part, by THC-mediated induction of the stable transcription factor, ΔFosB, and subsequent regulation of CB₁Rs. The purpose of the present study was to determine whether THC-mediated induction of ΔFosB in the striatum inhibits CB₁R desensitization in the striatum and output nuclei. This hypothesis was tested using bitransgenic mice with inducible expression of ΔFosB or ΔcJun, a dominant negative inhibitor of AP-1-mediated transcription, in specific forebrain regions. Mice were treated repeatedly with escalating doses of THC or vehicle for 6.5 days, and CB₁R-mediated G-protein activation was assessed using CP55,940-stimulated [(35)S]GTPγS autoradiography. Overexpression of ΔFosB in striatal dopamine type 1 receptor-containing (D1R) medium spiny neurons (MSNs) attenuated CB₁R desensitization in the substantia nigra, ventral tegmental area (VTA) and amygdala. Expression of ΔcJun in striatal D1R- and dopamine type 2 receptor (D2R)-containing MSNs enhanced CB₁R desensitization in the caudate-putamen and attenuated desensitization in the hippocampus and VTA. THC-mediated in vivo pharmacological effects were then assessed in ΔcJun-expressing mice. Tolerance to THC-mediated hypomotility was enhanced in ΔcJun-expressing mice. These data reveal that ΔFosB and possibly other AP-1 binding proteins regulate CB₁R signaling and adaptation in the striatum and limbic system. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Plasminogen Activator Inhibitor Type 1: A Possible Novel Biomarker of Late Pituitary Dysfunction after Mild Traumatic Brain Injury.

    Science.gov (United States)

    Frendl, Istvan; Katko, Monika; Galgoczi, Erika; Boda, Judit; Zsiros, Noemi; Nemeti, Zoltan; Bereczky, Zsuzsanna; Hudak, Renata; Kappelmayer, Janos; Erdei, Annamaria; Turchanyi, Bela; Nagy, Endre V

    2017-12-01

    More than 80% of traumatic brain injury (TBI) patients suffer from mild TBI (mTBI). However, even mTBI carries the risk of late pituitary dysfunction. A predictive biomarker at the time of injury that could identify patients who subsequently may develop permanent pituitary dysfunction would help to direct patients toward endocrine care. We enrolled 508 TBI patients (406 with mTBI) into our study. Blood samples were collected for identification of predictive biomarkers of late pituitary dysfunction at the time of admission. Follow-up blood samples were collected between 6 and 12 months after the TBI and were evaluated for pituitary function. Of the 406 mTBI patients, 76 were available for follow-up. Pre-existing mild pituitary dysfunction was found for 15 patients based on hormone levels at the time of injury. Of the remaining 61 patients, 10 have shown deficiency in at least one pituitary hormone: 4 had growth hormone deficiency, 3 gonadotropin, 2 thyrotropin, and 1 patient combined gonadotropin and thyrotropin deficiency. Hence, newly developed pituitary hormone deficiency was found in 16% of mTBI patients. Neither the cause of mTBI nor its complications were predictive of late pituitary dysfunction. Of the hemostasis parameters studied, lower plasminogen activator inhibitor type 1 (PAI-1) level at the time of injury was found to be predictive for the development of late pituitary dysfunction; sensitivity, specificity, and positive and negative predictive values were 80%, 67%, 32%, and 94%, respectively. Even mTBI carries a substantial risk of endocrine consequences. Serum PAI-1 level at the time of TBI may serve as a predictive biomarker of late pituitary dysfunction in mTBI patients.

  7. Cannabinoids: Well-Suited Candidates for the Treatment of Perinatal Brain Injury

    Directory of Open Access Journals (Sweden)

    José Martínez-Orgado

    2013-07-01

    Full Text Available Perinatal brain injury can be induced by a number of different damaging events occurring during or shortly after birth, including neonatal asphyxia, neonatal hypoxia-ischemia and stroke-induced focal ischemia. Typical manifestations of these conditions are the presence of glutamate excitoxicity, neuroinflammation and oxidative stress, the combination of which can potentially result in apoptotic-necrotic cell death, generation of brain lesions and long-lasting functional impairment. In spite of the high incidence of perinatal brain injury, the number of clinical interventions available for the treatment of the affected newborn babies is extremely limited. Hence, there is a dramatic need to develop new effective therapies aimed to prevent acute brain damage and enhance the endogenous mechanisms of long-term brain repair. The endocannabinoid system is an endogenous neuromodulatory system involved in the control of multiple central and peripheral functions. An early responder to neuronal injury, the endocannabinoid system has been described as an endogenous neuroprotective system that once activated can prevent glutamate excitotoxicity, intracellular calcium accumulation, activation of cell death pathways, microglia activation, neurovascular reactivity and infiltration of circulating leukocytes across the blood-brain barrier. The modulation of the endocannabinoid system has proven to be an effective neuroprotective strategy to prevent and reduce neonatal brain injury in different animal models and species. Also, the beneficial role of the endocannabinoid system on the control of the endogenous repairing responses (neurogenesis and white matter restoration to neonatal brain injury has been described in independent studies. This review addresses the particular effects of several drugs that modulate the activity of the endocannabinoid system on the progression of different manifestations of perinatal brain injury during both the acute and chronic

  8. A Review of the Therapeutic Antitumor Potential of Cannabinoids.

    Science.gov (United States)

    Bogdanović, Višnja; Mrdjanović, Jasminka; Borišev, Ivana

    2017-11-01

    The aim of this review is to discuss cannabinoids from a preclinical and clinical oncological perspective and provide the audience with a concise, retrospective overview of the most significant findings concerning the potential use of cannabinoids in cancer treatment. A literature survey of medical and scientific databases was conducted with a focus on the biological and medical potential of cannabinoids in cancer treatment. Cannabis sativa is a plant rich in more than 100 types of cannabinoids. Besides exogenous plant cannabinoids, mammalian endocannabinoids and synthetic cannabinoid analogues have been identified. Cannabinoid receptors type 1 (CB1) and type 2 (CB2) have been isolated and characterized from mammalian cells. Through cannabinoid receptor and non-receptor signaling pathways, cannabinoids show specific cytotoxicity against tumor cells, while protecting healthy tissue from apoptosis. The dual antiproliferative and proapoptotic effects of cannabinoids and associated signaling pathways have been investigated on a large panel of cancer cell lines. Cannabinoids also display potent anticancer activity against tumor xenografts, including tumors that express high resistance to standard chemotherapeutics. Few studies have investigated the possible synergistic effects of cannabinoids with standard oncology therapies, and are based on the preclinically confirmed concept of "cannabinoid sensitizers." Also, clinical trials aimed to confirm the antineoplastic activity of cannabinoids have only been evaluated on a small number of subjects, with no consensus conclusions regarding their effectiveness. A large number of cannabinoid compounds have been discovered, developed, and used to study the effects of cannabinoids on cancers in model systems. However, few clinical trials have been conducted on the use of cannabinoids in the treatment of cancers in humans. Further studies require extensive monitoring of the effects of cannabinoids alone or in combination with

  9. 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.

    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...

  10. The role of cannabinoids in adult neurogenesis

    Science.gov (United States)

    Prenderville, Jack A; Kelly, Áine M; Downer, Eric J

    2015-01-01

    The processes underpinning post-developmental neurogenesis in the mammalian brain continue to be defined. Such processes involve the proliferation of neural stem cells and neural progenitor cells (NPCs), neuronal migration, differentiation and integration into a network of functional synapses within the brain. Both intrinsic (cell signalling cascades) and extrinsic (neurotrophins, neurotransmitters, cytokines, hormones) signalling molecules are intimately associated with adult neurogenesis and largely dictate the proliferative activity and differentiation capacity of neural cells. Cannabinoids are a unique class of chemical compounds incorporating plant-derived cannabinoids (the active components of Cannabis sativa), the endogenous cannabinoids and synthetic cannabinoid ligands, and these compounds are becoming increasingly recognized for their roles in neural developmental processes. Indeed, cannabinoids have clear modulatory roles in adult neurogenesis, probably through activation of both CB1 and CB2 receptors. In recent years, a large body of literature has deciphered the signalling networks involved in cannabinoid-mediated regulation of neurogenesis. This timely review summarizes the evidence that the cannabinoid system is intricately associated with neuronal differentiation and maturation of NPCs and highlights intrinsic/extrinsic signalling mechanisms that are cannabinoid targets. Overall, these findings identify the central role of the cannabinoid system in adult neurogenesis in the hippocampus and the lateral ventricles and hence provide insight into the processes underlying post-developmental neurogenesis in the mammalian brain. PMID:25951750

  11. Cannabinoid Receptor Signaling in Central Regulation of Feeding Behavior: A Mini-Review

    Directory of Open Access Journals (Sweden)

    Marco Koch

    2017-05-01

    Full Text Available Cannabinoids are lipid messengers that modulate a variety of physiological processes and modify the generation of specific behaviors. In this regard, the cannabinoid receptor type 1 (CB1 represents the most relevant target molecule of cannabinoids so far. One main function of central CB1 signaling is to maintain whole body energy homeostasis. Thus, cannabinoids functionally interact with classical neurotransmitters in neural networks that control energy metabolism and feeding behavior. The promotion of CB1 signaling can increase appetite and stimulate feeding, while blockade of CB1 suppresses hunger and induces hypophagia. However, in order to treat overeating, pharmacological blockade of CB1 by the inverse agonist rimonabant not only suppressed feeding but also resulted in psychiatric side effects. Therefore, research within the last decade focused on deciphering the underlying cellular and molecular mechanisms of central cannabinoid signaling that control feeding and other behaviors, with the overall aim still being the identification of specific targets to develop safe pharmacological interventions for the treatment of obesity. Today, many studies unraveled the subcellular localization of CB1 and the function of cannabinoids in neurons and glial cells within circumscribed brain regions that represent integral parts of neural circuitries controlling feeding behavior. Here, these novel experimental findings will be summarized and recent advances in understanding the mechanisms of CB1-dependent cannabinoid signaling being relevant for central regulation of feeding behavior will be highlighted. Finally, presumed alternative pathways of cannabinoids that are not driven by CB1 activation but also contributing to control of feeding behavior will be introduced.

  12. The effects of cannabinoids on body temperature and brain catecholamine synthesis.

    Science.gov (United States)

    Bloom, A S; Johnson, K M; Dewey, W L

    1978-04-01

    delta9-Tetrahydrocannabinol, 11-OH-delta9-tetrahydrocannabinol and 9-nor-9beta-OH-hexahydrocannabinol produced hypothermia and increased catecholamine synthesis in mouse brain. The potencies of the effects of these compounds were correlated. Cannabinol and cannabidiol were inactive in both tests.

  13. Distinct Second Extracellular Loop Structures of the Brain Cannabinoid CB1 Receptor: Implication in Ligand Binding and Receptor Function

    Science.gov (United States)

    Shim, Joong-Youn; Rudd, James; Ding, Tomas T.

    2010-01-01

    The G-protein coupled receptor (GPCR) second extracellular loop (E2) is known to play an important role in receptor structure and function. The brain cannabinoid (CB1) receptor is unique in that it lacks the inter-loop E2 disulfide linkage to the transmembrane (TM) helical bundle, a characteristic of many GPCRs. Recent mutation studies of the CB1 receptor, however, suggest the presence of an alternative intra-loop disulfide bond between two E2 Cys residues. Considering the oxidation state of these Cys residues, we determine the molecular structures of the 17-residue E2 in the dithiol form (E2dithiol) and in the disulfide form (E2disulfide) of the CB1 receptor in a fully hydrated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer, employing a combination of simulated annealing (SA) and molecular dynamics (MD) simulation approaches. We characterize the CB1 receptor models with these two E2 forms, CB1(E2dithiol) and CB1(E2disulfide), by analyzing interaction energy, contact number, core crevice and cross-correlation. The results show that the distinct E2 structures interact differently with the TM helical bundle and uniquely modify the TM helical topology, suggesting that E2 plays a critical role in stabilizing receptor structure, regulating ligand binding, and ultimately modulating receptor activation. Further studies on the role of E2 of the CB1 receptor are warranted; particularly comparisons of the ligand-bound form with the present ligand-free form. PMID:21120862

  14. Endogenous cannabinoids and appetite.

    Science.gov (United States)

    Kirkham, T C; Williams, C M

    2001-06-01

    Since pre-history, Cannabis sativa has been exploited for its potent and manifold pharmacological actions. Amongst the most renowned of these actions is a tendency to provoke ravenous eating. The characterization of the psychoactive principals in cannabis (exogenous cannabinoids) and, more recently, the discovery of specific brain cannabinoid receptors and their endogenous ligands (endocannabinoids) has stimulated research into the physiological roles of endocannabinoid systems. In this review, we critically discuss evidence from the literature that describe studies on animals and human subjects to support endocannabinoid involvement in the control of appetite. We describe the hyperphagic actions of the exogenous cannabinoid, Delta9-tetrahydrocannabinol, and the endogenous CB1 ligands, anandamide and 2-arachidonylglycerol, and present evidence to support a specific role of endocannabinoid systems in appetitive processes related to the incentive and reward properties of food. A case is made for more comprehensive and systematic analyses of cannabinoid actions on eating, in the anticipation of improved therapies for disorders of appetite and body weight, and a better understanding of the biopsychological processes underlying hunger.

  15. Biodistribution of [{sup 18}f] SR144385 and [{sup 18}f] SR147963: selective radioligands for positron emission tomographic studies of brain cannabinoid receptors

    Energy Technology Data Exchange (ETDEWEB)

    Mathews, William B. E-mail: bmathews@petscan.nm.jhu.edu; Scheffel, Ursula; Finley, Paige; Ravert, Hayden T.; Frank, Richard A.; Rinaldi-Carmona, Murielle; Barth, Francis; Dannals, Robert F

    2000-11-01

    [{sup 18}F] SR144385 and [{sup 18}F] SR147963 were synthesized in a multistep reaction in which fluorine-18 was introduced by nucleophilic halogen displacement on a bromo precursor. The fluorine-18-labeled intermediate was deprotected and coupled with the appropriate alkyl amine to give the final products. Both radioligands had appropriate regional brain distribution for cannabinoid receptors with a target to nontarget ratio of 1.7 for [{sup 18}F] SR147963 and 2.5 for [{sup 18}F] SR144385 at 60 and 90 min postinjection, respectively. The uptake of both tracers was blocked with a 1 mg/kg dose of SR141716A.

  16. Synthetic Cannabinoids.

    Science.gov (United States)

    Mills, Brooke; Yepes, Andres; Nugent, Kenneth

    2015-07-01

    Synthetic cannabinoids (SCBs), also known under the brand names of "Spice," "K2," "herbal incense," "Cloud 9," "Mojo" and many others, are becoming a large public health concern due not only to their increasing use but also to their unpredictable toxicity and abuse potential. There are many types of SCBs, each having a unique binding affinity for cannabinoid receptors. Although both Δ-tetrahydrocannabinol (THC) and SCBs stimulate the same receptors, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), studies have shown that SCBs are associated with higher rates of toxicity and hospital admissions than is natural cannabis. This is likely due to SCBs being direct agonists of the cannabinoid receptors, whereas THC is a partial agonist. Furthermore, the different chemical structures of SCBs found in Spice or K2 may interact in unpredictable ways to elicit previously unknown, and the commercial products may have unknown contaminants. The largest group of users is men in their 20s who participate in polydrug use. The most common reported toxicities with SCB use based on studies using Texas Poison Control records are tachycardia, agitation and irritability, drowsiness, hallucinations, delusions, hypertension, nausea, confusion, dizziness, vertigo and chest pain. Acute kidney injury has also been strongly associated with SCB use. Treatment mostly involves symptom management and supportive care. More research is needed to identify which contaminants are typically found in synthetic marijuana and to understand the interactions between different SBCs to better predict adverse health outcomes.

  17. Type 1 narcolepsy

    DEFF Research Database (Denmark)

    Degn, Matilda; Kornum, Birgitte Rahbek

    2015-01-01

    Type 1 narcolepsy is a sleep disorder characterized by excessive daytime sleepiness with unintentional sleep attacks and cataplexy. The disorder is caused by a loss of hypocretinergic neurons in the brain. The specific loss of these neurons in narcolepsy is thought to result from an autoimmune...

  18. Antiaversive Effects of Cannabinoids: Is the Periaqueductal Gray Involved?

    Directory of Open Access Journals (Sweden)

    F. S. Guimarães

    2008-12-01

    Full Text Available Cannabinoids play an important role in activity-dependent changes in synaptic activity and can interfere in several brain functions, including responses to aversive stimuli. The regions responsible for their effects, however, are still unclear. Cannabinoid type 1 (CB1 receptors are widely distributed in the central nervous system and are present in the periaqueductal gray (PAG, a midbrain structure closely involved in responses related to aversive states. Accordingly, exposure to stressful stimuli increases endocannabinoid (eCB levels in the PAG, and local administration of CB1 agonists or drugs that facilitate eCB-mediated neurotransmission produces antinociceptive and antiaversive effects. To investigate if these drugs would also interfere in animal models that are sensitive to anxiolytic drugs, we verified the responses to intra-PAG injection of CB1 agonists in rats submitted to the elevated plus-maze, the Vogel punished licking test, or contextual aversive conditioning model. The drugs induced anxiolytic-like effects in all tests. The same was observed with the transient receptor potential vanilloid type 1 (TRPV1 antagonist capsazepine and with cannabidiol, a nonpsychotomimetic phytocannabinoid that produces anxiolytic-like effects after systemic administration in humans and laboratory animals. These results, therefore, suggest that the PAG could be an important site for the antiaversive effects of cannabinoids.

  19. Antiaversive effects of cannabinoids: is the periaqueductal gray involved?

    Science.gov (United States)

    Moreira, F A; Aguiar, D C; Campos, A C; Lisboa, S F; Terzian, A L; Resstel, L B; Guimarães, F S

    2009-01-01

    Cannabinoids play an important role in activity-dependent changes in synaptic activity and can interfere in several brain functions, including responses to aversive stimuli. The regions responsible for their effects, however, are still unclear. Cannabinoid type 1 (CB1) receptors are widely distributed in the central nervous system and are present in the periaqueductal gray (PAG), a midbrain structure closely involved in responses related to aversive states. Accordingly, exposure to stressful stimuli increases endocannabinoid (eCB) levels in the PAG, and local administration of CB1 agonists or drugs that facilitate eCB-mediated neurotransmission produces antinociceptive and antiaversive effects. To investigate if these drugs would also interfere in animal models that are sensitive to anxiolytic drugs, we verified the responses to intra-PAG injection of CB1 agonists in rats submitted to the elevated plus-maze, the Vogel punished licking test, or contextual aversive conditioning model. The drugs induced anxiolytic-like effects in all tests. The same was observed with the transient receptor potential vanilloid type 1 (TRPV1) antagonist capsazepine and with cannabidiol, a nonpsychotomimetic phytocannabinoid that produces anxiolytic-like effects after systemic administration in humans and laboratory animals. These results, therefore, suggest that the PAG could be an important site for the antiaversive effects of cannabinoids.

  20. 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.

  1. The anabolic steroid nandrolone alters cannabinoid self-administration and brain CB1 receptor density and function

    NARCIS (Netherlands)

    Struik, Dicky; Fadda, Paola; Zara, Tamara; Zamberletti, Erica; Rubino, Tiziana; Parolaro, Daniela; Fratta, Walter; Fattore, Liana

    Clinical and pre-clinical observations indicate that anabolic-androgenic steroids can induce neurobiological changes that alter the rewarding effects of drugs of abuse. In this study, we investigated the effect of the anabolic steroid nandrolone on the rewarding properties of the cannabinoid CBI

  2. Cannabinoid inhibits HIV-1 Tat-stimulated adhesion of human monocyte-like cells to extracellular matrix proteins

    Science.gov (United States)

    Raborn, Erinn S.; Jamerson, Melissa; Marciano-Cabral, Francine; Cabral, Guy A.

    2014-01-01

    Aims The aim of this study was to assess the effect of select cannabinoids on human immunodeficiency virus type 1 (HIV-1) transactivating (Tat) protein-enhanced monocyte-like cell adhesion to proteins of the extracellular matrix (ECM). Main Methods Collagen IV, laminin, or an ECM gel were used to construct extracellular matrix layers. Human U937 monocyte-like cells were exposed to Tat in the presence of Δ9-tetrahydrocannabinol (THC), CP55,940, and other select cannabinoids. Cell attachment to ECM proteins was assessed using an adhesion assay. Key findings THC and CP55,940 inhibited Tat-enhanced attachment of U937 cells to ECM proteins in a mode that was linked to the cannabinoid receptor type 2 (CB2R). The cannabinoid treatment of Tat-activated U937 cells was associated with altered β1-integrin expression and distribution of polymerized actin, suggesting a modality by which these cannabinoids inhibited adhesion to the ECM. Significance The blood-brain barrier (BBB) is a complex structure that is composed of cellular elements and an extracellular matrix (ECM). HIV-1 Tat promotes transmigration of monocytes across this barrier, a process that includes interaction with ECM proteins. The results indicate that cannabinoids that activate the CB2R inhibit the ECM adhesion process. Thus, this receptor has potential to serve as a therapeutic agent for ablating neuroinflammation associated with HIV-elicited influx of monocytes across the BBB. PMID:24742657

  3. Inverse agonism of cannabinoid CB1 receptor blocks the adhesion of encephalitogenic T cells in inflamed brain venules by a protein kinase A-dependent mechanism.

    Science.gov (United States)

    Rossi, Barbara; Zenaro, Elena; Angiari, Stefano; Ottoboni, Linda; Bach, Simona; Piccio, Laura; Pietronigro, Enrica C; Scarpini, Elio; Fusco, Mariella; Leon, Alberta; Constantin, Gabriela

    2011-04-01

    It is well known that the cannabinoid system has a significant role in the regulation of the immune responses. Cannabinoid receptors CB1 and CB2 are expressed on T lymphocytes and mediate the immunomodulatory effects of cannabinoids on T cell functions. Here we show that the treatment of proteolipid protein (PLP)139-151-specific T cells with SR141716A, a CB1 inverse agonist and prototype of the diarylpyrazoles series, induced a strong inhibition of firm adhesion in inflamed brain venules in intravital microscopy experiments. In contrast, SR144528, a potent CB2 inverse agonist, had no significant effect on both rolling and arrest of activated T cells. In addition, two analogs of SR141716A and CB1 inverse agonists, AM251 and AM281 inhibited encephalitogenic T cell adhesion suggesting that selective CB1 inverse agonism interfere with lymphocyte trafficking in the CNS. Flow cytometry experiments showed that CB1 inverse agonists have no effect on adhesion molecule expression suggesting that CB1 blockade interferes with signal transduction pathways controlling T cell adhesion in inflamed brain venules. In addition, integrin clustering was not altered after treatment with CB1 inverse agonists suggesting that adhesion blockade is not due to the modulation of integrin valency. Notably, the inhibitory effect exerted by AM251 and AM281 on the adhesive interactions was completely reverted in the presence of protein kinase A (PKA) inhibitor H89, suggesting that cAMP and PKA activation play a key role in the adhesion blockade mediated by CB1 inverse agonists. To further strengthen these results and unveil a previously unknown inhibitory role of cAMP on activated T cell adhesion in vivo in the context of CNS inflammation, we showed that intracellular increase of cAMP induced by treatment with Bt2cAMP, a permeable analog of cAMP, and phosphodiesterase (PDE) inhibitor theophylline efficiently blocked the arrest of encephalitogenic T cells in inflamed brain venules. Our data show

  4. Detection of GAD65 autoantibodies of type-1 diabetes using anti-GAD65-abs reagent produced from bovine brain tissue

    Directory of Open Access Journals (Sweden)

    Djoko W. Soeatmadji

    2005-12-01

    Full Text Available Clinically, type 1 diabetes may presents as type 2 diabetes which sometimes not easily differentiated. Perhaps only autoimmune markers of β-cells destruction could differentiate those two clinical conditions. Due to extremely high cost ( $ 150/test, examination of anti-glutamic acid decarboxylase-65 auto-antibodies (anti-GAD65Abs may not be routinely performed in most, if not all, clinical laboratories in Indonesia. Hence, the production of anti-GAD65 Abs reagent in Indonesia may reduce the cost and improve the quality of diabetes care in Indonesia. We produce reagent to detect anti-GAD65-Abs using bovine brain tissue as source of GAD enzyme in 3 steps. Step 1, isolation, purification of GAD65 from bovine brain tissue and used it as a primary antigen to stimulate the generation of anti-GAD65 antibodies in Wistar rat. Step 2, the purified GAD65 antibodies were than used as a secondary antibody to induce the production of anti-anti-GAD65-antibodies in Wistar rat and rabbit. Step 3. Labeling  anti-anti GAD65-antibodies with alkaline phoshpatase and peroxidase, and detecting anti-GAD65Abs previously detected using commercial kit. The anti-anti-GAD65- antibodies reagent produced in our laboratories  successfully identify anti-GAD65-Abs of type 1 diabetic patients previously detected  with commercial reagent. (Med J Indones 2005; 14: 197-203Keywords: GAD, type-1 Diabetes

  5. Glutaric Acidemia Type 1

    OpenAIRE

    Hedlund, Gary L.; Longo, Nicola; Pasquali, Marzia

    2006-01-01

    Glutaric acidemias comprise different disorders resulting in an increased urinary excretion of glutaric acid. Glutaric acidemia type 1 (GA-1) is an autosomal recessive disorder of lysine, hydroxylysine, and tryptophan metabolism caused by deficiency of glutaryl-CoA dehydrogenase. It results in the accumulation of 3-hydroxyglutaric and glutaric acid. Affected patients can present with brain atrophy and macrocephaly and with acute dystonia secondary to striatal degeneration in most cases trigge...

  6. Preclinical Science Regarding Cannabinoids as Analgesics: An Overview

    Directory of Open Access Journals (Sweden)

    ME Lynch

    2005-01-01

    Full Text Available Modern pharmacology of cannabinoids began in 1964 with the isolation and partial synthesis of delta-9-tetrahydrocannabinol, the main psychoactive agent in herbal cannabis. Since then, potent antinociceptive and antihyperalgesic effects of cannabinoid agonists in animal models of acute and chronic pain; the presence of cannabinoid receptors in pain-processing areas of the brain, spinal cord and periphery; and evidence supporting endogenous modulation of pain systems by cannabinoids has provided support that cannabinoids exhibit significant potential as analgesics. The present article presents an overview of the preclinical science.

  7. Animal models of cannabinoid reward

    Science.gov (United States)

    Panlilio, Leigh V; Justinova, Zuzana; Goldberg, Steven R

    2010-01-01

    The endogenous cannabinoid system is involved in numerous physiological and neuropsychological functions. Medications that target this system hold promise for the treatment of a wide variety of disorders. However, as reward is one of the most prominent of these functions, medications that activate this system must be evaluated for abuse potential. Meanwhile, cannabis is already being used chronically by millions of people, many of whom eventually seek treatment for cannabis dependence. Therefore, there is a need for procedures that can be used to: (i) better understand the mechanisms of cannabinoid reward; (ii) evaluate the abuse potential of new medications; and (iii) evaluate the effectiveness of medications developed for treating cannabis dependence. Animal models of cannabinoid reward provide a means of accomplishing these goals. In this review, we briefly describe and evaluate these models, their advantages and their shortcomings. Special emphasis is placed on intravenous cannabinoid self-administration in squirrel monkeys, a valid, reliable and flexible model that we have developed over the past decade. Although the conditions under which cannabinoid drugs have rewarding effects may be more restricted than with other drugs of abuse such as cocaine and heroin, work with these models indicates that cannabinoid reward involves similar brain mechanisms and produces the same kinds of reward-related behaviour. By continuing to use these animal models as tools in the development of new medications, it should be possible to take advantage of the potential benefits provided by the endocannabinoid system while minimizing its potential for harm. This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x PMID:20590560

  8. Abnormal brain activation in neurofibromatosis type 1: a link between visual processing and the default mode network.

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    Inês R Violante

    Full Text Available Neurofibromatosis type 1 (NF1 is one of the most common single gene disorders affecting the human nervous system with a high incidence of cognitive deficits, particularly visuospatial. Nevertheless, neurophysiological alterations in low-level visual processing that could be relevant to explain the cognitive phenotype are poorly understood. Here we used functional magnetic resonance imaging (fMRI to study early cortical visual pathways in children and adults with NF1. We employed two distinct stimulus types differing in contrast and spatial and temporal frequencies to evoke relatively different activation of the magnocellular (M and parvocellular (P pathways. Hemodynamic responses were investigated in retinotopically-defined regions V1, V2 and V3 and then over the acquired cortical volume. Relative to matched control subjects, patients with NF1 showed deficient activation of the low-level visual cortex to both stimulus types. Importantly, this finding was observed for children and adults with NF1, indicating that low-level visual processing deficits do not ameliorate with age. Moreover, only during M-biased stimulation patients with NF1 failed to deactivate or even activated anterior and posterior midline regions of the default mode network. The observation that the magnocellular visual pathway is impaired in NF1 in early visual processing and is specifically associated with a deficient deactivation of the default mode network may provide a neural explanation for high-order cognitive deficits present in NF1, particularly visuospatial and attentional. A link between magnocellular and default mode network processing may generalize to neuropsychiatric disorders where such deficits have been separately identified.

  9. Male and female rats differ in brain cannabinoid CB1 receptor density and function and in behavioural traits predisposing to drug addiction: effect of ovarian hormones.

    Science.gov (United States)

    Castelli, Maria Paola; Fadda, Paola; Casu, Angelo; Spano, Maria Sabrina; Casti, Alberto; Fratta, Walter; Fattore, Liana

    2014-01-01

    Sex-dependent differences are frequently observed in the biological and behavioural effects of substances of abuse, including cannabis. We recently demonstrated a modulating effect of sex and oestrous cycle on cannabinoid-taking and seeking behaviours. Here, we investigated the influence of sex and oestrogen in the regulation of cannabinoid CB1 receptor density and function, measured by [(3)H]CP55940 and CP55940-stimulated [(35)S]GTPγS binding autoradiography, respectively, in the prefrontal cortex (Cg1 and Cg3), caudate- putamen, nucleus accumbens, amygdala and hippocampus of male and cycling female rats, as well as ovariectomised (OVX) rats and OVX rats primed with oestradiol (10 µg/rat) (OVX+E). CB1 receptor density was significantly lower in the prefrontal cortex and amygdala of cycling females than in males and in OVX females, a difference that appeared to be oestradiol-dependent, because it was no more evident in the OVX+E group. CP55940-stimulated [(35)S]GTPγS binding was significantly higher in the Cg3 of OVX rats relative to cycling and OVX+E rats. No difference was observed in CB1 receptor density or function in any of the other brain areas analysed. Finally, sex and oestradiol were also found to affect motor activity, social behaviour and sensorimotor gating in rats tested in locomotor activity boxes, social interaction and prepulse inhibition tasks, respectively. Our findings provide biochemical evidence for sex- and hormone- dependent differences in the density and function of CB1 receptors in selected brain regions, and in behaviours associated with greater vulnerability to drug addiction, revealing a more vulnerable behavioural phenotype in female than in male rats.

  10. Induction of miR-155 after Brain Injury Promotes Type 1 Interferon and has a Neuroprotective Effect

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    Emily B. Harrison

    2017-07-01

    Full Text Available Traumatic brain injury (TBI produces profound and lasting neuroinflammation that has both beneficial and detrimental effects. Recent evidence has implicated microRNAs (miRNAs in the regulation of inflammation both in the periphery and the CNS. We examined the expression of inflammation associated miRNAs in the context of TBI using a mouse controlled cortical impact (CCI model and found increased levels of miR-21, miR-223 and miR-155 in the hippocampus after CCI. The expression of miR-155 was elevated 9-fold after CCI, an increase confirmed by in situ hybridization (ISH. Interestingly, expression of miR-155 was largely found in neuronal nuclei as evidenced by co-localization with DAPI in MAP2 positive neurons. In miR-155 knock out (KO mice expression of type I interferons IFNα and IFNβ, as well as IFN regulatory factor 1 and IFN-induced chemokine CXCL10 was decreased after TBI relative to wild type (WT mice. Unexpectedly, miR-155 KO mice had increased levels of microglial marker Iba1 and increased neuronal degeneration as measured by fluoro-jade C (FJC staining, suggesting a neuroprotective role for miR-155 in the context of TBI. This work demonstrates a role for miR-155 in regulation of the IFN response and neurodegeneration in the aftermath of TBI. While the presence of neuronal nuclear miRNAs has been described previously, their importance in disease states is relatively unknown. Here, we show evidence of dynamic regulation and pathological function of a nuclear miRNA in TBI.

  11. Cannabinoid Hyperemesis

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    Stephen Sullivan

    2010-01-01

    Full Text Available Cannabinoid hyperemesis syndrome is characterized by chronic, heavy use of cannabis, recurrent episodes of severe nausea and intractable vomiting, and abdominal pain. Temporary relief of symptoms is achieved by taking a hot bath or shower, and resolution of the problem when cannabis use is stopped. Failure to recognize the syndrome leads to misdiagnoses such as psychogenic vomiting, the cyclic vomiting syndrome, an eating disorder or ‘drug-seeking behaviour’, and may lead to extensive, expensive and unproductive investigations, psychiatric referrals and ineffective treatments. Other than stopping cannabis use, there is no proven treatment. Why a substance known for its antiemetic properties should cause such a syndrome is unknown.

  12. Therapeutic potential of cannabinoid-based drugs.

    Science.gov (United States)

    Klein, Thomas W; Newton, Catherine A

    2007-01-01

    Cannabinoid-based drugs modeled on cannabinoids originally isolated from marijuana are now known to significantly impact the functioning of the endocannabinoid system of mammals. This system operates not only in the brain but also in organs and tissues in the periphery including the immune system. Natural and synthetic cannabinoids are tricyclic terpenes, whereas the endogenous physiological ligands are eicosanoids. Several receptors for these compounds have been extensively described, CB1 and CB2, and are G protein-coupled receptors; however, cannabinoid-based drugs are also demonstrated to function independently of these receptors. Cannabinoids regulate many physiological functions and their impact on immunity is generally antiinflammatory as powerful modulators of the cytokine cascade. This anti-inflammatory potency has led to the testing of these drugs in chronic inflammatory laboratory paradigms and even in some human diseases. Psychoactive and nonpsychoactive cannabinoid-based drugs such as Delta9-tetrahydrocannabinol, cannabidiol, HU-211, and ajulemic acid have been tested and found moderately effective in clinical trials of multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain. Furthermore, although clinical trials are not yet reported, preclinical data with cannabinoid-based drugs suggest efficacy in other inflammatory diseases such as inflammatory bowel disease, Alzheimer's disease, atherosclerosis, and osteoporosis.

  13. Preparation of iodine-123 labeled AM251: a potential SPECT radioligand for the brain cannabinoid CB1 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Lan, Ruoxi; Makriyannis, Alexandros [Connecticut Univ., Molecular and Cell Biology Dept., Storrs, CT (United States); Gatley, S.J. [Brookhaven National Lab., Medical Dept., Upton, NY (United States)

    1996-10-01

    We report the synthesis and labeling with iodine-123 of N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251). This compound is an analog of the recently described cannabinoid receptor antagonist, SR141716A, in which a 4-chlorophenyl group is replaced by 4-iodophenyl. Labeling in good yield (62%) and radiochemical purity (> 95%), and high specific activity (> 2500 Ci/mmol) was achieved by an iododestannylation reaction using the tributyltin precursor, no carrier added I-123 iodide, and chloramine-T. (author).

  14. Signalling through the Type 1 Insulin-Like Growth Factor Receptor (IGF1R Interacts with Canonical Wnt Signalling to Promote Neural Proliferation in Developing Brain

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    Qichen Hu

    2012-05-01

    Full Text Available Signalling through the IGF1R [type 1 IGF (insulin-like growth factor receptor] and canonical Wnt signalling are two signalling pathways that play critical roles in regulating neural cell generation and growth. To determine whether the signalling through the IGF1R can interact with the canonical Wnt signalling pathway in neural cells in vivo, we studied mutant mice with altered IGF signalling. We found that in mice with blunted IGF1R expression specifically in nestin-expressing neural cells (IGF1RNestin–KO mice the abundance of neural β-catenin was significantly reduced. Blunting IGF1R expression also markedly decreased: (i the activity of a LacZ (β-galactosidase reporter transgene that responds to Wnt nuclear signalling (LacZTCF reporter transgene and (ii the number of proliferating neural precursors. In contrast, overexpressing IGF-I (insulin-like growth factor I in brain markedly increased the activity of the LacZTCF reporter transgene. Consistently, IGF-I treatment also markedly increased the activity of the LacZTCF reporter transgene in embryonic neuron cultures that are derived from LacZTCF Tg (transgenic mice. Importantly, increasing the abundance of β-catenin in IGF1RNestin–KO embryonic brains by suppressing the activity of GSK3β (glycogen synthase kinase-3β significantly alleviated the phenotypic changes induced by IGF1R deficiency. These phenotypic changes includes: (i retarded brain growth, (ii reduced precursor proliferation and (iii decreased neuronal number. Our current data, consistent with our previous study of cultured oligodendrocytes, strongly support the concept that IGF signalling interacts with canonical Wnt signalling in the developing brain to promote neural proliferation. The interaction of IGF and canonical Wnt signalling plays an important role in normal brain development by promoting neural precursor proliferation.

  15. The Pharmacologic and Clinical Effects of Illicit Synthetic Cannabinoids.

    Science.gov (United States)

    White, C Michael

    2017-03-01

    This article presents information on illicitly used synthetic cannabinoids. Synthetic cannabinoids are structurally heterogeneous and commonly used drugs of abuse that act as full agonists of the cannabinoid type-1 receptor but have a variety of additional pharmacologic effects. There are numerous cases of patient harm and death in the United States, Europe, and Australia with many psychological, neurological, cardiovascular, pulmonary, and renal adverse events. Although most users prefer using cannabis, there are convenience, legal, and cost reasons driving the utilization of synthetic cannabinoids. Clinicians should be aware of pharmacologic and clinical similarities and differences between synthetic cannabinoid and cannabis use, the limited ability to detect synthetic cannabinoids in the urine or serum, and guidance to treat adverse events. © 2016, The American College of Clinical Pharmacology.

  16. Markers of immune-mediated inflammation in the brains of young adults and adolescents with type 1 diabetes and fatal diabetic ketoacidosis. Is there a difference?

    Science.gov (United States)

    Hoffman, William H; Artlett, Carol M; Boodhoo, Dallas; Gilliland, Mary G F; Ortiz, Luis; Mulder, Dries; Tjan, David H T; Martin, Alvaro; Tatomir, Alexandru; Rus, Horea

    2017-06-01

    Due to the limited data on diabetic ketoacidosis and brain edema (DKA/BE) in children/adolescents and the lack of recent data on adults with type 1 diabetes (T1D), we addressed the question of whether neuroinflammation was present in the fatal DKA of adults. We performed immunohistochemistry (IHC) studies on the brains of two young adults with T1D and fatal DKA and compared them with two teenagers with poorly controlled diabetes and fatal DKA. C5b-9, the membrane attack complex (MAC) had significantly greater deposits in the grey and white matter of the teenagers than the young adults (p=0.03). CD59, a MAC assembly inhibitory protein was absent, possibly suppressed by the hyperglycemia in the teenagers but was expressed in the young adults despite comparable average levels of hyperglycemia. The receptor for advanced glycation end products (RAGE) had an average expression in the young adults significantly greater than in the teenagers (p=0.02). The autophagy marker Light Chain 3 (LC3) A/B was the predominant form of programmed cell death (PCD) in the teenage brains. The young adults had high expressions of both LC3A/B and TUNEL, an apoptotic cell marker for DNA fragmentation. BE was present in the newly diagnosed young adult with hyperglycemic hyperosmolar DKA and also in the two teenagers. Our data indicate that significant differences in neuroinflammatory components, initiated by the dysregulation of DKA and interrelated metabolic and immunologic milieu, are likely present in the brains of fatal DKA of teenagers when compared with young adults. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Characterization of the intrinsic activity for a novel class of cannabinoid receptor ligands: Indole quinuclidine analogs.

    Science.gov (United States)

    Franks, Lirit N; Ford, Benjamin M; Madadi, Nikhil R; Penthala, Narsimha R; Crooks, Peter A; Prather, Paul L

    2014-08-15

    Our laboratory recently reported that a group of novel indole quinuclidine analogs bind with nanomolar affinity to cannabinoid type-1 and type-2 receptors. This study characterized the intrinsic activity of these compounds by determining whether they exhibit agonist, antagonist, or inverse agonist activity at cannabinoid type-1 and/or type-2 receptors. Cannabinoid receptors activate Gi/Go-proteins that then proceed to inhibit activity of the downstream intracellular effector adenylyl cyclase. Therefore, intrinsic activity was quantified by measuring the ability of compounds to modulate levels of intracellular cAMP in intact cells. Concerning cannabinoid type-1 receptors endogenously expressed in Neuro2A cells, a single analog exhibited agonist activity, while eight acted as neutral antagonists and two possessed inverse agonist activity. For cannabinoid type-2 receptors stably expressed in CHO cells, all but two analogs acted as agonists; these two exceptions exhibited inverse agonist activity. Confirming specificity at cannabinoid type-1 receptors, modulation of adenylyl cyclase activity by all proposed agonists and inverse agonists was blocked by co-incubation with the neutral cannabinoid type-1 antagonist O-2050. All proposed cannabinoid type-1 receptor antagonists attenuated adenylyl cyclase modulation by cannabinoid agonist CP-55,940. Specificity at cannabinoid type-2 receptors was confirmed by failure of all compounds to modulate adenylyl cyclase activity in CHO cells devoid of cannabinoid type-2 receptors. Further characterization of select analogs demonstrated concentration-dependent modulation of adenylyl cyclase activity with potencies similar to their respective affinities for cannabinoid receptors. Therefore, indole quinuclidines are a novel structural class of compounds exhibiting high affinity and a range of intrinsic activity at cannabinoid type-1 and type-2 receptors. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Characterization of the intrinsic activity for a novel class of cannabinoid receptor ligands: Indole Quinuclidine analogues

    Science.gov (United States)

    Franks, Lirit N.; Ford, Benjamin M.; Madadi, Nikhil R.; Penthala, Narsimha R.; Crooks, Peter A.; Prather, Paul L.

    2014-01-01

    Our laboratory recently reported that a group of novel indole quinuclidine analogues bind with nanomolar affinity to cannabinoid type-1 and type-2 receptors. This study characterized the intrinsic activity of these compounds by determining whether they exhibit agonist, antagonist, or inverse agonist activity at cannabinoid type-1 and/or type-2 receptors. Cannabinoid receptors activate Gi/Go-proteins that then proceed to inhibit activity of the downstream intracellular effector adenylyl cyclase. Therefore, intrinsic activity was quantified by measuring the ability of compounds to modulate levels of intracellular cAMP in intact cells. Concerning cannabinoid type-1 receptors endogenously expressed in Neuro2A cells, a single analogue exhibited agonist activity, while eight acted as neutral antagonists and two possessed inverse agonist activity. For cannabinoid type-2 receptors stably expressed in CHO cells, all but two analogues acted as agonists; these two exceptions exhibited inverse agonist activity. Confirming specificity at cannabinoid type-1 receptors, modulation of adenylyl cyclase activity by all proposed agonists and inverse agonists was blocked by co-incubation with the neutral cannabinoid type-1 antagonist O-2050. All proposed cannabinoid type-1 receptor antagonists attenuated adenylyl cyclase modulation by cannabinoid agonist CP-55,940. Specificity at cannabinoid type-2 receptors was confirmed by failure of all compounds to modulate adenylyl cyclase activity in CHO cells devoid of cannabinoid type-2 receptors. Further characterization of select analogues demonstrated concentration-dependent modulation of adenylyl cyclase activity with potencies similar to their respective affinities for cannabinoid receptors. Therefore, indole quinuclidines are a novel structural class of compounds exhibiting high affinity and a range of intrinsic activity at cannabinoid type-1 and type-2 receptors. PMID:24858620

  19. Effects of cannabinoid drugs on aversive or rewarding drug-associated memory extinction and reconsolidation.

    Science.gov (United States)

    Stern, Cristina A J; de Carvalho, Cristiane R; Bertoglio, Leandro J; Takahashi, Reinaldo N

    2017-07-17

    Posttraumatic stress and drug use disorders may stem from aberrant memory formation. As the endocannabinoid (eCB) system has a pivotal role in emotional memory processing and related synaptic plasticity, here we seek to review and discuss accumulating evidence on how and where in the brain interventions targeting the eCB system would attenuate outcomes associated with traumatic events and/or drug addiction through memory extinction facilitation or reconsolidation disruption. Currently available data from mouse, rat, monkey and healthy human studies investigating the effects of cannabinoid drugs on extinction and reconsolidation of aversive memories are more consistent than those related to rewarding drug-associated memories. Interventions able to attenuate aversive memories by extinction facilitation or reconsolidation disruption have boosted the anandamide-induced activation of cannabinoid type-1 (CB1) receptors. A still limited number of studies report that CB1 receptor activation could also be effective in facilitating the extinction or disrupting the reconsolidation of rewarding drug-associated memories. The reinstatement of extinguished drug memories (relapse) is reduced by CB1 receptor antagonism. The cannabidiol has shown to be effective in any of the aforementioned cases, albeit its mechanism of action is not fully understood. Brain areas in which cannabinoid drugs induce these effects include the prefrontal cortex, amygdala, hippocampus, and/or nucleus accumbens. The potential role of 2-arachidonoylglycerol (2-AG) and cannabinoid type-2 (CB2) receptors in emotional memory extinction and reconsolidation is currently under investigation. Overall, preclinical data support a closer look into certain cannabinoid drugs owing to their safety and potential therapeutic value against stress-related and drug use disorders. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  20. Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors.

    Science.gov (United States)

    den Boon, Femke S; Chameau, Pascal; Schaafsma-Zhao, Qiluan; van Aken, Willem; Bari, Monica; Oddi, Sergio; Kruse, Chris G; Maccarrone, Mauro; Wadman, Wytse J; Werkman, Taco R

    2012-02-28

    The endocannabinoid (eCB) system is widely expressed throughout the central nervous system (CNS) and the functionality of type-1 cannabinoid receptors in neurons is well documented. In contrast, there is little knowledge about type-2 cannabinoid receptors (CB(2)Rs) in the CNS. Here, we show that CB(2)Rs are located intracellularly in layer II/III pyramidal cells of the rodent medial prefrontal cortex (mPFC) and that their activation results in IP(3)R-dependent opening of Ca(2+)-activated Cl(-) channels. To investigate the functional role of CB(2)R activation, we induced neuronal firing and observed a CB(2)R-mediated reduction in firing frequency. The description of this unique CB(2)R-mediated signaling pathway, controlling neuronal excitability, broadens our knowledge of the influence of the eCB system on brain function.

  1. Type 1 diabetes

    Science.gov (United States)

    Insulin-dependent diabetes; Juvenile onset diabetes; Diabetes - type 1; High blood sugar - type 1 diabetes ... Type 1 diabetes can occur at any age. It is most often diagnosed in children, adolescents, or young adults. Insulin is ...

  2. Synthesis, Biodistribution and In vitro Evaluation of Brain Permeable High Affinity Type 2 Cannabinoid Receptor Agonists [11C]MA2 and [18F]MA3

    Science.gov (United States)

    Ahamed, Muneer; van Veghel, Daisy; Ullmer, Christoph; Van Laere, Koen; Verbruggen, Alfons; Bormans, Guy M.

    2016-01-01

    The type 2 cannabinoid receptor (CB2) is a member of the endocannabinoid system and is known for its important role in (neuro)inflammation. A PET-imaging agent that allows in vivo visualization of CB2 expression may thus allow quantification of neuroinflammation. In this paper, we report the synthesis, radiosynthesis, biodistribution and in vitro evaluation of a carbon-11 ([11C]MA2) and a fluorine-18 ([18F]MA3) labeled analog of a highly potent N-arylamide oxadiazole CB2 agonist (EC50 = 0.015 nM). MA2 and MA3 behaved as potent CB2 agonist (EC50: 3 nM and 0.1 nM, respectively) and their in vitro binding affinity for hCB2 was found to be 87 nM and 0.8 nM, respectively. Also MA3 (substituted with a fluoro ethyl group) was found to have higher binding affinity and EC50 values when compared to the originally reported trifluoromethyl analog 12. [11C]MA2 and [18F]MA3 were successfully synthesized with good radiochemical yield, high radiochemical purity and high specific activity. In mice, both tracers were efficiently cleared from blood and all major organs by the hepatobiliary pathway and importantly these compounds showed high brain uptake. In conclusion, [11C]MA2 and [18F]MA3 are shown to be high potent CB2 agonists with good brain uptake, these favorable characteristics makes them potential PET probes for in vivo imaging of brain CB2 receptors. However, in view of its higher affinity and selectivity, further detailed evaluation of MA3 as a PET tracer for CB2 is warranted. PMID:27713686

  3. Synthesis, biodistribution and in vitro evaluation of brain permeable high affinity type 2 cannabinoid receptor agonists [11C]MA2 and [18F]MA3

    Directory of Open Access Journals (Sweden)

    Muneer Ahamed

    2016-09-01

    Full Text Available Abstract The type 2 cannabinoid receptor (CB2 is a member of the endocannabinoid system and is known for its important role in (neuroinflammation. A PET-imaging agent that allows in vivo visualization of CB2 expression may thus allow quantification of neuroinflammation. In this paper, we report the synthesis, radiosynthesis, biodistribution and in vitro evaluation of a carbon-11 ([11C]MA2 and a fluorine-18 ([18F]MA3 labeled analogue of a highly potent N-arylamide oxadiazole CB2 agonist (EC50 = 0.015 nM. MA2 and MA3 behaved as potent CB2 agonist (EC50: 3 nM and 0.1 nM, respectively and their in vitro binding affinity for hCB2 was found to be 87 nM and 0.8 nM, respectively. Also MA3 (substituted with a fluoro ethyl group was found to have higher binding affinity and EC50 values when compared to the originally reported trifluoromethyl analogue 12. [11C]MA2 and [18F]MA3 were successfully synthesized with good radiochemical yield, high radiochemical purity and high specific activity. In mice, both tracers were efficiently cleared from blood and all major organs by the hepatobiliary pathway and importantly these compounds showed high brain uptake. In conclusion, [11C]MA2 and [18F]MA3 are shown to be high potent CB2 agonists with good brain uptake, these favorable characteristics makes them potential PET probes for in vivo imaging of brain CB2 receptors. However in view of its higher affinity and selectivity, further detailed evaluation of MA3 as a PET tracer for CB2 is warranted.

  4. Focus on cannabinoids and synthetic cannabinoids.

    Science.gov (United States)

    Le Boisselier, R; Alexandre, J; Lelong-Boulouard, V; Debruyne, D

    2017-02-01

    The recent emergence of a multitude of synthetic cannabinoids (SCs) has generated a wealth of new information, suggesting the usefulness of state-of-the-art on lato sensu cannabinoids. By modulating a plurality of neurotransmission pathways, the endocannabinoid system is involved in many physiological processes that are increasingly explored. SCs desired and adverse effects are considered to be more intense than those observed with cannabis smoking, which is partly explained by the full agonist activity and higher affinity for cannabinoid receptors. Neurological and cardiovascular side effects observed after cannabinoid poisoning generally respond to conventional supportive care, but severe outcomes may occur in a minority of cases, mainly observed with SCs. The likelihood of severe abuse and addiction produced by SCs are of concern for the scientific community also interested in the potential therapeutic value of cannabinoids. © 2016 American Society for Clinical Pharmacology and Therapeutics.

  5. Cannabinoids and Pain

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    J Michael Walker

    2001-01-01

    Full Text Available Cannabinoids have been used to treat pain for many centuries. However, only during the past several decades have rigorous scientific methods been applied to understand the mechanisms of cannabinoid action. Cannabinoid receptors were discovered in the late 1980s and have been found to mediate the effects of cannabinoids on the nervous system. Several endocannabinoids were subsequently identified. Many studies of cannabinoid analgesia in animals during the past century showed that cannabinoids block all types of pain studied. These effects were found to be due to the suppression of spinal and thalamic nociceptive neurons, independent of any actions on the motor systems. Spinal, supraspinal and peripheral sites of cannabinoid analgesia have been identified. Endocannabinoids are released upon electrical stimulation of the periaqueductal gray, and in response to inflammation in the extremities. These observations and others thus suggest that a natural function of cannabinoid receptors and their endogenous ligands is to regulate pain sensitivity. The therapeutic potential of cannabinoids remains an important topic for future investigations, with previous work suggesting utility in clinical studies of cancer and surgical pain. New modes of delivery and/or new compounds lacking the psychotropic properties of the standard cannabinoid ligands offer promise for cannabinoid therapeutics for pain.

  6. Differences in basal cannabinoid CB1 receptor function in selective brain areas and vulnerability to voluntary alcohol consumption in Fawn Hooded and Wistar rats.

    Science.gov (United States)

    Ortiz, Sergio; Oliva, José M; Pérez-Rial, Sandra; Palomo, Tomás; Manzanares, Jorge

    2004-01-01

    To specify the functional activity of cannabinoid CB1 receptor in alcohol-preferring Fawn Hooded and alcohol nonpreferring Wistar rats under naïve conditions. Cannabinoid CB1 (WIN-55,212)-stimulated [35S]-GTPgammas binding autoradiography, and cannabinoid CB1 receptor gene expression were measured in rats of both strains that received only water. Cannabinoid CB1 receptor stimulated [35S]-GTPgammas binding was significantly lower in cingulate cortex (Cg), caudate-putamen (CPu), nucleus accumbens (Acc), ventromedial hypothalamic nucleus (VMN), amygdaloid area (AMG), fields (CA1, CA3) of the hippocampus and dentate gyrus (DG) in Fawn Hooded than in Wistar rats, whereas no differences were found either in substantia nigra pars reticulata (SNr) nor CA2 field of the hippocampus. In addition, cannabinoid CB1 receptor gene expression was lower in Cg, CPu, VMN and CA3 field of the hippocampus in Fawn Hooded than in Wistar rats. We speculate that lower cannabinoid function appears to be related to greater vulnerability to alcohol consumption. Cannabinoid CB1 receptor may represent a key target in the treatment of alcohol dependence.

  7. Expression and function of cannabinoid receptors CB1 and CB2 and their cognate cannabinoid ligands in murine embryonic stem cells.

    Directory of Open Access Journals (Sweden)

    Shuxian Jiang

    2007-07-01

    Full Text Available Characterization of intrinsic and extrinsic factors regulating the self-renewal/division and differentiation of stem cells is crucial in determining embryonic stem (ES cell fate. ES cells differentiate into multiple hematopoietic lineages during embryoid body (EB formation in vitro, which provides an experimental platform to define the molecular mechanisms controlling germ layer fate determination and tissue formation.The cannabinoid receptor type 1 (CB1 and cannabinoid receptor type 2 (CB2 are members of the G-protein coupled receptor (GPCR family, that are activated by endogenous ligands, the endocannabinoids. CB1 receptor expression is abundant in brain while CB2 receptors are mostly expressed in hematopoietic cells. However, the expression and the precise roles of CB1 and CB2 and their cognate ligands in ES cells are not known. We observed significant induction of CB1 and CB2 cannabinoid receptors during the hematopoietic differentiation of murine ES (mES-derived embryoid bodies. Furthermore, mES cells as well as ES-derived embryoid bodies at days 7 and 14, expressed endocannabinoids, the ligands for both CB1 and CB2. The CB1 and CB2 antagonists (AM251 and AM630, respectively induced mES cell death, strongly suggesting that endocannabinoids are involved in the survival of mES cells. Treatment of mES cells with the exogenous cannabinoid ligand Delta(9-THC resulted in the increased hematopoietic differentiation of mES cells, while addition of AM251 or AM630 blocked embryoid body formation derived from the mES cells. In addition, cannabinoid agonists induced the chemotaxis of ES-derived embryoid bodies, which was specifically inhibited by the CB1 and CB2 antagonists.This work has not been addressed previously and yields new information on the function of cannabinoid receptors, CB1 and CB2, as components of a novel pathway regulating murine ES cell differentiation. This study provides insights into cannabinoid system involvement in ES cell

  8. Expression and function of cannabinoid receptors CB1 and CB2 and their cognate cannabinoid ligands in murine embryonic stem cells.

    Science.gov (United States)

    Jiang, Shuxian; Fu, Yigong; Williams, John; Wood, Jodianne; Pandarinathan, Lakshmipathi; Avraham, Shiri; Makriyannis, Alexandros; Avraham, Shalom; Avraham, Hava Karsenty

    2007-07-25

    Characterization of intrinsic and extrinsic factors regulating the self-renewal/division and differentiation of stem cells is crucial in determining embryonic stem (ES) cell fate. ES cells differentiate into multiple hematopoietic lineages during embryoid body (EB) formation in vitro, which provides an experimental platform to define the molecular mechanisms controlling germ layer fate determination and tissue formation. The cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2) are members of the G-protein coupled receptor (GPCR) family, that are activated by endogenous ligands, the endocannabinoids. CB1 receptor expression is abundant in brain while CB2 receptors are mostly expressed in hematopoietic cells. However, the expression and the precise roles of CB1 and CB2 and their cognate ligands in ES cells are not known. We observed significant induction of CB1 and CB2 cannabinoid receptors during the hematopoietic differentiation of murine ES (mES)-derived embryoid bodies. Furthermore, mES cells as well as ES-derived embryoid bodies at days 7 and 14, expressed endocannabinoids, the ligands for both CB1 and CB2. The CB1 and CB2 antagonists (AM251 and AM630, respectively) induced mES cell death, strongly suggesting that endocannabinoids are involved in the survival of mES cells. Treatment of mES cells with the exogenous cannabinoid ligand Delta(9)-THC resulted in the increased hematopoietic differentiation of mES cells, while addition of AM251 or AM630 blocked embryoid body formation derived from the mES cells. In addition, cannabinoid agonists induced the chemotaxis of ES-derived embryoid bodies, which was specifically inhibited by the CB1 and CB2 antagonists. This work has not been addressed previously and yields new information on the function of cannabinoid receptors, CB1 and CB2, as components of a novel pathway regulating murine ES cell differentiation. This study provides insights into cannabinoid system involvement in ES cell survival and

  9. Pharmacology of cannabinoids.

    Science.gov (United States)

    Grotenhermen, Franjo

    2004-01-01

    Dronabinol (Delta 9-tetrahydocannabinol, THC), the main source of the pharmacological effects caused by the use of cannabis, is an agonist to both the CB1 and the CB2 subtype of cannabinoid receptors. It is available on prescription in several countries. The non-psychotropic cannabidiol (CBD), some analogues of natural cannabinoids and their metabolites, antagonists at the cannabinoid receptors and modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoid receptors are distributed in the central nervous system and many peripheral tissues including spleen, leukocytes; reproductive, urinary and gastrointestinal tracts; endocrine glands, arteries and heart. Five endogenous cannabinoids have been detected so far, of whom anandamide and 2-arachidonylglycerol are best characterized. There is evidence that besides the two cannabinoid receptor subtypes cloned so far additional cannabinoid receptor subtypes and vanilloid receptors are involved in the complex physiological functions of the cannabinoid system that include motor coordination, memory procession, control of appetite, pain modulation and neuroprotection. Strategies to modulate their activity include inhibition of re-uptake into cells and inhibition of their degradation to increase concentration and duration of action. Properties of cannabinoids that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, anti-inflammation, anti-allergic effects, sedation, improvement of mood, stimulation of appetite, anti-emesis, lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects.

  10. Cannabinoids: mechanisms and therapeutic applications in the CNS.

    Science.gov (United States)

    Drysdale, Alison J; Platt, Bettina

    2003-12-01

    Cannabinoids comprise three classes of compounds, the active components of marijuana (Cannabis sativa), as well as endogenous and synthetic derivatives. To date, two distinct cannabinoid receptors (CB1 and CB2) have been discovered, but evidence for further receptor types has been brought forward. The potential use of cannabinoids for medicinal purposes has long been known, but the mechanisms of action of both exogenously applied and endogenous cannabinoids are only partly established. For nervous system disorders, cannabinoids may be useful by modulating neurotransmission and calcium homeostasis as well as by anti-inflammatory and anti-oxidant actions. Some cannabinoids can also trigger cell death, which may be of therapeutic benefit in the treatment of malignant tumours. A number of both in vitro and in vivo models have provided promising but diverse evidence for cannabinoid protection in glutamate-mediated excitotoxicity, hypoxia and glucose deprivation, brain trauma, epilepsy and MS. Subsequent to many preclinical investigations, clinical trials are now underway in a variety of the above applications. Overall, the understanding of the therapeutic relevance of cannabinoids will rely on further investigations into the neuroprotective and neurotoxic potency of cannabinoids in animal models and humans, as much as on a further advancement of our general understanding of the endocannabinoid system and the development of specific compounds devoid of unwanted psychoactive side effects.

  11. Cannabinoids and autoimmune diseases: A systematic review.

    Science.gov (United States)

    Katchan, Valeria; David, Paula; Shoenfeld, Yehuda

    2016-06-01

    Cannabinoids have shown to have a variety effects on body systems. Through CB1 and CB2 receptors, amongst other, they exert an effect by modulating neurotransmitter and cytokine release. Current research in the role of cannabinoids in the immune system shows that they possess immunosuppressive properties. They can inhibit proliferation of leucocytes, induce apoptosis of T cells and macrophages and reduce secretion of pro-inflammatory cytokines. In mice models, they are effective in reducing inflammation in arthritis, multiple sclerosis, have a positive effect on neuropathic pain and in type 1 diabetes mellitus. They are effective as treatment for fibromyalgia and have shown to have anti-fibrotic effect in scleroderma. Studies in human models are scarce and not conclusive and more research is required in this field. Cannabinoids can be therefore promising immunosuppressive and anti-fibrotic agents in the therapy of autoimmune disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Functional interactions between endogenous cannabinoid and opioid systems: focus on alcohol, genetics and drug-addicted behaviors.

    Science.gov (United States)

    López-Moreno, J A; López-Jiménez, A; Gorriti, M A; de Fonseca, F Rodríguez

    2010-04-01

    Although the first studies regarding the endogenous opioid system and addiction were published during the 1940s, addiction and cannabinoids were not addressed until the 1970s. Currently, the number of opioid addiction studies indexed in PubMed-Medline is 16 times greater than the number of cannabinoid addiction reports. More recently, functional interactions have been demonstrated between the endogenous cannabinoid and opioid systems. For example, the cannabinoid brain receptor type 1 (CB1) and mu opioid receptor type 1 (MOR1) co-localize in the same presynaptic nerve terminals and signal through a common receptor-mediated G-protein pathway. Here, we review a great variety of behavioral models of drug addiction and alcohol-related behaviors. We also include data providing clear evidence that activation of the cannabinoid and opioid endogenous systems via WIN 55,512-2 (0.4-10 mg/kg) and morphine (1.0-10 mg/kg), respectively, produces similar levels of relapse to alcohol in operant alcohol self-administration tasks. Finally, we discuss genetic studies that reveal significant associations between polymorphisms in MOR1 and CB1 receptors and drug addiction. For example, the SNP A118G, which changes the amino acid aspartate to asparagine in the MOR1 gene, is highly associated with altered opioid system function. The presence of a microsatellite polymorphism of an (AAT)n triplet near the CB1 gene is associated with drug addiction phenotypes. But, studies exploring haplotypes with regard to both systems, however, are lacking.

  13. Pharmacokinetics of Cannabinoids

    Directory of Open Access Journals (Sweden)

    Iain J McGilveray

    2005-01-01

    Full Text Available Delta-9-tetrahydrocannabinol (Δ-9-THC is the main psychoactive ingredient of cannabis (marijuana. The present review focuses on the pharmacokinetics of THC, but also includes known information for cannabinol and cannabidiol, as well as the synthetic marketed cannabinoids, dronabinol (synthetic THC and nabilone. The variability of THC in plant material (0.3% to 30% leads to variability in tissue THC levels from smoking, which is, in itself, a highly individual process. THC bioavailability averages 30%. With a 3.55% THC cigarette, a peak plasma level of 152±86.3 ng/mL occured approximately 10 min after inhalation. Oral THC, on the other hand, is only 4% to 12% bioavailable and absorption is highly variable. THC is eliminated from plasma in a multiphasic manner, with low amounts detectable for over one week after dosing. A major active 11-hydroxy metabolite is formed after both inhalation and oral dosing (20% and 100% of parent, respectively. THC is widely distributed, particularly to fatty tissues, but less than 1% of an administered dose reaches the brain, while the spleen and body fat are long-term storage sites. The elimination of THC and its many metabolites (from all routes occurs via the feces and urine. Metabolites persist in the urine and feces for severalweeks. Nabilone is well absorbed and the pharmacokinetics, although variable, appear to be linear from oral doses of 1 mg to 4 mg (these doses show a plasma elimination half-life of approximately 2 h. As with THC, there is a high first-pass effect, and the feces to urine ratio of excretion is similar to other cannabinoids. Pharmacokineticpharmacodynamic modelling with plasma THC versus cardiac and psychotropic effects show that after equilibrium is reached, the intensity of effect is proportional to the plasma THC profile. Clinical trials have found that nabilone produces less tachycardia and less euphoria than THC for a similar antiemetic response.

  14. Type 1 Diabetes

    Science.gov (United States)

    ... develop in adults. Despite active research, type 1 diabetes has no cure. Treatment focuses on managing blood sugar levels with insulin, diet and lifestyle to prevent complications. Symptoms Type 1 diabetes signs and symptoms can appear relatively suddenly and ...

  15. Diabetes, Type 1

    OpenAIRE

    Riazi, Afsane; Bradley, Clare

    2000-01-01

    This chapter provides an overview of the role of psychological stress in Type 1 diabetes. Studies relating to stress and Type 1 diabetes onset and control, as well as the evidence relating to stress management training in people with Type 1 diabetes are discussed.

  16. Modulation of Network Oscillatory Activity and GABAergic Synaptic Transmission by CB1 Cannabinoid Receptors in the Rat Medial Entorhinal Cortex

    Directory of Open Access Journals (Sweden)

    Nicola H. Morgan

    2008-01-01

    Full Text Available Cannabinoids modulate inhibitory GABAergic neurotransmission in many brain regions. Within the temporal lobe, cannabinoid receptors are highly expressed, and are located presynaptically at inhibitory terminals. Here, we have explored the role of type-1 cannabinoid receptors (CB1Rs at the level of inhibitory synaptic currents and field-recorded network oscillations. We report that arachidonylcyclopropylamide (ACPA; 10 M, an agonist at CB1R, inhibits GABAergic synaptic transmission onto both superficial and deep medial entorhinal (mEC neurones, but this has little effect on network oscillations in beta/gamma frequency bands. By contrast, the CB1R antagonist/inverse agonist LY320135 (500 nM, increased GABAergic synaptic activity and beta/gamma oscillatory activity in superficial mEC, was suppressed, whilst that in deep mEC was enhanced. These data indicate that cannabinoid-mediated effects on inhibitory synaptic activity may be constitutively active in vitro, and that modulation of CB1R activation using inverse agonists unmasks complex effects of CBR function on network activity.

  17. Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB{sub 1} receptors and apoptotic cell death

    Energy Technology Data Exchange (ETDEWEB)

    Tomiyama, Ken-ichi; Funada, Masahiko, E-mail: mfunada@ncnp.go.jp

    2014-01-01

    The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced cytotoxicity in the forebrain cultures in a concentration-dependent manner. The cytotoxicity was suppressed by preincubation with the selective CB{sub 1} receptor antagonist AM251, but not with the selective CB{sub 2} receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrain cells. Synthetic cannabinoid treatment induced the activation of caspase-3, and preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity. These synthetic cannabinoids induced apoptosis through a caspase-3-dependent mechanism in the forebrain cultures. Our results indicate that the cytotoxicity of synthetic cannabinoids towards primary neuronal cells is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to neuronal damage or deficits in the brain. - Highlights: • Synthetic cannabinoids (classical cannabinoids, non-classical cannabinoids, and aminoalkylindole derivatives) induce cytotoxicity in mouse forebrain cultures. • Synthetic cannabinoid-induced cytotoxicity towards forebrain cultures is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and involves caspase-dependent apoptosis. • A high concentration of synthetic cannabinoids may be toxic to neuronal cells that express CB{sub 1} receptors.

  18. Cannabinoids and Innate Immunity: Taking a Toll on Neuroinflammation

    Directory of Open Access Journals (Sweden)

    Eric J. Downer

    2011-01-01

    Full Text Available The biologically active components of cannabis have therapeutic potential in neuroinflammatory disorders due to their anti-inflammatory propensity. Cannabinoids influence immune function in both the peripheral and the central nervous system (CNS, and the components of the cannabinoid system, the cannabinoid receptors and their endogenous ligands (endocannabinoids, have been detected on immune cells as well as in brain glia. Neuroinflammation is the complex innate immune response of neural tissue to control infection and eliminate pathogens, and Toll-like receptors (TLRs, a major family of pattern recognition receptors (PRRs that mediate innate immunity, have emerged as players in the neuroinflammatory processes underpinning various CNS diseases. This review will highlight evidence that cannabinoids interact with the immune system by impacting TLR-mediated signaling events, which may provide cues for devising novel therapeutic approaches for cannabinoid ligands.

  19. The neurobiology and evolution of cannabinoid signalling.

    Science.gov (United States)

    Elphick, M R; Egertová, M

    2001-03-29

    The plant Cannabis sativa has been used by humans for thousands of years because of its psychoactivity. The major psychoactive ingredient of cannabis is Delta(9)-tetrahydrocannabinol, which exerts effects in the brain by binding to a G-protein-coupled receptor known as the CB1 cannabinoid receptor. The discovery of this receptor indicated that endogenous cannabinoids may occur in the brain, which act as physiological ligands for CB1. Two putative endocannabinoid ligands, arachidonylethanolamide ('anandamide') and 2-arachidonylglycerol, have been identified, giving rise to the concept of a cannabinoid signalling system. Little is known about how or where these compounds are synthesized in the brain and how this relates to CB1 expression. However, detailed neuroanatomical and electrophysiological analysis of mammalian nervous systems has revealed that the CB1 receptor is targeted to the presynaptic terminals of neurons where it acts to inhibit release of 'classical' neurotransmitters. Moreover, an enzyme that inactivates endocannabinoids, fatty acid amide hydrolase, appears to be preferentially targeted to the somatodendritic compartment of neurons that are postsynaptic to CB1-expressing axon terminals. Based on these findings, we present here a model of cannabinoid signalling in which anandamide is synthesized by postsynaptic cells and acts as a retrograde messenger molecule to modulate neurotransmitter release from presynaptic terminals. Using this model as a framework, we discuss the role of cannabinoid signalling in different regions of the nervous system in relation to the characteristic physiological actions of cannabinoids in mammals, which include effects on movement, memory, pain and smooth muscle contractility. The discovery of the cannabinoid signalling system in mammals has prompted investigation of the occurrence of this pathway in non-mammalian animals. Here we review the evidence for the existence of cannabinoid receptors in non-mammalian vertebrates

  20. Expression of the cannabinoid CB1 receptor in the gymnotiform fish brain and its implications for the organization of the teleost pallium.

    Science.gov (United States)

    Harvey-Girard, Erik; Giassi, Ana C C; Ellis, William; Maler, Leonard

    2013-03-01

    Cannabinoid CB1 receptors (CB1R) are widely distributed in the brains of many vertebrates, but whether their functions are conserved is unknown. The weakly electric fish, Apteronotus leptorhynchus (Apt), has been well studied for its brain structure, behavior, sensory processing, and learning and memory. It therefore offers an attractive model for comparative studies of CB1R functions. We sequenced partial AptCB1R mRNAs and performed in situ hybridization to localize its expression. Partial AptCB1R protein sequence was highly conserved to zebrafish (90.7%) and mouse (81.9%) orthologs. AptCB1R mRNA was highly expressed in the telencephalon. Subpallial neurons (dorsal, central, intermediate regions and part of the ventral region, Vd/Vc/Vi, and Vv) expressed high levels of AptCB1R transcript. The central region of dorsocentral telencephalon (DC(core) ) strongly expressed CB1R mRNA; cells in DC(core) project to midbrain regions involved in electrosensory/visual function. The lateral and rostral regions of DC surrounding DC(core) (DC(shell) ) lack AptCB1R mRNA. The rostral division of the dorsomedial telencephalon (DM1) highly expresses AptCB1R mRNA. In dorsolateral division (DL) AptCB1R mRNA was expressed in a gradient that declined in a rostrocaudal manner. In diencephalon, AptCB1R RNA probe weakly stained the central-posterior (CP) and prepacemaker (PPn) nuclei. In mesencephalon, AptCB1R mRNA is expressed in deep layers of the dorsal (electrosensory) torus semicircularis (TSd). In hindbrain, AptCB1R RNA probe weakly labeled inhibitory interneurons in the electrosensory lateral line lobe (ELL). Unlike mammals, only few cerebellar granule cells expressed AptCB1R transcripts and these were located in the center of eminentia granularis pars posterior (EGp), a cerebellar region involved in feedback to ELL. Copyright © 2012 Wiley Periodicals, Inc.

  1. Cannabinoids and zebrafish

    NARCIS (Netherlands)

    Akhtar, Muhammad Tayyab

    2013-01-01

    Cannabinoids are a group of terpenophenolic compounds and are naturally found in the cannabis plant (Cannabis sativa L). Δ9-Tetrahydrocannabinol (Δ9-THC) is the psychoactive cannabinoid. The high lipophilicity of Δ9-THC is a hindering factor in the further development of this compound into a large

  2. Cannabinoids as Anticancer Drugs.

    Science.gov (United States)

    Ramer, Robert; Hinz, Burkhard

    2017-01-01

    The endocannabinoid system encompassing cannabinoid receptors, endogenous receptor ligands (endocannabinoids), as well as enzymes conferring the synthesis and degradation of endocannabinoids has emerged as a considerable target for pharmacotherapeutical approaches of numerous diseases. Besides palliative effects of cannabinoids used in cancer treatment, phytocannabinoids, synthetic agonists, as well as substances that increase endogenous endocannabinoid levels have gained interest as potential agents for systemic cancer treatment. Accordingly, cannabinoid compounds have been reported to inhibit tumor growth and spreading in numerous rodent models. The underlying mechanisms include induction of apoptosis, autophagy, and cell cycle arrest in tumor cells as well as inhibition of tumor cell invasion and angiogenic features of endothelial cells. In addition, cannabinoids have been shown to suppress epithelial-to-mesenchymal transition, to enhance tumor immune surveillance, and to support chemotherapeutics' effects on drug-resistant cancer cells. However, unwanted side effects include psychoactivity and possibly pathogenic effects on liver health. Other cannabinoids such as the nonpsychoactive cannabidiol exert a comparatively good safety profile while exhibiting considerable anticancer properties. So far experience with anticarcinogenic effects of cannabinoids is confined to in vitro studies and animal models. Although a bench-to-bedside conversion remains to be established, the current knowledge suggests cannabinoid compounds to serve as a group of drugs that may offer significant advantages for patients suffering from cancer diseases. The present review summarizes the role of the endocannabinoid system and cannabinoid compounds in tumor progression. © 2017 Elsevier Inc. All rights reserved.

  3. Long-term consequences of adolescent cannabinoid exposure in adult psychopathology

    Directory of Open Access Journals (Sweden)

    Justine eRenard

    2014-11-01

    Full Text Available Marijuana is the most widely used illicit drug among adolescents and young adults. Unique cognitive, emotional, and social changes occur during this critical period of development from childhood into adulthood. The adolescent brain is in a state of transition and differs from the adult brain with respect to both anatomy (e.g., neuronal connections and morphology and neurochemistry (e.g., dopamine, GABA, and glutamate. These changes are thought to support the emergence of adult cerebral processes and behaviors. The endocannabinoid system plays an important role in development by acting on synaptic plasticity, neuronal cell proliferation, migration, and differentiation. Delta-9-tetrahydrocanabinol (THC, the principal psychoactive component in marijuana, acts as an agonist of the cannabinoid type 1 receptor (CB1R. Thus, over-activation of the endocannabinoid system by chronic exposure to CB1R agonists (e.g. THC, CP-55,940, and WIN55,212-2 during adolescence can dramatically alter brain maturation and cause long-lasting neurobiological changes that ultimately affect the function and behavior of the adult brain. Indeed, emerging evidence from both human and animal studies demonstrates that early-onset marijuana use has long-lasting consequences on cognition; moreover, in humans, this use is associated with a two-fold increase in the risk of developing a psychotic disorder. Here, we review the relationship between cannabinoid exposure during adolescence and the increased risk of neuropsychiatric disorders, focusing on both clinical and animal studies.

  4. Non-Selective Cannabinoid Receptor Antagonists, Hinokiresinols Reduce Infiltration of Microglia/Macrophages into Ischemic Brain Lesions in Rat via Modulating 2-Arachidonolyglycerol-Induced Migration and Mitochondrial Activity.

    Directory of Open Access Journals (Sweden)

    Angela M A Anthony Jalin

    Full Text Available Growing evidence suggests that therapeutic strategies to modulate the post-ischemic inflammatory responses are promising approaches to improve stroke outcome. Although the endocannabinoid system has been emerged as an endogenous therapeutic target to regulate inflammation after stroke insult, the downstream mechanisms and their potentials for therapeutic intervention remain controversial. Here we identified trans- and cis-hinokiresinols as novel non-selective antagonists for two G-protein-coupled cannabinoid receptors, cannabinoid receptor type 1 and type 2. The Electric Cell-substrate Impedance Sensing and Boyden chamber migration assays using primary microglial cultures revealed that both hinokiresinols significantly inhibited an endocannabinoid, 2-arachidonoylglycerol-induced migration. Hinokiresinols modulated 2-arachidonoylglycerol-induced mitochondrial bioenergetics in microglia as evidenced by inhibition of ATP turnover and reduction in respiratory capacity, thereby resulting in impaired migration activity. In rats subjected to transient middle cerebral artery occlusion (1.5-h followed by 24-h reperfusion, post-ischemic treatment with hinokiresinols (2 and 7-h after the onset of ischemia, 10 mg/kg significantly reduced cerebral infarct and infiltration of ED1-positive microglial/macrophage cells into cerebral ischemic lesions in vivo. Co-administration of exogenous 2-AG (1 mg/kg, i.v., single dose at 2 h after starting MCAO abolished the protective effect of trans-hinokiresionol. These results suggest that hinokiresinols may serve as stroke treatment by targeting the endocannabinoid system. Alteration of mitochondrial bioenergetics and consequent inhibition of inflammatory cells migration may be a novel mechanism underlying anti-ischemic effects conferred by cannabinoid receptor antagonists.

  5. Combination Chemistry: Structure-Activity Relationships of Novel Psychoactive Cannabinoids.

    Science.gov (United States)

    Wiley, Jenny L; Marusich, Julie A; Thomas, Brian F

    2017-01-01

    Originally developed as research tools for use in structure-activity relationship studies, synthetic cannabinoids contributed to significant scientific advances in the cannabinoid field. Unfortunately, a subset of these compounds was diverted for recreational use beginning in the early 2000s. As these compounds were banned, they were replaced with additional synthetic cannabinoids with increasingly diverse chemical structures. This chapter focuses on integration of recent results with those covered in previous reviews. Whereas most of the early compounds were derived from the prototypic naphthoylindole JWH-018, currently popular synthetic cannabinoids include tetramethylcyclopropyl ketones and indazole-derived cannabinoids (e.g., AB-PINACA, AB-CHMINACA). Despite their structural differences, psychoactive synthetic cannabinoids bind with high affinity to CB1 receptors in the brain and, when tested, have been shown to activate these receptors and to produce a characteristic profile of effects, including suppression of locomotor activity, antinociception, hypothermia, and catalepsy, as well as Δ9-tetrahydrocannabinol (THC)-like discriminative stimulus effects in mice. When they have been tested, synthetic cannabinoids are often found to be more efficacious at activation of the CB1 receptor and more potent in vivo. Further, their chemical alteration by thermolysis during use and their uncertain stability and purity may result in exposure to degradants that differ from the parent compound contained in the original product. Consequently, while their intoxicant effects may be similar to those of THC, use of synthetic cannabinoids may be accompanied by unpredicted, and sometimes harmful, effects.

  6. Diabetes Type 1

    Science.gov (United States)

    Diabetes means your blood glucose, or blood sugar, levels are too high. With type 1 diabetes, your pancreas does not make insulin. Insulin is ... kidneys, nerves, and gums and teeth. Type 1 diabetes happens most often in children and young adults ...

  7. Type 1 Diabetes Facts

    Science.gov (United States)

    ... Contact Us Donate Events More Type 1 Diabetes Facts Type 1 diabetes (T1D) is an autoimmune disease ... of T1D The Complexity of Diagnosing T1D T1D Facts Insulin Types and Usage T1D Treatments Sign up ...

  8. Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors.

    NARCIS (Netherlands)

    den Boon, F.S.; Chameau, P.; Schaafsma-Zhao, Q.; van Aken, W.; Bari, M.; Oddi, S.; Kruse, C.G.; Maccarrone, M.; Wadman, W.J.; Werkman, T.R.

    2012-01-01

    The endocannabinoid (eCB) system is widely expressed throughout the central nervous system (CNS) and the functionality of type-1 cannabinoid receptors in neurons is well documented. In contrast, there is little knowledge about type-2 cannabinoid receptors (CB(2)Rs) in the CNS. Here, we show that

  9. Pharmacokinetics and pharmacodynamics of cannabinoids.

    Science.gov (United States)

    Grotenhermen, Franjo

    2003-01-01

    Delta(9)-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15-30 minutes, and taper off within 2-3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30-90 minutes, reach their maximum after 2-3 hours and last for about 4-12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial

  10. Cannabinoids and Psychosis.

    Science.gov (United States)

    D'Souza, Deepak Cyril; Radhakrishnan, Rajiv; Sherif, Mohamed; Cortes-Briones, Jose; Cahill, John; Gupta, Swapnil; Skosnik, Patrick D; Ranganathan, Mohini

    2016-01-01

    There is growing interest in the relationship between cannabis and psychosis. The link between cannabis use and psychosis comprises three distinct relationships: acute psychosis associated with cannabis intoxication, acute psychosis that lasts beyond the period of acute intoxication, and persistent psychosis not time-locked to exposure. Experimental studies reveal that cannabis, tetrahydrocannabinol (THC) and synthetic cannabinoids reliably produce transient positive, negative, and cognitive symptoms in healthy volunteers. Case-studies indicate that cannabinoids can induce acute psychosis which lasts beyond the period of acute intoxication and persisting as long as a month. Exposure to cannabis in adolescence is associated with an increased risk for later psychotic disorder in adulthood; this association is consistent, somewhat specific, shows a dose-response, and is biologically plausible. The link between cannabinoids and psychosis is greater with earlier age of exposure to cannabinoids, childhood abuse and genetic vulnerability. However, cannabinoids are neither necessary nor sufficient to cause a persistent psychotic disorder. More likely cannabinoids are a 'component cause' interacting with other known (family history) and unknown factors to result in psychosis outcomes. While more research is needed to better understand the relationship between cannabinoid use and psychosis, and the neural underpinnings of this link, clinicians should be mindful of the potential risk of psychosis especially in vulnerable populations, including adolescents and those with a psychosis diathesis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. Regulation of noradrenergic and serotonergic systems by cannabinoids: relevance to cannabinoid-induced effects.

    Science.gov (United States)

    Mendiguren, Aitziber; Aostri, Erik; Pineda, Joseba

    2018-01-01

    The cannabinoid system is composed of Gi/o protein-coupled cannabinoid type 1 receptor (CB1) and cannabinoid type 2 (CB2) receptor and endogenous compounds. The CB1 receptor is widely distributed in the central nervous system (CNS) and it is involved in the regulation of common physiological functions. At the neuronal level, the CB1 receptor is mainly placed at GABAergic and glutamatergic axon terminals, where it modulates excitatory and inhibitory synapses. To date, the involvement of CB2 receptor in the regulation of neurotransmission in the CNS has not been clearly shown. The majority of noradrenergic (NA) cells in mammalian tissues are located in the locus coeruleus (LC) while serotonergic (5-HT) cells are mainly distributed in the raphe nuclei including the dorsal raphe nucleus (DRN). In the CNS, NA and 5-HT systems play a crucial role in the control of pain, mood, arousal, sleep-wake cycle, learning/memory, anxiety, and rewarding behaviour. This review summarizes the electrophysiological, neurochemical and behavioural evidences for modulation of the NA/5-HT systems by cannabinoids and the CB1 receptor. Cannabinoids regulate the neuronal activity of NA and 5-HT cells and the release of NA and 5-HT by direct and indirect mechanisms. The interaction between cannabinoid and NA/5-HT systems may underlie several behavioural changes induced by cannabis such as anxiolytic and antidepressant effects or side effects (e.g. disruption of attention). Further research is needed to better understand different aspects of NA and 5-HT systems regulation by cannabinoids, which would be relevant for their use in therapeutics. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. The antitumor action of cannabinoids on glioma tumorigenesis.

    Science.gov (United States)

    Zogopoulos, Panagiotis; Korkolopoulou, Penelope; Patsouris, Efstratios; Theocharis, Stamatios

    2015-06-01

    Cannabinoids are a class of chemical compounds with a wide spectrum of pharmacological effects, mediated by two specific plasma membrane receptors (CB1 and CB2). Recently, CB1 and CB2 expression levels have been detected in human tumors, including those of brain. Cannabinoids-endocannabinoids exert anti-inflammatory, anti-proliferative, anti-invasive, anti-metastatic and pro-apoptotic effects in different cancer types, both in vitro and in vivo in animal models, after local or systemic administration. We present the available experimental and clinical data, to date, regarding the antitumor action of cannabinoids on the tumorigenesis of gliomas.

  13. Type 1 diabetes

    DEFF Research Database (Denmark)

    Green, Anders; Kyvik, Kirsten Ohm

    2001-01-01

    Prediction of Type 1 diabetes at individual level is relevant for any possible intervention before clinical disease develops. Currently available markers of Type 1 diabetes include genetic specificities and immune markers, in addition to a positive family history. This chapter reviews the measures...... and methods of importance in predicting Type 1 diabetes. Based on numerical examples it is demonstrated that available markers have a low level of performance, even when combined. Even so, combined marker information may allow for the identification of the large majority of the general population who...... is at very low disease risk. The impact at population level of predicting Type 1 diabetes varies between societies because the performance of markers depends on levels of disease risk and distribution of markers within a population. The incorporation of the influence of non-genetic etiological factors may...

  14. Type 1 diabetes

    OpenAIRE

    Atkinson, Mark A; Eisenbarth, George S; Michels, Aaron W

    2013-01-01

    Over the past decade, knowledge of the pathogenesis and natural history of type 1 diabetes has grown substantially, particularly with regard to disease prediction and heterogeneity, pancreatic pathology, and epidemiology. Technological improvements in insulin pumps and continuous glucose monitors help patients with type 1 diabetes manage the challenge of lifelong insulin administration. Agents that show promise for averting debilitating disease-associated complications have also been identifi...

  15. Activation of cannabinoid system in anterior cingulate cortex and orbitofrontal cortex modulates cost-benefit decision making.

    Science.gov (United States)

    Khani, Abbas; Kermani, Mojtaba; Hesam, Soghra; Haghparast, Abbas; Argandoña, Enrike G; Rainer, Gregor

    2015-06-01

    Despite the evidence for altered decision making in cannabis abusers, the role of the cannabinoid system in decision-making circuits has not been studied. Here, we examined the effects of cannabinoid modulation during cost-benefit decision making in the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC), key brain areas involved in decision making. We trained different groups of rats in a delay-based and an effort-based form of cost-benefit T-maze decision-making task. During test days, the rats received local injections of either vehicle or ACEA, a cannabinoid type-1 receptor (CB1R) agonist in the ACC or OFC. We measured spontaneous locomotor activity following the same treatments and characterized CB1Rs localization on different neuronal populations within these regions using immunohistochemistry. We showed that CB1R activation in the ACC impaired decision making such that rats were less willing to invest physical effort to gain high reward. Similarly, CB1R activation in the OFC induced impulsive pattern of choice such that rats preferred small immediate rewards to large delayed rewards. Control tasks ensured that the effects were specific for differential cost-benefit tasks. Furthermore, we characterized widespread colocalizations of CB1Rs on GABAergic axonal ends but few colocalizations on glutamatergic, dopaminergic, and serotonergic neuronal ends. These results provide first direct evidence that the cannabinoid system plays a critical role in regulating cost-benefit decision making in the ACC and OFC and implicate cannabinoid modulation of synaptic ends of predominantly interneurons and to a lesser degree other neuronal populations in these two frontal regions.

  16. Cannabis and Cannabinoids (PDQ)

    Science.gov (United States)

    ... inflammatory effects that may play a role in pain relief. Animal studies have shown that cannabinoids may prevent nerve problems (pain, numbness, tingling, swelling, and muscle weakness) caused by ...

  17. Laboratory detection of cannabinoids.

    Science.gov (United States)

    King, D L; Martel, P A; O'Donnell, C M

    1987-09-01

    Cannabis, or marijuana, has been known and used as a drug for many thousands of years. Recent interest in drug abuse and detection has spurred the development of several methodologies for cannabinoid detection. These methods include immunoassays and chromatography. Laboratories routinely performing cannabinoid testing use two or more methodologies; the accepted method is to screen with one methodology and confirm by a second. These methodologies vary widely in sensitivity, specificity, and time required for analysis. Although therapeutic applications of cannabis constituents often produce undesirable side effects, two cannabinoids, delta 9-THC and nabilone, have been approved for use as antiemetics in chemotherapy. Further investigations of cannabinoid pharmacology and structure-activity relationships may result in the development of promising new therapeutic agents.

  18. Prevention of Alzheimer's disease pathology by cannabinoids: Neuroprotection mediated by blockade of microglial activation

    OpenAIRE

    Ramírez, Belén G.; Blázquez, Cristina; Gómez del Pulgar, Teresa; Guzmán, Manuel; Ceballos, María L. de

    2005-01-01

    Alzheimer's disease (AD) is characterized by enhanced β-amyloid peptide (βA) deposition along with glial activation in senile plaques, selective neuronal loss, and cognitive deficits. Cannabinoids are neuroprotective agents against excitotoxicity in vitro and acute brain damage in vivo. This background prompted us to study the localization, expression, and function of cannabinoid receptors in AD and the possible protective role of cannabinoids after βA treatment, both in vivo and in vitro. He...

  19. Cannabinoids and haemostasis

    Directory of Open Access Journals (Sweden)

    Agnieszka Zakrzeska

    2016-07-01

    Full Text Available Elements of the endocannabinoid system (cannabinoid receptors CB1, CB2, CBPT and CBED, endocannabinoids, enzymes involved in the synthesis and metabolism of endocannabinoids are located on the structures involved in the process of hemostasis. An increasing level of endocannabinoids was also observed in some pathological conditions, which may occur in disorders of hemostasis. At the same time, disconcertingly, there is an increased number of reports about incidents of cardiovascular events in smokers of marijuana. Experimental and clinical studies demonstrated multidirectional, often contradictory, effects of cannabinoids on hemostasis, including effects of the compounds on platelets, vascular endothelium, fibrinolysis and plasma coagulation systems. The mechanisms of action of cannabinoids on homeostasis depend on the cannabinoid receptors CB1, CB2, CBPT and CBED, receptors of other systems stimulated by endocannabinoids, as well as metabolites of endocannabinoids and nitrogen oxide. The range of biological functions of endo- and plant cannabinoids, expanded to include the process of hemostasis, may constitute a condition for their recognition as a new factor responsible for thromboembolism in smokers of marijuana, in pathological disorders with increased levels of endocannabinoids and in individuals with polymorphisms of FAAH C385A and A385A. On the other hand, there are compelling reasons for anti‑hemostatic action of cannabinoids.

  20. Cannabinoids, inflammation, and fibrosis.

    Science.gov (United States)

    Zurier, Robert B; Burstein, Sumner H

    2016-11-01

    Cannabinoids apparently act on inflammation through mechanisms different from those of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs). As a class, the cannabinoids are generally free from the adverse effects associated with NSAIDs. Their clinical development thus provides a new approach to treatment of diseases characterized by acute and chronic inflammation and fibrosis. A concise survey of the anti-inflammatory actions of the phytocannabinoids Δ9-tetrahydrocannabinol (THC), cannabidiol, cannabichromene, and cannabinol is presented. Mention is also made of the noncannabinoid plant components and pyrolysis products, followed by a discussion of 3 synthetic preparations-Cesamet (nabilone; Meda Pharmaceuticals, Somerset, NJ, USA), Marinol (dronabinol; THC; AbbVie, Inc., North Chicago, IL, USA), and Sativex (Cannabis extract; GW Pharmaceuticals, Cambridge United Kingdom)-that have anti-inflammatory effects. A fourth synthetic cannabinoid, ajulemic acid (AJA; CT-3; Resunab; Corbus Pharmaceuticals, Norwood, MA, USA), is discussed in greater detail because it represents the most recent advance in this area and is currently undergoing 3 phase 2 clinical trials by Corbus Pharmaceuticals. The endogenous cannabinoids, including the closely related lipoamino acids, are then discussed. The review concludes with a presentation of a possible mechanism for the anti-inflammatory and antifibrotic actions of these substances. Thus, several cannabinoids may be considered candidates for development as anti-inflammatory and antifibrotic agents. Of special interest is their possible use for treatment of chronic inflammation, a major unmet medical need.-Zurier, R. B., Burstein, S. H. Cannabinoids, inflammation, and fibrosis. © FASEB.

  1. Diabetes mellitus type 1

    OpenAIRE

    Tøraasen, Lisa Vangen; Al-Sultan, Zainab

    2014-01-01

    Hvert år blir rundt 600 nordmenn diagnostisert med sykdommen diabetes type 1, og Norge er et av landene i verden med størst andel av barnediabetes. I dag er det 15 000- 20 000 personer i Norge som har diabetes type 1, og antall barn som får diabetes har fordoblet seg de siste 30 årene (Diabetesforbundet, 2014). Problemstillingen vår gikk ut på hvordan sykepleiere kan veilede og undervise ungdom med nyoppdaget diabetes type på sykehus. Ut i fra litteraturstudiet har vi arbeidet oss frem for å ...

  2. Diabetes mellitus type 1

    OpenAIRE

    Tøraasen, Lisa Vangen; Al-Sultan, Zainab

    2014-01-01

    Bacheloroppgave i sykepleie, 2014 Hvert år blir rundt 600 nordmenn diagnostisert med sykdommen diabetes type 1, og Norge er et av landene i verden med størst andel av barnediabetes. I dag er det 15 000- 20 000 personer i Norge som har diabetes type 1, og antall barn som får diabetes har fordoblet seg de siste 30 årene (Diabetesforbundet, 2014). Problemstillingen vår gikk ut på hvordan sykepleiere kan veilede og undervise ungdom med nyoppdaget diabetes type på sykehus. Ut i fra litteraturst...

  3. Type 1 Diabetes Facts

    Science.gov (United States)

    ... Type 1 Diabetes (T1D) Back Close What Is Diabetes? Causes of T1D The Complexity of Diagnosing T1D T1D ... about Insulin and T1D Learn More What Is Diabetes? Causes of T1D The Complexity of Diagnosing T1D T1D ...

  4. Cannabinoids in cancer pain management.

    Science.gov (United States)

    Huskey, Angela

    2006-01-01

    The clinical use of cannabinoids in cancer pain management is reviewed. The endocannabionoid system, cannabinoid receptors, evidence for analgesic effects, other uses in cancer and related issues are discussed.

  5. Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection.

    Science.gov (United States)

    Rosenberg, Evan C; Patra, Pabitra H; Whalley, Benjamin J

    2017-05-01

    The isolation and identification of the discrete plant cannabinoids in marijuana revived interest in analyzing historical therapeutic claims made for cannabis in clinical case studies and anecdotes. In particular, sources as old as the 11th and 15th centuries claimed efficacy for crude marijuana extracts in the treatment of convulsive disorders, prompting a particularly active area of preclinical research into the therapeutic potential of plant cannabinoids in epilepsy. Since that time, a large body of literature has accumulated describing the effects of several of the >100 individual plant cannabinoids in preclinical models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection. We surveyed the literature for relevant reports of such plant cannabinoid effects and critically reviewed their findings. We found that acute CB 1 R agonism in simple models of acute seizures in rodents typically produces anti-convulsant effects whereas CB 1 R antagonists exert converse effects in the same models. However, when the effects of such ligands are examined in more complex models of epilepsy, epileptogenesis and neuroprotection, a less simplistic narrative emerges. Here, the complex interactions between (i) brain regions involved in a given model, (ii) relative contributions of endocannabinoid signaling to modulation of synaptic transmission in such areas, (iii) multi-target effects, (iv) cannabinoid type 1 and type 2 receptor signaling interactions and, (v) timing, (vi) duration and (vii) localization of ligand administration suggest that there is both anti-epileptic therapeutic potential and a pro-epileptic risk in up- and down-regulation of endocannabinoid signaling in the central nervous system. Factors such receptor desensitization and specific pharmacology of ligands used (e.g. full vs partial agonists and neutral antagonists vs inverse agonists) also appear to play an important role in the effects reported. Furthermore, the effects of several plant

  6. Cannabinoid receptors in invertebrates.

    Science.gov (United States)

    McPartland, J M; Agraval, J; Gleeson, D; Heasman, K; Glass, M

    2006-03-01

    Two cannabinoid receptors, CB1 and CB2, are expressed in mammals, birds, reptiles, and fish. The presence of cannabinoid receptors in invertebrates has been controversial, due to conflicting evidence. We conducted a systematic review of the literature, using expanded search parameters. Evidence presented in the literature varied in validity, ranging from crude in vivo behavioural assays to robust in silico ortholog discovery. No research existed for several clades of invertebrates; we therefore tested for cannabinoid receptors in seven representative species, using tritiated ligand binding assays with [3H]CP55,940 displaced by the CB1-selective antagonist SR141716A. Specific binding of [3H]CP55,940 was found in neural membranes of Ciona intestinalis (Deuterstoma, a positive control), Lumbricusterrestris (Lophotrochozoa), and three ecdysozoans: Peripatoides novae-zealandiae (Onychophora), Jasus edwardi (Crustacea) and Panagrellus redivivus (Nematoda); the potency of displacement by SR141716A was comparable to measurements on rat cerebellum. No specific binding was observed in Actinothoe albocincta (Cnidaria) or Tethya aurantium (Porifera). The phylogenetic distribution of cannabinoid receptors may address taxonomic questions; previous studies suggested that the loss of CB1 was a synapomorphy shared by ecdysozoans. Our discovery of cannabinoid receptors in some nematodes, onychophorans, and crustaceans does not contradict the Ecdysozoa hypothesis, but gives it no support. We hypothesize that cannabinoid receptors evolved in the last common ancestor of bilaterians, with secondary loss occurring in insects and other clades. Conflicting data regarding Cnidarians precludes hypotheses regarding the last common ancestor of eumetazoans. No cannabinoid receptors are expressed in sponges, which probably diverged before the origin of the eumetazoan ancestor.

  7. PHARMACOLOGY OF CANNABINOIDS

    Directory of Open Access Journals (Sweden)

    Ilonka Ferjan

    2015-06-01

    Full Text Available The discovery of cannabinoid receptors and endocannabinoid system has led to the potential therapeutic use of cannabis derivatives. Cannabinoids acting through the CB1 receptors modulate the release of other neurotransmitters in central nervous system, whereas the activation of peripheral CB2 receptors results in decreased inflammatory response and increased apoptosis of some tumor cells populations. The cannabinoids have been authorized for chemotherapy-induced nausea and vomiting; stimulation of appetite; to alleviate neuropathic pain and spasticity in multiple sclerosis, and to reduce pain in cancer patients. Efficacy in other diseases and clinical conditions should be proven in ongoing or future clinical trials. Isolation and identification of different cannabinoids from cannabis and synthesis of novel, more selective, derivatives widens their therapeutic potential. However, there are numerous adverse effects reported, especially when cannabinoids formulations with unknown quantitative and qualitative composition are used. Addiction, tolerance, withdrawal symptoms, increased risk of acute myocardial re-infarction, and increased risk of psychosis or worsening of psychosis are the most common adverse effects of cannabinoids. Acute adverse effects e. g. severe central nervous system depression, are more pronounced in children than in adults. Potential cannabinoid medicines should be subject to the same regulations as other potential drugs. Safety and efficacy of any potential drug candidate, regardless whether it is plant-derived or synthesized, should be proven in non-clinical studies and clinical trials, as well as the marketing authorization must be issued by the appropriate drug authority. Patients deserve a quality manufactured product, which always contains the specified amount of "Remedium cardinale."

  8. Cannabinoid function in learning, memory and plasticity.

    Science.gov (United States)

    Riedel, G; Davies, S N

    2005-01-01

    Marijuana and its psychoactive constituents induce a multitude of effects on brain function. These include deficits in memory formation, but care needs to be exercised since many human studies are flawed by multiple drug abuse, small sample sizes, sample selection and sensitivity of psychological tests for subtle differences. The most robust finding with respect to memory is a deficit in working and short-term memory. This requires intact hippocampus and prefrontal cortex, two brain regions richly expressing CB1 receptors. Animal studies, which enable a more controlled drug regime and more constant behavioural testing, have confirmed human results and suggest, with respect to hippocampus, that exogenous cannabinoid treatment selectively affects encoding processes. This may be different in other brain areas, for instance the amygdala, where a predominant involvement in memory consolidation and forgetting has been firmly established. While cannabinoid receptor agonists impair memory formation, antagonists reverse these deficits or act as memory enhancers. These results are in good agreement with data obtained from electrophysiological recordings, which reveal reduction in neural plasticity following cannabinoid treatment, and increased plasticity following antagonist exposure. The mixed receptor properties of the pharmacological tool, however, make it difficult to define the exact role of any CB1 receptor population in memory processes with any certainty. This makes it all the more important that behavioural studies use selective administration of drugs to specific brain areas, rather than global administration to whole animals. The emerging role of the endogenous cannabinoid system in the hippocampus may be to facilitate the induction of long-term potentiation/the encoding of information. Administration of exogenous selective CB1 agonists may therefore disrupt hippocampus-dependent learning and memory by 'increasing the noise', rather than 'decreasing the signal' at

  9. Cannabinoids: is there a potential treatment role in epilepsy?

    Science.gov (United States)

    Blair, Robert E; Deshpande, Laxmikant S; DeLorenzo, Robert J

    2015-01-01

    Cannabinoids have been used medicinally for centuries, and in the last decade, attention has focused on their broad therapeutic potential particularly in seizure management. While some cannabinoids have demonstrated anticonvulsant activity in experimental studies, their efficacy for managing clinical seizures has not been fully established. This commentary will touch on our understanding of the brain endocannabinoid system's regulation of synaptic transmission in both physiological and pathophysiological conditions, and review the findings from both experimental and clinical studies on the effectiveness of cannabinoids to suppress epileptic seizures. At present, there is preliminary evidence that non-psychoactive cannabinoids may be useful as anticonvulsants, but additional clinical trials are needed to fully evaluate the efficacy and safety of these compounds for the treatment of epilepsy.

  10. The Synthetic Cannabinoids Phenomenon.

    Science.gov (United States)

    Karila, Laurent; Benyamina, Amine; Blecha, Lisa; Cottencin, Olivier; Billieux, Joël

    2016-01-01

    « Spice » is generally used to describe the diverse types of herbal blends that encompass synthetic cannabinoids on the market. The emergence of smokable herbal products containing synthetic cannabinoids, which mimic the effects of cannabis, appears to become increasingly popular, in the new psychoactive substances landscape. In 2014, the existence of 134 different types of synthetic cannabinoids were reported by the European Union Early Warning System. These drugs are mainly sold online as an alternative to controlled and regulated psychoactive substances. They appear to have a life cycle of about 1-2 years before being replaced by a next wave of products. Legislation controlling these designer drugs has been introduced in many countries with the objective to limit the spread of existing drugs and control potential new analogs. The majority of the synthetic cannabinoids are full agonists at the CB1 receptor and do not contain tobacco or cannabis. They are becoming increasingly popular in adolescents, students and clubbers as an abused substance. Relatively high incidence of adverse effects associated with synthetic cannabinoids use has been documented in the literature. Numerous fatalities linked with their use and abuse have been reported. In this paper, we will review the available data regarding the use and effects of synthetic cannabinoids in humans in order to highlight their impact on public health. To reach this objective, a literature search was performed on two representative databases (Pubmed, Google Scholar), the Erowid Center website (a US non-profit educational organization that provides information about psychoactive plants and chemicals), and various governmental websites. The terms used for the database search were: "synthetic cannabinoids", "spice", "new psychoactive substances", and/or "substance use disorder", and/or "adverse effects", and/or "fatalities". The search was limited to years 2005 to 2016 due to emerging scientific literature at

  11. Type 1 Immune Mechanisms Driven by the Response to Infection with Attenuated Rabies Virus Result in Changes in the Immune Bias of the Tumor Microenvironment and Necrosis of Mouse GL261 Brain Tumors.

    Science.gov (United States)

    Bongiorno, Emily K; Garcia, Samantha A; Sauma, Sami; Hooper, D Craig

    2017-06-01

    Immunotherapeutic strategies for malignant glioma have to overcome the immunomodulatory activities of M2 monocytes that appear in the circulation and as tumor-associated macrophages (TAMs). M2 cell products contribute to the growth-promoting attributes of the tumor microenvironment (TME) and bias immunity toward type 2, away from the type 1 mechanisms with antitumor properties. To drive type 1 immunity in CNS tissues, we infected GL261 tumor-bearing mice with attenuated rabies virus (RABV). These neurotropic viruses spread to CNS tissues trans-axonally, where they induce a strong type 1 immune response that involves Th1, CD8, and B cell entry across the blood-brain barrier and virus clearance in the absence of overt sequelae. Intranasal infection with attenuated RABV prolonged the survival of mice bearing established GL261 brain tumors. Despite the failure of virus spread to the tumor, infection resulted in significantly enhanced tumor necrosis, extensive CD4 T cell accumulation, and high levels of the proinflammatory factors IFN-γ, TNF-α, and inducible NO synthase in the TME merely 4 d postinfection, before significant virus spread or the appearance of RABV-specific immune mechanisms in CNS tissues. Although the majority of infiltrating CD4 cells appeared functionally inactive, the proinflammatory changes in the TME later resulted in the loss of accumulating M2 and increased M1 TAMs. Mice deficient in the Th1 transcription factor T-bet did not gain any survival advantage from RABV infection, exhibiting only limited tumor necrosis and no change in TME cytokines or TAM phenotype and highlighting the importance of type 1 mechanisms in this process. Copyright © 2017 by The American Association of Immunologists, Inc.

  12. Cannabinoids and gliomas.

    Science.gov (United States)

    Velasco, Guillermo; Carracedo, Arkaitz; Blázquez, Cristina; Lorente, Mar; Aguado, Tania; Haro, Amador; Sánchez, Cristina; Galve-Roperh, Ismael; Guzmán, Manuel

    2007-08-01

    Cannabinoids, the active components of Cannabis sativa L., act in the body by mimicking endogenous substances--the endocannabinoids--that activate specific cell surface receptors. Cannabinoids exert various palliative effects in cancer patients. In addition, cannabinoids inhibit the growth of different types of tumor cells, including glioma cells, in laboratory animals. They do so by modulating key cell signaling pathways, mostly the endoplasmic reticulum stress response, thereby inducing antitumoral actions such as the apoptotic death of tumor cells and the inhibition of tumor angiogenesis. Of interest, cannabinoids seem to be selective antitumoral compounds, as they kill glioma cells, but not their non-transformed astroglial counterparts. On the basis of these preclinical findings, a pilot clinical study of Delta(9)-tetrahydrocannabinol (THC) in patients with recurrent glioblastoma multiforme has been recently run. The good safety profile of THC, together with its possible growth-inhibiting action on tumor cells, justifies the setting up of future trials aimed at evaluating the potential antitumoral activity of cannabinoids.

  13. Neuropathology does not Correlate with Regional Differences in the Extent of Expansion of CTG Repeats in the Brain with Myotonic Dystrophy Type 1.

    Science.gov (United States)

    Itoh, Kyoko; Mitani, Maki; Kawamoto, Kunihiko; Futamura, Naonobu; Funakawa, Itaru; Jinnai, Kenji; Fushiki, Shinji

    2010-12-29

    Myotonic dystrophy (DM1) is known to be an adult-onset muscular dystrophy caused by the expansion of CTG repeats within the 3' untranslated region of the dystrophin myotonin protein kinase (DMPK) gene. The clinical features of DM1 include CNS symptoms, such as cognitive impairment and personality changes, the pathogenesis of which remains to be elucidated. We hypothesized that the distribution of neuropathological changes might be correlated with the extent of the length of the CTG repeats in the DMPK genes in DM1 patients. We studied the neuropathological changes in the brains of subjects with DM1 and investigated the extent of somatic instability in terms of CTG repeat expansion in the different brain regions of the same individuals by Southern blot analysis. The neuropathological changes included état criblé in the cerebral deep white matter and neurofibrillary tangles immunoreactive for phosphorylated tau in the hippocampus and entorhinal cortex, both of which were compatible with the subcortical dementia in DM1 patients. However, the length of the CTG repeats did not correlate with the regional differences in the extent of neuropathological changes. Our data suggested that pathomechanisms of dementia in DM1 might be more multifactorial rather than a toxic gain-of-function due to mutant RNA.

  14. [High-altitude hypoxia induces disorders of the brain-endocrine-immune network through activation of corticotropin-releasing factor and its type-1 receptors].

    Science.gov (United States)

    Chen, Xue-Qun; Kong, Fan-Ping; Zhao, Yang; Du, Ji-Zeng

    2012-11-01

    High-altitude hypoxia can induce physiological dysfunction and mountain sickness, but the underlying mechanism is not fully understood. Corticotrophin-releasing factor (CRF) and CRF type-i receptors (CRFR1) are members of the CRF family and the essential controllers of the physiological activity of the hypothalamo-pituitary-adrenal (HPA) axis and modulators of endocrine and behavioral activity in response to various stressors. We have previously found that high-altitude hypoxia induces disorders of the brain-endocrine-immune network through activation of CRF and CRFR1 in the brain and periphery that include activation of the HPA axis in a time- and dose-dependent manner, impaired or improved learning and memory, and anxiety-like behavioral change. Meanwhile, hypoxia induces dysfunctions of the hypothalamo-pituitary-endocrine and immune systems, including suppression of growth and development, as well as inhibition of reproductive, metabolic and immune functions. In contrast, the small mammals that live on the Qinghai-Tibet Plateau alpine meadow display low responsiveness to extreme high-altitude-hypoxia challenge, suggesting well-acclimatized genes and a physiological strategy that developed during evolution through interactions between the genes and environment. All the findings provide evidence for understanding the neuroendocrine mechanisms of hypoxia-induced physiological dysfunction. This review extends these findings.

  15. Alzheimer's disease; taking the edge off with cannabinoids?

    Science.gov (United States)

    Campbell, V A; Gowran, A

    2007-11-01

    Alzheimer's disease is an age-related neurodegenerative condition associated with cognitive decline. The pathological hallmarks of the disease are the deposition of beta-amyloid protein and hyperphosphorylation of tau, which evoke neuronal cell death and impair inter-neuronal communication. The disease is also associated with neuroinflammation, excitotoxicity and oxidative stress. In recent years the proclivity of cannabinoids to exert a neuroprotective influence has received substantial interest as a means to mitigate the symptoms of neurodegenerative conditions. In brains obtained from Alzheimer's patients alterations in components of the cannabinoid system have been reported, suggesting that the cannabinoid system either contributes to, or is altered by, the pathophysiology of the disease. Certain cannabinoids can protect neurons from the deleterious effects of beta-amyloid and are capable of reducing tau phosphorylation. The propensity of cannabinoids to reduce beta-amyloid-evoked oxidative stress and neurodegeneration, whilst stimulating neurotrophin expression neurogenesis, are interesting properties that may be beneficial in the treatment of Alzheimer's disease. Delta 9-tetrahydrocannabinol can also inhibit acetylcholinesterase activity and limit amyloidogenesis which may improve cholinergic transmission and delay disease progression. Targeting cannabinoid receptors on microglia may reduce the neuroinflammation that is a feature of Alzheimer's disease, without causing psychoactive effects. Thus, cannabinoids offer a multi-faceted approach for the treatment of Alzheimer's disease by providing neuroprotection and reducing neuroinflammation, whilst simultaneously supporting the brain's intrinsic repair mechanisms by augmenting neurotrophin expression and enhancing neurogenesis. The evidence supporting a potential role for the cannabinoid system as a therapeutic target for the treatment of Alzheimer's disease will be reviewed herewith.

  16. Cannabinoids Regulate the Diameter of Pericyte-Containing Retinal Capillaries in Rats

    Directory of Open Access Journals (Sweden)

    Yuan Zong

    2017-10-01

    Full Text Available Background/Aims: Cannabinoids are vasoactive substances that act as key regulators of arterial tone in the blood vessels supplying peripheral tissues and the central nervous system. We therefore investigated the effect of cannabinoids on retinal capillaries and pericytes. Methods: The effects of cannabinoids on capillary diameters were determined using an ex vivo whole-mount rat retinal model. Western blotting, quantitative PCR, and immunohistochemistry were performed to explore the underlying mechanism. Results: Endogenous cannabinoid 2-arachidonoylglycerol and anandamide and exogenous cannabinoid (R-(+-WIN55212-2 dilated the noradrenaline-precontracted capillaries in a concentration-dependent manner (1 µM to 0.1 mM. The extent of vasorelaxation was positively correlated with changes in pericyte width. The effects of R-(+-WIN55212-2 on vasorelaxation and pericyte width were inhibited by a cannabinoid receptor type-1 (CB1 antagonist, AM251 or rimonabant (SR141716A, the nitric oxide synthase inhibitor l-NAME, and the guanylate cyclase inhibitor ODQ. They were also abolished by the removal of the endothelium, but not by the cannabinoid receptor-2 antagonist SR144528, the endothelial cannabinoid receptor antagonist O-1918, or the cyclooxygenase inhibitor indomethacin. Conclusion: The exogenous cannabinoid R-(+-WIN55212-2 promotes the vasorelaxation of pericyte-containing rat retinal capillaries. This effect of R-(+-WIN55212-2 is dependent on CB1 and the nitric oxide–cyclic guanosine monophosphate pathway, and requires an intact endothelium.

  17. Diabetes Mellitus Type 1

    OpenAIRE

    Trydal, Kari

    2015-01-01

    Hvert år får rundt 300 barn og 600 voksne diabetes mellitus type 1, og til sammen har rundt 28 000 personer denne sykdommen i Norge i dag. Det er en kronisk metabolsk sykdom, med en absolutt insulinmangel. Gjennom litteratur og forskning er det vist, at for å forebygge senkomplikasjoner, trenger pasienten informasjon, undervisning og praktisk veiledning når det gjelder medisinering, kosthold og fysisk aktivitet, og motivering til å mestre sykdommen. I praksis vil sykepleier spille en aktiv ro...

  18. Laryngeal cleft type 1

    Directory of Open Access Journals (Sweden)

    Danilo de Assis Pereira

    2015-06-01

    Full Text Available The clinical itinerary and the institution of conservative therapy in a case of laryngeal cleft type 1 refers to a child born by cesarean section, Apgar 9 and 10, a history of placental nd abruption in the 2 month of pregnancy, with respiratory nd distress on the 2 day of life and difficulty in breast feeding mothers. Presented evidence of aspiration pneumonia. The videodeglutogram showed aspiration of large amounts of material contrasted during swallowing. In bronchoscopy was visualized formation of threadlike small slit making the diagnosis of laryngeal cleft. We then decided, by institution of conservative treatment with enteral nutrition training and thickened with swallowing.

  19. Spicing things up: synthetic cannabinoids.

    Science.gov (United States)

    Spaderna, Max; Addy, Peter H; D'Souza, Deepak Cyril

    2013-08-01

    Recently, products containing synthetic cannabinoids, collectively referred to as Spice, are increasingly being used recreationally. The availability, acute subjective effects-including self-reports posted on Erowid-laboratory detection, addictive potential, and regulatory challenges of the Spice phenomenon are reviewed. Spice is sold under the guise of potpourri or incense. Unlike delta-9-tetrahydrocannabinol, the synthetic cannabinoids present in Spice are high-potency, high-efficacy, cannabinoid receptor full agonists. Since standard urine toxicology does not test for the synthetic cannabinoids in Spice, it is often used by those who want to avoid detection of drug use. These compounds have not yet been subjected to rigorous testing in humans. Acute psychoactive effects include changes in mood, anxiety, perception, thinking, memory, and attention. Adverse effects include anxiety, agitation, panic, dysphoria, psychosis, and bizarre behavior. Psychosis outcomes associated with Spice provide additional data linking cannabinoids and psychosis. Adverse events necessitating intervention by Poison Control Centers, law enforcement, emergency responders, and hospitals are increasing. Despite statutes prohibiting the manufacture, distribution, and sale of Spice products, manufacturers are replacing banned compounds with newer synthetic cannabinoids that are not banned. There is an urgent need for better research on the effects of synthetic cannabinoids to help clinicians manage adverse events and to better understand cannabinoid pharmacology in humans. The reported psychosis outcomes associated with synthetic cannabinoids contribute to the ongoing debate on the association between cannabinoids and psychosis. Finally, drug detection tests for synthetic cannabinoids need to become clinically available.

  20. Spicing thing up: Synthetic cannabinoids

    Science.gov (United States)

    Spaderna, Max; Addy, Peter H; D’Souza, Deepak Cyril

    2013-01-01

    Rationale Recently, products containing synthetic cannabinoids, collectively referred to as Spice, are increasingly being used recreationally. Objectives The availability, acute subjective effects—including self-reports posted on Erowid—laboratory detection, addictive potential, and regulatory challenges of the Spice phenomenon are reviewed. Results Spice is sold under the guise of potpourri or incense. Unlike THC, the synthetic cannabinoids present in Spice are high-potency, high-efficacy, cannabinoid-receptor full agonists. Since standard urine toxicology does not test for the synthetic cannabinoids in Spice, it is often used by those who want to avoid detection of drug use. These compounds have not yet been subjected to rigorous testing in humans. Acute psychoactive effects include changes in mood, anxiety, perception, thinking, memory, and attention. Adverse effects include anxiety, agitation, panic, dysphoria, psychosis, and bizarre behavior. Psychosis outcomes associated with Spice provide additional data linking cannabinoids and psychosis. Adverse events necessitating intervention by Poison Control Centers, law enforcement, emergency responders, and hospitals are increasing. Despite statutes prohibiting the manufacture, distribution, and sale of Spice products, manufacturers are replacing banned compounds with newer synthetic cannabinoids that are not banned. Conclusions There is an urgent need for better research on the effects of synthetic cannabinoids to help clinicians manage adverse events and to better understand cannabinoid pharmacology in humans. The reported psychosis outcomes associated with synthetic cannabinoids contribute to the ongoing debate on the association between cannabinoids and psychosis. Finally, drug-detection tests for synthetic cannabinoids need to become clinically available. PMID:23836028

  1. Synthetic cannabinoids revealing adrenoleukodystrophy.

    Science.gov (United States)

    Fellner, Avi; Benninger, Felix; Djaldetti, Ruth

    2016-02-01

    We report a 41-year-old man who presented with a first generalized tonic-clonic seizure after recent consumption of a synthetic cannabinoid. MRI showed extensive bilateral, mainly frontal, white matter lesions. Blood analysis for very long chain fatty acids was compatible with adrenoleukodystrophy, and a missense mutation in the ABCD1 gene confirmed the diagnosis. We hypothesize that cannabinoid use might have contributed to metabolic decompensation with subacute worsening of the underlying condition. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Type 1 autoimmune pancreatitis

    Directory of Open Access Journals (Sweden)

    Zen Yoh

    2011-12-01

    Full Text Available Abstract Before the concept of autoimmune pancreatitis (AIP was established, this form of pancreatitis had been recognized as lymphoplasmacytic sclerosing pancreatitis or non-alcoholic duct destructive chronic pancreatitis based on unique histological features. With the discovery in 2001 that serum IgG4 concentrations are specifically elevated in AIP patients, this emerging entity has been more widely accepted. Classical cases of AIP are now called type 1 as another distinct subtype (type 2 AIP has been identified. Type 1 AIP, which accounts for 2% of chronic pancreatitis cases, predominantly affects adult males. Patients usually present with obstructive jaundice due to enlargement of the pancreatic head or thickening of the lower bile duct wall. Pancreatic cancer is the leading differential diagnosis for which serological, imaging, and histological examinations need to be considered. Serologically, an elevated level of IgG4 is the most sensitive and specific finding. Imaging features include irregular narrowing of the pancreatic duct, diffuse or focal enlargement of the pancreas, a peri-pancreatic capsule-like rim, and enhancement at the late phase of contrast-enhanced images. Biopsy or surgical specimens show diffuse lymphoplasmacytic infiltration containing many IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis. A dramatic response to steroid therapy is another characteristic, and serological or radiological effects are normally identified within the first 2 or 3 weeks. Type 1 AIP is estimated as a pancreatic manifestation of systemic IgG4-related disease based on the fact that synchronous or metachronous lesions can develop in multiple organs (e.g. bile duct, salivary/lacrimal glands, retroperitoneum, artery, lung, and kidney and those lesions are histologically identical irrespective of the organ of origin. Several potential autoantigens have been identified so far. A Th2-dominant immune reaction and the activation of

  3. Type 1 Tyrosinaemia

    LENUS (Irish Health Repository)

    Mannion, MA

    2016-06-01

    Tyrosinaemia type 1 (TYR1, OMIM# 276700) is a rare autosomal recessive disease that results from an enzyme defect that leads to a deficiency in fumarylacetoacetase (FAH)1. We present 3 cases of TYR1 in the Irish population over a 9 year period, the only cases known to have been diagnosed in Ireland since 1989. The common presenting symptom was hypoglycaemia and the diagnosis was made by the identification of the pathognomonic biomarker succinylacetone on urine organic acid analysis. We discuss the clinical presentation, biochemical and genetic results including one novel mutation. We also highlight the importance of early initiation of Nitisinone (NTBC), which reduces the complications of TYR1 and the incidence of liver transplantation in this population2.

  4. Cannabinoids: Medical implications.

    Science.gov (United States)

    Schrot, Richard J; Hubbard, John R

    2016-01-01

    Herbal cannabis has been used for thousands of years for medical purposes. With elucidation of the chemical structures of tetrahydrocannabinol (THC) and cannabidiol (CBD) and with discovery of the human endocannabinoid system, the medical usefulness of cannabinoids has been more intensively explored. While more randomized clinical trials are needed for some medical conditions, other medical disorders, like chronic cancer and neuropathic pain and certain symptoms of multiple sclerosis, have substantial evidence supporting cannabinoid efficacy. While herbal cannabis has not met rigorous FDA standards for medical approval, specific well-characterized cannabinoids have met those standards. Where medical cannabis is legal, patients typically see a physician who "certifies" that a benefit may result. Physicians must consider important patient selection criteria such as failure of standard medical treatment for a debilitating medical disorder. Medical cannabis patients must be informed about potential adverse effects, such as acute impairment of memory, coordination and judgment, and possible chronic effects, such as cannabis use disorder, cognitive impairment, and chronic bronchitis. In addition, social dysfunction may result at work/school, and there is increased possibility of motor vehicle accidents. Novel ways to manipulate the endocannbinoid system are being explored to maximize benefits of cannabinoid therapy and lessen possible harmful effects.

  5. Cannabinoids, endocannabinoids, and cancer.

    Science.gov (United States)

    Hermanson, Daniel J; Marnett, Lawrence J

    2011-12-01

    The endocannabinoid system consists of an array of endogenously produced bioactive lipids that activate cannabinoid receptors. Although the primary focus of endocannabinoid biology has been on neurological and psychiatric effects, recent work has revealed several important interactions between the endocannabinoid system and cancer. Several different types of cancer have abnormal regulation of the endocannabinoid system that contributes to cancer progression and correlates to clinical outcomes. Modulation of the endocannabinoid system by pharmacological agents in various cancer types reveals that it can mediate antiproliferative and apoptotic effects by both cannabinoid receptor-dependent and -independent pathways. Selective agonists and antagonists of the cannabinoid receptors, inhibitors of endocannabinoid hydrolysis, and cannabinoid analogs have been utilized to probe the pathways involved in the effects of the endocannabinoid system on cancer cell apoptosis, proliferation, migration, adhesion, and invasion. The antiproliferative and apoptotic effects produced by some of these pharmacological probes reveal that the endocannabinoid system is a promising new target for the development of novel chemotherapeutics to treat cancer.

  6. Cannabinoids and cancer.

    Science.gov (United States)

    Kogan, Natalya M

    2005-10-01

    Marijuana has been used in medicine for millennia, but it was not until 1964 that delta9-tetrahydrocannabinol (delta9-THC), its major psychoactive component, was isolated in pure form and its structure was elucidated. Shortly thereafter it was synthesized and became readily available. However, it took another decade until the first report on its antineoplastic activity appeared. In 1975, Munson discovered that cannabinoids suppress Lewis lung carcinoma cell growth. The mechanism of this action was shown to be inhibition of DNA synthesis. Antiproliferative action on some other cancer cells was also found. In spite of the promising results from these early studies, further investigations in this area were not reported until a few years ago, when almost simultaneously two groups initiated research on the antiproliferative effects of cannabinoids on cancer cells: Di Marzo's group found that cannabinoids inhibit breast cancer cell proliferation, and Guzman's group found that cannabinoids inhibit the growth of C6 glioma cell. Other groups also started work in this field, and today, a wide array of cancer cell lines that are affected is known, and some mechanisms involved have been elucidated.

  7. The role of cannabinoids in modulating emotional and non-emotional memory processes in the hippocampus

    Directory of Open Access Journals (Sweden)

    Irit eAkirav

    2011-06-01

    Full Text Available Cannabinoid agonists generally have a disruptive effect on memory, learning, and operant behavior that is considered to be hippocampus-dependent. Nevertheless, under certain conditions, cannabinoid receptor activation may facilitate neuronal learning processes. For example, CB1 receptors are essential for the extinction of conditioned fear associations, indicating an important role for this receptor in neuronal emotional learning and memory. This review examines the diverse effects of cannabinoids on hippocampal memory and plasticity. It shows how the effects of cannabinoid receptor activation may vary depending on the route of administration, the nature of the task (aversive or not, and whether it involves emotional memory formation (e.g. conditioned fear and extinction learning or non-emotional memory formation (e.g. spatial learning. It also examines the memory stage under investigation (acquisition, consolidation, retrieval, extinction, and the brain areas involved. Differences between the effects of exogenous and endogenous agonists are also discussed. The apparently biphasic effects of cannabinoids on anxiety is noted as this implies that the effects of cannabinoid receptor agonists on hippocampal learning and memory may be attributable to a general modulation of anxiety or stress levels and not to memory per se. The review concludes that cannabinoids have diverse effects on hippocampal memory and plasticity that cannot be categorized simply into an impairing or an enhancing effect. A better understanding of the involvement of cannabinoids in memory processes will help determine whether the benefits of the clinical use of cannabinoids outweigh the risks of possible memory impairments.

  8. CB1 AND CB2 CANNABINOID RECEPTOR EXPRESSION DURING DEVELOPMENT AND IN EPILEPTOGENIC DEVELOPMENTAL PATHOLOGIES

    NARCIS (Netherlands)

    Zurolo, E.; Iyer, A. M.; Spliet, W. G. M.; van Rijen, P. C.; Troost, D.; Gorter, J. A.; Aronica, E.

    2010-01-01

    Recent data support the involvement of the endocannabinoid signaling in early brain development, as well as a key role of cannabinoid receptors (CBR) in pathological conditions associated with unbalanced neuronal excitability and inflammation. Using immunocytochemistry, we explored the expression

  9. CB1 and CB2 cannabinoid receptor expression during development and in epileptogenic developmental pathologies

    NARCIS (Netherlands)

    Zurolo, E.; Iyer, A.M.; Spliet, W.G.M.; van Rijen, P.C.; Troost, D.; Gorter, J.A.; Aronica, E.

    2010-01-01

    Recent data support the involvement of the endocannabinoid signaling in early brain development, as well as a key role of cannabinoid receptors (CBR) in pathological conditions associated with unbalanced neuronal excitability and inflammation. Using immunocytochemistry, we explored the expression

  10. Type 1 diabetes mellitus.

    Science.gov (United States)

    Katsarou, Anastasia; Gudbjörnsdottir, Soffia; Rawshani, Araz; Dabelea, Dana; Bonifacio, Ezio; Anderson, Barbara J; Jacobsen, Laura M; Schatz, Desmond A; Lernmark, Åke

    2017-03-30

    Type 1 diabetes mellitus (T1DM), also known as autoimmune diabetes, is a chronic disease characterized by insulin deficiency due to pancreatic β-cell loss and leads to hyperglycaemia. Although the age of symptomatic onset is usually during childhood or adolescence, symptoms can sometimes develop much later. Although the aetiology of T1DM is not completely understood, the pathogenesis of the disease is thought to involve T cell-mediated destruction of β-cells. Islet-targeting autoantibodies that target insulin, 65 kDa glutamic acid decarboxylase, insulinoma-associated protein 2 and zinc transporter 8 - all of which are proteins associated with secretory granules in β-cells - are biomarkers of T1DM-associated autoimmunity that are found months to years before symptom onset, and can be used to identify and study individuals who are at risk of developing T1DM. The type of autoantibody that appears first depends on the environmental trigger and on genetic factors. The pathogenesis of T1DM can be divided into three stages depending on the absence or presence of hyperglycaemia and hyperglycaemia-associated symptoms (such as polyuria and thirst). A cure is not available, and patients depend on lifelong insulin injections; novel approaches to insulin treatment, such as insulin pumps, continuous glucose monitoring and hybrid closed-loop systems, are in development. Although intensive glycaemic control has reduced the incidence of microvascular and macrovascular complications, the majority of patients with T1DM are still developing these complications. Major research efforts are needed to achieve early diagnosis, prevent β-cell loss and develop better treatment options to improve the quality of life and prognosis of those affected.

  11. Update on the Role of Cannabinoid Receptors after Ischemic Stroke

    Directory of Open Access Journals (Sweden)

    Luciano S. A. Capettini

    2012-01-01

    Full Text Available Cannabinoids are considered as key mediators in the pathophysiology of inflammatory diseases, including atherosclerosis. In particular, they have been shown to reduce the ischemic injury after acute cardiovascular events, such as acute myocardial infarction and ischemic stroke. These protective and anti-inflammatory properties on peripheral tissues and circulating inflammatory have been demonstrated to involve their binding with both selective cannabinoid type 1 (CB1 and type 2 (CB2 transmembrane receptors. On the other hands, the recent discoveries of novel different classes of cannabinoids and receptors have increased the complexity of this system in atherosclerosis. Although only preliminary data have been reported on the activities of novel cannabinoid receptors, several studies have already investigated the role of CB1 and CB2 receptors in ischemic stroke. While CB1 receptor activation has been shown to directly reduce atherosclerotic plaque inflammation, controversial data have been shown on neurotransmission and neuroprotection after stroke. Given its potent anti-inflammatory activities on circulating leukocytes, the CB2 activation has been proven to produce protective effects against acute poststroke inflammation. In this paper, we will update evidence on different cannabinoid-triggered avenues to reduce inflammation and neuronal injury in acute ischemic stroke.

  12. Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation.

    Science.gov (United States)

    Ramírez, Belén G; Blázquez, Cristina; Gómez del Pulgar, Teresa; Guzmán, Manuel; de Ceballos, María L

    2005-02-23

    Alzheimer's disease (AD) is characterized by enhanced beta-amyloid peptide (betaA) deposition along with glial activation in senile plaques, selective neuronal loss, and cognitive deficits. Cannabinoids are neuroprotective agents against excitotoxicity in vitro and acute brain damage in vivo. This background prompted us to study the localization, expression, and function of cannabinoid receptors in AD and the possible protective role of cannabinoids after betaA treatment, both in vivo and in vitro. Here, we show that senile plaques in AD patients express cannabinoid receptors CB1 and CB2, together with markers of microglial activation, and that CB1-positive neurons, present in high numbers in control cases, are greatly reduced in areas of microglial activation. In pharmacological experiments, we found that G-protein coupling and CB1 receptor protein expression are markedly decreased in AD brains. Additionally, in AD brains, protein nitration is increased, and, more specifically, CB1 and CB2 proteins show enhanced nitration. Intracerebroventricular administration of the synthetic cannabinoid WIN55,212-2 to rats prevent betaA-induced microglial activation, cognitive impairment, and loss of neuronal markers. Cannabinoids (HU-210, WIN55,212-2, and JWH-133) block betaA-induced activation of cultured microglial cells, as judged by mitochondrial activity, cell morphology, and tumor necrosis factor-alpha release; these effects are independent of the antioxidant action of cannabinoid compounds and are also exerted by a CB2-selective agonist. Moreover, cannabinoids abrogate microglia-mediated neurotoxicity after betaA addition to rat cortical cocultures. Our results indicate that cannabinoid receptors are important in the pathology of AD and that cannabinoids succeed in preventing the neurodegenerative process occurring in the disease.

  13. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes

    Science.gov (United States)

    De Petrocellis, Luciano; Ligresti, Alessia; Moriello, Aniello Schiano; Allarà, Marco; Bisogno, Tiziana; Petrosino, Stefania; Stott, Colin G; Di Marzo, Vincenzo

    2011-01-01

    BACKGROUND AND PURPOSE Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) interact with transient receptor potential (TRP) channels and enzymes of the endocannabinoid system. EXPERIMENTAL APPROACH The effects of 11 pure cannabinoids and botanical extracts [botanical drug substance (BDS)] from Cannabis varieties selected to contain a more abundant cannabinoid, on TRPV1, TRPV2, TRPM8, TRPA1, human recombinant diacylglycerol lipase α (DAGLα), rat brain fatty acid amide hydrolase (FAAH), COS cell monoacylglycerol lipase (MAGL), human recombinant N-acylethanolamine acid amide hydrolase (NAAA) and anandamide cellular uptake (ACU) by RBL-2H3 cells, were studied using fluorescence-based calcium assays in transfected cells and radiolabelled substrate-based enzymatic assays. Cannabinol (CBN), cannabichromene (CBC), the acids (CBDA, CBGA, THCA) and propyl homologues (CBDV, CBGV, THCV) of CBD, cannabigerol (CBG) and THC, and tetrahydrocannabivarin acid (THCVA) were also tested. KEY RESULTS CBD, CBG, CBGV and THCV stimulated and desensitized human TRPV1. CBC, CBD and CBN were potent rat TRPA1 agonists and desensitizers, but THCV-BDS was the most potent compound at this target. CBG-BDS and THCV-BDS were the most potent rat TRPM8 antagonists. All non-acid cannabinoids, except CBC and CBN, potently activated and desensitized rat TRPV2. CBDV and all the acids inhibited DAGLα. Some BDS, but not the pure compounds, inhibited MAGL. CBD was the only compound to inhibit FAAH, whereas the BDS of CBC > CBG > CBGV inhibited NAAA. CBC = CBG > CBD inhibited ACU, as did the BDS of THCVA, CBGV, CBDA and THCA, but the latter extracts were more potent inhibitors. CONCLUSIONS AND IMPLICATIONS These results are relevant to the analgesic, anti-inflammatory and anti-cancer effects of cannabinoids and Cannabis extracts. LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011

  14. Pregnenolone can protect the brain from cannabis intoxication.

    Science.gov (United States)

    Vallée, Monique; Vitiello, Sergio; Bellocchio, Luigi; Hébert-Chatelain, Etienne; Monlezun, Stéphanie; Martin-Garcia, Elena; Kasanetz, Fernando; Baillie, Gemma L; Panin, Francesca; Cathala, Adeline; Roullot-Lacarrière, Valérie; Fabre, Sandy; Hurst, Dow P; Lynch, Diane L; Shore, Derek M; Deroche-Gamonet, Véronique; Spampinato, Umberto; Revest, Jean-Michel; Maldonado, Rafael; Reggio, Patricia H; Ross, Ruth A; Marsicano, Giovanni; Piazza, Pier Vincenzo

    2014-01-03

    Pregnenolone is considered the inactive precursor of all steroid hormones, and its potential functional effects have been largely uninvestigated. The administration of the main active principle of Cannabis sativa (marijuana), Δ(9)-tetrahydrocannabinol (THC), substantially increases the synthesis of pregnenolone in the brain via activation of the type-1 cannabinoid (CB1) receptor. Pregnenolone then, acting as a signaling-specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals a previously unknown paracrine/autocrine loop protecting the brain from CB1 receptor overactivation that could open an unforeseen approach for the treatment of cannabis intoxication and addiction.

  15. [Therapeutic applications and biomedical effects of cannabinoids; pharmacological starting points].

    Science.gov (United States)

    Killestein, J; Nelemans, S A

    1997-08-30

    A broad range of therapeutic applications has been suggested for cannabis or its pharmacologically active compound (tetrahydrocannabinol; THC) in many publications. Psychotropic side effects and the anecdotal character of the research have limited the pharmacotherapeutic use of THC until now. Therefore, the Netherlands Health Council recently decided negatively on this matter. Besides several cannabinoid receptor subtypes present in the central nervous system and peripheral tissues endogenous cannabinoids have been detected. These endogenous cannabinoids appear to play an important role in signal transduction, which may be starting points for therapy regarding: cardiovascular diseases, multiple sclerosis and spinal cord disorders. cerebrovascular accident and brain trauma, neurodegenerative diseases, epilepsy, pain management, glaucoma, oncologic and aids-related disorders such as nausea, vomiting and appetite problems.

  16. Cannabis, cannabinoids and reproduction.

    Science.gov (United States)

    Park, Boram; McPartland, John M; Glass, Michelle

    2004-02-01

    In most countries Cannabis is the most widely used illegal drug. Its use during pregnancy in developed nations is estimated to be approximately 10%. Recent evidence suggests that the endogenous cannabinoid system, now consisting of two receptors and multiple endocannabinoid ligands, may also play an important role in the maintenance and regulation of early pregnancy and fertility. The purpose of this review is therefore twofold, to examine the impact that cannabis use may have on fertility and reproduction, and to review the potential role of the endocannabinoid system in hormonal regulation, embryo implantation and maintenance of pregnancy.

  17. Exogenous and Endogenous Cannabinoids Suppress Inhibitory Neurotransmission in the Human Neocortex

    Science.gov (United States)

    Kovacs, Flora E; Knop, Tim; Urbanski, Michal J; Freiman, Ilka; Freiman, Thomas M; Feuerstein, Thomas J; Zentner, Josef; Szabo, Bela

    2012-01-01

    Activation of CB1 receptors on axon terminals by exogenous cannabinoids (eg, Δ9-tetrahydrocannabinol) and by endogenous cannabinoids (endocannabinoids) released by postsynaptic neurons leads to presynaptic inhibition of neurotransmission. The aim of this study was to characterize the effect of cannabinoids on GABAergic synaptic transmission in the human neocortex. Brain slices were prepared from neocortical tissues surgically removed to eliminate epileptogenic foci. Spontaneous GABAergic inhibitory postsynaptic currents (sIPSCs) were recorded in putative pyramidal neurons using patch-clamp techniques. To enhance the activity of cannabinoid-sensitive presynaptic axons, muscarinic receptors were continuously stimulated by carbachol. The synthetic cannabinoid receptor agonist WIN55212-2 decreased the cumulative amplitude of sIPSCs. The CB1 antagonist rimonabant prevented this effect, verifying the involvement of CB1 receptors. WIN55212-2 decreased the frequency of miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin, but did not change their amplitude, indicating that the neurotransmission was inhibited presynaptically. Depolarization of postsynaptic pyramidal neurons induced a suppression of sIPSCs. As rimonabant prevented this suppression, it is very likely that it was due to endocannabinods acting on CB1 receptors. This is the first demonstration that an exogenous cannabinoid inhibits synaptic transmission in the human neocortex and that endocannabinoids released by postsynaptic neurons suppress synaptic transmission in the human brain. Interferences of cannabinoid agonists and antagonists with synaptic transmission in the cortex may explain the cognitive and memory deficits elicited by these drugs. PMID:22048459

  18. Sesquiterpenoids from the Root of Panax ginseng Attenuates Lipopolysaccharide-Induced Depressive-Like Behavior through the Brain-Derived Neurotrophic Factor/Tropomyosin-Related Kinase B and Sirtuin Type 1/Nuclear Factor-κB Signaling Pathways.

    Science.gov (United States)

    Wang, Weidong; Liu, Xiaofeng; Liu, Jinping; Cai, Enbo; Zhao, Yan; Li, Haijun; Zhang, Lianxue; Li, Pingya; Gao, Yugang

    2018-01-10

    The previous study indicated sesquiterpenoids from the root of Panax ginseng (SPG) exhibited a significant antidepressant-like effect, which might be mediated by the modification of the dopaminergic, GABAergic, and glutamatergic systems. This study was to investigate antidepressant effects and mechanisms on the lipopolysaccharide (LPS)-induced depression-like behavior of SPG. In the tail suspension test (TST) and forced swimming test (FST), SPG (0.25 and 1 mg/kg, i.g.) and fluoxetine (20 mg/kg, i.p.) effectively reduced the immobility time. SPG treatment significantly reduced serum levels of IL-6 and TNF-α and increased suppressed superoxide dismutase (SOD) activity in the hippocampus. In addition, SPG effectively upregulated the brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB), and sirtuin type 1 (Sirt 1) expression in the hippocampus and downregulated the inhibitor of κB-α (IκB-α) and nuclear factor-κB (NF-κB) phosphorylation. These results suggested that SPG exhibited an antidepressant-like effect through the BDNF/TrkB and Sirt 1/NF-κB signaling pathways.

  19. Diabetes Type 1 - Multiple Languages

    Science.gov (United States)

    ... Are Here: Home → Multiple Languages → All Health Topics → Diabetes Type 1 URL of this page: https://medlineplus.gov/languages/ ... V W XYZ List of All Topics All Diabetes Type 1 - Multiple Languages To use the sharing features on ...

  20. Type 1 Diabetes and Sleep.

    Science.gov (United States)

    Farabi, Sarah S

    2016-02-01

    IN BRIEF In people with type 1 diabetes, sleep may be disrupted as a result of both behavioral and physiological aspects of diabetes and its management. This sleep disruption may negatively affect disease progression and development of complications. This review highlights key research findings regarding sleep in people with type 1 diabetes.

  1. Type 1 Diabetes and Sleep

    OpenAIRE

    Farabi, Sarah S.

    2016-01-01

    IN BRIEF In people with type 1 diabetes, sleep may be disrupted as a result of both behavioral and physiological aspects of diabetes and its management. This sleep disruption may negatively affect disease progression and development of complications. This review highlights key research findings regarding sleep in people with type 1 diabetes.

  2. Beyond THC: the new generation of cannabinoid designer drugs

    Directory of Open Access Journals (Sweden)

    Liana eFattore

    2011-09-01

    Full Text Available Synthetic cannabinoids are functionally similar to delta9-tetrahydrocannabinol (THC, the psychoactive principle of cannabis, and bind to the same cannabinoid receptors in the brain and peripheral organs. From 2008, synthetic cannabinoids were detected in herbal smoking mixtures sold on websites and in head shops under the brand name of Spice Gold, Yucatan Fire, Aroma, and others. Although these products (also known as Spice drugs or legal highs do not contain tobacco or cannabis, when smoked they produce effects similar to THC. Intoxication, withdrawal, psychosis and death have been recently reported after consumption, posing difficult social, political and health challenges. More than 140 different Spice products have been identified to date. The ability to induce strong cannabis-like psychoactive effects, along with the fact that they are readily available on the Internet, still legal in many countries, marketed as natural safe substances, and undetectable by conventional drug screening tests, has rendered these drugs very popular and particularly appealing to young and drug-naïve individuals seeking new experiences. An escalating number of compounds with cannabinoid receptor activity are currently being found as ingredients of Spice, of which almost nothing is known in terms of pharmacology, toxicology and safety. Since legislation started to control the synthetic cannabinoids identified in these herbal mixtures, many new analogs have appeared on the market. New cannabimimetic compounds are likely to be synthesized in the near future to replace banned synthetic cannabinoids, leading to a dog chasing its tail situation. Spice smokers are exposed to drugs that are extremely variable in composition and potency, and are at risk of serious, if not lethal, outcomes. Social and health professionals should maintain a high degree of alertness for Spice use and its possible psychiatric effects in vulnerable people.

  3. Effects of the cannabinoid CB1 receptor antagonist rimonabant on distinct measures of impulsive behavior in rats

    NARCIS (Netherlands)

    Pattij, Tommy; Janssen, Mieke; Schepers, Inga; González-Cuevas, Gustavo; Vries, de Taco; Schoffelmeer, Anton

    2007-01-01

    Rationale Pathological impulsivity is a prominent feature in several psychiatric disorders, but detailed understanding of the specific neuronal processes underlying impulsive behavior is as yet lacking. Objectives As recent findings have suggested involvement of the brain cannabinoid

  4. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes.

    Science.gov (United States)

    De Petrocellis, Luciano; Ligresti, Alessia; Moriello, Aniello Schiano; Allarà, Marco; Bisogno, Tiziana; Petrosino, Stefania; Stott, Colin G; Di Marzo, Vincenzo

    2011-08-01

    Cannabidiol (CBD) and Δ(9) -tetrahydrocannabinol (THC) interact with transient receptor potential (TRP) channels and enzymes of the endocannabinoid system. The effects of 11 pure cannabinoids and botanical extracts [botanical drug substance (BDS)] from Cannabis varieties selected to contain a more abundant cannabinoid, on TRPV1, TRPV2, TRPM8, TRPA1, human recombinant diacylglycerol lipase α (DAGLα), rat brain fatty acid amide hydrolase (FAAH), COS cell monoacylglycerol lipase (MAGL), human recombinant N-acylethanolamine acid amide hydrolase (NAAA) and anandamide cellular uptake (ACU) by RBL-2H3 cells, were studied using fluorescence-based calcium assays in transfected cells and radiolabelled substrate-based enzymatic assays. Cannabinol (CBN), cannabichromene (CBC), the acids (CBDA, CBGA, THCA) and propyl homologues (CBDV, CBGV, THCV) of CBD, cannabigerol (CBG) and THC, and tetrahydrocannabivarin acid (THCVA) were also tested. CBD, CBG, CBGV and THCV stimulated and desensitized human TRPV1. CBC, CBD and CBN were potent rat TRPA1 agonists and desensitizers, but THCV-BDS was the most potent compound at this target. CBG-BDS and THCV-BDS were the most potent rat TRPM8 antagonists. All non-acid cannabinoids, except CBC and CBN, potently activated and desensitized rat TRPV2. CBDV and all the acids inhibited DAGLα. Some BDS, but not the pure compounds, inhibited MAGL. CBD was the only compound to inhibit FAAH, whereas the BDS of CBC > CBG > CBGV inhibited NAAA. CBC = CBG > CBD inhibited ACU, as did the BDS of THCVA, CBGV, CBDA and THCA, but the latter extracts were more potent inhibitors. These results are relevant to the analgesic, anti-inflammatory and anti-cancer effects of cannabinoids and Cannabis extracts. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  5. Repeated administration of phytocannabinoid Δ(9)-THC or synthetic cannabinoids JWH-018 and JWH-073 induces tolerance to hypothermia but not locomotor suppression in mice, and reduces CB1 receptor expression and function in a brain region-specific manner.

    Science.gov (United States)

    Tai, S; Hyatt, W S; Gu, C; Franks, L N; Vasiljevik, T; Brents, L K; Prather, P L; Fantegrossi, W E

    2015-12-01

    These studies probed the relationship between intrinsic efficacy and tolerance/cross-tolerance between ∆(9)-THC and synthetic cannabinoid drugs of abuse (SCBs) by examining in vivo effects and cellular changes concomitant with their repeated administration in mice. Dose-effect relationships for hypothermic effects were determined in order to confirm that SCBs JWH-018 and JWH-073 are higher efficacy agonists than ∆(9)-THC in mice. Separate groups of mice were treated with saline, sub-maximal hypothermic doses of JWH-018 or JWH-073 (3.0mg/kg or 10.0mg/kg, respectively) or a maximally hypothermic dose of 30.0mg/kg ∆(9)-THC once per day for 5 consecutive days while core temperature and locomotor activity were monitored via biotelemetry. Repeated administration of all drugs resulted in tolerance to hypothermic effects, but not locomotor effects, and this tolerance was still evident 14 days after the last drug administration. Further studies treated mice with 30.0mg/kg ∆(9)-THC once per day for 4 days, then tested with SCBs on day 5. Mice with a ∆(9)-THC history were cross-tolerant to both SCBs, and this cross-tolerance also persisted 14 days after testing. Select brain regions from chronically treated mice were examined for changes in CB1 receptor expression and function. Expression and function of hypothalamic CB1Rs were reduced in mice receiving chronic drugs, but cortical CB1R expression and function were not altered. Collectively, these data demonstrate that repeated ∆(9)-THC, JWH-018 and JWH-073 can induce long-lasting tolerance to some in vivo effects, which is likely mediated by region-specific downregulation and desensitization of CB1Rs. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. [The pharmacology of cannabinoid derivatives: are there applications to treatment of pain?].

    Science.gov (United States)

    Beaulieu, P; Rice, A S C

    2002-06-01

    To present the cannabinoid system together with recent findings on the pharmacology of these compounds in the treatment of pain. Search through Medline database of articles published in French and English since 1966. Also use of other publications such as books on cannabis. All the relevant documents within the theme of this review were used. All the data linked to the present topic were searched. Recent advances have dramatically increased our understanding of cannabinoid pharmacology. The psychoactive constituents of Cannabis sativa have been isolated, synthetic cannabinoids described and an endocannabinoid system identified, together with its component receptors and ligands. Strong laboratory evidence now underwrites anecdotal claims of cannabinoid analgesia in inflammatory and neuropathic pain. Sites of analgesic action have been identified in brain, spinal cord and the periphery, with the latter two presenting attractive targets for divorcing the analgesic and psychotrophic effects of cannabinoids. Clinical trials are now required, but are hindered by a paucity of cannabinoids of suitable bioavailability and therapeutic ratio. The cannabinoid system is a major target in the treatment of pain and its therapeutic potential should be assessed in the near future by the performance of new clinical trials.

  7. Cannabinoid pharmacology: the first 66 years

    OpenAIRE

    Pertwee, Roger G.

    2006-01-01

    Research into the pharmacology of individual cannabinoids that began in the 1940s, several decades after the presence of a cannabinoid was first detected in cannabis, is concisely reviewed. Also described is how this pharmacological research led to the discovery of cannabinoid CB1 and CB2 receptors and of endogenous ligands for these receptors, to the development of CB1- and CB2-selective agonists and antagonists and to the realization that the endogenous cannabinoid system has significant ro...

  8. Effect of synthetic cannabinoid HU210 on memory deficits and neuropathology in Alzheimer's disease mouse model.

    Science.gov (United States)

    Chen, B; Bromley-Brits, K; He, G; Cai, F; Zhang, X; Song, W

    2010-05-01

    Cannabinoids have been shown to increase neurogenesis in adult brain, as well as protect neurons from excitotoxicity, calcium influx, inflammation, and ischemia. Recent studies have shown that synthetic cannabinoids can alleviate water maze impairments in rats treated with intracranial amyloid beta protein (Abeta); however it is unknown whether this effect is due to the cannabinoids' anti-inflammatory properties or whether it affects Abeta processing. Here we investigate whether cannabinoids have any effect on Alzheimer's disease in vivo. We found that HU210, a potent synthetic cannabinoid, did not improve water maze performance or a contextual fear conditioning task in an APP23/PS45 double transgenic mouse model of AD. HU210 had no effect on APP processing and Abeta generation, as well as neuritic plaque formation in the brains of AD transgenic mice. Our study showed that synthetic cannabinoid HU210 had no beneficial effects on AD neuropathology and behavioral deficits of AD model mice, which advises caution of such drug's application in AD therapies.

  9. The Analgesic Potential of Cannabinoids

    Science.gov (United States)

    Elikottil, Jaseena; Gupta, Pankaj; Gupta, Kalpna

    2013-01-01

    Historically and anecdotally cannabinoids have been used as analgesic agents. In recent years, there has been an escalating interest in developing cannabis-derived medications to treat severe pain. This review provides an overview of the history of cannabis use in medicine, cannabinoid signaling pathways, and current data from preclinical as well as clinical studies on using cannabinoids as potential analgesic agents. Clinical and experimental studies show that cannabis-derived compounds act as anti-emetic, appetite modulating and analgesic agents. However, the efficacy of individual products is variable and dependent upon the route of administration. Since opioids are the only therapy for severe pain, analgesic ability of cannabinoids may provide a much-needed alternative to opioids. Moreover, cannabinoids act synergistically with opioids and act as opioid sparing agents, allowing lower doses and fewer side effects from chronic opioid therapy. Thus, rational use of cannabis based medications deserves serious consideration to alleviate the suffering of patients due to severe pain. PMID:20073408

  10. Cannabinoids in health and disease

    Science.gov (United States)

    Kogan, Natalya M.; Mechoulam, Raphael

    2007-01-01

    Cannabis sativa L. preparations have been used in medicine for millenia. However, concern over the dangers of abuse led to the banning of the medicinal use of marijuana in most countries in the 1930s. Only recently, marijuana and individual natural and synthetic cannabinoid receptor agonists and antagonists, as well as chemically related compounds, whose mechanism of action is still obscure, have come back to being considered of therapeutic value. However, their use is highly restricted. Despite the mild addiction to cannabis and the possible enhancement of addiction to other substances of abuse, when combined with cannabis, the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases, such as anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Tourette's syndrome, Alzheimer's disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders, to name just a few, are being treated or have the potential to be treated by cannabinoid agonists/antagonists/cannabinoid-related compounds. In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable - instead, we need to work on the development of more selective cannabinoid receptor agonists/antagonists and related compounds, as well as on novel drugs of this family with better selectivity, distribution patterns, and pharmacokinetics, and - in cases where it is impossible to separate the desired clinical action and the psychoactivity - just to monitor these side effects carefully. PMID:18286801

  11. Cannabinoids: occurrence and medicinal chemistry.

    Science.gov (United States)

    Appendino, G; Chianese, G; Taglialatela-Scafati, O

    2011-01-01

    With an inventory of several hundreds secondary metabolites identified, Cannabis sativa L. (hemp) is one of the phytochemically best characterized plant species. The biomedical relevance of hemp undoubtedly underlies the wealth of data on its constituents and their biological activities, and cannabinoids, a class of unique meroterpenoids derived from the alkylation of an olivetollike alkyl resorcinol with a monoterpene unit, are the most typical constituents of Cannabis. In addition to the well-known psychotropic properties of Δ(9)-THC, cannabinoids have been reported to show potential in various fields of medicine, with the capacity to address unmet needs like the relief of chemotherapy-derived nausea and anorexia, and symptomatic mitigation of multiple sclerosis. Many of the potential therapeutic uses of cannabinoids are related to the interaction with (at least) two cannabinoid G-protein coupled receptors (CB1 and CB2). However, a number of activities, like the antibacterial or the antitumor properties are non totally dependent or fully independent from the interaction with these proteins. These pharmacological activities are particularly interesting since, in principle, they could be easily dissociated by the unwanted psychotropic effects. This review aims at giving readers a survey of the more recent advances in both phytochemistry of C. sativa, the medicinal chemistry of cannabinoids, and their distribution in plants, highlighting the impact that research in these hot fields could have for modern medicinal chemistry and pharmacology.

  12. CB1 Cannabinoid Receptors Modulate Kinase and Phosphatase Activity during Extinction of Conditioned Fear in Mice

    Science.gov (United States)

    Kamprath, Kornelia; Hermann, Heike; Lutz, Beat; Marsicano, Giovanni; Cannich, Astrid; Wotjak, Carsten T.

    2004-01-01

    Cannabinoid receptors type 1 (CB1) play a central role in both short-term and long-term extinction of auditory-cued fear memory. The molecular mechanisms underlying this function remain to be clarified. Several studies indicated extracellular signal-regulated kinases (ERKs), the phosphatidylinositol 3-kinase with its downstream effector AKT, and…

  13. Neurophysiological evidence for the presence of cannabinoid CB1 receptors in the laterodorsal tegmental nucleus

    DEFF Research Database (Denmark)

    Soni, Neeraj; Satpathy, Shankha; Kohlmeier, Kristi Anne

    2014-01-01

    Marijuana, which acts within the endocannabinoid (eCB) system as an agonist of the cannabinoid type 1 receptor (CB1R), exhibits addictive properties and has powerful actions on the state of arousal of an organism. The laterodorsal tegmental nucleus (LDT), as a component of the reticular activating...

  14. Cannabinoid modulation of drug reward and the implications of marijuana legalization.

    Science.gov (United States)

    Covey, Dan P; Wenzel, Jennifer M; Cheer, Joseph F

    2015-12-02

    Marijuana is the most popular illegal drug worldwide. Recent trends indicate that this may soon change; not due to decreased marijuana use, but to an amendment in marijuana's illegal status. The cannabinoid type 1 (CB1) receptor mediates marijuana's psychoactive and reinforcing properties. CB1 receptors are also part of the brain endocannabinoid (eCB) system and support numerous forms of learning and memory, including the conditioned reinforcing properties of cues predicting reward or punishment. This is accomplished via eCB-dependent alterations in mesolimbic dopamine function, which plays an obligatory role in reward learning and motivation. Presynaptic CB1 receptors control midbrain dopamine neuron activity and thereby shape phasic dopamine release in target regions, particularly the nucleus accumbens (NAc). By also regulating synaptic input to the NAc, CB1 receptors modulate NAc output onto downstream neurons of the basal ganglia motor circuit, and thereby support goal-directed behaviors. Abused drugs promote short- and long-term adaptations in eCB-regulation of mesolimbic dopamine function, and thereby hijack neural systems related to the pursuit of rewards to promote drug abuse. By pharmacologically targeting the CB1 receptors, marijuana has preferential access to this neuronal system and can potently alter eCB-dependent processing of reward-related stimuli. As marijuana legalization progresses, greater access to this drug should increase the utility of marijuana as a research tool to better understand the eCB system, which has the potential to advance cannabinoid-based treatments for drug addiction. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Cannabinoid pharmacology: the first 66 years.

    Science.gov (United States)

    Pertwee, Roger G

    2006-01-01

    Research into the pharmacology of individual cannabinoids that began in the 1940s, several decades after the presence of a cannabinoid was first detected in cannabis, is concisely reviewed. Also described is how this pharmacological research led to the discovery of cannabinoid CB(1) and CB(2) receptors and of endogenous ligands for these receptors, to the development of CB(1)- and CB(2)-selective agonists and antagonists and to the realization that the endogenous cannabinoid system has significant roles in both health and disease, and that drugs which mimic, augment or block the actions of endogenously released cannabinoids must have important therapeutic applications. Some goals for future research are identified.

  16. Cannabinoids in the Cardiovascular System.

    Science.gov (United States)

    Ho, Wing S V; Kelly, Melanie E M

    2017-01-01

    Cannabinoids are known to modulate cardiovascular functions including heart rate, vascular tone, and blood pressure in humans and animal models. Essential components of the endocannabinoid system, namely, the production, degradation, and signaling pathways of endocannabinoids have been described not only in the central and peripheral nervous system but also in myocardium, vasculature, platelets, and immune cells. The mechanisms of cardiovascular responses to endocannabinoids are often complex and may involve cannabinoid CB1 and CB2 receptors or non-CB1/2 receptor targets. Preclinical and some clinical studies have suggested that targeting the endocannabinoid system can improve cardiovascular functions in a number of pathophysiological conditions, including hypertension, metabolic syndrome, sepsis, and atherosclerosis. In this chapter, we summarize the local and systemic cardiovascular effects of cannabinoids and highlight our current knowledge regarding the therapeutic potential of endocannabinoid signaling and modulation. © 2017 Elsevier Inc. All rights reserved.

  17. Synthesis and Biological Evaluation of Thiophene-Based Cannabinoid Receptor Type 2 Radiotracers for PET Imaging

    Directory of Open Access Journals (Sweden)

    Ahmed Haider

    2016-07-01

    Full Text Available Over the past two decades, our understanding of the endocannabinoid system has greatly improved due to the wealth of results obtained from exploratory studies. Currently, two cannabinoid receptor subtypes have been well characterized. The cannabinoid receptor type 1 (CB1 is widely expressed in the central nervous system, while the levels of the cannabinoid receptor type 2 (CB2 in the brain and spinal cord of healthy individuals are relatively low. However, recent studies demonstrated a CB2 upregulation on activated microglia upon neuroinflammation, an indicator of neurodegeneration. Our research group aims to develop a suitable positron emission tomography (PET tracer to visualize the CB2 receptor in patients suffering from neurodegenerative diseases. Herein we report two novel thiophene-based 11C-labeled PET ligands designated [11C]AAT-015 and [11C]AAT-778. The reference compounds were synthesized using Gewald reaction conditions to obtain the aminothiophene intermediates, followed by amide formation. Saponification of the esters provided their corresponding precursors. Binding affinity studies revealed Ki values of 3.3 ± 0.5 nM (CB2 and 1.0 ± 0.2 µM (CB1 for AAT-015. AAT-778 showed similar Ki values of 4.3 ± 0.7 nM (CB2 and 1.1 ± 0.1 µM (CB1. Radiosynthesis was carried out under basic conditions using [11C]iodomethane as methylating agent. After semi-preparative HPLC purification both radiolabeled compounds were obtained in 99% radiochemical purity and the radiochemical yields ranged from 12 to 37%. Specific activity was between 96 - 449 GBq/µmol for both tracers. In order to demonstrate CB2 specificity of [11C]AAT-015 and [11C]AAT-778, we carried out autoradiography studies using CB2-positive mouse/rat spleen tissues. The obtained results revealed unspecific binding in spleen tissue that was not blocked by an excess of CB2-specific ligand GW402833. For in vivo analysis, [11C]AAT-015 was administered to healthy rats via tail

  18. Cannabinoids for fibromyalgia.

    Science.gov (United States)

    Walitt, Brian; Klose, Petra; Fitzcharles, Mary-Ann; Phillips, Tudor; Häuser, Winfried

    2016-07-18

    This review is one of a series on drugs used to treat fibromyalgia. Fibromyalgia is a clinically well-defined chronic condition of unknown aetiology characterised by chronic widespread pain that often co-exists with sleep problems and fatigue affecting approximately 2% of the general population. People often report high disability levels and poor health-related quality of life (HRQoL). Drug therapy focuses on reducing key symptoms and disability, and improving HRQoL. Cannabis has been used for millennia to reduce pain and other somatic and psychological symptoms. To assess the efficacy, tolerability and safety of cannabinoids for fibromyalgia symptoms in adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE to April 2016, together with reference lists of retrieved papers and reviews, three clinical trial registries, and contact with trial authors. We selected randomised controlled trials of at least four weeks' duration of any formulation of cannabis products used for the treatment of adults with fibromyalgia. Two review authors independently extracted the data of all included studies and assessed risk of bias. We resolved discrepancies by discussion. We performed analysis using three tiers of evidence. First tier evidence was derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for drop-outs; at least 200 participants in the comparison, eight to 12 weeks' duration, parallel design), second tier evidence from data that did not meet one or more of these criteria and were considered at some risk of bias but with adequate numbers (i.e. data from at least 200 participants) in the comparison, and third tier evidence from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both. We assessed the

  19. CB2 Cannabinoid Receptor Knockout in Mice Impairs Contextual Long-Term Memory and Enhances Spatial Working Memory

    Directory of Open Access Journals (Sweden)

    Yong Li

    2016-01-01

    Full Text Available Neurocognitive effects of cannabinoids have been extensively studied with a focus on CB1 cannabinoid receptors because CB1 receptors have been considered the major cannabinoid receptor in the nervous system. However, recent discoveries of CB2 cannabinoid receptors in the brain demand accurate determination of whether and how CB2 receptors are involved in the cognitive effects of cannabinoids. CB2 cannabinoid receptors are primarily involved in immune functions, but also implicated in psychiatric disorders such as schizophrenia and depression. Here, we examined the effects of CB2 receptor knockout in mice on memory to determine the roles of CB2 receptors in modulating cognitive function. Behavioral assays revealed that hippocampus-dependent, long-term contextual fear memory was impaired whereas hippocampus-independent, cued fear memory was normal in CB2 receptor knockout mice. These mice also displayed enhanced spatial working memory when tested in a Y-maze. Motor activity and anxiety of CB2 receptor knockout mice were intact when assessed in an open field arena and an elevated zero maze. In contrast to the knockout of CB2 receptors, acute blockade of CB2 receptors by AM603 in C57BL/6J mice had no effect on memory, motor activity, or anxiety. Our results suggest that CB2 cannabinoid receptors play diverse roles in regulating memory depending on memory types and/or brain areas.

  20. 76 FR 71351 - Prospective Grant of Exclusive License: Development of Cannabinoid(s) and Cannabidiol(s) Based...

    Science.gov (United States)

    2011-11-17

    ... Cannabinoid(s) and Cannabidiol(s) Based Therapeutics To Treat Hepatic Encephalopathy in Humans. AGENCY... be limited to: The development and sale of cannabinoid(s) and cannabidiol(s) based therapeutics as... chronic neurodegenerative diseases. Nonpsychoactive cannabinoids, such as Cannabidiol (CBD), are...

  1. Small Molecules from Nature Targeting G-Protein Coupled Cannabinoid Receptors: Potential Leads for Drug Discovery and Development

    Directory of Open Access Journals (Sweden)

    Charu Sharma

    2015-01-01

    Full Text Available The cannabinoid molecules are derived from Cannabis sativa plant which acts on the cannabinoid receptors types 1 and 2 (CB1 and CB2 which have been explored as potential therapeutic targets for drug discovery and development. Currently, there are numerous cannabinoid based synthetic drugs used in clinical practice like the popular ones such as nabilone, dronabinol, and Δ9-tetrahydrocannabinol mediates its action through CB1/CB2 receptors. However, these synthetic based Cannabis derived compounds are known to exert adverse psychiatric effect and have also been exploited for drug abuse. This encourages us to find out an alternative and safe drug with the least psychiatric adverse effects. In recent years, many phytocannabinoids have been isolated from plants other than Cannabis. Several studies have shown that these phytocannabinoids show affinity, potency, selectivity, and efficacy towards cannabinoid receptors and inhibit endocannabinoid metabolizing enzymes, thus reducing hyperactivity of endocannabinoid systems. Also, these naturally derived molecules possess the least adverse effects opposed to the synthetically derived cannabinoids. Therefore, the plant based cannabinoid molecules proved to be promising and emerging therapeutic alternative. The present review provides an overview of therapeutic potential of ligands and plants modulating cannabinoid receptors that may be of interest to pharmaceutical industry in search of new and safer drug discovery and development for future therapeutics.

  2. Thujone exhibits low affinity for cannabinoid receptors but fails to evoke cannabimimetic responses.

    Science.gov (United States)

    Meschler, J P; Howlett, A C

    1999-03-01

    Absinthe, an abused drug in the early 1900s, has been speculated to activate the receptors responsible for marijuana intoxication (the CB1 cannabinoid receptor) (Nature 253:365-356; 1975). To test this hypothesis, we investigated oil of wormwood (Artemisia absinthium) the active plant product found in absinthe, and thujone, the active compound found in oil of wormwood. Radioligand receptor binding assays employing membrane preparations from rat brains containing CB1 cannabinoid receptors, and human tonsils containing CB2 receptors, demonstrated that thujone displaced [3H]CP55940, a cannabinoid agonist, only at concentrations above 10 microM. HPLC analysis of oil of wormwood revealed that only the fractions having mobility close to thujone displaced [3H]CP55940 from the CB1 cannabinoid receptor. [35S]GTPgammaS binding assays revealed that thujone failed to stimulate G-proteins even at 0.1 mM. Thujone failed to inhibit forskolin-stimulated adenylate cyclase activity in N18TG2 membranes at 1 mM. Rats administered thujone exhibited different behavioral characteristics compared with rats administered a potent cannabinoid agonist, levonantradol. Therefore, the hypothesis that activation of cannabinoid receptors is responsible for the intoxicating effects of thujone is not supported by the present data.

  3. Evaluation of the In Vivo and Ex Vivo Binding of Novel BC1 Cannabinoid Receptor Radiotracers

    Energy Technology Data Exchange (ETDEWEB)

    Miller, A.; Gatley, J.; Gifford, A.

    2002-01-01

    The primary active ingredient of marijuana, 9-tetrahydrocannabinol, exerts its psychoactive effects by binding to cannabinoid CB1 receptors. These receptors are found throughout the brain with high concentrations in the hippocampus and cerebellum. The current study was conducted to evaluate the binding of a newly developed putative cannabinoid antagonist, AM630, and a classical cannabinoid 8-tetrahydrocannabinol as potential PET and/or SPECT imaging agents for brain CB1 receptors. For both of these ligands in vivo and ex vivo studies in mice were conducted. AM630 showed good overall brain uptake (as measure by %IA/g) and a moderately rapid clearance from the brain with a half-clearance time of approximately 30 minutes. However, AM630 did not show selective binding to CB1 cannabinoid receptors. Ex vivo autoradiography supported the lack of selective binding seen in the in vivo study. Similar to AM630, 8-tetrahydrocanibol also failed to show selective binding to CB1 receptor rich brain areas. The 8-tetrahydrocanibol showed moderate overall brain uptake and relatively slow brain clearance as compared to AM630. Further studies were done with AM2233, a cannabinoid ligand with a similar structure as AM630. These studies were done to develop an ex vivo binding assay to quantify the displacement of [131I]AM2233 binding by other ligands in Swiss-Webster and CB1 receptor knockout mice. By developing this assay we hoped to determine the identity of an unknown binding site for AM2233 present in the hippocampus of CB1 knockout mice. Using an approach based on incubation of brain slices prepared from mice given intravenous [131I]AM2233 in either the presence or absence of AM2233 (unlabelled) it was possible to demonstrate a significant AM2233-displacable binding in the Swiss-Webster mice. Future studies will determine if this assay is appropriate for identifying the unknown binding site for AM2233 in the CB1 knockout mice.

  4. Barn og diabetes type 1

    OpenAIRE

    Ramstad, Marte Elise; Sagbakken, Sina Bekkelund

    2017-01-01

    Bacheloroppgave sykepleie, 2017 Bakgrunn: Vi har valgt denne problemstillingen fordi diabetes type 1 er svært utbredt hos barn i Norge. Videre har vi lite erfaringer med barn og ønsket å lære mer om denne pasientgruppen. Vi ønsket videre å se på hvordan vi kan undervise og veilede for å gi god og hensiktsmessig sykepleie til barn og deres familier. Hensikt: Finne ut hvordan sykepleier kan fremme egenomsorg hos barn med diabetes gjennom veiledning og undervisning. Dette er noe som sykepl...

  5. Cannabinoids, eating behaviour, and energy homeostasis.

    Science.gov (United States)

    Romero-Zerbo, Silvana Y; Bermúdez-Silva, Francisco J

    2014-01-01

    Soon after the discovery of cannabis by western societies, its psychotropic effects overshadowed its medical benefits. However, investigation into the molecular action of the main constituents of cannabis has led to the discovery of an intercellular signalling system, called the endocannabinoid system (ECS). The ECS comprises a set of molecular components, including enzymes, signalling lipids and G-protein coupled receptors, which has an outstanding role in modulating eating behaviour and energy homeostasis. Interestingly, evidence has shown that the ECS is present at the central and peripheral nervous system, modulating the function of the hypothalamus, the brain reward system and the brainstem, and coordinating the crosstalk between these brain structures and peripheral organs. Indeed, the ECS is present and functional in metabolically relevant peripheral tissues, directly modulating their physiology. In the context of a global obesity pandemic, these discoveries are highly suggestive in order to design novel pharmaceutical tools to fight obesity and related morbidities. In fact, a cannabinoid-based first generation of drugs was developed and marketed. Their failure, due to central side-effects, is leading to a second generation of these drugs unable to cross the blood-brain barrier, as well as other ECS-focused strategies that are still in the pipeline. In the next few years we will hopefully know whether such an important player in energy homeostasis can be successfully targeted without significantly affecting other vital processes related to mood and sense of well-being. Copyright © 2013 John Wiley & Sons, Ltd.

  6. Autoimmune Polyglandular Syndrome Type 1

    Directory of Open Access Journals (Sweden)

    Vedeswari C Ponranjini

    2012-01-01

    Full Text Available Autoimmune Polyglandular Syndrome (APS Type 1 is a rare hereditary disorder that damages organs in the body. This disease entity is the result of a mutation in the AIRE gene. It is characterized by three classic clinical features - hypoparathyroidism, Addison′s disease, and chronic mucocutaneous candidiasis. For a patient to be diagnosed as having APS Type 1 syndrome at least two of these features needs to be present. The third entity may develop as the disease progresses. We report a case of a 35-year-old female patient with a history of seizure from the age of 11 years, who was managed with anticonvulsant drugs. With worsening of the seizure episodes, patient was diagnosed to have hypoparathyroidism together with the manifestations of oral candidiasis, nails dystrophy, enamel hypoplasia, and hypogonadism. A diagnosis of APS-1 was considered. The facility for genetic analysis of the AIRE gene mutation was not accessible, as the test costs were prohibitive and not affordable for the patient. Patient management was directed to treating individual disease components. However, cerebral and dental changes were irreversible.

  7. The use of cannabinoids as anticancer agents.

    Science.gov (United States)

    Velasco, Guillermo; Hernández-Tiedra, Sonia; Dávila, David; Lorente, Mar

    2016-01-04

    It is well-established that cannabinoids exert palliative effects on some cancer-associated symptoms. In addition evidences obtained during the last fifteen years support that these compounds can reduce tumor growth in animal models of cancer. Cannabinoids have been shown to activate an ER-stress related pathway that leads to the stimulation of autophagy-mediated cancer cell death. In addition, cannabinoids inhibit tumor angiogenesis and decrease cancer cell migration. The mechanisms of resistance to cannabinoid anticancer action as well as the possible strategies to develop cannabinoid-based combinational therapies to fight cancer have also started to be explored. In this review we will summarize these observations (that have already helped to set the bases for the development of the first clinical studies to investigate the potential clinical benefit of using cannabinoids in anticancer therapies) and will discuss the possible future avenues of research in this area. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  8. An update on PPAR activation by cannabinoids.

    Science.gov (United States)

    O'Sullivan, Saoirse Elizabeth

    2016-06-01

    Some cannabinoids activate the different isoforms of PPARs (α, β and γ), as shown through the use of reporter gene assays, binding studies, selective antagonists and knockout studies. Activation of all isoforms, but primarily PPARα and γ, mediates some (but not all) of the analgesic, neuroprotective, neuronal function modulation, anti-inflammatory, metabolic, anti-tumour, gastrointestinal and cardiovascular effects of some cannabinoids, often in conjunction with activation of the more traditional target sites of action such as the cannabinoid CB1 and CB2 receptors and the TRPV1 ion channel. PPARs also mediate some of the effects of inhibitors of endocannabinoid degradation or transport. Cannabinoids may be chaperoned to the PPARs by fatty acid binding proteins. The aims of this review are to update the evidence supporting PPAR activation by cannabinoids and to review the physiological responses to cannabinoids that are mediated, and not mediated, by PPAR activation. © 2016 The British Pharmacological Society.

  9. Labelling and biological evaluation of [{sup 11}C]methoxy-Sch225336: a radioligand for the cannabinoid-type 2 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Evens, Nele [Laboratory for Radiopharmacy, K.U.Leuven, Leuven 3000 (Belgium); Bosier, Barbara [Department of Pharmaceutical Chemistry and Radiopharmacy, U.C.L., Brussels 1200 (Belgium); Lavey, Brian J.; Kozlowski, Joseph A. [Schering Plough Research Institute, Kenilworth, NJ 07033 (United States); Vermaelen, Peter [Division of Nuclear Medicine, K.U.Leuven, Leuven 3000 (Belgium); Baudemprez, Luc; Busson, Roger [Laboratory of Medicinal Chemistry, K.U.Leuven, Leuven 3000 (Belgium); Lambert, Didier M. [Department of Pharmaceutical Chemistry and Radiopharmacy, U.C.L., Brussels 1200 (Belgium); Van Laere, Koen [Division of Nuclear Medicine, K.U.Leuven, Leuven 3000 (Belgium); Verbruggen, Alfons M. [Laboratory for Radiopharmacy, K.U.Leuven, Leuven 3000 (Belgium); Bormans, Guy M. [Laboratory for Radiopharmacy, K.U.Leuven, Leuven 3000 (Belgium)], E-mail: guy.bormans@pharm.kuleuven.be

    2008-10-15

    Introduction: The cannabinoid type 2 receptor (CB{sub 2} receptor) is part of the endocannabinoid system and has been suggested as mediator of a number of central and peripheral inflammatory processes. In the present study, we have synthesized N-[(1s)-1-[4-[[4-methoxy-2-[(4-[{sup 11}C]methoxyphenyl)sulfonyl) -phenyl]sulfonyl] phenyl]ethyl]methanesulfonamide ([{sup 11}C]methoxy-Sch225336) and evaluated this new tracer agent as a potential positron emission tomography radioligand for the in vivo visualization of CB{sub 2} receptors. Methods: Sch225336 was demethylated and the resulting phenol precursor was radiolabelled with a carbon-11 methyl group by methylation using [{sup 11}C]methyl iodide, followed by purification by high-performance liquid chromatography. The log P of [{sup 11}C]methoxy-Sch225336 and its biodistribution in normal mice were determined. Enhancement of brain uptake by inhibition of blood-brain barrier (BBB) efflux transporters was studied. Mouse plasma was analysed to quantify the formation of radiometabolites. The affinity of Sch225336 for the human cannabinoid type 1 and type 2 receptor was determined. Results: [{sup 11}C]methoxy-Sch225336 was obtained with a decay corrected radiochemical yield of about 30% and a specific activity of 88.8 GBq/{mu}mol (end of synthesis). After intravenous injection in mice, the compound is rapidly cleared from the blood through the hepatobiliary pathway and does not show particular retention in any of the major organs. Polar metabolites were found in mouse plasma. Brain uptake was low despite the favourable log P value of 2.15, which is partly due to efflux by BBB pumps. Conclusion: [{sup 11}C]methoxy-Sch225336 is a good candidate for in vivo imaging of the CB{sub 2} receptor, although the low blood-brain barrier penetration limits its potential for central nervous system imaging.

  10. Genetics Home Reference: type 1 diabetes

    Science.gov (United States)

    ... Home Health Conditions Type 1 diabetes Type 1 diabetes Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Type 1 diabetes is a disorder characterized by abnormally high blood ...

  11. Cannabinoids for cancer treatment: progress and promise.

    Science.gov (United States)

    Sarfaraz, Sami; Adhami, Vaqar M; Syed, Deeba N; Afaq, Farrukh; Mukhtar, Hasan

    2008-01-15

    Cannabinoids are a class of pharmacologic compounds that offer potential applications as antitumor drugs, based on the ability of some members of this class to limit inflammation, cell proliferation, and cell survival. In particular, emerging evidence suggests that agonists of cannabinoid receptors expressed by tumor cells may offer a novel strategy to treat cancer. Here, we review recent work that raises interest in the development and exploration of potent, nontoxic, and nonhabit forming cannabinoids for cancer therapy.

  12. What causes type 1 diabetes?

    DEFF Research Database (Denmark)

    Buschard, Karsten

    2011-01-01

    To study type 1 diabetes (T1D), excellent animal models exist, both spontaneously diabetic and virus-induced. Based on knowledge from these, this review focuses on the environmental factors leading to T1D, concentrated into four areas which are: (1) The thymus-dependent immune system: T1D is a T...... the T1D process, even if initiated by virus. Theoretically, the risk from immunotherapy elicits a higher frequency of malignancy. (2) The activity of the beta cells: Resting beta cells display less antigenicity and are less sensitive to immune destruction. Beta-cell rest can be induced by giving insulin...... externally in metabolic doses or by administering potassium-channel openers. Both procedures prevent T1D in animal models, whereas no good human data exist due to the risk of hypoglycemia. (3) NKT cells: According to the hygiene hypothesis, stimulation of NKT cells by non-pathogen microbes gives rise to less...

  13. [Sport and type 1 diabetes].

    Science.gov (United States)

    Büsser, C; Meyer, P; Philippe, J; Jornayvaz, F R

    2013-06-05

    Physical activity is recognised to be an efficient measure in improving glycemic control in the treatment of type 2 diabetes. This evidence is lacking in type I diabetes but type 1I diabetics benefit from the same advantages like the general population. For many type I diabetics, especially younger patients, sport represents an important modality in the treatment of their disease but also of their quality of life. However, this is often a challenge for the patient as well as for the physician regarding the metabolic consequences (hypo- but also hyperglycemia) which can appear in relation with physical activity. There are existing general recommendations concerning the intake of carbohydrates and the reduction of insulin doses but those have to be adapted individually for each patient and depend significantly on different sports and on the intensity of sport.

  14. Cannabinoids in the treatment of cancer.

    Science.gov (United States)

    Alexander, Amy; Smith, Paul F; Rosengren, Rhonda J

    2009-11-18

    Cannabinoids, the active components of the hemp plant Cannabis sativa, along with their endogenous counterparts and synthetic derivatives, have elicited anti-cancer effects in many different in vitro and in vivo models of cancer. While the various cannabinoids have been examined in a variety of cancer models, recent studies have focused on the role of cannabinoid receptor agonists (both CB(1) and CB(2)) in the treatment of estrogen receptor-negative breast cancer. This review will summarize the anti-cancer properties of the cannabinoids, discuss their potential mechanisms of action, as well as explore controversies surrounding the results.

  15. Therapeutic potential of cannabinoids in neurodegenerative disorders: a selective review.

    Science.gov (United States)

    Velayudhan, Latha; Van Diepen, Erik; Marudkar, Mangesh; Hands, Oliver; Suribhatla, Srinivas; Prettyman, Richard; Murray, Jonathan; Baillon, Sarah; Bhattacharyya, Sagnik

    2014-01-01

    The endocannabinoid system (ECS) is now recognised as an important modulator of various central nervous system processes. More recently, an increasing body of evidence has accumulated to suggest antioxidant, anti-inflammatory and neuroprotective roles of ECS. In this review we discuss the role and therapeutic potential of ECS in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, Huntington's disease, Tourette's syndrome, brain ischemia and amyotrophic lateral sclerosis (ALS). Elements of the ECS, such as fatty acid amide hydrolase or the cannabinoid receptors are now considered as promising pharmacological targets for some diseases. Although still preliminary, recent reports suggest that modulation of the ECS may constitute a novel approach for the treatment of AD. There are windows of opportunity in conditions caused by acute events such as trauma and ischemia as well in conditions that may involve altered functionality of the target receptors of the ECS, such as in AD. The ECS changes in Parkinson's disease could be compensatory as well as pathogenic of the illness process and needs further understanding and clinical studies are still in the preliminary stage. There is not enough evidence to support use of cannabinoids in treating Huntington's disease, tics and obsessive compulsive behaviour in Tourette's syndrome. Evidence on therapeutic use of cannabinoids in multiple sclerosis and ALS is currently limited. A major challenge for future research is the development of novel compounds with more selectivity for various components of the ECS which could target different neurotoxic pathways and be used in combination therapy.

  16. Cannabinoids for treatment of Alzheimer's disease: moving toward the clinic.

    Science.gov (United States)

    Aso, Ester; Ferrer, Isidre

    2014-01-01

    The limited effectiveness of current therapies against Alzheimer's disease (AD) highlights the need for intensifying research efforts devoted to developing new agents for preventing or retarding the disease process. During the last few years, targeting the endogenous cannabinoid system has emerged as a potential therapeutic approach to treat Alzheimer. The endocannabinoid system is composed by a number of cannabinoid receptors, including the well-characterized CB1 and CB2 receptors, with their endogenous ligands and the enzymes related to the synthesis and degradation of these endocannabinoid compounds. Several findings indicate that the activation of both CB1 and CB2 receptors by natural or synthetic agonists, at non-psychoactive doses, have beneficial effects in Alzheimer experimental models by reducing the harmful β-amyloid peptide action and tau phosphorylation, as well as by promoting the brain's intrinsic repair mechanisms. Moreover, endocannabinoid signaling has been demonstrated to modulate numerous concomitant pathological processes, including neuroinflammation, excitotoxicity, mitochondrial dysfunction, and oxidative stress. The present paper summarizes the main experimental studies demonstrating the polyvalent properties of cannabinoid compounds for the treatment of AD, which together encourage progress toward a clinical trial.

  17. Cannabinoids cases in polish athletes

    Directory of Open Access Journals (Sweden)

    A Pokrywka

    2009-07-01

    Full Text Available The aim of this study was to investigate the number of cases and the profiles of Polish athletes who had occasionally been using marijuana or hashish throughout the period of 1998-2004, with respect to: sex, age, and discipline of sport as well as the period of testing (in- and out-of-competition. Results of the study were compared with some data reported by other WADA accredited anti-doping laboratories. Totally, 13 631 urine samples taken from Polish athletes of both sexes, aged 10-67 years, performing 46 disciplines of sport were tested. Cannabinoids were detected in 267 samples. Among Polish athletes the relative number of positive THC (tetrahydrocannabinol samples was one of the highest in Europe. The group of young Polish athletes (aged 16-24 years was the most THC-positive. THC-positive cases were noted more frequently in male athletes tested during out of competitions. The so-called contact sports (rugby, ice hockey, skating, boxing, badminton, body building and acrobatic sports were those sports, where the higher risk of cannabis use was observed. The legal interpretation of some positive cannabinoids results would be difficult because of some accidental and unintentional use of the narcotics by sportsmen. It was concluded that national anti-doping organizations (NADO’s, which are competent to judge whether the anti-doping rules were violated, should take into account the possibility of non-intentional doping use of cannabinoids via passive smoking of marijuana.

  18. Puberty and type 1 diabetes

    Science.gov (United States)

    Chowdhury, Subhankar

    2015-01-01

    Various data on type 1 diabetes mellitus (T1DM) have showed that the incidence of T1DM peaks at puberty. However, diabetes control and complications could be adversely affected by the physiological changes of puberty. In early years of insulin therapy, severe growth retardation with pubertal delay, like in Mauriac syndrome, have been reported. Insulin and leptin are metabolic factors, circulating in the periphery, which participate in the hypothalamic control of metabolism and reproduction. Insulin may be an important regulator of leptin in humans. Increased levels of advanced glycation end products suppress activation of the gonadotropin-releasing hormone (GnRH) pulse generator, resulting in pubertal delay. Glycemic control deteriorates during puberty as the lean body mass doubles mainly over a period of 25 years, which increases insulin requirement. There is also an increase in insulin resistance over the period of puberty. In normal individuals, fasting and postprandial insulin concentrations reach a peak in both sexes in mid to late puberty. Puberty, at all stages, has the worst insulin resistance. It has been observed that an excessive GH secretion in T1DM during puberty has significant effects on ketogenesis. Adolescent T1DM tends to decompensate very rapidly and develop ketoacidosis when the late night insulin dose is omitted. Adolescence is a critical developmental phase that presents unique challenges and opportunities to individuals with diabetes, their families and their healthcare providers. PMID:25941652

  19. Puberty and type 1 diabetes

    Directory of Open Access Journals (Sweden)

    Subhankar Chowdhury

    2015-01-01

    Full Text Available Various data on type 1 diabetes mellitus (T1DM have showed that the incidence of T1DM peaks at puberty. However, diabetes control and complications could be adversely affected by the physiological changes of puberty. In early years of insulin therapy, severe growth retardation with pubertal delay, like in Mauriac syndrome, have been reported. Insulin and leptin are metabolic factors, circulating in the periphery, which participate in the hypothalamic control of metabolism and reproduction. Insulin may be an important regulator of leptin in humans. Increased levels of advanced glycation end products suppress activation of the gonadotropin-releasing hormone (GnRH pulse generator, resulting in pubertal delay. Glycemic control deteriorates during puberty as the lean body mass doubles mainly over a period of 25 years, which increases insulin requirement. There is also an increase in insulin resistance over the period of puberty. In normal individuals, fasting and postprandial insulin concentrations reach a peak in both sexes in mid to late puberty. Puberty, at all stages, has the worst insulin resistance. It has been observed that an excessive GH secretion in T1DM during puberty has significant effects on ketogenesis. Adolescent T1DM tends to decompensate very rapidly and develop ketoacidosis when the late night insulin dose is omitted. Adolescence is a critical developmental phase that presents unique challenges and opportunities to individuals with diabetes, their families and their healthcare providers.

  20. Brittle type 1 diabetes mellitus.

    Science.gov (United States)

    Bertuzzi, Federico; Verzaro, Roberto; Provenzano, Vincenzo; Ricordi, Camillo

    2007-01-01

    A small group of patients affected by type 1 diabetes mellitus is characterized by a severe instability of glycemic values with frequent and unpredictable hypoglycemic and/or ketoacidosis episodes which cannot be explained by errors of patients or diabetologists. The quality of life of these patients is dramatically compromised in particular because of the frequency of acute events, hospital recoveries and precocious appearance of chronic complications. This clinical condition has been defined as "brittle diabetes". A precise quantification of these patients is difficult because diagnostic criteria are still not well defined and it is often difficult to verify errors of patients in terms of inappropriate conduct with the pathology. Even more than the other kinds of diabetes, therapy is based on education, glycemic control, intensive therapy and strict interaction between physicians and patients. The introduction of insulin analogous, with either ultra-fast and ultra-slow action and the use of subcutaneous insulin pumps have significantly increased the possibility of treating the most of these cases. However, there is a minority of patients resistant to the therapy. In similar cases, pancreas or islet transplantation represents an effective therapeutic option entailing good expected outcomes. The main limiting factor of beta cell function replacement by transplantation is so far represented by the potentially severe side effects of the immunosuppression therapy necessary to avoid graft rejection and recurrence of autoimmunity.

  1. Progressive decrease in N-acetylaspartate/Creatine ratio in a teenager with type 1 diabetes and repeated episodes of ketoacidosis without clinically apparent cerebral edema: Evidence for permanent brain injury.

    Science.gov (United States)

    Wootton-Gorges, S L; Buonocore, M H; Caltagirone, R A; Kuppermann, N; Glaser, N S

    2010-04-01

    Recent data suggest that DKA may contribute to cognitive impairment in children with type 1 DM. We measured the NAA/Cr ratio in a teenager during and following 2 separate episodes of DKA without clinically apparent cerebral edema. The NAA/Cr ratio decreased during DKA and improved following recovery. However, the NAA/Cr value was lower after the second episode of DKA (1.76) than after the first (1.97). These findings provide support for the hypothesis that neuronal injury may result from DKA.

  2. Involvement of the cannabinoid CB1 receptor in modulation of dopamine output in the prefrontal cortex associated with food restriction in rats.

    Directory of Open Access Journals (Sweden)

    Laura Dazzi

    Full Text Available Increase in dopamine output on corticolimbic structures, such as medial prefrontal cortex (mPFC and nucleus accumbens, has been related to reward effects associated with palatable food or food presentation after a fasting period. The endocannabinoid system regulates feeding behavior through a modulatory action on different neurotransmitter systems, including the dopaminergic system. To elucidate the involvement of type 1 cannabinoid receptors in the regulation of dopamine output in the mPFC associated with feeding in hungry rats, we restricted the food availability to a 2-h period daily for 3 weeks. In food-restricted rats the extracellular dopamine concentration in the mPFC increased starting 80 min before food presentation and returned to baseline after food removal. These changes were attenuated in animals treated with the CB1 receptor antagonist SR141716. To better understand how food restriction can change the response of mesocortical dopaminergic neurons, we studied several components of the neuronal circuit that regulates dopamine output in the mPFC. Patch-clamp experiments revealed that the inhibitory effect of the CB1 receptor agonist WIN 55,212-2 on GABAergic sIPSC frequency was diminished in mPFC neurons of FR compared to fed ad libitum rats. The basal sIPSC frequency resulted reduced in mPFC neurons of food-restricted rats, suggestive of an altered regulation of presynaptic GABA release; these changes were accompanied by an enhanced excitability of mPFC and ventral tegmental area neurons. Finally, type 1 cannabinoid receptor expression in the mPFC was reduced in food-restricted rats. Together, our data support an involvement of the endocannabinoid system in regulation of dopamine release in the mPFC through changes in GABA inhibitory synapses and suggest that the emphasized feeding-associated increase in dopamine output in the mPFC of food-restricted rats might be correlated with an altered expression and function of type 1

  3. Neurofibromatosis type 1 growth charts.

    Science.gov (United States)

    Clementi, M; Milani, S; Mammi, I; Boni, S; Monciotti, C; Tenconi, R

    1999-12-03

    Growth abnormalities such as macrocephaly and short stature have been described and are considered a consistent finding in neurofibromatosis type 1 (NF1), one of the most common autosomal dominant disorders in man. We present here a clinical study on the growth profile of a sample of NF1 patients collected through a population-based registry that covers three contiguous regions of North-East Italy (NEI-NF Registry). Auxometric traits of 528 NF1 patients have been measured with the aim of drawing growth charts for height, weight, and head circumference (OFC). Height velocity charts were based on a subset of 143 children who underwent multiple measurements. No differences in height were apparent between NF1 and normal subjects up to age 7 (girls) and 12 (boys) years; subsequently, the 50th centile of NF1 subjects tends to overlap with the 25th centile of normal subjects, and the 3rd centile is much lower in NF1 subjects than in normal subjects, mainly during adolescence. The negatively skewed distribution of height seems to indicate that height growth impairment affects only a proportion of NF1 subjects; height growth impairment does not seem related to disease severity. As for weight, our data suggest that slight overweight is a characteristic of adult NF1 subjects (mainly among males), independent of disease severity. Height growth velocity is normal during childhood for both sexes, whereas the pubertal spurt is slightly anticipated and reduced in NF1 boys but not in girls. Our data confirm previous observations that macrocrania affects most NF1 subjects; the shape of the head growth curve is similar in NF1 and normal girls, whereas NF1 boys present an OFC pubertal growth spurt much more pronounced and delayed than normal boys. The disproportion between OFC and height seems to be related to disease severity in boys but not in girls. Growth charts presented here can be useful in neurofibromatosis clinics for the identification of the effects of secondary growth

  4. Cannabis and Cannabinoids for Chronic Pain.

    Science.gov (United States)

    Romero-Sandoval, E Alfonso; Kolano, Ashley L; Alvarado-Vázquez, P Abigail

    2017-10-05

    The purpose of this study was to provide the most up-to-date scientific evidence of the potential analgesic effects, or lack thereof, of the marijuana plant (cannabis) or cannabinoids, and of safety or tolerability of their long-term use. We found that inhaled (smoked or vaporized) cannabis is consistently effective in reducing chronic non-cancer pain. Oral cannabinoids seem to improve some aspects of chronic pain (sleep and general quality of life), or cancer chronic pain, but they do not seem effective in acute postoperative pain, abdominal chronic pain, or rheumatoid pain. The available literature shows that inhaled cannabis seems to be more tolerable and predictable than oral cannabinoids. Cannabis or cannabinoids are not universally effective for pain. Continued research on cannabis constituents and improving bioavailability for oral cannabinoids is needed. Other aspects of pain management in patients using cannabis require further open discussion: concomitant opioid use, medical vs. recreational cannabis, abuse potential, etc.

  5. Transmembrane Helical Domain of the Cannabinoid CB1 Receptor

    OpenAIRE

    Shim, Joong-Youn

    2009-01-01

    Brain cannabinoid (CB1) receptors are G-protein coupled receptors and belong to the rhodopsin-like subfamily. A homology model of the inactive state of the CB1 receptor was constructed using the x-ray structure of β2-adrenergic receptor (β2AR) as the template. We used 105 ns duration molecular-dynamics simulations of the CB1 receptor embedded in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer to gain some insight into the structure and function of the CB1 receptor. As judged...

  6. Interferon-γ causes mood abnormalities by altering cannabinoid CB1 receptor function in the mouse striatum.

    Science.gov (United States)

    Mandolesi, Georgia; Bullitta, Silvia; Fresegna, Diego; Gentile, Antonietta; De Vito, Francesca; Dolcetti, Ettore; Rizzo, Francesca R; Strimpakos, Georgios; Centonze, Diego; Musella, Alessandra

    2017-12-01

    Interferon-γ (IFN-γ) has been implicated in the pathogenesis of multiple sclerosis (MS) and in its animal model, experimental autoimmune encephalomyelitis (EAE). The type-1 cannabinoid receptors (CB1Rs) are heavily involved in MS pathophysiology, and a growing body of evidence suggests that mood disturbances reflect specific effects of proinflammatory cytokines on neuronal activity. Here, we investigated whether IFN-γ could exert a role in the anxiety- and depressive-like behavior observed in mice with EAE, and in the modulation of CB1Rs. Anxiety and depression in fact are often diagnosed in MS, and have already been shown to depend on cannabinoid system. We performed biochemical, behavioral and electrophysiological experiments to assess the role of IFN-γ on mood control and on synaptic transmission in mice. Intracerebroventricular delivery of IFN-γ caused a depressive- and anxiety-like behavior in mice, associated with the selective dysfunction of CB1Rs controlling GABA transmission in the striatum. EAE induction was associated with increased striatal expression of IFN-γ, and with CB1R transmission deficits, which were rescued by pharmacological blockade of IFN-γ. IFN-γ was unable to replicate the effects of EAE on excitatory and inhibitory transmission in the striatum, but mimicked the effects of EAE on CB1R function in this brain area. Overall these results indicate that IFN-γ exerts a relevant control on mood, through the modulation of CB1R function. A better understanding of the biological pathways underling the psychological disorders during neuroinflammatory conditions is crucial for developing effective therapeutic strategies. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Cannabinoid CB1 receptors in distinct circuits of the extended amygdala determine fear responsiveness to unpredictable threat.

    Science.gov (United States)

    Lange, M D; Daldrup, T; Remmers, F; Szkudlarek, H J; Lesting, J; Guggenhuber, S; Ruehle, S; Jüngling, K; Seidenbecher, T; Lutz, B; Pape, H C

    2017-10-01

    The brain circuits underlying behavioral fear have been extensively studied over the last decades. Although the vast majority of experimental studies assess fear as a transient state of apprehension in response to a discrete threat, such phasic states of fear can shift to a sustained anxious apprehension, particularly in face of diffuse cues with unpredictable environmental contingencies. Unpredictability, in turn, is considered an important variable contributing to anxiety disorders. The networks of the extended amygdala have been suggested keys to the control of phasic and sustained states of fear, although the underlying synaptic pathways and mechanisms remain poorly understood. Here, we show that the endocannabinoid system acting in synaptic circuits of the extended amygdala can explain the fear response profile during exposure to unpredictable threat. Using fear training with predictable or unpredictable cues in mice, combined with local and cell-type-specific deficiency and rescue of cannabinoid type 1 (CB1) receptors, we found that presynaptic CB1 receptors on distinct amygdala projections to bed nucleus of the stria terminalis (BNST) are both necessary and sufficient for the shift from phasic to sustained fear in response to an unpredictable threat. These results thereby identify the causal role of a defined protein in a distinct brain pathway for the temporal development of a sustained state of anxious apprehension during unpredictability of environmental influences, reminiscent of anxiety symptoms in humans.

  8. Feeding induced by cannabinoids is mediated independently of the melanocortin system.

    Directory of Open Access Journals (Sweden)

    Puspha Sinnayah

    2008-05-01

    Full Text Available Cannabinoids, the active components of marijuana, stimulate appetite, and cannabinoid receptor-1 (CB1-R antagonists suppress appetite and promote weight loss. Little is known about how CB1-R antagonists affect the central neurocircuitry, specifically the melanocortin system that regulates energy balance.Here, we show that peripherally administered CB1-R antagonist (AM251 or agonist equally suppressed or stimulated feeding respectively in A(y , which lack a functional melanocortin system, and wildtype mice, demonstrating that cannabinoid effects on feeding do not require melanocortin circuitry. CB1-R antagonist or agonist administered into the ventral tegmental area (VTA equally suppressed or stimulated feeding respectively, in both genotypes. In addition, peripheral and central cannabinoid administration similarly induced c-Fos activation in brain sites suggesting mediation via motivational dopaminergic circuitry. Amperometry-detected increases in evoked dopamine (DA release by the CB1-R antagonist in nucleus accumbens slices indicates that AM251 modulates DA release from VTA terminals.Our results demonstrate that the effects of cannabinoids on energy balance are independent of hypothalamic melanocortin circuitry and is primarily driven by the reward system.

  9. Role of the endogenous cannabinoid system in nicotine addiction: novel insights

    Directory of Open Access Journals (Sweden)

    Islam Hany Gamaleddin

    2015-03-01

    Full Text Available Several lines of evidence have shown that the endogenous cannabinoids are implicated in several neuropsychiatric diseases. Notably, preclinical and human clinical studies have shown a pivotal role of the cannabinoid system in nicotine addiction. The CB1 receptor inverse agonist/antagonist rimonabant (also known as SR141716 was effective to decrease nicotine-taking and nicotine-seeking in rodents, as well as the elevation of dopamine induced by nicotine in brain reward area. Rimonabant has been shown to improve the ability of smokers to quit smoking in randomized clinical trials. However, rimonabant was removed from the market due to increased risk of psychiatric side effects observed in humans. Recently, other components of the endogenous cannabinoid system have been explored. Here, we present the recent advances on the understanding of the role of the different components of the cannabinoid system on nicotine’s effects. Those recent findings suggest possible alternative ways of modulating the cannabinoid system that could have implication for nicotine dependence treatment.

  10. Exposure to a Highly Caloric Palatable Diet during the Perinatal Period Affects the Expression of the Endogenous Cannabinoid System in the Brain, Liver and Adipose Tissue of Adult Rat Offspring.

    Directory of Open Access Journals (Sweden)

    María Teresa Ramírez-López

    Full Text Available Recent studies have linked gestational exposure to highly caloric diets with a disrupted endogenous cannabinoid system (ECS. In the present study, we have extended these studies by analyzing the impact of the exposure to a palatable diet during gestation and lactation on a the adult expression of endocannabinoid-related behaviors, b the metabolic profile of adult offspring and c the mRNA expression of the signaling machinery of the ECS in the hypothalamus, the liver and the adipose tissue of adult offspring of both sexes. Exposure to a palatable diet resulted in a sex-dimorphic and perinatal diet specific feeding behaviors, including the differential response to the inhibitory effects of the cannabinoid receptor inverse agonist AM251, b features of metabolic syndrome including increased adiposity, hyperleptinemia, hypertriglyceridemia and hypercholesterolemia and c tissue and sex-specific changes in the expression of both CB1 and CB2 receptors and in that of the endocannabinoid-degrading enzymes FAAH and MAGL, being the adipose tissue the most affected organ analyzed. Since the effects were observed in adult animals that were weaned while consuming a normal diet, the present results indicate that the ECS is one of the targets of maternal programming of the offspring energy expenditure. These results clearly indicate that the maternal diet has long-term effects on the development of pups through multiple alterations of signaling homeostatic pathways that include the ECS. The potential relevance of these alterations for the current obesity epidemic is discussed.

  11. Short- and long-term cognitive effects of chronic cannabinoids administration in late-adolescence rats.

    Directory of Open Access Journals (Sweden)

    Hila Abush

    Full Text Available The use of cannabis can impair cognitive function, especially short-term memory. A controversial question is whether long-term cannabis use during the late-adolescence period can cause irreversible deficits in higher brain function that persist after drug use stops. In order to examine the short- and long-term effects of chronic exposure to cannabinoids, rats were administered chronic i.p. treatment with the CB1/CB2 receptor agonist WIN55,212-2 (WIN; 1.2 mg/kg for two weeks during the late adolescence period (post-natal days 45-60 and tested for behavioral and electrophysiological measures of cognitive performance 24 hrs, 10 and 30 days after the last drug injection. The impairing effects of chronic WIN on short-term memory in the water maze and the object recognition tasks as well as long-term potentiation (LTP in the ventral subiculum (vSub-nucleus accumbens (NAc pathway were temporary as they lasted only 24 h or 10 d after withdrawal. However, chronic WIN significantly impaired hippocampal dependent short-term memory measured in the object location task 24 hrs, 10, 30, and 75 days after the last drug injection. Our findings suggest that some forms of hippocampal-dependent short-term memory are sensitive to chronic cannabinoid administration but other cognitive impairments are temporary and probably result from a residue of cannabinoids in the brain or acute withdrawal effects from cannabinoids. Understanding the effects of cannabinoids on cognitive function may provide us with tools to overcome these impairments and for cannabinoids to be more favorably considered for clinical use.

  12. The orexigenic effect of ghrelin is mediated through central activation of the endogenous cannabinoid system.

    Directory of Open Access Journals (Sweden)

    Blerina Kola

    2008-03-01

    Full Text Available Ghrelin and cannabinoids stimulate appetite, this effect possibly being mediated by the activation of hypothalamic AMP-activated protein kinase (AMPK, a key enzyme in appetite and metabolism regulation. The cannabinoid receptor type 1 (CB1 antagonist rimonabant can block the orexigenic effect of ghrelin. In this study, we have elucidated the mechanism of the putative ghrelin-cannabinoid interaction.The effects of ghrelin and CB1 antagonist rimonabant in wild-type mice, and the effect of ghrelin in CB1-knockout animals, were studied on food intake, hypothalamic AMPK activity and endogenous cannabinoid content. In patch-clamp electrophysiology experiments the effect of ghrelin was assessed on the synaptic inputs in parvocellular neurons of the hypothalamic paraventricular nucleus, with or without the pre-administration of a CB1 antagonist or of cannabinoid synthesis inhibitors.Ghrelin did not induce an orexigenic effect in CB1-knockout mice. Correspondingly, both the genetic lack of CB1 and the pharmacological blockade of CB1 inhibited the effect of ghrelin on AMPK activity. Ghrelin increased the endocannabinoid content of the hypothalamus in wild-type mice and this effect was abolished by rimonabant pre-treatment, while no effect was observed in CB1-KO animals. Electrophysiology studies showed that ghrelin can inhibit the excitatory inputs on the parvocellular neurons of the paraventricular nucleus, and that this effect is abolished by administration of a CB1 antagonist or an inhibitor of the DAG lipase, the enzyme responsible for 2-AG synthesis. The effect is also lost in the presence of BAPTA, an intracellular calcium chelator, which inhibits endocannabinoid synthesis in the recorded parvocellular neuron and therefore blocks the retrograde signaling exerted by endocannabinoids. In summary, an intact cannabinoid signaling pathway is necessary for the stimulatory effects of ghrelin on AMPK activity and food intake, and for the inhibitory effect

  13. CB1 Cannabinoid Receptors Modulate Kinase and Phosphatase Activity During Extinction of Conditioned Fear in Mice

    OpenAIRE

    Cannich, Astrid; Carsten T. Wotjak; Kamprath, Kornelia; Hermann, Heike; Lutz, Beat; Marsicano, Giovanni

    2004-01-01

    Cannabinoid receptors type 1 (CB1) play a central role in both short-term and long-term extinction of auditory-cued fear memory. The molecular mechanisms underlying this function remain to be clarified. Several studies indicated extracellular signal-regulated kinases (ERKs), the phosphatidylinositol 3-kinase with its downstream effector AKT, and the phosphatase calcineurin as potential molecular substrates of extinction behavior. To test the involvement of these kinase and phosphatase activit...

  14. Genetics Home Reference: spinocerebellar ataxia type 1

    Science.gov (United States)

    ... Email Facebook Twitter Home Health Conditions SCA1 Spinocerebellar ataxia type 1 Printable PDF Open All Close All ... to view the expand/collapse boxes. Description Spinocerebellar ataxia type 1 ( SCA1 ) is a condition characterized by ...

  15. Insulin requirements in type 1 diabetic pregnancy

    DEFF Research Database (Denmark)

    Callesen, Nicoline; Ringholm, Lene; Stage, Edna

    2012-01-01

    To evaluate the insulin requirements in women with type 1 diabetes during twin pregnancy compared with singleton pregnancy.......To evaluate the insulin requirements in women with type 1 diabetes during twin pregnancy compared with singleton pregnancy....

  16. Immunoactive effects of cannabinoids: considerations for the therapeutic use of cannabinoid receptor agonists and antagonists

    Science.gov (United States)

    Greineisen, William E.; Turner., Helen

    2013-01-01

    The active constituents of Cannabis sativa have been used for centuries as recreational drugs and medicinal agents. Today, marijuana is the most prevalent drug of abuse in the United States and, conversely, therapeutic use of marijuana constituents are gaining mainstream clinical and political acceptance. Given the documented contributions of endocannabinoid signaling to a range of physiological systems, including cognitive function, and the control of eating behaviors, it is unsurprising that cannabinoid receptor agonists and antagonists are showing significant clinical potential. In addition to the neuroactive effects of cannabinoids, an emerging body of data suggests that both endogenous and exogenous cannabinoids are potently immunoactive. The central premise of this review article is that the immunological effects of cannabinoids should be considered in the context of each prescribing decision. We present evidence that the immunological effects of cannabinoid receptor agonists and antagonists are highly relevant to the spectrum of disorders for which cannabinoid therapeutics are currently offered. PMID:20219697

  17. Designing microorganisms for heterologous biosynthesis of cannabinoids.

    Science.gov (United States)

    Carvalho, Ângela; Hansen, Esben Halkjær; Kayser, Oliver; Carlsen, Simon; Stehle, Felix

    2017-06-01

    During the last decade, the use of medical Cannabis has expanded globally and legislation is getting more liberal in many countries, facilitating the research on cannabinoids. The unique interaction of cannabinoids with the human endocannabinoid system makes these compounds an interesting target to be studied as therapeutic agents for the treatment of several medical conditions. However, currently there are important limitations in the study, production and use of cannabinoids as pharmaceutical drugs. Besides the main constituent tetrahydrocannabinolic acid, the structurally related compound cannabidiol is of high interest as drug candidate. From the more than 100 known cannabinoids reported, most can only be extracted in very low amounts and their pharmacological profile has not been determined. Today, cannabinoids are isolated from the strictly regulated Cannabis plant, and the supply of compounds with sufficient quality is a major problem. Biotechnological production could be an attractive alternative mode of production. Herein, we explore the potential use of synthetic biology as an alternative strategy for synthesis of cannabinoids in heterologous hosts. We summarize the current knowledge surrounding cannabinoids biosynthesis and present a comprehensive description of the key steps of the genuine and artificial pathway, systems biotechnology needs and platform optimization. © FEMS 2017.

  18. Enhancing Brain Pregnenolone May Protect Cannabis Intoxication but Should Not Be Considered as an Anti-addiction Therapeutic: Hypothesizing Dopaminergic Blockade and Promoting Anti-Reward.

    Science.gov (United States)

    Blum, Kenneth; Oscar-Berman, Marlene; Braverman, Eric R; Febo, Marcelo; Li, Mona; Gold, Mark S

    Many US states now embrace the medical and recreational use of Cannabis. Changes in the laws have heightened interest and encouraged research into both cannabinoid products and the potential harms of Cannabis use, addiction, and intoxication. Some research into those harms will be reviewed here and misgivings about the use of Pregnenolone, to treat cannabis addiction and intoxication explained. Pregnenolone considered the inactive precursor of all steroid hormones, has recently been shown to protect the brain from Cannabis intoxication. The major active ingredient of Cannabis sativa (marijuana), Δ(9)-tetrahydrocannabinol (THC) enhances Pregnenolone synthesis in the brain via stimulation of the type-1 cannabinoid (CB1) receptor. This steroid has been shown to inhibit the activity of the CB1 receptor thereby reducing many of the effects of THC. While this mechanism seems correct, in our opinion, Vallee et al., incorrectly suggest that blocking CB1 receptors could open unforeseen approaches to the treatment of cannabis intoxication and addiction. In this hypothesis, we caution the scientific community that, other CB1 receptor blockers, such as, Rimonabant (SR141718) have been pulled off the market in Europe. In addition, CB1 receptor blockers were rejected by the FDA due to mood changes including suicide ideation. Blocking CB1 receptors would result in reduced neuronal release of Dopamine by disinhibition of GABA signaling. Long-term blockade of cannabinoid receptors could occur with raising Pregnenolone brain levels, may induce a hypodopaminergic state, and lead to aberrant substance and non-substance (behavioral) addictions.

  19. New Trend in Narcotic Drugs Synthetic Cannabinoids

    Directory of Open Access Journals (Sweden)

    Selahattin Artuç

    2014-12-01

    Full Text Available Natural cannabis (Δ9-THC, tetrahydrocannabinol is obtained from Indian hemp plant (Cannabis sativa and it acts on cannabinoid receptors expressed as CB1, CB2. The therapeutic effects of cannabis is known from far away times. At the present time, some drugs containing kannabinoid are used for medical purposes. Synthetic cannabinoids’ chemical structure is quite different than natural cannabis. Cannabinoid receptor affinity and activity are greater than the natural cannabis. Substances containing synthetic cannabinoids are generally called “Spice”, “K2” abroad and, “Bonzai” or “Jamaica” in Turkey. Legal sale of herbal mixtures containing synthetic cannabinoids at places called “head shop” and “smart shop” in some countries and having easily access to them from the internet is an attractive feature for users. Moreover the impact stronger than cannabis, affordability, easy accessibility and getting rid of standard material tests contribute to increasing use of synthetic cannabinoids. As there is absence of reference standards of synthetic cannabinoids, it is not easy to identify them. In order to overcome legal barriers, new cannabinomimetic analogs are presented to market constantly. When taking into consideration of the increase of the use of synthetic cannabinoids, it is expected to be one of the most problematic drugs in the near future. Due to the widespread abuse of synthetic cannabinoids, further investigation of these substances is needed for better identification of their pharmacology and toxicology and to make appropriate legal planning and arrangements. Keywords: Synthetic cannabinoid, bonzai, narcotic drug.

  20. Cannabinoids and cancer: causation, remediation, and palliation.

    Science.gov (United States)

    Hall, Wayne; Christie, MacDonald; Currow, David

    2005-01-01

    This review discusses three different associations between cannabinoids and cancer. First, it assesses evidence that smoking of cannabis preparations may cause cancers of the aerodigestive and respiratory system. There have been case reports of upper-respiratory-tract cancers in young adults who smoke cannabis, but evidence from a few epidemiological cohort studies and case-control studies is inconsistent. Second, there is mixed evidence on the effects of THC and other cannabinoids on cancers: in some in vitro and in vivo studies THC and some synthetic cannabinoids have had antineoplastic effects, but in other studies THC seems to impair the immune response to cancer. As yet there is no evidence that THC or other cannabinoids have anticancer effects in humans. Third, Delta(9)-tetrahydrocannabinol (THC) may treat the symptoms and side-effects of cancer, and there is evidence that it and other cannabinoids may be useful adjuvant treatments that improve appetite, reduce nausea and vomiting, and alleviate moderate neuropathic pain in patients with cancer. The main challenge for the medical use of cannabinoids is the development of safe and effective methods of use that lead to therapeutic effects but that avoid adverse psychoactive effects. Furthermore, medical, legal, and regulatory obstacles hinder the smoking of cannabis for medical purposes. These very different uses of cannabinoids are in danger of being confused in public debate, especially in the USA where some advocates for the medical use of cannabinoids have argued for smoked cannabis rather than pharmaceutical cannabinoids. We review the available evidence on these three issues and consider their implications for policy.

  1. Human Laboratory Studies on Cannabinoids and Psychosis.

    Science.gov (United States)

    Sherif, Mohamed; Radhakrishnan, Rajiv; D'Souza, Deepak Cyril; Ranganathan, Mohini

    2016-04-01

    Some of the most compelling evidence supporting an association between cannabinoid agonists and psychosis comes from controlled laboratory studies in humans. Randomized, double-blind, placebo-controlled, crossover laboratory studies demonstrate that cannabinoid agonists, including phytocannabinoids and synthetic cannabinoids, produce a wide range of positive, negative, and cognitive symptoms and psychophysiologic deficits in healthy human subjects that resemble the phenomenology of schizophrenia. These effects are time locked to drug administration, are dose related, and are transient and rarely necessitate intervention. The magnitude of effects is similar to the effects of ketamine but qualitatively distinct from other psychotomimetic drugs, including ketamine, amphetamine, and salvinorin A. Cannabinoid agonists have also been shown to transiently exacerbate symptoms in individuals with schizophrenia in laboratory studies. Patients with schizophrenia are more vulnerable than healthy control subjects to the acute behavioral and cognitive effects of cannabinoid agonists and experience transient exacerbation of symptoms despite treatment with antipsychotic medications. Furthermore, laboratory studies have failed to demonstrate any "beneficial" effects of cannabinoid agonists in individuals with schizophrenia-challenging the cannabis self-medication hypothesis. Emerging evidence suggests that polymorphisms of several genes related to dopamine metabolism (e.g., COMT, DAT1, and AKT1) may moderate the effects of cannabinoid agonists in laboratory studies. Cannabinoid agonists induce dopamine release, although the magnitude of release does not appear to be commensurate to the magnitude and spectrum of their acute psychotomimetic effects. Interactions between the endocannabinoid, gamma-aminobutyric acid, and glutamate systems and their individual and interactive effects on neural oscillations provide a plausible mechanism underlying the psychotomimetic effects of

  2. Endo-cannabinoids system and the toxicity of cannabinoids with a biotechnological approach

    Science.gov (United States)

    Niaz, Kamal; Khan, Fazlullah; Maqbool, Faheem; Momtaz, Saeideh; Ismail Hassan, Fatima; Nobakht-Haghighi, Navid; Rahimifard, Mahban; Abdollahi, Mohammad

    2017-01-01

    Cannabinoids have shown diverse and critical effects on the body systems, which alter the physiological functions. Synthetic cannabinoids are comparatively innovative misuse drugs with respect to their nature of synthesis. Synthetic cannabinoids therapy in healthy, chain smokers, and alcoholic individuals cause damage to the immune and nervous system, eventually leading to intoxication throughout the body. Relevant studies were retrieved using major electronic databases such as PubMed, EMBASE, Medline, Scopus, and Google Scholar. The extensive use of Cannabis Sativa L. (C. Sativa) and its derivatives/analogues such as the nonpsychoactive dimethyl heptyl homolog (CBG-DMH), and tetrahydrocannabivarin (THCV) amongst juveniles and adults have been enhanced in recent years. Cannabinoids play a crucial role in the induction of respiratory, reproductive, immune and carcinogenic effects; however, potential data about mutagenic and developmental effects are still insufficient. The possible toxicity associated with the prolong use of cannabinoids acts as a tumor promoter in animal models and humans. Particular synthetic cannabinoids and analogues have low affinity for CB1 or CB2 receptors, while some synthetic members like Δ9-THC have high affinity towards these receptors. Cannabinoids and their derivatives have a direct or indirect association with acute and long-term toxicity. To reduce/attenuate cannabinoids toxicity, pharmaceutical biotechnology and cloning methods have opened a new window to develop cannabinoids encoding the gene tetrahydrocannabinolic acid (THCA) synthase. Plant revolution and regeneration hindered genetic engineering in C. Sativa. The genetic culture suspension of C. Sativa can be transmuted by the use of Agrobacterium tumefaciens to overcome its toxicity. The main aim of the present review was to collect evidence of the endo-cannabinoid system (ECS), cannabinoids toxicity, and the potential biotechnological approach of cannabinoids synthesis. PMID

  3. Cannabinoids in intestinal inflammation and cancer.

    Science.gov (United States)

    Izzo, Angelo A; Camilleri, Michael

    2009-08-01

    Emerging evidence suggests that cannabinoids may exert beneficial effects in intestinal inflammation and cancer. Adaptive changes of the endocannabinoid system have been observed in intestinal biopsies from patients with inflammatory bowel disease and colon cancer. Studies on epithelial cells have shown that cannabinoids exert antiproliferative, antimetastatic and apoptotic effects as well as reducing cytokine release and promoting wound healing. In vivo, cannabinoids - via direct or indirect activation of CB(1) and/or CB(2) receptors - exert protective effects in well-established models of intestinal inflammation and colon cancer. Pharmacological elevation of endocannabinoid levels may be a promising strategy to counteract intestinal inflammation and colon cancer.

  4. Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors

    Energy Technology Data Exchange (ETDEWEB)

    Rajasekaran, Maheswari; Brents, Lisa K.; Franks, Lirit N. [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Moran, Jeffery H. [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States); Arkansas Department of Public Health, Public Health Laboratory, Little Rock, AR 72205 (United States); Prather, Paul L., E-mail: pratherpaull@uams.edu [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States)

    2013-06-01

    K2 or Spice is an emerging drug of abuse that contains synthetic cannabinoids, including JWH-018 and JWH-073. Recent reports indicate that monohydroxylated metabolites of JWH-018 and JWH-073 retain high affinity and activity at cannabinoid type-1 receptors (CB{sub 1}Rs), potentially contributing to the enhanced toxicity of K2 compared to marijuana. Since the parent compounds also bind to cannabinoid type-2 receptors (CB{sub 2}Rs), this study investigated the affinity and intrinsic activity of JWH-018, JWH-073 and several monohydroxylated metabolites at human CB{sub 2}Rs (hCB{sub 2}Rs). The affinity of cannabinoids for hCB{sub 2}Rs was determined by competition binding studies employing CHO-hCB{sub 2} membranes. Intrinsic activity of compounds was assessed by G-protein activation and adenylyl cyclase (AC)-inhibition in CHO-hCB{sub 2} cells. JWH-073, JWH-018 and several of their human metabolites exhibit nanomolar affinity and act as potent agonists at hCB{sub 2}Rs. Furthermore, a major omega hydroxyl metabolite of JWH-073 (JWH-073-M5) binds to CB{sub 2}Rs with 10-fold less affinity than the parent molecule, but unexpectedly, is equipotent in regulating AC-activity when compared to the parent molecule. Finally, when compared to CP-55,940 and Δ{sup 9}-tetrahydrocannabinol (Δ{sup 9}-THC), JWH-018, JWH-018-M5 and JWH-073-M5 require significantly less CB{sub 2}R occupancy to produce similar levels of AC-inhibition, indicating that these compounds may more efficiently couple CB{sub 2}Rs to AC than the well characterized cannabinoid agonists examined. These results indicate that JWH-018, JWH-073 and several major human metabolites of these compounds exhibit high affinity and demonstrate distinctive signaling properties at CB{sub 2}Rs. Therefore, future studies examining pharmacological and toxicological properties of synthetic cannabinoids present in K2 products should consider potential actions of these drugs at both CB{sub 1} and CB{sub 2}Rs. - Highlights: • JWH-018

  5. Cannabinoid-based drugs targeting CB1 and TRPV1, the sympathetic nervous system, and arthritis.

    Science.gov (United States)

    Lowin, Torsten; Straub, Rainer H

    2015-09-06

    Chronic inflammation in rheumatoid arthritis (RA) is accompanied by activation of the sympathetic nervous system, which can support the immune system to perpetuate inflammation. Several animal models of arthritis already demonstrated a profound influence of adrenergic signaling on the course of RA. Peripheral norepinephrine release from sympathetic terminals is controlled by cannabinoid receptor type 1 (CB1), which is activated by two major endocannabinoids (ECs), arachidonylethanolamine (anandamide) and 2-arachidonylglycerol. These ECs also modulate function of transient receptor potential channels (TRPs) located on sensory nerve fibers, which are abundant in arthritic synovial tissue. TRPs not only induce the sensation of pain but also support inflammation via secretion of pro-inflammatory neuropeptides. In addition, many cell types in synovial tissue express CB1 and TRPs. In this review, we focus on CB1 and transient receptor potential vanilloid 1 (TRPV1)-mediated effects on RA since most anti-inflammatory mechanisms induced by cannabinoids are attributed to cannabinoid receptor type 2 (CB2) activation. We demonstrate how CB1 agonism or antagonism can modulate arthritic disease. The concept of functional antagonism with continuous CB1 activation is discussed. Since fatty acid amide hydrolase (FAAH) is a major EC-degrading enzyme, the therapeutic possibility of FAAH inhibition is studied. Finally, the therapeutic potential of ECs is examined since they interact with cannabinoid receptors and TRPs but do not produce central side effects.

  6. Cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction.

    Science.gov (United States)

    Hedlund, Petter

    2014-01-01

    To review knowledge on cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction. Review of MEDLINE using defined search terms, and manual analysis. Articles published in English were included. Components of the endocannabinoid system—cannabinoid (CB)receptor types 1 and 2, anandamide, and fatty acid amide hydrolase (FAAH), which degrades anandamide and related fatty-acid amides—have been located to lower urinary tract tissues of mice, rats, monkeys, and humans. Studies have located CB receptors in urothelium and sensory nerves and FAAH in the urothelium. CB receptor- and FAAH-related activities have also been reported in the lumbosacral spinal cord. Data on supraspinal CB functions in relation to micturition are lacking. Cannabinoids are reported to reduce sensory activity of isolated tissues, cause antihyperalgesia in animal studies of bladder inflammation, affect urodynamics parameters reflecting sensory functions in animals models, and appear to have effects on storage symptoms in humans. FAAH inhibitors have affected sensory bladder functions and reduced bladder overactivity in rat models. Cannabinoids may modify nerve-mediated functions of isolated lower urinary tract tissues. Evidence suggests components of the endocannabinoid system are involved in regulation of bladder function, possibly at several levels of the micturition pathway. It is unclear if either CB receptor has a dominant role in modification of sensory signals or if differences exist at peripheral and central nervous sites. Amplification of endocannabinoid activity by FAAH inhibitors may be an attractive drug target in specific pathways involved in LUTS.

  7. Cannabinoids, Endocannabinoids, and Related Analogs in Inflammation

    National Research Council Canada - National Science Library

    Burstein, Sumner H; Zurier, Robert B

    2009-01-01

    ..., and finally, noncannabinoid components of Cannabis that show anti-inflammatory action. It is intended to be an update on the topic of the involvement of cannabinoids in the process of inflammation...

  8. Antitumorigenic effects of cannabinoids beyond apoptosis.

    Science.gov (United States)

    Freimuth, Nadine; Ramer, Robert; Hinz, Burkhard

    2010-02-01

    According to the World Health Organization, the cases of death caused by cancer will have been doubled until the year 2030. By 2010, cancer is expected to be the number one cause of death. Therefore, it is necessary to explore novel approaches for the treatment of cancer. Over past years, the antitumorigenic effects of cannabinoids have emerged as an exciting field in cancer research. Apart from their proapoptotic and antiproliferative action, recent research has shown that cannabinoids may likewise affect tumor cell angiogenesis, migration, invasion, adhesion, and metastasization. This review will summarize the data concerning the influence of cannabinoids on these locomotive processes beyond modulation of cancer cell apoptosis and proliferation. The findings discussed here provide a new perspective on the antitumorigenic potential of cannabinoids.

  9. Cannabinoids and Cytochrome P450 Interactions.

    Science.gov (United States)

    Zendulka, Ondřej; Dovrtělová, Gabriela; Nosková, Kristýna; Turjap, Miroslav; Šulcová, Alexandra; Hanuš, Lumír; Juřica, Jan

    2016-01-01

    This review consists of three parts, representing three different possibilities of interactions between cannabinoid receptor ligands of both exogenous and endogenous origin and cytochrome P450 enzymes (CYPs). The first part deals with cannabinoids as CYP substrates, the second summarizes current knowledge on the influence of various cannabinoids on the metabolic activity of CYP, and the third outline a possible involvement of the endocannabinoid system and cannabinoid ligands in the regulation of CYP liver activity. We performed a structured search of bibliographic and drug databases for peer-reviewed literature using focused review questions. Biotransformation via a hydrolytic pathway is the major route of endocannabinoid metabolism and the deactivation of substrates is characteristic, in contrast to the minor oxidative pathway via CYP involved in the bioactivation reactions. Phytocannabinoids are extensively metabolized by CYPs. The enzymes CYP2C9, CYP2C19, and CYP3A4 catalyze most of their hydroxylations. Similarly, CYP represents a major metabolic pathway for both synthetic cannabinoids used therapeutically and drugs that are abused. In vitro experiments document the mostly CYP inhibitory activity of the major phytocannabinoids, with cannabidiol as the most potent inhibitor of many CYPs. The drug-drug interactions between cannabinoids and various drugs at the CYP level are reported, but their clinical relevance remains unclear. The direct activation/inhibition of nuclear receptors in the liver cells by cannabinoids may result in a change of CYP expression and activity. Finally, we hypothesize the interplay of central cannabinoid receptors with numerous nervous systems, resulting in a hormone-mediated signal towards nuclear receptors in hepatocytes.

  10. Cannabinoids - a new weapon against cancer?

    Science.gov (United States)

    Pokrywka, Małgorzata; Góralska, Joanna; Solnica, Bogdan

    2016-12-29

    Cannabis has been cultivated by man since Neolithic times. It was used, among others for fiber and rope production, recreational purposes and as an excellent therapeutic agent. The isolation and characterization of the structure of one of the main active ingredients of cannabis - Δ9 - tetrahydrocannabinol as well the discovery of its cannabinoid binding receptors CB1 and CB2, has been a milestone in the study of the possibilities of the uses of Cannabis sativa and related products in modern medicine. Many scientific studies indicate the potential use of cannabinoids in the fight against cancer. Experiments carried out on cell lines in vitro and on animal models in vivo have shown that phytocannabinoids, endocannabinoids, synthetic cannabinoids and their analogues can lead to inhibition of the growth of many tumor types, exerting cytostatic and cytotoxic neoplastic effect on cells thereby negatively influencing neo-angiogenesis and the ability of cells to metastasize. The main molecular mechanism leading to inhibition of proliferation of cancer cells by cannabinoids is apoptosis. Studies have shown, however, that the process of apoptosis in cells, treated with recannabinoids, is a consequence of induction of endoplasmic reticulum stress and autophagy. On the other hand, in the cellular context and dosage dependence, cannabinoids may enhance the proliferation of tumor cells by suppressing the immune system or by activating mitogenic factors. Leading from this there is a an obvious need to further explore cannabinoid associated molecular pathways making it possible to develop safe therapeutic drug agents for patients in the future.

  11. Eating disorders in type 1 diabetes

    DEFF Research Database (Denmark)

    Nash, J.; Skinner, T. C.

    2005-01-01

    There is some debate in the literature as to whether there is an increased risk of developing eating disorders in individuals with type 1 diabetes. This review located 12 empirical studies of eating pathology in females with type 1 diabetes. Review of these papers indicates...... that there is no evidence for an increase in the rates of anorexia or bulimia, in females with type 1 diabetes. However, the data do suggest that eating disorders not otherwise specified (EDNOS) are more prevalent in individuals with type 1 diabetes. Key features of these articles are reviewed and discussed....

  12. Vitamin D and Type 1 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    К.S. Biliaieva

    2016-04-01

    Full Text Available The article presents data concerning the problem of vitamin D deficiency in adolescents with diabetes mellitus type 1. A correlation between vitamin D deficiency and compensation of the disease is shown. The examination of adolescent patients suffering from type 1 diabetes mellitus found a connection between levels of vitamin D, duration and the degree of type 1 diabetes compensation. Further studies are focused on studying the impact and the correction of vitamin D status in children with diabetes mellitus type 1, on improving the glycemic control and quality of life of a patient.

  13. Are cannabinoids effective for epilepsy?

    Directory of Open Access Journals (Sweden)

    Javier Peña

    2017-03-01

    Full Text Available Resumen En el último tiempo se han descrito diversos beneficios con el uso de canabinoides en diferentes situaciones clínicas. Dentro de ellas se ha planteado un posible efecto en el control de la epilepsia, pero la real utilidad clínica es tema de debate. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en múltiples bases de datos, identificamos cinco revisiones sistemáticas que en conjunto incluyen cuatro estudios aleatorizados. Extrajimos los datos y realizamos una síntesis mediante tablas de resumen de los resultados utilizando el método GRADE. Concluimos que no está claro si los cannabinoides disminuyen la frecuencia de las convulsiones porque la certeza de la evidencia es muy baja, pero probablemente se asocian a efectos adversos frecuentes.

  14. Synthesis of deuterium labeled cannabinoids

    Energy Technology Data Exchange (ETDEWEB)

    Banijamali, A.R.; Abou-Taleb, N.; Van der Schyf, C.J.; Charalambous, A.; Makriyannis, A.

    1988-01-01

    Several methods for the specific deuteration of cannabinoids are described. Deuteration of the phenolic ring was accomplished by treatment with BF/sub 3/center dotEt/sub 2/O followed by quenching with a solution of Na/sub 2/ CO/sub 3/ in D/sub 2/ O resulting in deuterium incorporation in both the 2 and 4 positions. Regioselective incorporation of deuterium into either the 2 or 4 position of ..delta../sup 8/-THC was achieved using Florisil spiked with either D/sub 2/O or H/sub 2/O. Deuteration at positions 8, 10 and 11 was achieved by addition of DC1 gas to the appropriate tetrahydrocannabinol to form 9-chlorohexahydrocannabinol labeled at either of the above positions, followed by elimination of hydrogen- or deuterium chloride with potassium-tert-amylate. UV irradiation of specifically labeled ..delta../sup 8/-THC gave the correspondingly labeled ..delta..sup(9,11)-THC.

  15. Cannabinoids for the treatment of dementia.

    Science.gov (United States)

    Krishnan, Sarada; Cairns, Ruth; Howard, Robert

    2009-04-15

    Following the discovery of an endogenous cannabinoid system and the identification of specific cannabinoid receptors in the central nervous system, much work has been done to investigate the main effects of these compounds. There is increasing evidence that the cannabinoid system may regulate neurodegenerative processes such as excessive glutamate production, oxidative stress and neuroinflammation. Neurodegeneration is a feature common to the various types of dementia and this has led to interest in whether cannabinoids may be clinically useful in the treatment of people with dementia. Recent studies have also shown that cannabinoids may have more specific effects in interrupting the pathological process in Alzheimer's disease. To determine from available research whether cannabinoids are clinically effective in the treatment of dementia. The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 11 April 2008 using the terms: cannabis or cannabinoid* or endocannabinoid* or cannabidiol or THC or CBD or dronabinol or delta-9-tetrahydrocannabinol or marijuana or marihuana or hashish. The CDCIG Specialized Register contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many clinical trials registries and grey literature sources. All double-blind and single (rater)-blind randomized placebo controlled trials assessing the efficacy of cannabinoids at any dose in the treatment of people with dementia. Two reviewers independently examined the retrieved studies for inclusion according to the selection criteria. They then independently assessed the methodological quality of selected trials and extracted data where possible. Only one study met the inclusion criteria. The data in the study report were presented in such a way that they could not be extracted for further analysis and

  16. Immunogenetics of type 1 diabetes mellitus

    African Journals Online (AJOL)

    EL-HAKIM

    Egypt J Pediatr Allergy Immunol 2008; 6(1): 3-12. 3. Immunogenetics of type 1 diabetes mellitus. Azza A. G. Tantawy. Professor of Pediatrics, Ain Shams University, Cairo. Introduction. Type 1 diabetes mellitus (T1D) is one of the most common autoimmune diseases with several million people already affected around the ...

  17. Type 1 Diabetes: What Is It?

    Science.gov (United States)

    ... Videos for Educators Search English Español Type 1 Diabetes: What Is It? KidsHealth / For Parents / Type 1 ... español Diabetes tipo 1: ¿Qué es? What Is Diabetes? Diabetes is a disease that affects how the ...

  18. Genetic Variations in the Human Cannabinoid Receptor Gene Are Associated with Happiness

    Science.gov (United States)

    Matsunaga, Masahiro; Isowa, Tokiko; Yamakawa, Kaori; Fukuyama, Seisuke; Shinoda, Jun; Yamada, Jitsuhiro; Ohira, Hideki

    2014-01-01

    Happiness has been viewed as a temporary emotional state (e.g., pleasure) and a relatively stable state of being happy (subjective happiness level). As previous studies demonstrated that individuals with high subjective happiness level rated their current affective states more positively when they experience positive events, these two aspects of happiness are interrelated. According to a recent neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of the human cannabinoid receptor 1 gene is associated with sensitivity to positive emotional stimuli. Thus, we hypothesized that our genetic traits, such as the human cannabinoid receptor 1 genotypes, are closely related to the two aspects of happiness. In Experiment 1, 198 healthy volunteers were used to compare the subjective happiness level between cytosine allele carriers and thymine-thymine carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used positron emission tomography with 20 healthy participants to compare the brain responses to positive emotional stimuli of cytosine allele carriers to that of thymine-thymine carriers. Compared to thymine-thymine carriers, cytosine allele carriers have a higher subjective happiness level. Regression analysis indicated that the cytosine allele is significantly associated with subjective happiness level. The positive mood after watching a positive film was significantly higher for the cytosine allele carriers compared to the thymine-thymine carriers. Positive emotion-related brain region such as the medial prefrontal cortex was significantly activated when the cytosine allele carriers watched the positive film compared to the thymine-thymine carriers. Thus, the human cannabinoid receptor 1 genotypes are closely related to two aspects of happiness. Compared to thymine-thymine carriers, the cytosine allele carriers of the human cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli, exhibited greater magnitude

  19. Genetic variations in the human cannabinoid receptor gene are associated with happiness.

    Science.gov (United States)

    Matsunaga, Masahiro; Isowa, Tokiko; Yamakawa, Kaori; Fukuyama, Seisuke; Shinoda, Jun; Yamada, Jitsuhiro; Ohira, Hideki

    2014-01-01

    Happiness has been viewed as a temporary emotional state (e.g., pleasure) and a relatively stable state of being happy (subjective happiness level). As previous studies demonstrated that individuals with high subjective happiness level rated their current affective states more positively when they experience positive events, these two aspects of happiness are interrelated. According to a recent neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of the human cannabinoid receptor 1 gene is associated with sensitivity to positive emotional stimuli. Thus, we hypothesized that our genetic traits, such as the human cannabinoid receptor 1 genotypes, are closely related to the two aspects of happiness. In Experiment 1, 198 healthy volunteers were used to compare the subjective happiness level between cytosine allele carriers and thymine-thymine carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used positron emission tomography with 20 healthy participants to compare the brain responses to positive emotional stimuli of cytosine allele carriers to that of thymine-thymine carriers. Compared to thymine-thymine carriers, cytosine allele carriers have a higher subjective happiness level. Regression analysis indicated that the cytosine allele is significantly associated with subjective happiness level. The positive mood after watching a positive film was significantly higher for the cytosine allele carriers compared to the thymine-thymine carriers. Positive emotion-related brain region such as the medial prefrontal cortex was significantly activated when the cytosine allele carriers watched the positive film compared to the thymine-thymine carriers. Thus, the human cannabinoid receptor 1 genotypes are closely related to two aspects of happiness. Compared to thymine-thymine carriers, the cytosine allele carriers of the human cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli, exhibited greater magnitude

  20. Genetic variations in the human cannabinoid receptor gene are associated with happiness.

    Directory of Open Access Journals (Sweden)

    Masahiro Matsunaga

    Full Text Available Happiness has been viewed as a temporary emotional state (e.g., pleasure and a relatively stable state of being happy (subjective happiness level. As previous studies demonstrated that individuals with high subjective happiness level rated their current affective states more positively when they experience positive events, these two aspects of happiness are interrelated. According to a recent neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of the human cannabinoid receptor 1 gene is associated with sensitivity to positive emotional stimuli. Thus, we hypothesized that our genetic traits, such as the human cannabinoid receptor 1 genotypes, are closely related to the two aspects of happiness. In Experiment 1, 198 healthy volunteers were used to compare the subjective happiness level between cytosine allele carriers and thymine-thymine carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used positron emission tomography with 20 healthy participants to compare the brain responses to positive emotional stimuli of cytosine allele carriers to that of thymine-thymine carriers. Compared to thymine-thymine carriers, cytosine allele carriers have a higher subjective happiness level. Regression analysis indicated that the cytosine allele is significantly associated with subjective happiness level. The positive mood after watching a positive film was significantly higher for the cytosine allele carriers compared to the thymine-thymine carriers. Positive emotion-related brain region such as the medial prefrontal cortex was significantly activated when the cytosine allele carriers watched the positive film compared to the thymine-thymine carriers. Thus, the human cannabinoid receptor 1 genotypes are closely related to two aspects of happiness. Compared to thymine-thymine carriers, the cytosine allele carriers of the human cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli, exhibited greater

  1. Chronic psychoemotional stress impairs cannabinoid-receptor-mediated control of GABA transmission in the striatum.

    Science.gov (United States)

    Rossi, Silvia; De Chiara, Valentina; Musella, Alessandra; Kusayanagi, Hajime; Mataluni, Giorgia; Bernardi, Giorgio; Usiello, Alessandro; Centonze, Diego

    2008-07-16

    Exposure to stressful events has a myriad of consequences in animals and in humans, and triggers synaptic adaptations in many brain areas. Stress might also alter cannabinoid-receptor-mediated transmission in the brain, but no physiological study has addressed this issue so far. In the present study, we found that social defeat stress, induced in mice by exposure to aggression, altered cannabinoid CB(1)-receptor-mediated control of synaptic transmission in the striatum. In fact, the presynaptic inhibition of GABAergic IPSCs induced by the cannabinoid CB(1) receptor agonist HU210 [(6aR)-trans-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol] was reduced after a single stressful episode and fully abolished after 3 and 7 d of stress exposure. Repeated psychoemotional stress also impaired the sensitivity of GABA synapses to endocannabinoids mobilized by group I metabotropic glutamate receptor stimulation, whereas the cannabinoid CB(1)-mediated control of glutamate transmission was unaffected by repeated exposure to an aggressor. Corticosteroids released in response to the activation of the hypothalamic-pituitary-adrenal axis played a major role in the synaptic defects observed in stressed animals, because these alterations were fully prevented by pharmacological blockade of glucocorticoid receptors and were mimicked by corticosterone injections. The recovery of stress-induced synaptic defects was favored when stressed mice were given access to a running wheel or to sucrose consumption, which function as potent natural rewards. A similar rescuing effect was obtained by a single injection of cocaine, a psychostimulant with strong rewarding properties. Targeting cannabinoid CB(1) receptors or endocannabinoid metabolism might be a valuable option to treat stress-associated neuropsychiatric conditions.

  2. Multitarget cannabinoids as novel strategy for Alzheimer disease.

    Science.gov (United States)

    González-Naranjo, Pedro; Campillo, Nuria E; Pérez, Concepción; Páez, Juan A

    2013-03-01

    During the last years the development of approaches to multitarget drug design and discovery is gaining acceptance. The cannabinoids are potentially excellent multi-target drug candidates because of their interesting pharmacological profiles, among which stands out the dual capacity of cannabinoid ligands to act as cannabinoid agonist and cholinesterase inhibitors. In this article, inhibition, kinetics studies and docking simulations with a representative set of cannabinoids are presented. The results of these studies showed the inhibitory capacity of some agonist cannabinoids with selectivity at AChE or BuChE enzymes. The kinetic and modelling studies allowed us to postulate the potential mode of action and the binding site of the cannabinoids. In general, the studied cannabinoids showed a mixed type inhibition mode of action. The exception to this behaviour was found for the agonist CP-55,940 that showed a non-competitive inhibition, suggesting that this cannabinoid only binds to the peripheral site.

  3. Sustainable Production of Cannabinoids with Supercritical Carbon Dioxide Technologies

    NARCIS (Netherlands)

    Perrotin-Brunel, H.

    2011-01-01

    This thesis concerns the production of natural compounds from plant material for pharmaceutical and food applications. It describes the production (extraction and isolation) of cannabinoids, the active components present in cannabis. Many cannabinoids have medicinal properties but not all

  4. Cannabinoid and Cholinergic Systems Interact during Performance of a Short-Term Memory Task in the Rat

    Science.gov (United States)

    Goonawardena, Anushka V.; Robinson, Lianne; Hampson, Robert E.; Riedel, Gernot

    2010-01-01

    It is now well established that cannabinoid agonists such as [delta][superscript 9]-tetrahydrocannabinol (THC), anandamide, and WIN 55,212-2 (WIN-2) produce potent and specific deficits in working memory (WM)/short-term memory (STM) tasks in rodents. Although mediated through activation of CB1 receptors located in memory-related brain regions such…

  5. Current Knowledge on Cannabinoids in Oral Fluid

    Science.gov (United States)

    Lee, Dayong; Huestis, Marilyn A.

    2015-01-01

    Oral fluid (OF) is a new biological matrix for clinical and forensic drug testing, offering non-invasive and directly observable sample collection reducing adulteration potential, ease of multiple sample collections, lower biohazard risk during collection, recent exposure identification, and stronger correlation with blood than urine concentrations. Because cannabinoids are usually the most prevalent analytes in illicit drug testing, application of OF drug testing requires sufficient scientific data to support sensitive and specific OF cannabinoid detection. This review presents current knowledge on OF cannabinoids, evaluating pharmacokinetic properties, detection windows, and correlation with other biological matrices and impairment from field applications and controlled drug administration studies. In addition, on-site screening technologies, confirmatory analytical methods, drug stability, and effects of sample collection procedure, adulterants, and passive environmental exposure are reviewed. Delta-9-tetrahydrocannabinol OF concentrations could be > 1000 μg/L shortly after smoking, whereas minor cannabinoids are detected at 10-fold and metabolites at 1000-fold lower concentrations. OF research over the past decade demonstrated that appropriate interpretation of test results requires a comprehensive understanding of distinct elimination profiles and detection windows for different cannabinoids, which are influenced by administration route, dose, and drug use history. Thus, each drug testing program should establish cutoff criteria, collection/analysis procedures, and storage conditions tailored to its purposes. Building a scientific basis for OF testing is on-going, with continuing OF cannabinoids research on passive environmental exposure, drug use history, donor physiological conditions, and oral cavity metabolism needed to better understand mechanisms of cannabinoid OF disposition and expand OF drug testing applicability. PMID:23983217

  6. Interactions of the opioid and cannabinoid systems in reward: Insights from knockout studies

    Directory of Open Access Journals (Sweden)

    Katia eBefort

    2015-02-01

    Full Text Available The opioid system consists of three receptors, mu, delta, and kappa, which are activated by endogenous opioid peptides (enkephalins, endorphins and dynorphins. The endogenous cannabinoid system comprises lipid neuromodulators (endocannabinoids, enzymes for their synthesis and their degradation and two well-characterized receptors, cannabinoid receptors CB1 and CB2. These systems play a major role in the control of pain as well as in mood regulation, reward processing and the development of addiction. Both opioid and cannabinoid receptors are coupled to G proteins and are expressed throughout the brain reinforcement circuitry. Extending classical pharmacology, research using genetically modified mice has provided important progress in the identification of the specific contribution of each component of these endogenous systems in vivo on reward process. This review will summarize available genetic tools and our present knowledge on the consequences of gene knockout on reinforced behaviors in both systems, with a focus on their potential interactions. A better understanding of opioid-cannabinoid interactions may provide novel strategies for therapies in addicted individuals.

  7. Cannabinoid Receptors: A Novel Target for Therapy of Prostate Cancer

    Science.gov (United States)

    2007-02-01

    cannabinoids, the active components of Cannabis sativa linnaeus (marijuana) and their derivatives are drawing renewed attention because of their diverse...its treatment has become a challenging issue. In recent years, cannabinoids, the active components of Cannabis sativa linnaeus (marijuana) and their...the therapeutic potential of cannabinoids under in vivo situation on cell proliferation, apoptosis, markers of angiogenesis and PSA levels. We

  8. Pharmacological actions and therapeutic uses of cannabis and cannabinoids.

    Science.gov (United States)

    Kumar, R N; Chambers, W A; Pertwee, R G

    2001-11-01

    This review highlights the pharmacology, pharmacokinetics, pharmacological actions, therapeutic uses and adverse effects of cannabinoids. The effect of cannabinoids on anaesthesia is mentioned briefly. Important advances have taken place in cannabinoid research over the last few years and have led to the discovery of novel ligands. The possible clinical applications of these ligands and the direction of future research are discussed.

  9. Understanding Functional Residues of the Cannabinoid CB1 Receptor for Drug Discovery

    OpenAIRE

    Shim, Joong-Youn

    2010-01-01

    The brain cannabinoid (CB1) receptor that mediates numerous physiological processes in response to marijuana and other psychoactive compounds is a G protein coupled receptor (GPCR) and shares common structural features with many rhodopsin class GPCRs. For the rational development of therapeutic agents targeting the CB1 receptor, understanding of the ligand-specific CB1 receptor interactions responsible for unique G protein signals is crucial. For a more than a decade, a combination of mutagen...

  10. Relationship of Cannabinoid CB1 Receptor and Cholecystokinin Immunoreactivity in Monkey Dorsolateral Prefrontal Cortex

    OpenAIRE

    Eggan, Stephen M.; Melchitzky, Darlene S.; Sesack, Susan R.; Fish, Kenneth N.; Lewis, David A.

    2010-01-01

    Exposure to cannabis impairs cognitive functions reliant on the circuitry of the dorsolateral prefrontal cortex (DLPFC) and increases the risk of schizophrenia. The actions of cannabis are mediated via the brain cannabinoid 1 receptor (CB1R), which in rodents is heavily localized to the axon terminals of cortical GABA basket neurons that contain cholecystokinin (CCK). Differences in the laminar distribution of CB1R-immunoreactive (IR) axons have been reported between rodent and monkey neocort...

  11. The therapeutic potential of cannabis and cannabinoids.

    Science.gov (United States)

    Grotenhermen, Franjo; Müller-Vahl, Kirsten

    2012-07-01

    Cannabis-based medications have been a topic of intense study since the endogenous cannabinoid system was discovered two decades ago. In 2011, for the first time, a cannabis extract was approved for clinical use in Germany. Selective literature review. Cannabis-based medications exert their effects mainly through the activation of cannabinoid receptors (CB1 and CB2). More than 100 controlled clinical trials of cannabinoids or whole-plant preparations for various indications have been conducted since 1975. The findings of these trials have led to the approval of cannabis-based medicines (dronabinol, nabilone, and a cannabis extract [THC:CBD=1:1]) in several countries. In Germany, a cannabis extract was approved in 2011 for the treatment of moderate to severe refractory spasticity in multiple sclerosis. It is commonly used off label for the treatment of anorexia, nausea, and neuropathic pain. Patients can also apply for government permission to buy medicinal cannabis flowers for self-treatment under medical supervision. The most common side effects of cannabinoids are tiredness and dizziness (in more than 10% of patients), psychological effects, and dry mouth. Tolerance to these side effects nearly always develops within a short time. Withdrawal symptoms are hardly ever a problem in the therapeutic setting. There is now clear evidence that cannabinoids are useful for the treatment of various medical conditions.

  12. Cannabinoids in late-onset Alzheimer's disease.

    Science.gov (United States)

    Ahmed, Aia; van der Marck, M A; van den Elsen, Gah; Olde Rikkert, Mgm

    2015-06-01

    Given the lack of effective treatments for late-onset Alzheimer's disease (LOAD) and the substantial burden on patients, families, health care systems, and economies, finding an effective therapy is one of the highest medical priorities. The past few years have seen a growing interest in the medicinal uses of cannabinoids, the bioactive components of the cannabis plant, including the treatment of LOAD and other physical conditions that are common in older people. Several in vitro and in vivo studies have demonstrated that cannabinoids can reduce oxidative stress, neuroinflammation, and the formation of amyloid plaques and neurofibrillary tangles, the key hallmarks of LOAD. In addition, in population-based studies, cannabinoids reduced dementia-related symptoms (e.g., behavioral disturbances). The current article provides an overview of the potential of cannabinoids in the treatment of LOAD and related neuropsychiatric symptoms in older people. We also discuss the efficacy, safety, and pharmacokinetics of cannabinoid-based drugs in older people with dementia. © 2015 American Society for Clinical Pharmacology and Therapeutics.

  13. Leaner and greener analysis of cannabinoids.

    Science.gov (United States)

    Mudge, Elizabeth M; Murch, Susan J; Brown, Paula N

    2017-05-01

    There is an explosion in the number of labs analyzing cannabinoids in marijuana (Cannabis sativa L., Cannabaceae) but existing methods are inefficient, require expert analysts, and use large volumes of potentially environmentally damaging solvents. The objective of this work was to develop and validate an accurate method for analyzing cannabinoids in cannabis raw materials and finished products that is more efficient and uses fewer toxic solvents. An HPLC-DAD method was developed for eight cannabinoids in cannabis flowers and oils using a statistically guided optimization plan based on the principles of green chemistry. A single-laboratory validation determined the linearity, selectivity, accuracy, repeatability, intermediate precision, limit of detection, and limit of quantitation of the method. Amounts of individual cannabinoids above the limit of quantitation in the flowers ranged from 0.02 to 14.9% w/w, with repeatability ranging from 0.78 to 10.08% relative standard deviation. The intermediate precision determined using HorRat ratios ranged from 0.3 to 2.0. The LOQs for individual cannabinoids in flowers ranged from 0.02 to 0.17% w/w. This is a significant improvement over previous methods and is suitable for a wide range of applications including regulatory compliance, clinical studies, direct patient medical services, and commercial suppliers.

  14. Prolonged oral cannabinoid administration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance in Tg APP 2576 mice

    Directory of Open Access Journals (Sweden)

    Martín-Moreno Ana María

    2012-01-01

    Full Text Available Abstract Background Alzheimer's disease (AD brain shows an ongoing inflammatory condition and non-steroidal anti-inflammatories diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and anti-inflammatory agents with therapeutic potential. Methods We have studied the effects of prolonged oral administration of transgenic amyloid precursor protein (APP mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.2 mg/kg/day in the drinking water during 4 months on inflammatory and cognitive parameters, and on 18F-fluoro-deoxyglucose (18FDG uptake by positron emission tomography (PET. Results Novel object recognition was significantly reduced in 11 month old Tg APP mice and 4 month administration of JWH was able to normalize this cognitive deficit, although WIN was ineffective. Wild type mice cognitive performance was unaltered by cannabinoid administration. Tg APP mice showed decreased 18FDG uptake in hippocampus and cortical regions, which was counteracted by oral JWH treatment. Hippocampal GFAP immunoreactivity and cortical protein expression was unaffected by genotype or treatment. In contrast, the density of Iba1 positive microglia was increased in Tg APP mice, and normalized following JWH chronic treatment. Both cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-α mRNA expression found in the AD model. Increased cortical β-amyloid (Aβ levels were significantly reduced in the mouse model by both cannabinoids. Noteworthy both cannabinoids enhanced Aβ transport across choroid plexus cells in vitro. Conclusions In summary we have shown that chronically administered cannabinoid showed marked beneficial effects concomitant with inflammation reduction and increased Aβ clearance.

  15. Preclinical studies on the reinforcing effects of cannabinoids. A tribute to the scientific research of Dr. Steve Goldberg

    Science.gov (United States)

    Tanda, Gianluigi

    2016-01-01

    Rationale The reinforcing effects of most abused drugs have been consistently demonstrated and studied in animal models, although those of marijuana were not, until the demonstration fifteen years ago that THC could serve as a reinforcer in self-administration (SA) procedures in squirrel monkeys. Until then, those effects were inferred using indirect assessments. Objectives The aim of this manuscript is to review the primary preclinical procedures used to indirectly and directly infer reinforcing effects of cannabinoid drugs. Methods Results will be reviewed from studies of cannabinoid-discrimination, intracranial-self-stimulation (ICSS), conditioned place preference (CPP), as well as change in levels of dopamine assessed in brain areas related to reinforcement, and finally from self-administration procedures. For each procedure, an evaluation will be made of the predictive validity in detecting the potential abuse liability of cannabinoids based on seminal papers, with the addition of selected reports from more recent years especially those from Dr. Goldberg’s research group. Results and Conclusions ICSS and CPP do not provide consistent results for the assessment of potential for abuse of cannabinoids. However, drug-discrimination and neurochemistry procedures appear to detect potential for abuse of cannabinoids, as well as several novel “designer cannabinoid drugs.” Though after 15 years it remains somewhat problematic transfer the self-administration model of marijuana abuse from squirrel monkeys to other species, studies with the former species have substantially advanced the field, and several reports have been published with consistent self-administration of cannabinoid agonists in rodents. PMID:27026633

  16. Prolonged oral cannabinoid administration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance in Tg APP 2576 mice.

    Science.gov (United States)

    Martín-Moreno, Ana María; Brera, Begoña; Spuch, Carlos; Carro, Eva; García-García, Luis; Delgado, Mercedes; Pozo, Miguel A; Innamorato, Nadia G; Cuadrado, Antonio; de Ceballos, María L

    2012-01-16

    Alzheimer's disease (AD) brain shows an ongoing inflammatory condition and non-steroidal anti-inflammatories diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and anti-inflammatory agents with therapeutic potential. We have studied the effects of prolonged oral administration of transgenic amyloid precursor protein (APP) mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.2 mg/kg/day in the drinking water during 4 months) on inflammatory and cognitive parameters, and on ¹⁸F-fluoro-deoxyglucose (¹⁸FDG) uptake by positron emission tomography (PET). Novel object recognition was significantly reduced in 11 month old Tg APP mice and 4 month administration of JWH was able to normalize this cognitive deficit, although WIN was ineffective. Wild type mice cognitive performance was unaltered by cannabinoid administration. Tg APP mice showed decreased ¹⁸FDG uptake in hippocampus and cortical regions, which was counteracted by oral JWH treatment. Hippocampal GFAP immunoreactivity and cortical protein expression was unaffected by genotype or treatment. In contrast, the density of Iba1 positive microglia was increased in Tg APP mice, and normalized following JWH chronic treatment. Both cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-α mRNA expression found in the AD model. Increased cortical β-amyloid (Aβ) levels were significantly reduced in the mouse model by both cannabinoids. Noteworthy both cannabinoids enhanced Aβ transport across choroid plexus cells in vitro. In summary we have shown that chronically administered cannabinoid showed marked beneficial effects concomitant with inflammation reduction and increased Aβ clearance.

  17. Liraglutide for treating type 1 diabetes

    DEFF Research Database (Denmark)

    Dejgaard, Thomas Fremming; Frandsen, Christian Seerup; Holst, Jens Juul

    2016-01-01

    INTRODUCTION: Many persons with type 1 diabetes do not achieve glycemic targets, why new treatments, complementary to insulin, are of interest. Liraglutide, a long-acting glucagon-like peptide-1 receptor agonist could be a potential pharmacological supplement to insulin. This review discusses...... the mechanism of actions, efficacy and safety of liraglutide as add-on to insulin in persons with type 1 diabetes. AREAS COVERED: Physiological and clinical data on liraglutide in type 1 diabetes were reviewed. We searched the Cochrane library, MEDLINE and EMBASE, with the final search performed February 16...... there was no clinically relevant effect on HbA1c. Adverse events were mostly transient gastrointestinal side effects, primarily nausea. Based on the available data, liraglutide cannot be recommended as add-on therapy to insulin in persons with type 1 diabetes with the aim to improve glycemic control. Ongoing trials...

  18. Human intestinal microbiota and type 1 diabetes.

    Science.gov (United States)

    Vaarala, Outi

    2013-10-01

    The role of intestinal microbiota in immune-mediated diseases, such as type 1 diabetes, has deservedly received a lot of attention. Evidently, changes in the intestinal microbiota are associated with type 1 diabetes as demonstrated by recent studies. Children with beta-cell autoimmunity have shown low abundance of butyrate-producing bacteria and increase in the abundance of members of the Bacteroidetes phylum in fecal microbiota. These alterations could explain increased gut permeability, subclinical small intestinal inflammation, and dysregulation of oral tolerance in type 1 diabetes. However, these studies do not provide evidence of the causative role of the gut microbiota in the development of beta-cell autoimmunity, yet. In animal models, the composition of gut microbiota modulates the function of both innate and adaptive immunity, and intestinal bacteria are regulators of autoimmune diabetes. Thus, prevention of type 1 diabetes could, in the future, be based on the interventions targeted to the gut microbiota.

  19. Maculopathy and spinocerebellar ataxia type 1

    DEFF Research Database (Denmark)

    Lebranchu, Pierre; Le Meur, Guylène; Magot, Armelle

    2013-01-01

    Autosomal dominant cerebellar ataxia is a rare heterogeneous group of diseases characterized by cerebellar symptoms, often associated with other multisystemic signs. Mild optic neuropathy has been associated with spinocerebellar ataxia type 1 (SCA1), but macular dysfunction has been reported...

  20. Ophthalmological manifestations in segmental neurofibromatosis type 1

    OpenAIRE

    Ruggieri, M; PAVONE, P.; Polizzi, A.; Pietro, M. Di; Scuderi, A.; Gabriele, A; Spalice, A.; Iannetti, P

    2004-01-01

    Aims: To study the ophthalmological manifestations in individuals with the typical features of neurofibromatosis type 1 (NF1) circumscribed to one or more body segments, usually referred to as segmental NF1.

  1. Cell therapy for type 1 diabetes

    National Research Council Canada - National Science Library

    Muir, K R; Lima, M J; Docherty, H M; Docherty, K

    2014-01-01

    Cell therapy in the form of human islet transplantation has been a successful form of treatment for patients with type 1 diabetes for over 10 years, but is significantly limited by lack of suitable donor material...

  2. Lisch spots in neurofibromatosis type 1

    Directory of Open Access Journals (Sweden)

    Saxena Rajesh

    1991-01-01

    Full Text Available The eyes of 28 patients of Neurofibromatosis type 1 were examined. Lisch spots were present in all the patients above 20 years. Their clinical appearance is being presented as seen in Indian subjects.

  3. Intraventricular Brain Injection of Adeno-Associated Virus Type 1 (AAV1) in Neonatal Mice Results in Complementary Patterns of Neuronal Transduction to AAV2 and Total Long-Term Correction of Storage Lesions in the Brains of β-Glucuronidase-Deficient Mice

    Science.gov (United States)

    Passini, Marco A.; Watson, Deborah J.; Vite, Charles H.; Landsburg, Daniel J.; Feigenbaum, Alyson L.; Wolfe, John H.

    2003-01-01

    Inherited metabolic disorders that affect the central nervous system typically result in pathology throughout the brain; thus, gene therapy strategies need to achieve widespread delivery. We previously found that although intraventricular injection of the neonatal mouse brain with adeno-associated virus serotype 2 (AAV2) results in dispersed gene delivery, many brain structures were poorly transduced. This limitation may be overcome by using different AAV serotypes because the capsid proteins use different cellular receptors for entry, which may allow enhanced global targeting of the brain. We tested this with AAV1 and AAV5 vectors. AAV5 showed very limited brain transduction after neonatal injection, even though it has different transduction patterns than AAV2 in adult brain injections. In contrast, AAV1 vectors, which have not been tested in the brain, showed robust widespread transduction. Complementary patterns of transduction between AAV1 and AAV2 were established and maintained in the adult brain after neonatal injection. In the majority of structures, AAV1 transduced many more cells than AAV2. Both vectors transduced mostly neurons, indicating that differential expression of receptors on the surfaces of neurons occurs in the developing brain. The number of cells positive for a vector-encoded secreted enzyme (β-glucuronidase) was notably greater and more widespread in AAV1-injected brains. A comprehensive analysis of AAV1-treated brains from β-glucuronidase-deficient mice (mucopolysaccharidosis type VII) showed complete reversal of pathology in all areas of the brain for at least 1 year, demonstrating that the combination of this serotype and experimental strategy is therapeutically effective for treating global neurometabolic disorders. PMID:12768022

  4. Intraventricular Brain Injection of Adeno-Associated Virus Type 1 (AAV1) in Neonatal Mice Results in Complementary Patterns of Neuronal Transduction to AAV2 and Total Long-Term Correction of Storage Lesions in the Brains of β-Glucuronidase-Deficient Mice

    OpenAIRE

    Passini, Marco A; Watson, Deborah J; Vite, Charles H; Landsburg, Daniel J.; Feigenbaum, Alyson L.; Wolfe, John H

    2003-01-01

    Inherited metabolic disorders that affect the central nervous system typically result in pathology throughout the brain; thus, gene therapy strategies need to achieve widespread delivery. We previously found that although intraventricular injection of the neonatal mouse brain with adeno-associated virus serotype 2 (AAV2) results in dispersed gene delivery, many brain structures were poorly transduced. This limitation may be overcome by using different AAV serotypes because the capsid proteins...

  5. Intraventricular brain injection of adeno-associated virus type 1 (AAV1) in neonatal mice results in complementary patterns of neuronal transduction to AAV2 and total long-term correction of storage lesions in the brains of beta-glucuronidase-deficient mice.

    Science.gov (United States)

    Passini, Marco A; Watson, Deborah J; Vite, Charles H; Landsburg, Daniel J; Feigenbaum, Alyson L; Wolfe, John H

    2003-06-01

    Inherited metabolic disorders that affect the central nervous system typically result in pathology throughout the brain; thus, gene therapy strategies need to achieve widespread delivery. We previously found that although intraventricular injection of the neonatal mouse brain with adeno-associated virus serotype 2 (AAV2) results in dispersed gene delivery, many brain structures were poorly transduced. This limitation may be overcome by using different AAV serotypes because the capsid proteins use different cellular receptors for entry, which may allow enhanced global targeting of the brain. We tested this with AAV1 and AAV5 vectors. AAV5 showed very limited brain transduction after neonatal injection, even though it has different transduction patterns than AAV2 in adult brain injections. In contrast, AAV1 vectors, which have not been tested in the brain, showed robust widespread transduction. Complementary patterns of transduction between AAV1 and AAV2 were established and maintained in the adult brain after neonatal injection. In the majority of structures, AAV1 transduced many more cells than AAV2. Both vectors transduced mostly neurons, indicating that differential expression of receptors on the surfaces of neurons occurs in the developing brain. The number of cells positive for a vector-encoded secreted enzyme (beta-glucuronidase) was notably greater and more widespread in AAV1-injected brains. A comprehensive analysis of AAV1-treated brains from beta-glucuronidase-deficient mice (mucopolysaccharidosis type VII) showed complete reversal of pathology in all areas of the brain for at least 1 year, demonstrating that the combination of this serotype and experimental strategy is therapeutically effective for treating global neurometabolic disorders.

  6. Auditory Impairment in Young Type 1 Diabetics.

    Science.gov (United States)

    Hou, Yanlian; Xiao, Xiaoyan; Ren, Jianmin; Wang, Yajuan; Zhao, Faming

    2015-10-01

    More attention has recently been focused on auditory impairment of young type 1 diabetics. This study aimed to evaluate auditory function of young type 1 diabetics and the correlation between clinical indexes and hearing impairment. We evaluated the auditory function of 50 type 1 diabetics and 50 healthy subjects. Clinical indexes were measured along with analyzing their relation of auditory function. Type 1 diabetic patients demonstrated a deficit with elevated thresholds at right ear and left ear when compared to healthy controls (p p V and interwave I-V) and left ear (wave III, V and interwave I-III, I-V) in diabetic group significantly increased compared to those in control subjects (p p p p p <0.01). Type 1 diabetics exerted higher auditory threshold, slower auditory conduction time and cochlear impairment. HDL-cholesterol, diabetes duration, systemic blood pressure, microalbuminuria, GHbA1C, triglyceride, and age may affect the auditory function of type 1 diabetics. Copyright © 2015 IMSS. Published by Elsevier Inc. All rights reserved.

  7. Cannabinoid receptors in the kidney.

    Science.gov (United States)

    Hryciw, Deanne H; McAinch, Andrew J

    2016-09-01

    The endocannabinoid system modulates cell signaling targets that are essential for energy homeostasis. Endocannabinoids bind to G protein-coupled receptors in the central nervous system and periphery, including the kidney. Modulation of cannabinoid receptor 1 (CB1) and CB2 activity in the kidney in diabetes and obesity has been identified as potential therapeutic target to reduce albuminuria and renal fibrosis. This review will highlight the results of recent studies that have identified a role for CB1 and CB2 in normal and pathological renal conditions. CB1 and CB2 have been reported to play key roles in renal function and dysfunction. Recent studies have determined that antagonism of CB1 and agonism of CB2 in diabetic nephropathy and obesity associated kidney disease can reduce albuminuria, potentially by acting on both the glomeruli and tubules. Emerging studies have also identified a role for CB1 in renal diseases associated with fibrosis, with CB1 upregulated in multiple models of human nephropathies. Emerging studies using isolated cells, rodent models, and human studies have identified a critical role for the endocannabinoid system in renal function and disease. Thus, therapeutics that modulate the activity of CB1 and CB2 in renal disease could become clinically relevant.

  8. Cannabinoids – a new weapon against cancer?

    Directory of Open Access Journals (Sweden)

    Małgorzata Pokrywka

    2016-12-01

    Full Text Available Cannabis has been cultivated by man since Neolithic times. It was used, among others for fiber and rope production, recreational purposes and as an excellent therapeutic agent. The isolation and characterization of the structure of one of the main active ingredients of cannabis – Δ9 – tetrahydrocannabinol as well the discovery of its cannabinoid binding receptors CB1 and CB2, has been a milestone in the study of the possibilities of the uses of Cannabis sativa and related products in modern medicine. Many scientific studies indicate the potential use of cannabinoids in the fight against cancer. Experiments carried out on cell lines in vitro and on animal models in vivo have shown that phytocannabinoids, endocannabinoids, synthetic cannabinoids and their analogues can lead to inhibition of the growth of many tumor types, exerting cytostatic and cytotoxic neoplastic effect on cells thereby negatively influencing neo-angiogenesis and the ability of cells to metastasize.The main molecular mechanism leading to inhibition of proliferation of cancer cells by cannabinoids is apoptosis. Studies have shown, however, that the process of apoptosis in cells, treated with recannabinoids, is a consequence of induction of endoplasmic reticulum stress and autophagy. On the other hand, in the cellular context and dosage dependence, cannabinoids may enhance the proliferation of tumor cells by suppressing the immune system or by activating mitogenic factors. Leading from this there is a an obvious need to further explore cannabinoid associated molecular pathways making it possible to develop safe therapeutic drug agents for patients in the future.

  9. Comparison of outcome expectancies for synthetic cannabinoids and botanical marijuana.

    Science.gov (United States)

    Lauritsen, Kirstin J; Rosenberg, Harold

    2016-07-01

    Although initially developed for medical purposes, synthetic cannabinoids have also been consumed for recreational purposes. To evaluate whether agreement with positive and negative outcome expectancies differed for synthetic cannabinoids versus botanical marijuana, and assess reported reasons for using synthetic cannabinoids. Using a web-based recruitment and data collection procedure, 186 adults who had used both synthetic cannabinoids and botanical marijuana and 181 adults who had used botanical marijuana but not synthetic cannabinoids, completed measures of outcome expectancies and other relevant questionnaires. A significant interaction revealed that participants who had used both synthetic cannabinoids and botanical marijuana indicated lower agreement with positive expectancies for synthetic cannabinoids, and higher agreement with positive expectancies for botanical marijuana, than did those participants who used only botanical marijuana. There was no interaction between type of drug and use history on agreement with negative expectancies, and participants agreed more strongly with negative outcome expectancies for synthetic cannabinoids than for botanical marijuana whether they had used one or both types of these drugs. The most frequently provided reasons for using synthetic cannabinoids included availability, perceived legality, cost, curiosity, and social interaction. Given growing public acceptance of recreational and medical marijuana, coupled with negative perceptions and increasing regulation of synthetic cannabinoid compounds, botanical marijuana is likely to remain more available and more popular than synthetic cannabinoids.

  10. Cannabinoid Markers in Biological Fluids and Tissues: Revealing Intake.

    Science.gov (United States)

    Huestis, Marilyn A; Smith, Michael L

    2018-02-01

    Understanding cannabis and synthetic cannabinoid intake history is vital for treating drug dependence, investigating cannabinoid effects, and providing information to healthcare personnel, medical examiners, and public health officials; this is particularly relevant today with cannabis medicalization and legalization. Required information includes identifying exposure, time of use, frequency of use, relapse, withdrawal, and predicting cannabinoid effects. Recent controlled cannabinoid administration studies enable the development of models and markers to better identify patterns of intake and exposure. Future challenges include developing behavioral markers of cannabis impairment, bringing to market breathalyzers for cannabinoid detection, and identifying markers of recent cannabis intake in diverse biological matrices. We posit that biological monitoring of cannabinoids and metabolites will improve the characterization of cannabis and synthetic cannabinoid intake history. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. [18F]MK-9470 PET measurement of cannabinoid CB1 receptor availability in chronic cannabis users

    OpenAIRE

    Ceccarini, Jenny; Kuepper, Rebecca; Kemels, Dieter; van Os, Jim; Henquet, Cécile; Van Laere, Koen

    2015-01-01

    Δ9 -Tetrahydrocannabinol, the main psychoactive component of cannabis, exerts its central effects through activation of the cerebral type 1 cannabinoid (CB1 ) receptor. Pre-clinical studies have provided evidence that chronic cannabis exposure is linked to decreased CB1 receptor expression and this is thought to be a component underlying drug tolerance and dependence. In this study, we make first use of the selective high-affinity positron emission tomography (PET) ligand [18 F]MK-9470 to obt...

  12. Insulin resistance in type 1 diabetes mellitus.

    Science.gov (United States)

    Kaul, Kirti; Apostolopoulou, Maria; Roden, Michael

    2015-12-01

    For long the presence of insulin resistance in type 1 diabetes has been questioned. Detailed metabolic analyses revealed 12%-61% and up to 20% lower whole-body (skeletal muscle) and hepatic insulin sensitivity in type 1 diabetes, depending on the population studied. Type 1 diabetes patients feature impaired muscle adenosine triphosphate (ATP) synthesis and enhanced oxidative stress, predominantly relating to hyperglycemia. They may also exhibit abnormal fasting and postprandial glycogen metabolism in liver, while the role of hepatic energy metabolism for insulin resistance remains uncertain. Recent rodent studies point to tissue-specific differences in the mechanisms underlying insulin resistance. In non-obese diabetic mice, increased lipid availability contributes to muscle insulin resistance via diacylglycerol/protein kinase C isoforms. Furthermore, humans with type 1 diabetes respond to lifestyle modifications or metformin by 20%-60% increased whole-body insulin sensitivity, likely through improvement in both glycemic control and oxidative phosphorylation. Intensive insulin treatment and islet transplantation also increase but fail to completely restore whole-body and hepatic insulin sensitivity. In conclusion, insulin resistance is a feature of type 1 diabetes, but more controlled trials are needed to address its contribution to disease progression, which might help to optimize treatment and reduce comorbidities. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Type 1 Diabetes in Young Adulthood

    Science.gov (United States)

    Monaghan, Maureen; Helgeson, Vicki; Wiebe, Deborah

    2015-01-01

    Type 1 diabetes has traditionally been studied as a chronic illness of childhood. However, young adulthood is a critical time for the development and integration of lifelong diabetes management skills, and research is starting to identify unique challenges faced by youth with diabetes as they age into adulthood. Most young adults experience multiple transitions during this unstable developmental period, including changes in lifestyle (e.g., education, occupation, living situation), changes in health care, and shifting relationships with family members, friends, and intimate others. Young adults with type 1 diabetes must navigate these transitions while also assuming increasing responsibility for their diabetes care and overall health. Despite these critical health and psychosocial concerns, there is a notable lack of evidence-based clinical services and supports for young adults with type 1 diabetes. We review relevant evolving concerns for young adults with type 1 diabetes, including lifestyle considerations, health care transitions, psychosocial needs, and changes in supportive networks, and how type 1 diabetes impacts and is impacted by these key developmental considerations. Specific avenues for intervention and future research are offered. PMID:25901502

  14. Adrenal incidentaloma in neurofibromatosis type 1

    Directory of Open Access Journals (Sweden)

    Tančić-Gajić Milina

    2008-01-01

    Full Text Available INTRODUCTION Neurofibromatosis type 1 is one of the most common genetically transmitted diseases with a high index of spontaneous mutations and extremely varied and unpredictable clinical manifestations. It is diagnosed by the existence of certain clinical criteria. The presence of numerous localised cutaneous neurofibromas or a plexiform neurofibroma is virtually pathognomonic of neurofibromatosis type 1. The incidence of pheochromocytoma in neurofibromatosis type 1 is 0.1-5.7%. CASE OUTLINE A 56-year old female patient was admitted for further evaluation of incidental adrenal tumour previously diagnosed on computerized tomography (CT. She had previously unrecognized neurofibromatosis type 1 and a clinical picture which could remind of pheochromocytoma. None of the catecholamine samples in 24 hr urine indicated functionally active pheochromocytoma. Chromogranin A was moderately increased. Decision for operation was made after performing the image techniques. Adrenal incidentaloma had features of pheochromocytoma on abdominal magnetic resonance imaging (MRI, with positive 131I-MIBG (iodine 131-labelled metaiodobenzylguanidine scintigraphy. After being treated with phenoxybenzamine and propranolol, she was operated on. The pathohistological finding showed the case of left adrenal pheochromocytoma. CONCLUSION Detailed diagnostic procedure for pheochromocytoma should be performed with patients having neurofibromatosis type 1 and adrenal incidentaloma. Pheochromocytomas are rare tumours with fatal outcome if not duly recognized and cured.

  15. Cannabinoids and omega-3/6 endocannabinoids as cell death and anticancer modulators.

    Science.gov (United States)

    Brown, Iain; Cascio, Maria G; Rotondo, Dino; Pertwee, Roger G; Heys, Steven D; Wahle, Klaus W J

    2013-01-01

    Cannabinoids-endocannaboids are possible preventatives of common diseases including cancers. Cannabinoid receptors (CB(½), TRPV1) are central components of the system. Many disease-ameliorating effects of cannabinoids-endocannabinoids are receptor mediated, but many are not, indicating non-CBR signaling pathways. Cannabinoids-endocannabinoids are anti-inflammatory, anti-proliferative, anti-invasive, anti-metastatic and pro-apoptotic in most cancers, in vitro and in vivo in animals. They signal through p38, MAPK, JUN, PI3, AKT, ceramide, caspases, MMPs, PPARs, VEGF, NF-κB, p8, CHOP, TRB3 and pro-apoptotic oncogenes (p53,p21 waf1/cip1) to induce cell cycle arrest, autophagy, apoptosis and tumour inhibition. Paradoxically they are pro-proliferative and anti-apoptotic in some cancers. Differences in receptor expression and concentrations of cannabinoids in cancer and immune cells can elicit anti- or pro-cancer effects through different signal cascades (p38MAPK or PI3/AKT). Similarities between effects of cannabinoids-endocannabinoids, omega-3 LCPUFA and CLAs/CLnAs as anti-inflammatory, antiangiogenic, anti-invasive anti-cancer agents indicate common signaling pathways. Evidence in vivo and in vitro shows EPA and DHA can form endocannabinoids that: (i) are ligands for CB(½) receptors and possibly TRPV-1, (ii) have non-receptor mediated bioactivity, (iii) induce cell cycle arrest, (iii) increase autophagy and apoptosis, and (iv) augment chemotherapeutic actions in vitro. They can also form bioactive, eicosanoid-like products that appear to be non-CBR ligands but have effects on PPARs and NF-kB transcription factors. The use of cannabinoids in cancer treatment is currently limited to chemo- and radio-therapy-associated nausea and cancer-associated pain apart from one trial on brain tumours in patients. Further clinical studies are urgently required to determine the true potential of these intriguing, low toxicity compounds in cancer therapy. Particularly in view of

  16. Outcomes in type 1 diabetic pregnancies

    DEFF Research Database (Denmark)

    Jensen, Dorte Møller; Damm, Peter; Moelsted-Pedersen, Lars

    2004-01-01

    OBJECTIVE: The aim of this study was to compare pregnancy outcomes in type 1 diabetic pregnancies with the background population. RESEARCH DESIGN AND METHODS: This nationwide prospective multicenter study took place in eight Danish centers treating pregnant women with type 1 diabetes during 1993...... population. Six of the perinatal deaths (16%) were related to congenital malformations. Only 34% of women performed daily home monitoring of blood glucose at conception, and 58% received preconceptional guidance. Pregnancies with serious adverse outcomes (perinatal death and/or congenital malformations) were......, daily self-monitoring was associated with a reduction in serious adverse outcomes. The caesarean section rate was 55.9 and 12.6%, respectively, and the risk of preterm delivery was 41.7 and 6.0%, respectively. CONCLUSIONS: Type 1 diabetic pregnancies are still complicated by considerably higher rates...

  17. Dehydroepiandrosterone in the type 1 diabetes mellitus.

    Science.gov (United States)

    Duskova, M; Hruskovicova, H; Hill, M; Starka, L

    2012-04-01

    Dehydroepiandrosterone (DHEA) is believed to exert, besides others, positive effects on the insulin resistance or its secretion and glucose metabolism. There are several reports dealing with the DHEA levels and its effects in the type 2 diabetes mellitus, but less information is available on the type 1 diabetic subjects. Recently, a report dealing with the lack of the age-dependent decline of the DHEA levels in the type 2 diabetic subjects was published. The aim of the present study was to answer the question whether a comparable change in the aging pattern of the DHEA and its sulphate could be detected in the type 1 diabetes mellitus. The data regarding the DHEA and dehydroepiandrosterone sulphate (DHEA-S) concentrations in the serum obtained from 116 patients with the type 1 diabetes mellitus and 259 controls were gathered from the database of the Institute of Endocrinology (Prague, Czech Republic). No significant differences in the level of the DHEA-S were found between the type 1 diabetics and controls either in men or women. However, lower DHEA levels were found in the type 1 diabetic women, but not in men. The age-dependent declines of both the DHEA and DHEA-S were similar to those in controls. In contrast to the type 2 diabetes, the levels of DHEA-S in the type 1 diabetic patients were practically identical with those in controls. In contrast to men, in women, the DHEA basal levels were lower than those seen in controls. The age dependence of both hormones followed the pattern of the decline in controls.

  18. Cannabinoid receptor CB2 modulates axon guidance

    DEFF Research Database (Denmark)

    Duff, Gabriel; Argaw, Anteneh; Cecyre, Bruno

    2013-01-01

    Navigation of retinal projections towards their targets is regulated by guidance molecules and growth cone transduction mechanisms. Here, we present in vitro and in vivo evidences that the cannabinoid receptor 2 (CB2R) is expressed along the retino-thalamic pathway and exerts a modulatory action ...

  19. Interactions of Cannabinoids With Biochemical Substrates

    Directory of Open Access Journals (Sweden)

    Brian F Thomas

    2017-05-01

    Full Text Available Recent decades have seen much progress in the identification and characterization of cannabinoid receptors and the elucidation of the mechanisms by which derivatives of the Cannabis sativa plant bind to receptors and produce their physiological and psychological effects. The information generated in this process has enabled better understanding of the fundamental physiological and psychological processes controlled by the central and peripheral nervous systems and has fostered the development of natural and synthetic cannabinoids as therapeutic agents. A negative aspect of this decades-long effort is the proliferation of clandestinely synthesized analogs as recreational street drugs with dangerous effects. Currently, the interactions of cannabinoids with their biochemical substrates are extensively but inadequately understood, and the clinical application of derived and synthetic receptor ligands remains quite limited. The wide anatomical distribution and functional complexity of the cannabinoid system continue to indicate potential for both therapeutic and side effects, which offers challenges and opportunities for medicinal chemists involved in drug discovery and development.

  20. Constipation in adults with neurofibromatosis type 1

    DEFF Research Database (Denmark)

    Ejerskov, Cecilie; Krogh, Klaus; Ostergaard, John R

    2017-01-01

    BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal-dominant disease characterised by symptoms of the skin, eyes, nervous system and bones. A previous study indicated that constipation, large rectal diameters and prolonged colorectal transit times are common in children with NF1. The aim...

  1. Learning Disabilities in Neurofibromatosis Type 1

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2006-12-01

    Full Text Available The frequency of specific leaning disabilities (SLD in neurofibromatosis type 1 (NF1 was determined in a cohort of 81 patients (43 males, 38 females; mean age 11 years 6 months; age range 8-16 followed at Children's Hospital, Westmead, NSW, Australia.

  2. Neurofibromatosis type 1: Surgical Perspectives | Nthumba | Annals ...

    African Journals Online (AJOL)

    Introduction: Neurofi bromatosis type 1 (NF1) affects about 1 in 3000 people. The indications for surgical intervention in patients with NF1 are not always clear-cut. In low-income economies, where scarcity of resources and skilled manpower often dictate levels of healthcare, a broad knowledge base of NF1 is required in ...

  3. Boston Keratoprosthesis Type 1 in Chemical Burns.

    Science.gov (United States)

    Salvador-Culla, Borja; Kolovou, Paraskevi E; Arzeno, Linnette; Martínez, Santiago; López, Miguel A

    2016-06-01

    To describe and further analyze the long-term results in visual acuity (VA), anatomical retention, and rate of complications from patients who underwent Boston keratoprosthesis (B-Kpro) type 1 after ocular chemical burns in the Dominican Republic. A retrospective review of 42 eyes (22 OD:20 OS) of 36 patients who underwent B-Kpro type 1 implantation after severe ocular burn at Hospital Elías Santana in Santo Domingo, Dominican Republic, between April 2006 and October 2014, were included. Demographics, VA, anatomical retention, and the rates of postoperative complications and concurrent surgeries were evaluated. The excellent anatomical retention rates and visual outcomes presented in this study support the remarkable capability of B-Kpro type 1 to restore functional VA in eyes with severe chemical injuries. However, strict control of the postoperative complications is necessary for long-term success. In conclusion, the use of a B-Kpro type 1 after severe chemical burn is a viable option in patients otherwise condemned to the high risk of failure associated with conventional corneal grafts.

  4. Effects of cannabinoid and vanilloid receptor agonists and their interaction on learning and memory in rats.

    Science.gov (United States)

    Shiri, Mariam; Komaki, Alireza; Oryan, Shahrbanoo; Taheri, Masoumeh; Komaki, Hamidreza; Etaee, Farshid

    2017-04-01

    Despite previous findings on the effects of cannabinoid and vanilloid systems on learning and memory, the effects of the combined stimulation of these 2 systems on learning and memory have not been studied. Therefore, in this study, we tested the interactive effects of cannabinoid and vanilloid systems on learning and memory in rats by using passive avoidance learning (PAL) tests. Forty male Wistar rats were divided into the following 4 groups: (1) control (DMSO+saline), (2) WIN55,212-2, (3) capsaicin, and (4) WIN55,212-2 + capsaicin. On test day, capsaicin, a vanilloid receptor type 1 (TRPV1) agonist, or WIN55,212-2, a cannabinoid receptor (CB1/CB2) agonist, or both substances were injected intraperitoneally. Compared to the control group, the group treated with capsaicin (TRPV1 agonist) had better scores in the PAL acquisition and retention test, whereas treatment with WIN55,212-2 (CB1/CB2 agonist) decreased the test scores. Capsaicin partly reduced the effects of WIN55,212-2 on PAL and memory. We conclude that the acute administration of a TRPV1 agonist improves the rats' cognitive performance in PAL tasks and that a vanilloid-related mechanism may underlie the agonistic effect of WIN55,212-2 on learning and memory.

  5. Cannabinoid Receptors CB1 and CB2 Modulate the Electroretinographic Waves in Vervet Monkeys

    Directory of Open Access Journals (Sweden)

    Joseph Bouskila

    2016-01-01

    Full Text Available The expression patterns of the cannabinoid receptor type 1 (CB1R and the cannabinoid receptor type 2 (CB2R are well documented in rodents and primates. In vervet monkeys, CB1R is present in the retinal neurons (photoreceptors, horizontal cells, bipolar cells, amacrine cells, and ganglion cells and CB2R is exclusively found in the retinal glia (Müller cells. However, the role of these cannabinoid receptors in normal primate retinal function remains elusive. Using full-field electroretinography in adult vervet monkeys, we recorded changes in neural activity following the blockade of CB1R and CB2R by the intravitreal administration of their antagonists (AM251 and AM630, resp. in photopic and scotopic conditions. Our results show that AM251 increases the photopic a-wave amplitude at high flash intensities, whereas AM630 increases the amplitude of both the photopic a- and b-waves. In scotopic conditions, both blockers increased the b-wave amplitude but did not change the a-wave amplitude. These findings suggest an important role of CB1R and CB2R in primate retinal function.

  6. Cannabinoid Receptors CB1 and CB2 Modulate the Electroretinographic Waves in Vervet Monkeys

    Science.gov (United States)

    Bouskila, Joseph; Harrar, Vanessa; Javadi, Pasha; Beierschmitt, Amy; Palmour, Roberta; Casanova, Christian; Bouchard, Jean-François; Ptito, Maurice

    2016-01-01

    The expression patterns of the cannabinoid receptor type 1 (CB1R) and the cannabinoid receptor type 2 (CB2R) are well documented in rodents and primates. In vervet monkeys, CB1R is present in the retinal neurons (photoreceptors, horizontal cells, bipolar cells, amacrine cells, and ganglion cells) and CB2R is exclusively found in the retinal glia (Müller cells). However, the role of these cannabinoid receptors in normal primate retinal function remains elusive. Using full-field electroretinography in adult vervet monkeys, we recorded changes in neural activity following the blockade of CB1R and CB2R by the intravitreal administration of their antagonists (AM251 and AM630, resp.) in photopic and scotopic conditions. Our results show that AM251 increases the photopic a-wave amplitude at high flash intensities, whereas AM630 increases the amplitude of both the photopic a- and b-waves. In scotopic conditions, both blockers increased the b-wave amplitude but did not change the a-wave amplitude. These findings suggest an important role of CB1R and CB2R in primate retinal function. PMID:27069692

  7. Cannabinoids for Symptom Management and Cancer Therapy: The Evidence.

    Science.gov (United States)

    Davis, Mellar P

    2016-07-01

    Cannabinoids bind not only to classical receptors (CB1 and CB2) but also to certain orphan receptors (GPR55 and GPR119), ion channels (transient receptor potential vanilloid), and peroxisome proliferator-activated receptors. Cannabinoids are known to modulate a multitude of monoamine receptors. Structurally, there are 3 groups of cannabinoids. Multiple studies, most of which are of moderate to low quality, demonstrate that tetrahydrocannabinol (THC) and oromucosal cannabinoid combinations of THC and cannabidiol (CBD) modestly reduce cancer pain. Dronabinol and nabilone are better antiemetics for chemotherapy-induced nausea and vomiting (CINV) than certain neuroleptics, but are not better than serotonin receptor antagonists in reducing delayed emesis, and cannabinoids have largely been superseded by neurokinin-1 receptor antagonists and olanzapine; both cannabinoids have been recommended for breakthrough nausea and vomiting among other antiemetics. Dronabinol is ineffective in ameliorating cancer anorexia but does improve associated cancer-related dysgeusia. Multiple cancers express cannabinoid receptors directly related to the degree of anaplasia and grade of tumor. Preclinical in vitro and in vivo studies suggest that cannabinoids may have anticancer activity. Paradoxically, cannabinoid receptor antagonists also have antitumor activity. There are few randomized smoked or vaporized cannabis trials in cancer on which to judge the benefits of these forms of cannabinoids on symptoms and the clinical course of cancer. Smoked cannabis has been found to contain Aspergillosis. Immunosuppressed patients should be advised of the risks of using "medical marijuana" in this regard. Copyright © 2016 by the National Comprehensive Cancer Network.

  8. New insights into antimetastatic and antiangiogenic effects of cannabinoids.

    Science.gov (United States)

    Ramer, Robert; Hinz, Burkhard

    2015-01-01

    Cannabinoids exert antitumorigenic effects via multiple mechanisms. Of these, antimetastatic and antiangiogenic actions have attracted considerable interest in the past years. Regarding the underlying antimetastatic mechanism, several studies revealed cannabinoids to alter the gene expression of cancer cells toward a less-aggressive phenotype and to modulate their secretomic profile. Cannabinoids likewise modulate the release of factors from tumor cells that subsequently suppress the chemoattraction of vessel cells thereby conferring antiangiogenesis. Among the diverse mediators of cannabinoids' antitumorigenic action, the tissue inhibitor of matrix metalloproteinases-1, which is released from cancer cells upon cannabinoid treatment, has been implicated as a pivotal factor conferring both anti-invasive properties of cancer cells as well as antiangiogenic capacities of endothelial cells. In addition, cannabinoids have been shown to inhibit angiogenic capacities of endothelial cells directly via suppressing their proliferation, tube formation, and migration. This chapter reviews the cell- and substance-specific antitumorigenic mechanisms of cannabinoids with particular consideration of their antimetastatic/anti-invasive and antiangiogenic actions. In addition, beneficial interactions of cannabinoids with currently used chemotherapeutics as well as the influence of cannabinoids on tumor-immune surveillance are addressed. Collectively, the currently available data suggest cannabinoids as a potential tool in modern cancer pharmacotherapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Control of Inhibition by the Direct Action of Cannabinoids on GABAA Receptors

    NARCIS (Netherlands)

    Golovko, Tatiana; Min, R.; Lozovaya, Natalia; Falconer, Caroline; Yatsenko, Natalia; Tsintsadze, Timur; Tsintsadze, Vera; Ledent, Catherine; Harvey, Robert J; Belelli, Delia; Lambert, Jeremy J; Rozov, Andrei; Burnashev, Nail

    Cannabinoids are known to regulate inhibitory synaptic transmission via activation of presynaptic G protein-coupled cannabinoid CB1 receptors (CB1Rs). Additionally, recent studies suggest that cannabinoids can also directly interact with recombinant GABAA receptors (GABAARs), potentiating currents

  10. [Glucose transporter protein type 1 (GLUT-1) deficiency syndrome].

    Science.gov (United States)

    Ramm-Pettersen, Anette; Selmer, Kaja Kristine; Nakken, Karl O

    2011-05-06

    Glucose is the brain's main source of energy. To pass the blood-brain barrier, glucose transporter protein type 1 (GLUT-1) is essential. Mutations in the SLC2A1 gene which codes for GLUT-1 may therefore compromise the supply of glucose to the brain. The aim of this review is to describe the clinical consequences of such mutations, with special emphasis on GLUT-1 encephalopathy. This review is based on a non-systematic literature search in PubMed and the authors' experience within the field. Epileptic or epilepsy-like are usually the first symptom in children with the GLUT-1 deficiency syndrome. Later on these children suffer delayed psychomotor development, microcephaly, ataxia, spasticity or movement disorders. EEG abnormalities may develop. GLUT-1 deficiency syndrome should be suspected in children with epilepsy-like seizures and delayed development combined with a low content of glucose in spinal fluid. The diagnosis is confirmed by genetic testing. Treatment is a ketogenic diet, as ketone bodies pass the blood-brain barrier using other transport proteins than GLUT-1. GLUT-1-deficiency syndrome is a rare metabolic encephalopathy which is not well known and probably underdiagnosed. An early diagnosis and early start of a ketogenic diet may give these children a normal or nearly normal life.

  11. Cannabinoid CB1 Receptors Are Localized in Striated Muscle Mitochondria and Regulate Mitochondrial Respiration

    Science.gov (United States)

    Mendizabal-Zubiaga, Juan; Melser, Su; Bénard, Giovanni; Ramos, Almudena; Reguero, Leire; Arrabal, Sergio; Elezgarai, Izaskun; Gerrikagoitia, Inmaculada; Suarez, Juan; Rodríguez De Fonseca, Fernando; Puente, Nagore; Marsicano, Giovanni; Grandes, Pedro

    2016-01-01

    The cannabinoid type 1 (CB1) receptor is widely distributed in the brain and peripheral organs where it regulates cellular functions and metabolism. In the brain, CB1 is mainly localized on presynaptic axon terminals but is also found on mitochondria (mtCB1), where it regulates cellular respiration and energy production. Likewise, CB1 is localized on muscle mitochondria, but very little is known about it. The aim of this study was to further investigate in detail the distribution and functional role of mtCB1 in three different striated muscles. Immunoelectron microscopy for CB1 was used in skeletal muscles (gastrocnemius and rectus abdominis) and myocardium from wild-type and CB1-KO mice. Functional assessments were performed in mitochondria purified from the heart of the mice and the mitochondrial oxygen consumption upon application of different acute delta-9-tetrahydrocannabinol (Δ9-THC) concentrations (100 nM or 200 nM) was monitored. About 26% of the mitochondrial profiles in gastrocnemius, 22% in the rectus abdominis and 17% in the myocardium expressed CB1. Furthermore, the proportion of mtCB1 versus total CB1 immunoparticles was about 60% in the gastrocnemius, 55% in the rectus abdominis and 78% in the myocardium. Importantly, the CB1 immunolabeling pattern disappeared in muscles of CB1-KO mice. Functionally, acute 100 nM or 200 nM THC treatment specifically decreased mitochondria coupled respiration between 12 and 15% in wild-type isolated mitochondria of myocardial muscles but no significant difference was noticed between THC treated and vehicle in mitochondria isolated from CB1-KO heart. Furthermore, gene expression of key enzymes involved in pyruvate synthesis, tricarboxylic acid (TCA) cycle and mitochondrial respiratory chain was evaluated in the striated muscle of CB1-WT and CB1-KO. CB1-KO showed an increase in the gene expression of Eno3, Pkm2, and Pdha1, suggesting an increased production of pyruvate. In contrast, no significant difference was

  12. Cannabinoid CB1 Receptors Are Localized in Striated Muscle Mitochondria and Regulate Mitochondrial Respiration

    Directory of Open Access Journals (Sweden)

    Juan Mendizabal-Zubiaga

    2016-10-01

    Full Text Available The cannabinoid type 1 (CB1 receptor is widely distributed in the brain and peripheral organs where it regulates cellular functions and metabolism. In the brain, CB1 is mainly localized on presynaptic axon terminals but is also found on mitochondria (mtCB1, where it regulates cellular respiration and energy production. Likewise, CB1 is localized on muscle mitochondria, but very little is known about it. The aim of this study was to further investigate in detail the distribution and functional role of mtCB1 in three different striated muscles. Immunoelectron microscopy for CB1 was used in skeletal muscles (gastrocnemius and rectus abdominis and myocardium from wild-type and CB1-KO mice. Functional assessments were performed in mitochondria purified from the heart of the mice and the mitochondrial oxygen consumption upon application of different acute delta-9-tetrahidrocannabinol (Δ9-THC concentrations (100 nM or 200 nM was monitored. About 26% of the mitochondrial profiles in gastrocnemius, 22% in the rectus abdominis and 17% in the myocardium expressed CB1. Furthermore, the proportion of mtCB1 versus total CB1 immunoparticles was about 60% in the gastrocnemius, 55% in the rectus abdominis and 78% in the myocardium. Importantly, the CB1 immunolabeling pattern disappeared in muscles of CB1-KO mice. Functionally, acute 100 nM or 200 nM THC treatment specifically decreased mitochondria coupled respiration between 12% and 15% in wild-type isolated mitochondria of myocardial muscles but no significant difference was noticed between THC treated and vehicle in mitochondria isolated from CB1-KO heart. Furthermore, gene expression of key enzymes involved in pyruvate synthesis, tricarboxylic acid (TCA cycle and mitochondrial respiratory chain was evaluated in the striated muscle of CB1-WT and CB1-KO. CB1-KO showed an increase in the gene expression of Eno3, Pkm2, and Pdha1, suggesting an increased production of pyruvate. In contrast, no significant

  13. Cannabinoid receptor-interacting protein Crip1a modulates CB1 receptor signaling in mouse hippocampus.

    Science.gov (United States)

    Guggenhuber, Stephan; Alpar, Alan; Chen, Rongqing; Schmitz, Nina; Wickert, Melanie; Mattheus, Tobias; Harasta, Anne E; Purrio, Martin; Kaiser, Nadine; Elphick, Maurice R; Monory, Krisztina; Kilb, Werner; Luhmann, Heiko J; Harkany, Tibor; Lutz, Beat; Klugmann, Matthias

    2016-05-01

    The cannabinoid type 1 receptor (Cnr1, CB1R) mediates a plethora of physiological functions in the central nervous system as a presynaptic modulator of neurotransmitter release. The recently identified cannabinoid receptor-interacting protein 1a (Cnrip1a, CRIP1a) binds to the C-terminal domain of CB1R, a region known to be important for receptor desensitization and internalization. Evidence that CRIP1a and CB1R interact in vivo has been reported, but the neuroanatomical distribution of CRIP1a is unknown. Moreover, while alterations of hippocampal CRIP1a levels following limbic seizures indicate a role in controlling excessive neuronal activity, the physiological function of CRIP1a in vivo has not been investigated. In this study, we analyzed the spatial distribution of CRIP1a in the hippocampus and examined CRIP1a as a potential modulator of CB1R signaling. We found that Cnrip1a mRNA is co-expressed with Cnr1 mRNA in pyramidal neurons and interneurons of the hippocampal formation. CRIP1a protein profiles were largely segregated from CB1R profiles in mossy cell terminals but not in hippocampal CA1 region. CB1R activation induced relocalization to close proximity with CRIP1a. Adeno-associated virus-mediated overexpression of CRIP1a specifically in the hippocampus revealed that CRIP1a modulates CB1R activity by enhancing cannabinoid-induced G protein activation. CRIP1a overexpression extended the depression of excitatory currents by cannabinoids in pyramidal neurons of the hippocampus and diminished the severity of chemically induced acute epileptiform seizures. Collectively, our data indicate that CRIP1a enhances hippocampal CB1R signaling in vivo.

  14. Metformin in adults with type 1 diabetes

    DEFF Research Database (Denmark)

    Petrie, John R; Chaturvedi, Nish; Ford, Ian

    2017-01-01

    AIMS: Cardiovascular (CV) disease is a major cause of reduced life expectancy in type 1 diabetes (T1D). Intensive insulin therapy prevents CV complications but is constrained by hypoglycaemia and weight gain. Adjunct metformin reduces insulin dose requirement and stabilizes weight...... but there are no data on its cardiovascular effects. We have therefore initiated an international double-blind, randomized, placebo-controlled trial (REMOVAL: REducing with MetfOrmin Vascular Adverse Lesions in type 1 diabetes) to examine whether metformin reduces progression of atherosclerosis in adults with T1D....... Individuals ≥40 years of age with T1D for ≥5 years are eligible if they have ≥3 of 10 specified CV risk factors. The enrolment target is 500 participants in 17 international centres. MATERIALS AND METHODS: After 12 weeks of single-blind placebo-controlled run-in, participants with ≥ 70% adherence...

  15. Reporting Severe Hypoglycemia in Type 1 Diabetes

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, Ulrik; Thorsteinsson, Birger

    2017-01-01

    PURPOSE OF REVIEW: To describe potential factors influencing reporting of severe hypoglycemia in adult patients with type 1 diabetes and to analyze their effect on reported rates of severe hypoglycemia. RECENT FINDINGS: Reported rates of severe hypoglycemia defined as need for third party...... by partners report higher rates of severe hypoglycemia. There is a large variation between studies reporting incidence and prevalence of severe hypoglycemia in patients with type 1 diabetes, mainly explained by definition of severity, methods of reporting, and patient selection. These findings call...... hypoglycemia are 0.02-0.5 events per patient-year and 1-29%, respectively. When subjects with recurrent severe hypoglycemia in the past or suffering from impaired hypoglycemia awareness are excluded from participation in studies, lower rates are reported. Studies applying anonymous reporting or reporting...

  16. Genetic risk factors for type 1 diabetes

    DEFF Research Database (Denmark)

    Pociot, Flemming; Lernmark, Åke

    2016-01-01

    Type 1 diabetes is diagnosed at the end of a prodrome of β-cell autoimmunity. The disease is most likely triggered at an early age by autoantibodies primarily directed against insulin or glutamic acid decarboxylase, or both, but rarely against islet antigen-2. After the initial appearance of one...... of the three stages can differ. Type 1 diabetes could serve as a disease model for organ-specific autoimmune disorders such as coeliac disease, thyroiditis, and Addison's disease, which show similar early markers of a prolonged disease process before clinical diagnosis....... of these autoantibody biomarkers, a second, third, or fourth autoantibody against either islet antigen-2 or the ZnT8 transporter might also appear. The larger the number of β-cell autoantibody types, the greater the risk of rapid progression to clinical onset of diabetes. This association does not necessarily mean...

  17. Erythropoietin during hypoglycaemia in type 1 diabetes

    DEFF Research Database (Denmark)

    Kristensen, Peter Lommer; Høi-Hansen, Thomas; Olsen, Niels Vidiendal

    2009-01-01

    AIMS: Preservation of cognitive function during hypoglycaemic episodes is crucial for patients with insulin-treated diabetes to avoid severe hypoglycaemic events. Erythropoietin has neuroprotective potential. However, the role of erythropoietin during hypoglycaemia is unclear. The aim of the stud....... CONCLUSIONS: Hypoglycaemia triggers a rise in plasma erythropoietin in patients with type 1 diabetes. The response is influenced by basal RAS activity. Erythropoietin may carry a neuroprotective potential during hypoglycaemia....... was to explore plasma erythropoietin response to hypoglycaemia and the relationship to basal renin-angiotensin system (RAS) activity and cognitive function. METHODS: We performed a single-blinded, controlled, cross-over study with induced hypoglycaemia or maintained glycaemic level. Nine patients with type 1......AIMS: Preservation of cognitive function during hypoglycaemic episodes is crucial for patients with insulin-treated diabetes to avoid severe hypoglycaemic events. Erythropoietin has neuroprotective potential. However, the role of erythropoietin during hypoglycaemia is unclear. The aim of the study...

  18. Increased expression of cannabinoid CB₁ receptors in Achilles tendinosis.

    Directory of Open Access Journals (Sweden)

    Emmelie Björklund

    Full Text Available BACKGROUND: The endogenous cannabinoid system is involved in the control of pain. However, little is known as to the integrity of the cannabinoid system in human pain syndromes. Here we investigate the expression of the cannabinoid receptor 1 (CB₁ in human Achilles tendons from healthy volunteers and from patients with Achilles tendinosis. METHODOLOGY: Cannabinoid CB₁ receptor immunoreactivity (CB₁IR was evaluated in formalin-fixed biopsies from individuals suffering from painful Achilles tendinosis in comparison with healthy human Achilles tendons. PRINCIPAL FINDINGS: CB₁IR was seen as a granular pattern in the tenocytes. CB₁IR was also observed in the blood vessel wall and in the perineurium of the nerve. Quantification of the immunoreactivity in tenocytes showed an increase of CB₁ receptor expression in tendinosis tissue compared to control tissue. CONCLUSION: Expression of cannabinoid receptor 1 is increased in human Achilles tendinosis suggesting that the cannabinoid system may be dysregulated in this disorder.

  19. Increased Expression of Cannabinoid CB1 Receptors in Achilles Tendinosis

    Science.gov (United States)

    Björklund, Emmelie; Forsgren, Sture; Alfredson, Håkan; Fowler, Christopher J.

    2011-01-01

    Background The endogenous cannabinoid system is involved in the control of pain. However, little is known as to the integrity of the cannabinoid system in human pain syndromes. Here we investigate the expression of the cannabinoid receptor 1 (CB1) in human Achilles tendons from healthy volunteers and from patients with Achilles tendinosis. Methodology Cannabinoid CB1 receptor immunoreactivity (CB1IR) was evaluated in formalin-fixed biopsies from individuals suffering from painful Achilles tendinosis in comparison with healthy human Achilles tendons. Principal Findings CB1IR was seen as a granular pattern in the tenocytes. CB1IR was also observed in the blood vessel wall and in the perineurium of the nerve. Quantification of the immunoreactivity in tenocytes showed an increase of CB1 receptor expression in tendinosis tissue compared to control tissue. Conclusion Expression of cannabinoid receptor 1 is increased in human Achilles tendinosis suggesting that the cannabinoid system may be dysregulated in this disorder. PMID:21931835

  20. Effects of cannabinoids and their receptors on viral infections.

    Science.gov (United States)

    Tahamtan, Alireza; Tavakoli-Yaraki, Masoumeh; Rygiel, Tomasz P; Mokhtari-Azad, Talat; Salimi, Vahid

    2016-01-01

    Cannabinoids, the active ingredient in marijuana, and their derivatives have received remarkable attention in the last two decades because they can affect tumor growth and metastasis. There is a large body of evidence from in vivo and in vitro models showing that cannabinoids and their receptors influence the immune system, viral pathogenesis, and viral replication. The present study reviews current insights into the role of cannabinoids and their receptors on viral infections. The results reported here indicate that cannabinoids and their receptors have different sequels for viral infection. Although activation or inhibition of cannabinoid receptors in the majority of viral infections are proper targets for development of safe and effective treatments, caution is required before using pharmaceutical cannabinoids as a treatment agent for patients with viral infections. © 2015 Wiley Periodicals, Inc.

  1. Cannabinoid-induced autophagy: Protective or death role?

    Science.gov (United States)

    Costa, Lia; Amaral, Cristina; Teixeira, Natércia; Correia-da-Silva, Georgina; Fonseca, Bruno M

    2016-01-01

    Autophagy, the "self-digestion" mechanism of the cells, is an evolutionary conserved catabolic process that targets portions of cytoplasm, damaged organelles and proteins for lysosomal degradation, which plays a crucial role in development and disease. Cannabinoids are active compounds of Cannabis sativa and the most prevalent psychoactive substance is Δ(9)-tetrahydrocannabinol (THC). Cannabinoid compounds can be divided in three types: the plant-derived natural products (phytocannabinoids), the cannabinoids produced endogenously (endocannabinoids) and the synthesized compounds (synthetic cannabinoids). Various studies reported a cannabinoid-induced autophagy mechanism in cancer and non-cancer cells. In this review we focus on the recent advances in the cannabinoid-induced autophagy and highlight the molecular mechanisms involved in these processes. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Exploring diabetes type 1-related stigma.

    Science.gov (United States)

    Abdoli, Samereh; Abazari, Parvaneh; Mardanian, Leila

    2013-01-01

    Empowerment of people with diabetes means integrating diabetes with identity. However, others' stigmatization can influence it. Although diabetes is so prevalent among Iranians, there is little knowledge about diabetes-related stigma in Iran. The present study explored diabetes-related stigma in people living with type 1 diabetes in Isfahan. A conventional content analysis was used with in-depth interview with 26 people with and without diabetes from November 2011 to July 2012. A person with type 1 diabetes was stigmatized as a miserable human (always sick and unable, death reminder, and intolerable burden), rejected marriage candidate (busy spouse, high-risk pregnant), and deprived of a normal life [prisoner of (to must), deprived of pleasure]. Although, young adults with diabetes undergo all aspects of the social diabetes-related stigma; in their opinion they were just deprived of a normal life. It seems that in Isfahan, diabetes-related stigma is of great importance. In this way, conducting an appropriate intervention is necessary to improve the empowerment process in people with type 1 diabetes in order to reduce the stigma in the context.

  3. Damping properties of type 1 fimbriae

    CERN Document Server

    Zakrisson, Johan; Axner, Ove; Andersson, Magnus

    2014-01-01

    Type 1 fimbriae mediate adhesion of uropathogenic Escherichia coli (UPEC) to host cells. It has been hypothesized that fimbriae can, by their ability to uncoil under exposure to force, reduce fluid shear stress on the adhesin-receptor interaction by which the bacterium adheres to the surface. In this work we develop a model that describes how the force on the adhesin-receptor interaction of a type 1 fimbriae varies as a bacterium is affected by a time dependent fluid flow mimicking in vivo conditions. The model combines in vivo hydrodynamic conditions with previously assessed biomechanical properties of the fimbriae. Numerical methods are used to solve for the motion and adhesion force under the presence of time dependent fluid profiles. It is found that a bacterium tethered with a type 1 pilus will experience significantly reduced shear stress for moderate to high flow velocities and that the maximum stress the adhesin will experience is limited to ~120 pN, which is sufficient to activate the conformational ...

  4. 75 FR 71635 - Schedules of Controlled Substances: Temporary Placement of Five Synthetic Cannabinoids Into...

    Science.gov (United States)

    2010-11-24

    ... with these synthetic cannabinoids and their related products including agitation, anxiety, vomiting... cannabinoids is geared towards teens and young adults. Despite disclaimers that the products are not intended...

  5. Central functional response to the novel peptide cannabinoid, hemopressin.

    Science.gov (United States)

    Dodd, Garron T; Worth, Amy A; Hodkinson, Duncan J; Srivastava, Raj K; Lutz, Beat; Williams, Steve R; Luckman, Simon M

    2013-08-01

    Hemopressin is the first peptide ligand to be described for the CB₁ cannabinoid receptor. Hemopressin acts as an inverse agonist in vivo and can cross the blood-brain barrier to both inhibit appetite and induce antinociception. Despite being highly effective, synthetic CB₁ inverse agonists are limited therapeutically due to unwanted, over dampening of central reward pathways. However, hemopressin appears to have its effect on appetite by affecting satiety rather than reward, suggesting an alternative mode of action which might avoid adverse side effects. Here, to resolve the neuronal circuitry mediating hemopressin's actions, we have combined blood-oxygen-level-dependent, pharmacological-challenge magnetic resonance imaging with c-Fos functional activity mapping to compare brain regions responsive to systemic administration of hemopressin and the synthetic CB₁ inverse agonist, AM251. Using these complementary methods, we demonstrate that hemopressin activates distinct neuronal substrates within the brain, focused mainly on the feeding-related circuits of the mediobasal hypothalamus and in nociceptive regions of the periaqueductal grey (PAG) and dorsal raphe (DR). In contrast to AM251, there is a distinct lack of activation of the brain reward centres, such as the ventral tegmental area, nucleus accumbens and orbitofrontal cortex, which normally form a functional activity signature for the central action of synthetic CB₁ receptor inverse agonists. Thus, hemopressin modulates the function of key feeding-related brain nuclei of the mediobasal hypothalamus, and descending pain pathways of the PAG and DR, and not higher limbic structures. Thus, hemopressin may offer behaviourally selective effects on nociception and appetite, without engaging reward pathways. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. Cannabinoider i behandling av kroniske smertetilstander : En systematisk litteraturgjennomgang

    OpenAIRE

    Viken, Erlend; Osnes, John Erik

    2006-01-01

    Objective: To establish whether cannabis is an effective and safe analgesic in chronic painful conditions. Background: The medical applications of Cannabis have long been a focus of public and scientific interest. Cannabinoids are the active compounds extracted from the Cannabis Sativa plant. Recently there has been renewed interest in cannabinoids for medicinal purposes. The discovery of cannabinoid CB1/CB2 receptors and endogenous ligands, has shed new light on the therapeutic potential...

  7. The Endocannabinoid/Endovanilloid N-Arachidonoyl Dopamine (NADA) and Synthetic Cannabinoid WIN55,212-2 Abate the Inflammatory Activation of Human Endothelial Cells*

    Science.gov (United States)

    Wilhelmsen, Kevin; Khakpour, Samira; Tran, Alphonso; Sheehan, Kayla; Schumacher, Mark; Xu, Fengyun; Hellman, Judith

    2014-01-01

    Although cannabinoids, such as Δ9-tetrahydrocannabinol, have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, because they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In this study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel transient receptor potential cation channel vanilloid type 1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, transient receptor potential cation channel vanilloid type 1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation. PMID:24644287

  8. The endocannabinoid/endovanilloid N-arachidonoyl dopamine (NADA) and synthetic cannabinoid WIN55,212-2 abate the inflammatory activation of human endothelial cells.

    Science.gov (United States)

    Wilhelmsen, Kevin; Khakpour, Samira; Tran, Alphonso; Sheehan, Kayla; Schumacher, Mark; Xu, Fengyun; Hellman, Judith

    2014-05-09

    Although cannabinoids, such as Δ(9)-tetrahydrocannabinol, have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, because they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In this study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel transient receptor potential cation channel vanilloid type 1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, transient receptor potential cation channel vanilloid type 1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation.

  9. Impact of cannabis, cannabinoids and endocannabinoids in the lungs

    Directory of Open Access Journals (Sweden)

    Caroline Turcotte

    2016-09-01

    Full Text Available Since the identification of cannabinoid receptors in the 1990s, a research field has been dedicated to exploring the role of the cannabinoid system in immunity and the inflammatory response in human tissues and animal models. Although the cannabinoid system is present and crucial in many human tissues, studying the impact of cannabinoids on the lungs is particularly relevant because of their contact with exogenous cannabinoids is the context of marijuana consumption. In the past two decades, the scientific community has gathered a large body of evidence supporting that the activation of the cannabinoid system alleviates pain and reduces inflammation. In the context of lung inflammation, exogenous and endogenous cannabinoids have shown therapeutic potential because of their inhibitory effects on immune cell recruitment and functions. On the other hand, cannabinoids were shown to be deleterious to lung function and to impact respiratory pathogen clearance. In this review, we present the existing data on the regulation of lung immunity and inflammation by phytocannabinoids, synthetic cannabinoids and endocannabinoids.

  10. Dendritic Cell Regulation by Cannabinoid-Based Drugs

    Directory of Open Access Journals (Sweden)

    Mattias Svensson

    2010-08-01

    Full Text Available Cannabinoid pharmacology has made important advances in recent years after the cannabinoid system was discovered. Studies in experimental models and in humans have produced promising results using cannabinoid-based drugs for the treatment of obesity and cancer, as well as neuroinflammatory and chronic inflammatory diseases. Moreover, as we discuss here, additional studies also indicates that these drugs have immunosuppressive and anti-inflammatory properties including modulation of immune cell function. Thus, manipulation of the endocannabinoid system in vivo may provide novel therapeutic strategies against inflammatory disorders. At least two types of cannabinoid receptors, cannabinoid 1 and cannabinoid 2 receptors are expressed on immune cells such as dendritic cells (DC. Dendritic cells are recognized for their critical role in initiating and maintaining immune responses. Therefore, DC are potential targets for cannabinoid-mediated modulation. Here, we review the effects of cannabinoids on DC and provide some perspective concerning the therapeutic potential of cannabinoids for the treatment of human diseases involving aberrant inflammatory processes.

  11. A Gut Gone to Pot: A Case of Cannabinoid Hyperemesis Syndrome due to K2, a Synthetic Cannabinoid

    OpenAIRE

    Anene Ukaigwe; Paras Karmacharya; Anthony Donato

    2014-01-01

    Cannabinoid Hyperemesis Syndrome (CHS) was first described in 2004. Due to its novelty, CHS is often unrecognized by clinicians leading to expensive workup of these patients with cyclical symptoms. It may take up to 9 years to diagnose CHS. CHS is characterized by cyclical nausea and vomiting, abdominal pain, and an unusual compulsion to take hot showers in the presence of chronic use of cannabinoids. Cannabicyclohexanol is a synthetic cannabinoid, popularly known as K2 spice. It is a popular...

  12. Teleconsultation in type 1 diabetes mellitus (TELEDIABE).

    Science.gov (United States)

    Bertuzzi, Federico; Stefani, Ilario; Rivolta, Benedetta; Pintaudi, Basilio; Meneghini, Elena; Luzi, Livio; Mazzone, Antonino

    2018-02-01

    The growing incidence of diabetes and the need to contain healthcare costs empower the necessity to identify new models of care. Telemedicine offers an acknowledged instrument to provide clinical health care at a distance, increasing patient compliance and the achievement of therapeutical goals. The objective was to test the feasibility and the efficacy in the improvement of the glycemic control of the teleconsultation for patients with type 1 diabetes mellitus. A randomized open-label, parallel arms, controlled trial was conducted in two diabetes centers in Italy. Participants affected by type 1 diabetes mellitus have been randomly (1:1) assigned to receive their visits as standard or a web-based care. Patients in the teleconsultation group can arrange their appointments on a Web site and can also have access to web educational courses or to nutritional and psychological counseling. The primary outcome was the assessment of glycemic control by HbA1c measurement after a 12-month follow-up. Overall 74 participants were followed for 1 year. HbA1c changes were not statistically different within (p = 0.56 for standard care group; p = 0.45 for telemedicine group) and between (p = 0.60) groups when considering differences from baseline to the end of the study. Patients randomized to teleconsultation reported reduced severe hypoglycemic episodes (p = 0.03). In addition, they were largely satisfied with the activities, perceived a good improvement in the self-management of the diabetes, and reported to have a time saving and a cost reduction. In conclusion, TELEDIABE proposes a new system for the management of patients with type 1 diabetes mellitus.

  13. Insulinbehandling af voksne med type 1-diabetes

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, Ulrik; Thorsteinsson, Birger

    2015-01-01

    treatment can be delivered with insulin pumps. Adjustments of insulin dosing can be rationally based on dosing algorithms. This requires frequent glucose measurements and knowledge about dietary carbohydrate content. Today, the treatment and its complexity are individualized according to needs and wishes......Whereas insulin treatment of type 1 diabetes formerly was limited by the availability of one or a few types of insulin with suboptimal pharmacokinetic properties, insulin analogues with more fitting physiological action profiles have now been developed and ultimately near-physiological insulin...

  14. Type 1 diabetes mellitus in Bhutan

    Directory of Open Access Journals (Sweden)

    Tashi Wangdi

    2015-01-01

    Full Text Available Bhutan is a South Asian country with a total population of 733,643. Bhutan has a very low burden of type 1 diabetes mellitus (T1DM, while that of type 2 diabetes mellitus is very high and increasing at alarming rates. Bhutan has a notably high proportion of over-weight and obese population. First case of T1DM was detected in 2006 and all the detected patients are in the age range of 14-15 years. The challenges in T1DM management include lack of knowledge among health care workers and patients, and limited access to health care services because of the difficult terrain.

  15. Therapeutic perspectives in type-1 diabetes

    CERN Document Server

    SINGH, PRACHI; TUPALLY, KARNAKER R; PODDAR, KINGSHUK; Tan, Aaron; VENKATESAN, VENKY; PAREKH, HARENDRA S; PASTORIN, GIORGIA

    2016-01-01

    This book provides critical insights into and appraisals of recent breakthroughs in type 1 diabetes modulation, with a particular emphasis on the potential impact of current prevention and treatment strategies. It also discusses recent successes and failures in clinical trials. Presenting an comprehensive overview of the disease, it is especially useful for newcomers in the field. It also includes illustrations, which make it easy for the reader to grasp the basic concepts involved. Furthermore, the tables include concise and easy-to-understand information on current clinical trials.

  16. Real life with type 1 diabetes mellitus.

    Science.gov (United States)

    Yagnik, Deepak

    2015-04-01

    Type 1 diabetes mellitus (T1DM) is a form of diabetes mellitus that results from the autoimmune destruction of the insulin-producing beta cells in the pancreas. Those affected by this disorder have a challenging life, both in terms of health and social adjustments. Various "alternative medicines" are offered to them in an effort to cure. Research has shown that good control over diabetes can be maintained through regular self-monitoring of blood glucose and frequent checking of diabetic complications. Here, I describe a female with T1DM and her journey with the disorder.

  17. Type 1 diabetes mellitus in Bhutan.

    Science.gov (United States)

    Wangdi, Tashi

    2015-04-01

    Bhutan is a South Asian country with a total population of 733,643. Bhutan has a very low burden of type 1 diabetes mellitus (T1DM), while that of type 2 diabetes mellitus is very high and increasing at alarming rates. Bhutan has a notably high proportion of over-weight and obese population. First case of T1DM was detected in 2006 and all the detected patients are in the age range of 14-15 years. The challenges in T1DM management include lack of knowledge among health care workers and patients, and limited access to health care services because of the difficult terrain.

  18. Insulinbehandling af voksne med type 1-diabetes

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, Ulrik; Thorsteinsson, Birger

    2015-01-01

    Whereas insulin treatment of type 1 diabetes formerly was limited by the availability of one or a few types of insulin with suboptimal pharmacokinetic properties, insulin analogues with more fitting physiological action profiles have now been developed and ultimately near-physiological insulin...... treatment can be delivered with insulin pumps. Adjustments of insulin dosing can be rationally based on dosing algorithms. This requires frequent glucose measurements and knowledge about dietary carbohydrate content. Today, the treatment and its complexity are individualized according to needs and wishes...

  19. Cannabinoid Hyperemesis Syndrome: A Paradoxical Cannabis Effect

    Directory of Open Access Journals (Sweden)

    Ivonne Marie Figueroa-Rivera

    2015-01-01

    Full Text Available Despite well-established antiemetic properties of marijuana, there has been increasing evidence of a paradoxical effect in the gastrointestinal tract and central nervous system, given rise to a new and underrecognized clinical entity called the Cannabinoid Hyperemesis Syndrome. Reported cases in the medical literature have established a series of patients exhibiting a classical triad of symptoms: cyclic vomiting, chronic marijuana use, and compulsive bathing. We present a case of a 29-year-old man whose clinical presentation strongly correlates with cannabinoid hyperemesis syndrome. Despite a diagnosis of exclusion, this syndrome should be considered plausible in the setting of a patient with recurrent intractable vomiting and a strong history of cannabis use as presented in this case.

  20. Implication of cannabinoids in neurological diseases.

    Science.gov (United States)

    Alsasua del Valle, Angela

    2006-01-01

    1. Preparations from Cannabis sativa (marijuana) have been used for many centuries both medicinally and recreationally. 2. Recent advances in the knowledge of its pharmacological and chemical properties in the organism, mainly due to Delta(9)-tetrahydrocannabinol, and the physiological roles played by the endocannabinoids have opened up new strategies in the treatment of neurological and psychiatric diseases. 3. Potential therapeutic uses of cannabinoid receptor agonists include the management of spasticity and tremor in multiple sclerosis/spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, cancer, and vasodilation that accompanies advanced cirrhosis. CB(1) receptor antagonists have therapeutic potential in Parkinson's disease. 4. Dr. Julius Axelrod also contributed in studies on the neuroprotective actions of cannabinoids.

  1. Are cannabinoids effective in multiple sclerosis?

    Directory of Open Access Journals (Sweden)

    Rodrigo Meza

    2017-03-01

    Full Text Available Resumen En el último tiempo, se han descrito diversos beneficios con el uso de cannabinoides en diferentes situaciones clínicas. Dentro de ellas se ha planteado un posible efecto en el control de la esclerosis múltiple, pero la real utilidad clínica es tema de debate. Para responder a esta pregunta utilizamos la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en múltiples bases de datos. Identificamos 25 revisiones sistemáticas que en conjunto incluyen 35 estudios que responden la pregunta de interés, entre ellos 26 estudios aleatorizados. Extrajimos los datos, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. Concluimos que el uso de cannabinoides en esclerosis múltiple no reduce la espasticidad ni el dolor, y probablemente se asocia a efectos adversos frecuentes.

  2. Influence of 22-day treatment on the anticonvulsant properties of cannabinoids.

    Science.gov (United States)

    Karler, R; Borys, H K; Turkanis, S A

    1982-08-01

    Mice were given delta-9-tetrahydrocannabinol (delta-9-THC) cannabidiol (CBD) or phenytoin (PHT) daily for 22 days. Drug activity was measured weekly in three different anticonvulsant tests: the maximal electroshock threshold, the 60-Hz-electroshock threshold and the 6-Hz-electroshock threshold. In order to correlate potential pharmacodynamic and pharmacokinetic changes resulting from repeated treatment, brain-drug concentrations were determined at each test time. The results from the delta-9-THC study indicate that, although tolerance developed in all three tests, there were no changes in the brain-drug concentration. For CBD the pharmacodynamics were strikingly different: an increase in sensitivity to the drug developed in two of the tests, tolerance in only one test. Here again, there were no changes in brain-drug concentrations. The results of the PHT study differed from both the cannabinoids, for tolerance developed in one test, an increase in sensitivity in one test, and the activity was unchanged in the third test. Again, the brain concentrations remained constant throughout. The results demonstrate that both tolerance and increased sensitivity can develop concomitantly with anticonvulsant effects of the cannabinoids and PHT, and that these modifications in drug activity appear to result from cellular or functional rather than dispositional changes.

  3. Human Immunodeficiency Virus Type 1 Infection of Neural Xenografts

    Science.gov (United States)

    Cvetkovich, Therese A.; Lazar, Eliot; Blumberg, Benjamin M.; Saito, Yoshihiro; Eskin, Thomas A.; Reichman, Richard; Baram, David A.; del Cerro, Coca; Gendelman, Howard E.; del Cerro, Manuel; Epstein, Leon G.

    1992-06-01

    Human immunodeficiency virus type 1 (HIV-1) infection is highly specific for its human host. To study HIV-1 infection of the human nervous system, we have established a small animal model in which second-trimester (11 to 17.5 weeks) human fetal brain or neural retina is transplanted to the anterior chamber of the eye of immunosuppressed adult rats. The human xenografts vascularized, formed a blood-brain barrier, and differentiated, forming neurons and glia. The xenografts were infected with cell-free HIV-1 or with HIV-1-infected human monocytes. Analysis by polymerase chain reaction revealed HIV-1 sequences in DNA from xenograft tissue exposed to HIV-1 virions, and in situ hybridization demonstrated HIV-1 mRNA localized in macrophages and multinucleated giant cells. Pathological damage was observed only in neural xenografts containing HIV-1-infected human monocytes, supporting the hypothesis that these cells mediate neurotoxicity. This small animal model allows the study of direct and indirect effects of HIV-1 infection on developing human fetal neural tissues, and it should prove useful in evaluating antiviral therapies, which must ultimately target HIV-1 infection of the brain.

  4. Synthetic Cannabinoids: Epidemiology, Pharmacodynamics, and Clinical Implications*

    Science.gov (United States)

    Castaneto, Marisol S.; Gorelick, David A.; Desrosiers, Nathalie A.; Hartman, Rebecca L.; Pirard, Sandrine; Huestis, Marilyn A.

    2014-01-01

    Background Synthetic cannabinoids (SC) are a heterogeneous group of compounds developed to probe the endogenous cannabinoid system or as potential therapeutics. Clandestine laboratories subsequently utilized published data to develop SC variations marketed as abuseable “designer drugs.” In the early 2000’s, SC became popular as “legal highs” under brand names such as “Spice” and “K2,” in part due to their ability to escape detection by standard cannabinoid screening tests. The majority of SC detected in herbal products have greater binding affinity to the cannabinoid CB1 receptor than does Δ9-tetrahydrocannabinol (THC), the primary psychoactive compound in the cannabis plant, and greater affinity at the CB1 than the CB2 receptor. In-vitro and animal in-vivo studies show SC pharmacological effects 2-100 times more potent than THC, including analgesic, anti-seizure, weight-loss, anti-inflammatory, and anti-cancer growth effects. SC produce physiological and psychoactive effects similar to THC, but with greater intensity, resulting in medical and psychiatric emergencies. Human adverse effects include nausea and vomiting, shortness of breath or depressed breathing, hypertension, tachycardia, chest pain, muscle twitches, acute renal failure, anxiety, agitation, psychosis, suicidal ideation, and cognitive impairment. Long-term or residual effects are unknown. Due to these public health consequences, many SC are classified as controlled substances. However, frequent structural modification by clandestine laboratories results in a stream of novel SC that may not be legally controlled or detectable by routine laboratory tests. Methods We present here a comprehensive review, based on a systematic electronic literature search, of SC epidemiology and pharmacology and their clinical implications. PMID:25220897

  5. Synthetic cannabinoids: epidemiology, pharmacodynamics, and clinical implications.

    Science.gov (United States)

    Castaneto, Marisol S; Gorelick, David A; Desrosiers, Nathalie A; Hartman, Rebecca L; Pirard, Sandrine; Huestis, Marilyn A

    2014-11-01

    Synthetic cannabinoids (SC) are a heterogeneous group of compounds developed to probe the endogenous cannabinoid system or as potential therapeutics. Clandestine laboratories subsequently utilized published data to develop SC variations marketed as abusable designer drugs. In the early 2000s, SC became popular as "legal highs" under brand names such as Spice and K2, in part due to their ability to escape detection by standard cannabinoid screening tests. The majority of SC detected in herbal products have greater binding affinity to the cannabinoid CB1 receptor than does Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive compound in the cannabis plant, and greater affinity at the CB1 than the CB2 receptor. In vitro and animal in vivo studies show SC pharmacological effects 2-100 times more potent than THC, including analgesic, anti-seizure, weight-loss, anti-inflammatory, and anti-cancer growth effects. SC produce physiological and psychoactive effects similar to THC, but with greater intensity, resulting in medical and psychiatric emergencies. Human adverse effects include nausea and vomiting, shortness of breath or depressed breathing, hypertension, tachycardia, chest pain, muscle twitches, acute renal failure, anxiety, agitation, psychosis, suicidal ideation, and cognitive impairment. Long-term or residual effects are unknown. Due to these public health consequences, many SC are classified as controlled substances. However, frequent structural modification by clandestine laboratories results in a stream of novel SC that may not be legally controlled or detectable by routine laboratory tests. We present here a comprehensive review, based on a systematic electronic literature search, of SC epidemiology and pharmacology and their clinical implications. Published by Elsevier Ireland Ltd.

  6. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb.

    Science.gov (United States)

    Izzo, Angelo A; Borrelli, Francesca; Capasso, Raffaele; Di Marzo, Vincenzo; Mechoulam, Raphael

    2009-10-01

    Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetrahydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetrahydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.

  7. Treatment of Tourette Syndrome with Cannabinoids

    Directory of Open Access Journals (Sweden)

    Kirsten R. Müller-Vahl

    2013-01-01

    Full Text Available Cannabinoids have been used for hundred of years for medical purposes. To day, the cannabinoid delta-9-tetrahydrocannabinol (THC and the cannabis extract nabiximols are approved for the treatment of nausea, anorexia and spasticity, respectively. In Tourette syndrome (TS several anecdotal reports provided evidence that marijuana might be effective not only in the suppression of tics, but also in the treatment of associated behavioural problems. At the present time there are only two controlled trials available investigating the effect of THC in the treatment of TS. Using both self and examiner rating scales, in both studies a significant tic reduction could be observed after treatment with THC compared to placebo, without causing significant adverse effects. Available data about the effect of THC on obsessive-compulsive symptoms are inconsistent. According to a recent Cochrane review on the efficacy of cannabinoids in TS, definite conclusions cannot be drawn, because longer trials including a larger number of patients are missing. Notwithstanding this appraisal, by many experts THC is recommended for the treatment of TS in adult patients, when first line treatments failed to improve the tics. In treatment resistant adult patients, therefore, treatment with THC should be taken into consideration.

  8. Quantification of Cannabinoid Content in Cannabis

    Science.gov (United States)

    Tian, Y.; Zhang, F.; Jia, K.; Wen, M.; Yuan, Ch.

    2015-09-01

    Cannabis is an economically important plant that is used in many fields, in addition to being the most commonly consumed illicit drug worldwide. Monitoring the spatial distribution of cannabis cultivation and judging whether it is drug- or fiber-type cannabis is critical for governments and international communities to understand the scale of the illegal drug trade. The aim of this study was to investigate whether the cannabinoids content in cannabis could be spectrally quantified using a spectrometer and to identify the optimal wavebands for quantifying the cannabinoid content. Spectral reflectance data of dried cannabis leaf samples and the cannabis canopy were measured in the laboratory and in the field, respectively. Correlation analysis and the stepwise multivariate regression method were used to select the optimal wavebands for cannabinoid content quantification based on the laboratory-measured spectral data. The results indicated that the delta-9-tetrahydrocannabinol (THC) content in cannabis leaves could be quantified using laboratory-measured spectral reflectance data and that the 695 nm band is the optimal band for THC content quantification. This study provides prerequisite information for designing spectral equipment to enable immediate quantification of THC content in cannabis and to discriminate drug- from fiber-type cannabis based on THC content quantification in the field.

  9. [Therapeutical use of the cannabinoids in psychiatry].

    Science.gov (United States)

    Crippa, José Alexandre S; Zuardi, Antonio Waldo; Hallak, Jaime E C

    2010-05-01

    To review the main advances related to the potential therapeutic use of cannabinoid compounds in psychiatry. A search was performed in the online databases PubMed, ScieELO, and Lilacs for studies and literature reviews concerning therapeutic applications of cannabinoids in psychiatry, especially cannabidiol, rimonabant, Delta(9)-tetrahydrocannabinol, and their analogues. Cannabidiol was found to have therapeutic potential with antipsychotic, anxiolytic, and antidepressant properties, in addition to being effective in other conditions. Delta(9)-tetrahydrocannabinol and its analogues were shown to have anxiolytic effects in the treatment of cannabis dependence and to function as an adjuvant in the treatment of schizophrenia, although additional studies are necessary to support this finding. Rimonabant was effective in the treatment of the subjective and physiological symptoms of cannabis intoxication and functioned as an adjuvant in the treatment of tobacco addiction. The potential to induce adverse reactions such as depression and anxiety restrained the clinical use of this CB(1) antagonist. Cannabinoids may be of great therapeutic interest to psychiatry; however, further controlled trials are necessary to confirm the existing findings and to establish the safety of such compounds.

  10. The discovery of a cannabinoid receptor

    Energy Technology Data Exchange (ETDEWEB)

    Devane, W.A.

    1989-01-01

    A tritiated form of CP-55,940, a Pfizer cannabinoid analog that is 20- to 100-fold more potent than {Delta}{sup 9}-tetrahydrocannabinol in various in vivo and in vitro models of cannabimimetric activity, was used as the tool with which to probe for a cannabinoid receptor in rat cortical membranes. The bound and free ligand were successfully separated using a centrifugation assay. Specific binding was saturable, rapidly attained, and completely reversible. The K{sub D}'s derived from kinetic analysis of binding agreed well with the K{sub D}'s derived from saturation and displacement analysis. The ({sup 3}H)CP-55,940 binding site exhibited high affinity with a K{sub D} of 68 pM as determined by LIGAND analysis of homologous displacement studies. The ability of other cannabinoid drugs to displace ({sup 3}H)CP-55,940 binding correlated well with the potency of these drugs in in vivo and in vitro models of cannabimimetic activity. The K{sub i} of {Delta}{sup 9}-THC was 1.6 nM. Cannabidiol and cannabigerol, which both lack psychoactivity in man, displaced specific binding by less than 50% at 1 {mu}M.

  11. Nocturnal Sleep Dynamics Identify Narcolepsy Type 1.

    Science.gov (United States)

    Pizza, Fabio; Vandi, Stefano; Iloti, Martina; Franceschini, Christian; Liguori, Rocco; Mignot, Emmanuel; Plazzi, Giuseppe

    2015-08-01

    To evaluate the reliability of nocturnal sleep dynamics in the differential diagnosis of central disorders of hypersomnolence. Cross-sectional. Sleep laboratory. One hundred seventy-five patients with hypocretin-deficient narcolepsy type 1 (NT1, n = 79), narcolepsy type 2 (NT2, n = 22), idiopathic hypersomnia (IH, n = 22), and "subjective" hypersomnolence (sHS, n = 52). None. Polysomnographic (PSG) work-up included 48 h of continuous PSG recording. From nocturnal PSG conventional sleep macrostructure, occurrence of sleep onset rapid eye movement period (SOREMP), sleep stages distribution, and sleep stage transitions were calculated. Patient groups were compared, and receiver operating characteristic (ROC) curve analysis was used to test the diagnostic utility of nocturnal PSG data to identify NT1. Sleep macrostructure was substantially stable in the 2 nights of each diagnostic group. NT1 and NT2 patients had lower latency to rapid eye movement (REM) sleep, and NT1 patients showed the highest number of awakenings, sleep stage transitions, and more time spent in N1 sleep, as well as most SOREMPs at daytime PSG and at multiple sleep latency test (MSLT) than all other groups. ROC curve analysis showed that nocturnal SOREMP (area under the curve of 0.724 ± 0.041, P narcolepsy type 1 among central disorders of hypersomnolence. © 2015 Associated Professional Sleep Societies, LLC.

  12. Teenage pregnancy in type 1 diabetes mellitus.

    Science.gov (United States)

    Carmody, David; Doyle, Aoife; Firth, Richard G R; Byrne, Maria M; Daly, Sean; Mc Auliffe, Fionnuala; Foley, Micheal; Coulter-Smith, Samuel; Kinsley, Brendan T

    2010-03-01

    Younger maternal age at delivery has been linked to adverse reproductive outcomes. Pregnancy complicated by type 1 diabetes mellitus (T1DM) is also associated with adverse pregnancy outcomes. Optimising diabetic glycaemic control prior to pregnancy is known to reduce the rate of congenital abnormalities and improve pregnancy outcomes. Teenage pregnancies are not usually planned and little data exist on teenage pregnancy complicated by T1DM. We sought to identify the glycemic control achieved in teenage pregnancy with T1DM and to clarify if there is an associated increase in adverse pregnancy outcomes compared to those seen in older women with T1DM. We compared outcomes in 18 teenagers (TG) with 582 older women with T1DM (CON) from 1995-2007. TG booked to the combined diabetes-obstetrical service at a median gestational age of 11 weeks (range 6-22) compared to 7 weeks in CON (range 4-40, p teenage women with T1DM book later to specialised care and have worse glycaemic control in pregnancy compared to older women with T1DM. This group also appear to be more insulin resistant than older women in early pregnancy. Our data would suggest that teenagers with type 1 diabetes mellitus may constitute a high-risk group for adverse pregnancy outcomes.

  13. [Cardiovascular disease in type 1 diabetes mellitus].

    Science.gov (United States)

    Wajchenberg, Bernardo Léo; Rassi, Nelson; Feitosa, Alina Coutinho R; Lerário, Antonio Carlos; Betti, Roberto Tadeu Barcelos

    2008-03-01

    The association between type 1 diabetes and coronary heart disease has become very clear since the late 1970. It has been demonstrated that there is an important increased risk in morbidity and mortality caused by coronary artery disease in young adults with type 1 diabetes compared with the non diabetic population. The underlying pathogeneses is still poorly understood. While the role of glycemic control in the development of microvascular disease complication is well established its role in CVD in patients with DM1 remains unclear with epidemiologic studies reporting conflicting data. Recent findings from the DCCT/EDIC showed that prior intensive diabetes treatment during the DCCT was associated with less atherosclerosis, largely because of reduced level of HbA1c during the DCCT. The improvement of glycemic control itself appeared to be particularly effective in younger patients with shorter duration of the disease. Other analyses suggested the glycemia may have a stronger effect on CAD in patients without than in those with albuminúria. Other major determinants of coronary artery disease are the components of metabolic syndrome and the surrogate measure of insulin resistence: eGDR. It is proposed that patients with DM1 should have aggressive medical therapy, risk factor modification and careful monitoring not only of his blood sugar but also of the other processes involved in the atherosclerotic process, mostly the ones with family history of type 2 diabetes.

  14. The cannabinoid receptor 1 associates with NMDA receptors to produce glutamatergic hypofunction: implications in psychosis and schizophrenia.

    Directory of Open Access Journals (Sweden)

    Pilar eSánchez-Blázquez

    2014-01-01

    Full Text Available The endocannabinoid system is widespread throughout the central nervous system and its type 1 receptor (CB1 plays a crucial role in preventing the neurotoxicity caused by activation of glutamate N-methyl-D-aspartate receptors (NMDARs. Indeed, it is the activity of NMDARs themselves that provides the demands on the endogenous cannabinoids in order to control their calcium currents. Therefore, a physiological role of this system is to maintain NMDAR activity within safe limits, thereby protecting neural cells from excitotoxicity. Thus, cannabinoids may be able to control NMDAR overactivation-related neural dysfunctions; however the major obstacles to the therapeutic utilization of these compounds are their psychotropic effects and negative influence on cognitive performance. Studies in humans have indicated that abuse of smoked cannabis can promote psychosis and even circumstantially precipitate symptoms of schizophrenia, although the latter appears to require a prior vulnerability in the individual. It is possible that cannabinoids provoke psychosis/schizophrenia reflecting a mechanism common to neuroprotection the reduction of NMDAR activity. Cannabinoids are proposed to produce such effect by reducing the pre-synaptic release of glutamate or interfering with postsynaptic NMDAR-regulated signaling pathways. The efficacy of such control requires the endocannabinoid system to apply its negative influence in a manner that is proportional to the strength of NMDAR signaling. Thus, cannabinoids acting at the wrong time or exerting an inappropriate influence on their receptors may cause NMDAR hypofunction. The purpose of the present review is to draw the attention of the reader to the newly described functional and physical CB1-NMDAR association, which may elucidate the scenario required for the rapid and efficacious control of NMDAR activity. Whether alterations in these mechanisms may increase NMDAR hypofunction leading to vulnerability to

  15. Cannabinoid receptor expression in peripheral arterial chemoreceptors during postnatal development.

    Science.gov (United States)

    McLemore, Gabrielle L; Cooper, Reed Z B; Richardson, Kimberlei A; Mason, Ariel V; Marshall, Cathleen; Northington, Frances J; Gauda, Estelle B

    2004-10-01

    Prenatal exposure to tobacco smoke increases risk of sudden infant death syndrome (SIDS). Marijuana is frequently smoked in conjunction with tobacco, and perinatal exposure to marijuana is associated with increased incidence of SIDS. Abnormalities in peripheral arterial chemoreceptor responses during sleep may be operative in infants at risk for SIDS, and nicotine exposure adversely affects peripheral arterial chemoreceptor responses. To determine whether marijuana could potentially affect the activity of peripheral arterial chemoreceptors during early postnatal development, we used in situ hybridization histochemistry to characterize the pattern and level of mRNA expression for cannabinoid type 1 receptor (CB1R) in the carotid body, superior cervical ganglia (SCG), and nodose-petrosal-jugular ganglia (NG-PG-JG) complex in newborn rats. We used immunohistochemistry and light, confocal, and electron microscopy to characterize the pattern of CB1R and tyrosine hydroxylase protein expression. CB1R mRNA expression was intense in the NG-PG-JG complex, low to moderate in the SCG, and sparse in the carotid body. With maturation, CB1R gene expression significantly increased (P peripheral arterial chemoreceptors. The novel finding of nuclear localization of CB1Rs in peripheral ganglion cells suggests that these receptors may have an, as yet, undetermined role in nuclear signaling in sensory and autonomic neurons.

  16. Quadrupole-time-of-flight mass spectrometry screening for synthetic cannabinoids in herbal blends.

    Science.gov (United States)

    Ibáñez, María; Bijlsma, Lubertus; van Nuijs, Alexander L N; Sancho, Juan V; Haro, Gonzalo; Covaci, Adrian; Hernández, Félix

    2013-06-01

    'Legal highs' are novel substances which are intended to elicit a psychoactive response. They are sold from 'head shops', the internet and from street suppliers and may be possessed without legal restriction. Several months ago, a 19-year-old woman came searching for medical treatment as she had health problems caused by smoking legal highs. The substances were sold as herbal blends in plastic bags under four different labels. In this work, samples of these herbal blends have been analysed to investigate the presence of psychoactive substances without any reference standard being available at the laboratory. A screening strategy for a large number of synthetic and natural cannabinoids has been applied based on the use of ultra-high pressure liquid chromatography coupled to quadrupole-time of flight mass spectrometry (UHPLC-QTOF MS) under MS(E) mode. A customized home-made database containing literature-based exact masses for parent and product ions of around 200 synthetic and natural cannabinoids was compiled. The presence of the (de)protonated molecule measured at its accurate mass was evaluated in the samples. When a peak was detected, collision-induced dissociation fragments and characteristic isotopic ions were also evaluated and used for tentative identification. After this tentative identification, four synthetic cannabinoids (JWH-081, JWH-250, JWH-203 and JWH-019) were unequivocally confirmed by subsequent acquisition of reference standards. The presence in the herbal blends of these synthetic cannabinoids might explain the psychotic and catatonic symptoms observed in the patient, as JWH compounds could act as potent agonists of CB1 and CB2 receptors located in the Limbic System and Basal ganglia of the human brain. Copyright © 2013 John Wiley & Sons, Ltd.

  17. Vascular Dysfunction in a Transgenic Model of Alzheimer's Disease: Effects of CB1R and CB2R Cannabinoid Agonists.

    Science.gov (United States)

    Navarro-Dorado, Jorge; Villalba, Nuria; Prieto, Dolores; Brera, Begoña; Martín-Moreno, Ana M; Tejerina, Teresa; de Ceballos, María L

    2016-01-01

    There is evidence of altered vascular function, including cerebrovascular, in Alzheimer's disease (AD) and transgenic models of the disease. Indeed vasoconstrictor responses are increased, while vasodilation is reduced in both conditions. β-Amyloid (Aβ) appears to be responsible, at least in part, of alterations in vascular function. Cannabinoids, neuroprotective and anti-inflammatory agents, induce vasodilation both in vivo and in vitro. We have demonstrated a beneficial effect of cannabinoids in models of AD by preventing glial activation. In this work we have studied the effects of these compounds on vessel density in amyloid precursor protein (APP) transgenic mice, line 2576, and on altered vascular responses in aortae isolated ring. First we showed increased collagen IV positive vessels in AD brain compared to control subjects, with a similar increase in TgAPP mice, which was normalized by prolonged oral treatment with the CB1/CB2 mixed agonist WIN 55,212-2 (WIN) and the CB2 selective agonist JWH-133 (JWH). In Tg APP mice the vasoconstriction induced by phenylephrine and the thromboxane agonist U46619 was significantly increased, and no change in the vasodilation to acetylcholine (ACh) was observed. Tg APP displayed decreased vasodilation to both cannabinoid agonists, which were able to prevent decreased ACh relaxation in the presence of Aβ. In summary, we have confirmed and extended the existence of altered vascular responses in Tg APP mice. Moreover, our results suggest that treatment with cannabinoids may ameliorate the vascular responses in AD-type pathology.

  18. Deletion of CB2 cannabinoid receptors reduces synaptic transmission and long-term potentiation in the mouse hippocampus.

    Science.gov (United States)

    Li, Yong; Kim, Jimok

    2016-03-01

    The effects of cannabinoids are mostly mediated by two types of cannabinoid receptors--CB1 receptors in the nervous system and CB2 receptors in the immune system. However, CB2 cannabinoid receptors have recently been discovered in the brain and also implicated in neurophysiological functions. The deletion of CB2 receptors in mice induces long-term memory deficits and schizophrenia-like behaviors, implying that endogenous activity of CB2 receptors might be involved in neuropsychiatric effects. Little is known about the cellular mechanisms by which physiological activation of CB2 receptors modulates neuronal functions. We aimed to determine how deletion of CB2 receptors in mice affects synaptic transmission and plasticity. Electrophysiological and morphological studies indicated that CB2 receptor knockout resulted in decreases in excitatory synaptic transmission, long-term potentiation, and dendritic spine density in the hippocampus. Our data imply that endogenous activity of CB2 receptors might contribute to the maintenance of synaptic functions and the expression of normal long-term potentiation. This study provides insights into the role of CB2 cannabinoid receptors in regulating cognitive functions such as long-term memory. © 2016 Wiley Periodicals, Inc.

  19. Ligand-Induced Regulation and Localization of Cannabinoid CB1 and Dopamine D2L Receptor HeterodimersS⃞

    OpenAIRE

    Przybyla, Julie A.; Val J Watts

    2010-01-01

    The cannabinoid CB1 (CB1) and dopamine D2 (D2) receptors are coexpressed in the basal ganglia, an area of the brain involved in such processes as cognition, motor function, and emotional control. Several lines of evidence suggest that CB1 and D2 receptors may oligomerize, providing a unique pharmacology in vitro and in vivo. However, limited information exists on the regulation of CB1 and D2 receptor ...

  20. Genetics Home Reference: leukocyte adhesion deficiency type 1

    Science.gov (United States)

    ... Health Conditions Leukocyte adhesion deficiency type 1 Leukocyte adhesion deficiency type 1 Printable PDF Open All Close ... to view the expand/collapse boxes. Description Leukocyte adhesion deficiency type 1 is a disorder that causes ...

  1. Human stem cell modeling in neurofibromatosis type 1 (NF1).

    Science.gov (United States)

    Wegscheid, Michelle L; Anastasaki, Corina; Gutmann, David H

    2017-04-06

    The future of precision medicine is heavily reliant on the use of human tissues to identify the key determinants that account for differences between individuals with the same disorder. This need is exemplified by the neurofibromatosis type 1 (NF1) neurogenetic condition. As such, individuals with NF1 are born with a germline mutation in the NF1 gene, but may develop numerous distinct neurological problems, ranging from autism and attention deficit to brain and peripheral nerve sheath tumors. Coupled with accurate preclinical mouse models, the availability of NF1 patient-derived induced pluripotent stem cells (iPSCs) provides new opportunities to define the critical factors that underlie NF1-associated nervous system disease pathogenesis and progression. In this review, we discuss the generation and potential applications of iPSC technology to the study of NF1. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Emerging adulthood and Type 1 diabetes

    DEFF Research Database (Denmark)

    Vallis, M; Willaing, I; Holt, R I G

    2018-01-01

    AIMS: To compare clinical, psychological, education and social variables in emerging adults (aged 18-30 years) with Type 1 diabetes with their adult counterparts aged >30 years. METHODS: A single assessment multinational sample was surveyed as part of the larger second Diabetes Attitudes, Wishes...... experience and family support) and diabetes education factors. RESULTS: Emerging adults differed from adults aged >30 years with regard to a number of psychosocial variables. Emerging adults reported better overall quality of life, social support and support from their healthcare team compared with adults...... aged >30 years of age; however, emerging adults experienced greater diabetes-specific distress and were less engaged in self-management. Diabetes education was related to a number of indicators, while experience of discrimination was harmful, but these impacts did not differ between emerging adults...

  3. Type 1 diabetes and multiple sclerosis

    DEFF Research Database (Denmark)

    Nielsen, Nete M; Westergaard, Tine; Frisch, Morten

    2006-01-01

    BACKGROUND: Type 1 diabetes mellitus (T1D) and multiple sclerosis (MS) contribute considerably to the burden of autoimmune diseases in young adults. Although HLA patterns of T1D and MS are considered mutually exclusive, individual and familial co-occurrence of the 2 diseases has been reported...... Multiple Sclerosis Register were used to identify patients with T1D, defined as patients in whom diabetes was diagnosed before age 20 years (N = 6078), and patients with MS (N = 11 862). First-degree relatives (N = 14,771) of patients with MS were identified from family information in the Danish Civil....... OBJECTIVE: To assess the co-occurrence of T1D and MS by estimating the risk for MS in patients with T1D and the risk for T1D in first-degree relatives of patients with MS. DESIGN, SETTING, AND PARTICIPANTS: Two population-based disease registers, the Danish Hospital Discharge Register and the Danish...

  4. Camp for Youth With Type 1 Diabetes.

    Science.gov (United States)

    Fegan-Bohm, Kelly; Weissberg-Benchell, Jill; DeSalvo, Daniel; Gunn, Sheila; Hilliard, Marisa

    2016-08-01

    Camps for youth with type 1 diabetes (T1D) have grown in size and scope since they first emerged in the 1920s. Anecdotal evidence suggests that attending camp with other youth with T1D is beneficial, largely attributed to sharing fun, active experiences and removing the isolation of living with diabetes. However, few studies have evaluated the psychosocial and medical impacts of T1D camp attendance during and after camp sessions. In addition, T1D camps have been a setting for numerous studies on a variety of T1D-related research questions not related to camp itself, such as testing novel diabetes management technologies in an active, non-laboratory setting. This paper reviews the evidence of psychosocial and medical outcomes associated with T1D camp attendance across the globe, provides an overview of other research conducted at camp, and offers recommendations for future research conducted at T1D camp.

  5. Research progress of spinocerebellar ataxia type 1

    Directory of Open Access Journals (Sweden)

    Lin-wei ZHANG

    2014-05-01

    Full Text Available Spinocerebellar ataxia type 1 (SCA1 is a kind of autosomal dominant genetic neurodegenerative disorder. To date, the pathogenesis of SCA1 remains unclear. Studies in numerous SCA1 experimental models, including transgenic mice, transgenic drosophila and induced pluripotent stem cells, have shown that phosphorylation of S776 in mutant ataxin-1, molecular chaperones, ubiquitin-proteasome system and down-regulation of several components of RAS-MAPK-MSK1 pathway may involve in the pathogenesis of SCA1. In this review, the clinical and pathological features of SCA1, and the latest advances of pathogenesis, model systems and therapeutic exploration will be briefly summarized. doi: 10.3969/j.issn.1672-6731.2014.05.017

  6. Type 1 diabetes care updates: Tanzania

    Directory of Open Access Journals (Sweden)

    Kandi Catherine Muze

    2015-01-01

    Full Text Available Tanzania is located in east Africa with a population of 45 million. The country′s population is growing at 2.5% annually. The International Diabetes Federation Child Sponsorship Program was launched in Tanzania in 2005. The number of type 1 diabetes mellitus children enrolled in the changing diabetes in children program in Tanzania has augmented from almost below 50 in 2005 to over 1200 in 2014. The country had an overall trend of HbA1c value of 14% in 2005 while the same has reduced over the years to 10% in 2012-13. The program has been able to reduce the proportion of patients with HbA1c values of 11-14%; from 71.9% in 2008 to 49.8% in 2012-13. The challenges, which CDiC faces are misdiagnosis, low public awareness, and stigma especially in the reproductive age/adolescent groups.

  7. Type 1 neurofibromatosis with periodontal manifestations

    Directory of Open Access Journals (Sweden)

    Pramod Kumar

    2016-01-01

    Full Text Available Neurofibromatosis type 1 (NF1 also known as von Recklinghausen's disease is an autosomal dominant disease transmitted with a high degree of penetrance. The disease is expressed in different forms. NF1 accounts for almost 90% of the cases although nine types have been described to date. We report one such case of a 36-year-old female who presented with multiple nodules on the body. He was diagnosed to have NF1, having satisfied the diagnostic criteria for the same. Oral manifestations can be found in almost 72% of NF1 patients. This case report highlights the clinical features and diagnostic criteria of NF1, the prevalence and the significance of intraoral neurofibromas and the need for the dental practitioner to be aware of this condition.

  8. Statins, bone, and neurofibromatosis type 1

    Directory of Open Access Journals (Sweden)

    Korf Bruce R

    2008-07-01

    Full Text Available Abstract Neurofibromatosis type 1 (NF1 is a dominantly inherited multi-system disorder. Major features include pigmentary abnormalities, benign tumors of the nerve sheath (neurofibromas, malignant tumors, learning disabilities, and skeletal dysplasia. The NF1 gene functions as a tumor suppressor, but haploinsuffiency probably accounts for some aspects of the non-tumor phenotype. The protein product, neurofibromin, is a Ras GTPase-activating protein, and various Ras pathway inhibitors are being tested in preclinical models and clinical trials for effectiveness in treating NF1 complications. This month in BMC Medicine, a paper by Kolanczyk et al describes a preclinical mouse model for tibial dysplasia and provides evidence that the drug lovastatin – in use to treat cardiovascular disease – may be beneficial, opening the door to clinical trials in humans.

  9. Teenage pregnancy in type 1 diabetes mellitus.

    LENUS (Irish Health Repository)

    Carmody, David

    2010-03-01

    Younger maternal age at delivery has been linked to adverse reproductive outcomes. Pregnancy complicated by type 1 diabetes mellitus (T1DM) is also associated with adverse pregnancy outcomes. Optimising diabetic glycaemic control prior to pregnancy is known to reduce the rate of congenital abnormalities and improve pregnancy outcomes. Teenage pregnancies are not usually planned and little data exist on teenage pregnancy complicated by T1DM. We sought to identify the glycemic control achieved in teenage pregnancy with T1DM and to clarify if there is an associated increase in adverse pregnancy outcomes compared to those seen in older women with T1DM. We compared outcomes in 18 teenagers (TG) with 582 older women with T1DM (CON) from 1995-2007. TG booked to the combined diabetes-obstetrical service at a median gestational age of 11 weeks (range 6-22) compared to 7 weeks in CON (range 4-40, p < 0.02). Glycaemic was worse in TG compared to CON at 13, 26 and 35 weeks gestation, despite higher insulin doses. First trimester miscarriage rate did not differ between groups. Major congenital anomaly rate was 6.2% (1\\/16) compared to 3.2% in CON. This preliminary study has demonstrated that pregnant teenage women with T1DM book later to specialised care and have worse glycaemic control in pregnancy compared to older women with T1DM. This group also appear to be more insulin resistant than older women in early pregnancy. Our data would suggest that teenagers with type 1 diabetes mellitus may constitute a high-risk group for adverse pregnancy outcomes.

  10. Type 1 lepra reaction in histoid leprosy.

    Science.gov (United States)

    Singh, Nidhi; Kumari, Rashmi; Gupta, Divya; Thappa, Devinder Mohan; Ganesh, Rajesh Nachiappa

    2015-01-01

    Lepra reaction in histoid leprosy (HL) is rare; there are few reports of type 2 lepra reaction in HL. We report a 42-year-old woman with HL in type 1 lepra reaction after 10 weeks of multibacillary multi-drug therapy (MBMDT). A 42-year-old woman presented with asymptomatic multiple papules, plaques, and nodules over the face, trunk, and extremities and no history of prior treatment with anti-leprosy drugs. A biopsy of a skin nodule on the forearm revealed spindle-shaped, non-vacuolated histiocytes in a whorled pattern with abundant acid-fast bacilli (AFB). The patient was diagnosed with HL and started on MBMDT. Ten weeks later, she developed pruritic, painful, erythematous, and edematous papules, plaques, and nodules over the face, trunk, and extremities, without constitutional symptoms. Histopathology revealed an atrophic epidermis, preserved grenz zone, and papillary dermal edema. Elongated AFB were visible on Fite's stain. The MBMDT was continued, along with nonsteroidal anti-inflammatory drugs and antihistamines, but pruritus, pain, erythema, and edema persisted, and new skin lesions appeared. The patient was started on prednisolone at 0.75 mg/kg body weight/day. Prednisolone resulted in symptomatic relief and the healing of ulcerated papules within four weeks. Treatment was tapered and stopped after 20 weeks. Histoid leprosy is considered a variant of lepromatous leprosy, which rarely involves a lepra reaction. Pruritus and ulceration of skin lesions as manifestations of type 1 lepra reaction in HL have not been reported previously. These symptoms manifested after 10 weeks of MBMDT and responded well to oral prednisolone. © 2014 The International Society of Dermatology.

  11. Functional role of cannabinoid receptors in urinary bladder

    Directory of Open Access Journals (Sweden)

    Pradeep Tyagi

    2010-01-01

    Full Text Available Cannabinoids, the active components of Cannabis sativa (marijuana, and their derivatives produce a wide spectrum of central and peripheral effects, some of which may have clinical applications. The discovery of specific cannabinoid receptors and a family of endogenous ligands of those receptors has attracted much attention to the general cannabinoid pharmacology. In recent years, studies on the functional role of cannabinoid receptors in bladder have been motivated by the therapeutic effects of cannabinoids on voiding dysfunction in multiple sclerosis patients. In this review, we shall summarize the literature on the expression of cannabinoid receptors in urinary bladder and the peripheral influence of locally and systemically administered cannabinoids in the bladder. The ongoing search for cannabinoid-based therapeutic strategies devoid of psychotropic effects can be complemented with local delivery into bladder by the intravesical route. A greater understanding of the role of the peripheral CB 1 and CB 2 receptor system in lower urinary tract is necessary to allow the development of new treatment for pelvic disorders.

  12. Multiple sclerosis following treatment with a cannabinoid receptor-1 antagonist

    NARCIS (Netherlands)

    van Oosten, B. W.; Killestein, J.; Mathus-Vliegen, E. M. H.; Polman, C. H.

    2004-01-01

    Laboratory research including animal models of human disease suggests that cannabinoids might have therapeutic potential in multiple sclerosis (MS). We have recently seen a 46-year-old woman who developed MS after starting treatment with a cannabinoid receptor antagonist for obesity. The occurrence

  13. Cannabinoids in the management of spasticity associated with multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Anna Maria Malfitano

    2008-08-01

    Full Text Available Anna Maria Malfitano, Maria Chiara Proto, Maurizio BifulcoDipartimento di Scienze Farmaceutiche, Università degli Studi di SalernoAbstract: The endocannabinoid system and cannabinoid-based treatments have been involved in a wide number of diseases. In particular, several studies suggest that cannabinoids and endocannabinoids may have a key role in the pathogenesis and therapy of multiple sclerosis (MS. In this study we highlight the main findings reported in literature about the relevance of cannabinoid drugs in the management and treatment of MS. An increasing body of evidence suggests that cannabinoids have beneficial effects on the symptoms of MS, including spasticity and pain. In this report we focus on the effects of cannabinoids in the relief of spasticity describing the main findings in vivo, in the mouse experimental allergic encephalomyelitis model of MS. We report on the current treatments used to control MS symptoms and the most recent clinical studies based on cannabinoid treatments, although long-term studies are required to establish whether cannabinoids may have a role beyond symptom amelioration in MS.Keywords: cannabinoids, multiple sclerosis, spasticity

  14. Cannabinoids and Pain: Sites and Mechanisms of Action.

    Science.gov (United States)

    Starowicz, Katarzyna; Finn, David P

    2017-01-01

    The endocannabinoid system, consisting of the cannabinoid1 receptor (CB1R) and cannabinoid2 receptor (CB2R), endogenous cannabinoid ligands (endocannabinoids), and metabolizing enzymes, is present throughout the pain pathways. Endocannabinoids, phytocannabinoids, and synthetic cannabinoid receptor agonists have antinociceptive effects in animal models of acute, inflammatory, and neuropathic pain. CB1R and CB2R located at peripheral, spinal, or supraspinal sites are important targets mediating these antinociceptive effects. The mechanisms underlying the analgesic effects of cannabinoids likely include inhibition of presynaptic neurotransmitter and neuropeptide release, modulation of postsynaptic neuronal excitability, activation of the descending inhibitory pain pathway, and reductions in neuroinflammatory signaling. Strategies to dissociate the psychoactive effects of cannabinoids from their analgesic effects have focused on peripherally restricted CB1R agonists, CB2R agonists, inhibitors of endocannabinoid catabolism or uptake, and modulation of other non-CB1R/non-CB2R targets of cannabinoids including TRPV1, GPR55, and PPARs. The large body of preclinical evidence in support of cannabinoids as potential analgesic agents is supported by clinical studies demonstrating their efficacy across a variety of pain disorders. © 2017 Elsevier Inc. All rights reserved.

  15. The effects of synthetic cannabinoids on executive function.

    Science.gov (United States)

    Cohen, K; Kapitány-Fövény, M; Mama, Y; Arieli, M; Rosca, P; Demetrovics, Z; Weinstein, A

    2017-04-01

    There is a growing use of novel psychoactive substances (NPSs) including synthetic cannabinoids. Synthetic cannabinoid products have effects similar to those of natural cannabis but the new synthetic cannabinoids are more potent and dangerous and their use has resulted in various adverse effects. The purpose of the study was to assess whether persistent use of synthetic cannabinoids is associating with impairments of executive function in chronic users. A total of 38 synthetic cannabinoids users, 43 recreational cannabis users, and 41 non-user subjects were studied in two centers in Hungary and Israel. Computerized cognitive function tests, the classical Stroop word-color task, n-back task, and a free-recall memory task were used. Synthetic cannabinoid users performed significantly worse than both recreational and non-cannabis users on the n-back task (less accuracy), the Stroop task (overall slow responses and less accuracy), and the long-term memory task (less word recall). Additionally, they have also shown higher ratings of depression and anxiety compared with both recreational and non-users groups. This study showed impairment of executive function in synthetic cannabinoid users compared with recreational users of cannabis and non-users. This may have major implications for our understanding of the long-term consequences of synthetic cannabinoid based drugs.

  16. Cannabinoids:their role in pain and palliation.

    Science.gov (United States)

    McCarberg, Bill H

    2007-01-01

    Controversy is associated with the issue of cannabis and cannabinoids in clinical care in the United States. Recent research has demonstrated the underlying mechanisms of cannabinoid analgesia via endocannabinoids, an endogenous system of retrograde neuromodulatory messengers that work in tandem with endogenous opioids. Additional receptor and non-receptor mechanisms of cannabinoid drugs have pertinent activity, including anti-carcinogenesis and neuroprotection, that may be of key importance in aging and terminal patient populations. The results of clinical trials with synthetic and plant-based cannabinoids suggest that the role of formulation and delivery system is critical in optimizing the risk-benefit profile of cannabinoid products. Synergy between opioids and cannabinoids may produce opioid-sparing effects, as well as extend the duration of analgesia and reduce opioid tolerance and dependence. This article reviews the mechanism of action of cannabinoids, examines marketed agents and those in clinical trials, and addresses their role in treatment of chronic pain, cancer, neurodegenerative diseases, and HIV/ AIDS. The ability of cannabinoid medicines to treat pain, associated sleep disorders, appetite loss, muscle spasm and a wide variety of other symptoms suggests that such agents may in the future play an important role in palliative care.

  17. Do cannabinoids have a role in cancer pain management?

    Science.gov (United States)

    Farquhar-Smith, W Paul

    2009-03-01

    Historically cannabinoids have been used for both therapy and recreation, yet the elucidation of the endocannabinoid system and their chemistry has been relatively recent. Prohibition of cannabis has meant few clinical trials, especially in cancer pain. This review will consider previous animal and clinical data and assess more recent investigations of clinical effectiveness of cannabinoids in pain and specifically cancer pain. Meta-analyses based on historical studies question the utility of cannabinoids in pain due to modest analgesia and problematic central side effects. However, there has been a resurgence in clinical trials of cannabis extracts and analogues. New data have contributed to the understanding of how cannabinoids work and proposed how to obtain analgesia unfettered by adverse effects. Moreover, recent clinical trials have demonstrated the current role of cannabinoids may be to attain small but significant benefit in refractory chronic and cancer pain. Cannabinoids may be a useful addition to current analgesic treatments. The evidence supports a possible role for cannabinoids in refractory cancer pain. However, to realize the full potential of cannabinoids suggested by preclinical data, it is likely that peripheral CB1 or CB2 receptors or modulation of endocannabinoids will have to be targeted to achieve analgesia without dose limiting side effects.

  18. Endogenous cannabinoid system as a modulator of food intake.

    Science.gov (United States)

    Cota, D; Marsicano, G; Lutz, B; Vicennati, V; Stalla, G K; Pasquali, R; Pagotto, U

    2003-03-01

    The ability of Cannabis sativa (marijuana) to increase hunger has been noticed for centuries, although intensive research on its molecular mode of action started only after the characterization of its main psychoactive component Delta(9)-tetrahydrocannabinol in the late 1960s. Despite the public concern related to the abuse of marijuana and its derivatives, scientific studies have pointed to the therapeutic potentials of cannabinoid compounds and have highlighted their ability to stimulate appetite, especially for sweet and palatable food. Later, the discovery of specific receptors and their endogenous ligands (endocannabinoids) suggested the existence of an endogenous cannabinoid system, providing a physiological basis for biological effects induced by marijuana and other cannabinoids. Epidemiological reports describing the appetite-stimulating properties of cannabinoids and the recent insights into the molecular mechanisms underlying cannabinoid action have proposed a central role of the cannabinoid system in obesity. The aim of this review is to provide an extensive overview on the role of this neuromodulatory system in feeding behavior by summarizing the most relevant data obtained from human and animal studies and by elucidating the interactions of the cannabinoid system with the most important neuronal networks and metabolic pathways involved in the control of food intake. Finally, a critical evaluation of future potential therapeutical applications of cannabinoid antagonists in the therapy of obesity and eating disorders will be discussed.

  19. Functional role of cannabinoid receptors in urinary bladder.

    Science.gov (United States)

    Tyagi, Pradeep; Tyagi, Vikas; Yoshimura, Naoki; Chancellor, Michael

    2010-01-01

    Cannabinoids, the active components of Cannabis sativa (maijuana), and their derivatives produce a wide spectrum of central and peripheral effects, some of which may have clinical applications. The discovery of specific cannabinoid receptors and a family of endogenous ligands of those receptors has attracted much attention to the general cannabinoid pharmacology. In recent years, studies on the functional role of cannabinoid receptors in bladder have been motivated by the therapeutic effects of cannabinoids on voiding dysfunction in multiple sclerosis patients. In this review, we shall summarize the literature on the expression of cannabinoid receptors in urinary bladder and the peripheral influence of locally and systemically administered cannabinoids in the bladder. The ongoing search for cannabinoid-based therapeutic strategies devoid of psychotropic effects can be complemented with local delivery into bladder by the intravesical route. A greater understanding of the role of the peripheral CB(1) and CB(2) receptor system in lower urinary tract is necessary to allow the development of new treatment for pelvic disorders.

  20. Cannabinoids and Dementia: A Review of Clinical and Preclinical Data

    Directory of Open Access Journals (Sweden)

    Michael Halpern

    2010-08-01

    Full Text Available The endocannabinoid system has been shown to be associated with neurodegenerative diseases and dementia. We review the preclinical and clinical data on cannabinoids and four neurodegenerative diseases: Alzheimer’s disease (AD, Huntington’s disease (HD, Parkinson’s disease (PD and vascular dementia (VD. Numerous studies have demonstrated an involvement of the cannabinoid system in neurotransmission, neuropathology and neurobiology of dementias. In addition, several candidate compounds have demonstrated efficacy in vitro. However, some of the substances produced inconclusive results in vivo. Therefore, only few trials have aimed to replicate the effects seen in animal studies in patients. Indeed, the literature on cannabinoid administration in patients is scarce. While preclinical findings suggest causal treatment strategies involving cannabinoids, clinical trials have only assessed the suitability of cannabinoid receptor agonists, antagonists and cannabidiol for the symptomatic treatment of dementia. Further research is needed, including in vivo models of dementia and human studies.

  1. Safety Issues Concerning the Medical Use of Cannabis and Cannabinoids

    Directory of Open Access Journals (Sweden)

    Mark A Ware

    2005-01-01

    Full Text Available Safety issues are a major barrier to the use of cannabis and cannabinoid medications for clinical purposes. Information on the safety of herbal cannabis may be derived from studies of recreational cannabis use, but cannabis exposure and effects may differ widely between medical and recreational cannabis users. Standardized, quality-controlled cannabinoid products are available in Canada, and safety profiles of approved medications are available through the Canadian formulary. In the present article, the evidence behind major safety issues related to cannabis use is summarized, with the aim of promoting informed dialogue between physicians and patients in whom cannabinoid therapy is being considered. Caution is advised in interpreting these data, because clinical experience with cannabinoid use is in the early stages. There is a need for long-term safety monitoring of patients using cannabinoids for a wide variety of conditions, to further guide therapeutic decisions and public policy.

  2. Synthetic cannabinoid hyperemesis resulting in rhabdomyolysis and acute renal failure.

    Science.gov (United States)

    Argamany, Jacqueline R; Reveles, Kelly R; Duhon, Bryson

    2016-04-01

    Synthetic cannabinoid usage has increased in the past decade. Concurrently, emergency management of associated adverse effects due to synthetic cannabinoid usage has also risen. Reported toxicities include psychosis, seizures, cardiotoxicity, acute kidney injury, and death. While cannabis was first described as a cause of acute hyperemesis in 2004, a more recent case series also describes the association between cannabinoid hyperemesis and risk of acute renal failure. Synthetic cannabinoids have also been reported to cause acute hyperemesis and acute renal failure; however, the risk of rhabdomyolysis-induced renal failure has yet to be elucidated. In this article, we report the first known case of synthetic cannabinoid hyperemesis leading to rhabdomyolysis and acute renal failure.

  3. The arguments for and against cannabinoids application in glaucomatous retinopathy.

    Science.gov (United States)

    Panahi, Yunes; Manayi, Azadeh; Nikan, Marjan; Vazirian, Mahdi

    2017-02-01

    Glaucoma represents several optic neuropathies leading to irreversible blindness through progressive retinal ganglion cell (RGC) loss. Reduction of intraocular pressure (IOP) is known as the only modifiable factor in the treatment of this disorder. Application of exogenous cannabinoids to lower IOP has attracted attention of scientists as potential agents for the treatment of glaucoma. Accordingly, neuroprotective effect of these agents has been recently described through modulation of endocannabinoid system in the eye. In the present work, pertinent information regarding ocular endocannabinoid system, mechanism of exogenous cannabinoids interaction with the ocular endocannabinoid system to reduce IOP, and neuroprotection property of cannabinoids will be discussed according to current scientific literature. In addition to experimental studies, bioavailability of cannabinoids, clinical surveys, and adverse effects of application of cannabinoids in glaucoma will be reviewed. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  4. Atrial Natriuretic Peptide (ANP) in early pregnancy is associated with development of preeclampsia in type 1 diabetes

    DEFF Research Database (Denmark)

    Nielsen, Lene Ringholm; Pedersen-Bjergaard, Ulrik; Thorsteinsson, Birger

    2011-01-01

    The vasoactive markers of cardiac overload Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP) are elevated in preeclampsia. This study documents higher ANP concentrations as early as at 9 weeks in type 1 diabetic women subsequently developing preeclampsia suggesting...

  5. The streetlight effect in type 1 diabetes.

    Science.gov (United States)

    Battaglia, Manuela; Atkinson, Mark A

    2015-04-01

    In the nearly 100 years since the discovery of therapeutic insulin, significant research efforts have been directed at finding the underlying cause of type 1 diabetes (T1D) and developing a "cure" for the disease. While progress has clearly been made toward each of these goals, neither vision has been fulfilled. With increasing pressure from both public and private funders of diabetes research, growing impatience of those with T1D at the lack of practical discoveries, increased competition for research funds, uncertainties on the reproducibility of published scientific data, and questions regarding the value of animal models, the current research environment has become extraordinarily difficult to traverse from the perspective of investigators. As a result, there is an increasing pressure toward performance of what might be considered "safe" research, where the aim is to affirm existing dogmas rather than to pioneer efforts involving unconventional thought. Psychologists refer to this practice as "observational bias" while cartoonists label the process the "streetlight effect." In this Perspective, we consider notions in T1D research that should be subject to bold question and provide additional concepts, many somewhat orphan to research efforts, whose investigation could lead to a means for truly identifying the cause of and a cure for T1D. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  6. Pregnancy in women with type 1 diabetes

    DEFF Research Database (Denmark)

    Colstrup, Miriam; Mathiesen, Elisabeth R; Damm, Peter

    2013-01-01

    Abstract Objective: In 1989 the St. Vincent declaration set a five-year target for approximating outcomes of pregnancies in women with diabetes to those of the background population. We investigated and quantified the risk of adverse pregnancy outcomes in pregnant women with type 1 diabetes (T1DM......) to evaluate if the goals of the 1989 St. Vincent Declaration have been obtained concerning foetal and neonatal complications. Methods: Twelve population-based studies published within the last 10 years with in total 14 099 women with T1DM and 4 035 373 women from the background population were identified....... The prevalence of four foetal and neonatal complications was compared. Results: In women with T1DM versus the background population, congenital malformations occurred in 5.0% (2.2-9.0) (weighted mean and range) versus 2.1% (1.5-2.9), relative risk (RR) = 2.4, perinatal mortality in 2.7% (2.0-6.6) versus 0.72% (0...

  7. Lung parenchima changes in neurofibromatosis type 1

    Directory of Open Access Journals (Sweden)

    Ilić Aleksandra

    2016-01-01

    Full Text Available Introduction. Neurofibromatosis type 1 (NF1, also known as von Recklinghausen disease, is one of the most common single-gene disorders (mutation on chromosome 17q and usually associated with cutaneous, musculoskeletal and neurological disorders in humans. NF1 is generally complicated with one or more neurobehavioral disorders or tumors located in the peripheral nervous system such as neurofibromas, peripheral nerve sheath tumor, pheochromocytoma, etc. In the available medical literature, the thoracic manifestations of NF1 have been rarely described in these patients. There are few reports about intrathoracic neurogenic tumors, kyphoscoliosis, pneumonitis and pulmonary fibrosis in patients with NF1. Case report. A 65-year-old female was admitted to the Intensive Care Unit at the Lung Clinic of Belgrade University Clinical Center of Serbia. The patient’s general condition was poor with shortness of breath and present cyanosis. At the same time, the skin changes similar to NF1 were noticed, which were additionally documented by her medical history and diagnosed as NF1. After the application of noninvasive mechanical ventilation and other emergency respiratory medicine measures, the patient soon felt better. The parenchymal changes were viewed by subsequent X-rays and CT scanning of the thorax. Conclusion. This is a case report presenting the NF1 associated with the abnormality of lung parenchyma established during diagnostic procedures at the Intensive Care Unit, Clinic of Pulmonology.

  8. Type 1 diabetes guidelines: Are they enough?

    Directory of Open Access Journals (Sweden)

    Abdul Abdul Zargar

    2015-01-01

    Full Text Available The discovery of insulin by Banting and Best in 1922 changed the landscape of type 1 diabetes mellitus (T1DM. Guidelines on T1DM should be evidence based and should emphasize comprehensive risk management. Guidelines would improve awareness amongst governments, state health care providers and the general public about the serious long-term implications of poorly managed diabetes and of the essential resources needed for optimal care. T1DM requires lifelong daily medication, regular control as well as access to facilities to manage acute and chronic complications. American Diabetes Association 2014 guidelines recommends annual nephropathy screening for albumin levels; random spot urine sample for albumin-to-creatinine ratio at start of puberty or age ≥10 years, whichever is earlier, once the child has had diabetes for 5 years. Hypertension should be screened for in T1DM patients by measuring blood pressure at each routine visit. Dyslipidemia in T1DM patients is important and patients should be screened if there is a family history of hypercholesterolemia or a cardiovascular event before the age of 55 years exists or if family history is unknown. Retinopathy is another important complication of diabetes and patients should be subjected to an initial dilated and comprehensive eye examination. Basic diabetes training should be provided for school staff, and they should be assigned with responsibilities for the care of diabetic children. Self-management should be allowed at all school settings for students.

  9. Autonomic thermoregulatory dysfunction in neurofibromatosis type 1

    Directory of Open Access Journals (Sweden)

    Luciana G Madeira

    Full Text Available ABSTRACT Objective Neurofibromatosis type 1 (NF1 causes neural and cutaneous disorders and reduced exercise capacity. Exercise/heat exposure increasing internal temperature must be compensated by eccrine sweat function and warmed skin vasodilation. We suspected NF1 could adversely affect eccrine sweat function and/or vascular thermoregulatory responses (VTR. Methods The eccrine sweat function and VTR of 25 NF1 volunteers (14 males, 11 females; 16–57 years old were compared with 23 non-NF1 controls matched by sex, age, height and weight (CG. Sweating was induced by 1 pilocarpine 1% iontophoresis (PILO; and 2 by passive heating (HEAT via the lower third of the legs being immersed in 42°C water for one hour. Previously established eccrine sweat function and VTR protocols were used. Results The NF1 group showed: a lower sweat rate than the CG group during PILO; b a smaller diastolic pressure decrease; and c higher tympanic temperatures than controls during HEAT (p < 0.05. Conclusion Reduced sweating and vascular thermoregulatory responses suggest autonomic dysfunction in NF1 individuals.

  10. [NARCOLEPSY WITH CATAPLEXY: TYPE 1 NARCOLEPSY].

    Science.gov (United States)

    Dauvilliers, Yves; Lopez, Régis

    2016-06-01

    Narcolepsy with cataplexy or narcolepsy type 1 in a rare, disabling sleep disorder, with a prevalence of 20 to 30 per 100,000. Its onset peaks in the second decade. The main features are excessive daytime sleepiness and cataplexy or sudden less of muscle tone triggered by emotional situations. Other less consistent symptoms include hypnagogic hallucinations, sleep paralysis, disturbed nighttime sleep, and weight gain. Narcolepsy with cataplexy remains a clinical diagnosis but nighttime and daytime polysomnography (multiple sleep latency tests) are useful to document mean sleep latency below 8 min and at least two sleep-onset REM periods. HLA typing shows an association with HLA DQB1*0602 in more than 92% of cases but was not included in the new diagnostic criteria. In contrast, a low hypocretin-1/orexin-A levels (values below 110 pg/mL) in the cerebrospinal fluid was highly specific for narcolepsy with cataplexy and was included in the recent diagnostic criteria for narcolepsy. The deficiency of the hypocretin system is well-established in human narcoleptics with a reduction of cerebrospinal fluid hypocretin levels in relation with an early loss of hypocretin neurons. The cause of human narcolepsy remains unknown, however an autoimmune process in most probable acting on a highly genetic background with environmental factors such as streptococcal infections, and H1N1 AS03-adjuvanted vaccine named Pandemrix.

  11. The Genetic Architecture of Type 1 Diabetes

    Directory of Open Access Journals (Sweden)

    Samuel T Jerram

    2017-08-01

    Full Text Available Type 1 diabetes (T1D is classically characterised by the clinical need for insulin, the presence of disease-associated serum autoantibodies, and an onset in childhood. The disease, as with other autoimmune diseases, is due to the interaction of genetic and non-genetic effects, which induce a destructive process damaging insulin-secreting cells. In this review, we focus on the nature of this interaction, and how our understanding of that gene–environment interaction has changed our understanding of the nature of the disease. We discuss the early onset of the disease, the development of distinct immunogenotypes, and the declining heritability with increasing age at diagnosis. Whilst Human Leukocyte Antigens (HLA have a major role in causing T1D, we note that some of these HLA genes have a protective role, especially in children, whilst other non-HLA genes are also important. In adult-onset T1D, the disease is often not insulin-dependent at diagnosis, and has a dissimilar immunogenotype with reduced genetic predisposition. Finally, we discuss the putative nature of the non-genetic factors and how they might interact with genetic susceptibility, including preliminary studies of the epigenome associated with T1D.

  12. Mosaic Neurofibromatosis Type 1: A Systematic Review.

    Science.gov (United States)

    García-Romero, Maria Teresa; Parkin, Patricia; Lara-Corrales, Irene

    2016-01-01

    Confusion is widespread regarding segmental or mosaic neurofibromatosis type 1 (MNF1). Physicians should use the same terms and be aware of its comorbidities and risks. The objective of the current study was to identify and synthesize data for cases of MNF1 published from 1977 to 2012 to better understand its significance and associations. After a literature search in PubMed, we reviewed all available relevant articles and abstracted and synthetized the relevant clinical data about manifestations, associated findings, family history and genetic testing. We identified 111 articles reporting 320 individuals. Most had pigmentary changes or neurofibromas only. Individuals with pigmentary changes alone were identified at a younger age. Seventy-six percent had localized MNF1 restricted to one segment; the remainder had generalized MNF1. Of 157 case reports, 29% had complications associated with NF1. In one large case series, 6.5% had offspring with complete NF1. The terms "segmental" and "type V" neurofibromatosis should be abandoned, and the correct term, mosaic NF1 (MNF1), should be used. All individuals with suspected MNF1 should have a complete physical examination, genetic testing of blood and skin, counseling, and health surveillance. © 2015 Wiley Periodicals, Inc.

  13. Tuberculoid leprosy and Type 1 lepra reaction.

    Science.gov (United States)

    Bongiorno, M R; Pistone, G; Noto, S; Aricò, M

    2008-09-01

    A patient is described with tuberculoid leprosy and Type 1 (lepra) reaction from Sicily a non-endemic region, who lived previously in Manila from 2000 to 2005. The skin lesions became acutely inflamed and edematous. The plaques were painless to touch or pinprick, and there was swelling of the nerves in the fibro-osseous tunnels under the surface of the skin, including both the ulnar nerve at the elbow, and the posterior tibial nerve (medial malleolus). During the course of electro-neurographic studies, conduction velocity in the motory nerves indicated a slowing-down. The diagnosis of leprosy was confirmed by residence in an endemic area for about 5 years, by simultaneous skin lesions and peripheral nerve abnormalities, and by skin biopsy. Outside of endemic areas, diagnosis remains a challenge for physicians for mainly two reasons. Firstly, the incubation period of leprosy is uniquely long among bacterial diseases and varies from a month to over 40 years. Secondly, outside leprosy-endemic areas, the diagnosis of leprosy is usually not considered, and patients are likely to be examined by a wide range of specialists. Physicians outside endemic areas should consider leprosy as a possible differential diagnosis if a patient from leprosy-endemic regions presents with painless skin lesions, nerve enlargement, or persistent skin lesions.

  14. Early life origin of type 1 diabetes.

    Science.gov (United States)

    Knip, Mikael; Luopajärvi, Kristiina; Härkönen, Taina

    2017-11-01

    Type 1 diabetes (T1D) is perceived as a chronic immune-mediated disease with a subclinical prodromal period characterized by selective loss of insulin-producing beta cells in the pancreatic islets in genetically susceptible subjects. The incidence of T1D has increased manifold in most developed countries after World War II in parallel with a series of other immune-mediated diseases. T1D results from gene-environmental interactions. The appearance of disease-associated autoantibodies into the peripheral circulation is the first detectable sign of the initiation of the disease process leading to clinical T1D. The first autoantibodies may appear already before the age of 6 months and the seroconversion rate peaks during the second year of life. This implies that exogenous factors involved in the pathogenesis of T1D must be operative in early life, some of them most likely already during pregnancy. Here, we discuss putative endogenous factors that may contribute to the development of T1D during fetal and early postnatal life. Many environmental factors operative in early life have been implicated in the pathogenesis of T1D, but relatively few have been firmly confirmed.

  15. The Genetic Architecture of Type 1 Diabetes

    Science.gov (United States)

    Jerram, Samuel T.; Leslie, Richard David

    2017-01-01

    Type 1 diabetes (T1D) is classically characterised by the clinical need for insulin, the presence of disease-associated serum autoantibodies, and an onset in childhood. The disease, as with other autoimmune diseases, is due to the interaction of genetic and non-genetic effects, which induce a destructive process damaging insulin-secreting cells. In this review, we focus on the nature of this interaction, and how our understanding of that gene–environment interaction has changed our understanding of the nature of the disease. We discuss the early onset of the disease, the development of distinct immunogenotypes, and the declining heritability with increasing age at diagnosis. Whilst Human Leukocyte Antigens (HLA) have a major role in causing T1D, we note that some of these HLA genes have a protective role, especially in children, whilst other non-HLA genes are also important. In adult-onset T1D, the disease is often not insulin-dependent at diagnosis, and has a dissimilar immunogenotype with reduced genetic predisposition. Finally, we discuss the putative nature of the non-genetic factors and how they might interact with genetic susceptibility, including preliminary studies of the epigenome associated with T1D. PMID:28829396

  16. Cannabinoid CB1 receptor agonists do not decrease, but may increase, acoustic trauma-induced tinnitus in rats

    Directory of Open Access Journals (Sweden)

    Yiwen eZheng

    2015-03-01

    Full Text Available Tinnitus has been suggested to arise from neuronal hyperactivity in auditory areas of the brain and anti-epileptic drugs are sometimes used to provide relief from tinnitus. Recently, the anti-epileptic properties of the cannabinoid drugs have gained increasing interest; however, the use of cannabinoids as a form of treatment for tinnitus is controversial. In the present study, we tested whether a combination of delta-9-tetrahydrocannabinol (delta-9-THC and cannabidiol (CBD, delivered in a 1:1 ratio, could affect tinnitus perception in a rat model of acoustic trauma-induced tinnitus. Following sham treatment or acoustic trauma, the animals were divided into the following groups: 1 sham (i.e. no acoustic trauma with vehicle treatment; 2 sham with drug treatment (i.e. delta-9-THC + CBD; 3 acoustic trauma-exposed exhibiting tinnitus, with drug treatment; and 4 acoustic trauma-exposed exhibiting no tinnitus, with drug treatment. The animals received either the vehicle or the cannabinoid drugs every day, 30 min before the tinnitus behavioural testing. Acoustic trauma caused a significant increase in the auditory brainstem response (ABR thresholds in the exposed animals, indicating hearing loss; however, there was a partial recovery over 6 months. Acoustic trauma did not always result in tinnitus; however among those that did exhibit tinnitus, some of them had tinnitus at multiple frequencies while others had it only at a single frequency. The cannabinoids significantly increased the number of tinnitus animals in the exposed-tinnitus group, but not in the sham group. The results suggest that cannabinoids may promote the development of tinnitus, especially when there is pre-existing hearing damage.

  17. Human studies of cannabinoids and medicinal cannabis.

    Science.gov (United States)

    Robson, P

    2005-01-01

    Cannabis has been known as a medicine for several thousand years across many cultures. It reached a position of prominence within Western medicine in the nineteenth century but became mired in disrepute and legal controls early in the twentieth century. Despite unremitting world-wide suppression, recreational cannabis exploded into popular culture in the 1960s and has remained easily obtainable on the black market in most countries ever since. This ready availability has allowed many thousands of patients to rediscover the apparent power of the drug to alleviate symptoms of some of the most cruel and refractory diseases known to humankind. Pioneering clinical research in the last quarter of the twentieth century has given some support to these anecdotal reports, but the methodological challenges to human research involving a pariah drug are formidable. Studies have tended to be small, imperfectly controlled, and have often incorporated unsatisfactory synthetic cannabinoid analogues or smoked herbal material of uncertain composition and irregular bioavailability. As a result, the scientific evaluation of medicinal cannabis in humans is still in its infancy. New possibilities in human research have been opened up by the discovery of the endocannabinoid system, a rapidly expanding knowledge of cannabinoid pharmacology, and a more sympathetic political environment in several countries. More and more scientists and clinicians are becoming interested in exploring the potential of cannabis-based medicines. Future targets will extend beyond symptom relief into disease modification, and already cannabinoids seem to offer particular promise in the treatment of certain inflammatory and neurodegenerative conditions. This chapter will begin with an outline of the development and current status of legal controls pertaining to cannabis, following which the existing human research will be reviewed. Some key safety issues will then be considered, and the chapter will conclude with

  18. Cannabinoids and the regulation of ingestive behaviour.

    Science.gov (United States)

    Vickers, S P; Kennett, G A

    2005-03-01

    Over past centuries, Cannabis sativa (Delta(9)-tetrahydrocannabinol being the principal active ingredient) has been used extensively for both medicinal and recreational uses, and one widely reported effect is the onset of a ravenous appetite and eating behaviour. The pharmacological properties of such exogenous cannabinoids are mediated through the activation of two receptor subtypes, the CB(1) and CB(2) receptors. A number of endogenous ligands for these receptors, the endocannabinoids, have now also been identified allowing their effects on ingestive behaviour to be determined. In a number of species, including man, the administration of exogenous and endogenous cannabinoids leads to robust increases in food intake and can promote body weight gain. These effects are believed to be mediated through activation of the CB(1) receptor. Conversely, experiments with selective CB(1) receptor antagonists have demonstrated reductions in food intake and body weight with repeated compound administration. These reductions in body weight appear to be greater in obese animals and may be the result of a dual effect on both food intake and metabolic processes. Such findings have led to a number of pharmaceutical companies developing selective CB(1) receptor antagonists for the treatment of obesity. The most advanced compound is Sanofi-Synthelabo's inverse agonist, rimonabant (Acomplia; SR-141716), and early Phase III results have recently demonstrated significant reductions in body weight, waist circumference and improvement of lipid and glucose metabolism in overweight and obese humans. Accordingly, the cannabinoid system appears to have an important role in the regulation of ingestive behaviour in man and animals.

  19. Cannabinoid hyperemesis syndrome with extreme hydrophilia

    Directory of Open Access Journals (Sweden)

    Enuh HA

    2013-08-01

    Full Text Available Hilary A Enuh,1 Julia Chin,1 Jay Nfonoyim21Department of Medicine, 2Critical Care Unit, Richmond University Medical Center, Staten Island, NY, USAAbstract: Marijuana is the most widely used recreational drug in the US. Hyperemetic hydrophilic syndrome is a previously described but infrequently recognized condition of cannabinoid abuse with hyperemesis and obsessive hot showering. We present a 47-year-old male known marijuana addict with intractable abdominal pain who could not wait for physical examination, meal, or medication, because of obsessive compulsive warm baths. He had a history of epilepsy and addiction to marijuana, which he took on the day of admission. He presented to the hospital with a seizure, complicated by nausea, vomiting, and severe abdominal pain. His examination was unremarkable, except for mild epigastric tenderness. His laboratory and radiological tests were within normal limits, except for a positive urine drug screen for marijuana and opiates. He took himself immediately to the bathroom and remained under a hot shower with the exception of two 15-minute breaks for the rest of the day. He stated that it made him feel better than medication. Receiving medication and even eating was a problem because of this compulsive showering. Abstinence from marijuana during the hospital stay made the patient's nausea and vomiting resolve significantly. Cannabinoid hyperemesis is a differential diagnosis among patients with intractable nausea, vomiting, and obsessive hot bathing. The syndrome is an unmistakable indication of marijuana addiction. A thorough history and observation is very valuable. Recognition of this entity will reduce unnecessary testing and utilization of health care resources.Keywords: cannabinoid, compulsive bathing, cyclic vomiting, hyperemesis, hydrophilia, marijuana

  20. Cannabinoids – a new weapon against cancer?

    OpenAIRE

    Małgorzata Pokrywka; Joanna Góralska; Bogdan Solnica

    2016-01-01

    Cannabis has been cultivated by man since Neolithic times. It was used, among others for fiber and rope production, recreational purposes and as an excellent therapeutic agent. The isolation and characterization of the structure of one of the main active ingredients of cannabis – Δ9 – tetrahydrocannabinol as well the discovery of its cannabinoid binding receptors CB1 and CB2, has been a milestone in the study of the possibilities of the uses of Cannabis sativa and related products in modern m...

  1. Constipation in children with neurofibromatosis type 1.

    Science.gov (United States)

    Pedersen, Cecilie E; Krogh, Klaus; Siggaard, Charlotte; Joensson, Iben M; Haagerup, Annette

    2013-02-01

    Neurofibromatosis type 1 (NF1) is a hereditary, heterogenic, and multiorganic disease. The NF1 phenotype shows great variability in expressivity and often includes symptoms from the central and peripheral nervous systems. Bowel symptoms have been reported, but gastrointestinal function in NF1 remains to be described in detail. In this first systematic study of bowel function in children with NF1, we aimed to investigate symptoms of constipation and test the hypotheses that children with NF1 have abnormally large rectum and prolonged colonic transit time (CTT). A total of 20 children with NF1 (age 8.2 ± 2.4 years) were evaluated with medical history; clinical examination; digital rectal examination; bowel and dietary diaries; Rome III criteria; measurement of rectal diameter by transabdominal ultrasound; and radiographic estimation of CTT. The control group for assessment of rectal diameter comprised 23 healthy children (mean age 9.1 ± 2.7 years). A total of 6 children with NF1 (30%) were constipated according to Rome III criteria. Average rectal diameter was significantly larger than for healthy children (32.9 ± 7.2 mm vs 21.4 ± 5.9 mm, P children was 53 hours (range 26-101). Compared with existing normative data, CTT was prolonged (>84 hours) in 3 (19%). Symptoms of constipation were surprisingly common in children with NF1. Correspondingly, rectal diameters were abnormally large and a higher proportion than expected had prolonged CTT. The underlying pathophysiology remains obscure, but we hypothesise that abnormalities of the enteric nervous system or disturbed cellular growth could be present.

  2. Ophthalmological manifestations in segmental neurofibromatosis type 1

    Science.gov (United States)

    Ruggieri, M; Pavone, P; Polizzi, A; Pietro, M Di; Scuderi, A; Gabriele, A; Spalice, A; Iannetti, P

    2004-01-01

    Aims: To study the ophthalmological manifestations in individuals with the typical features of neurofibromatosis type 1 (NF1) circumscribed to one or more body segments, usually referred to as segmental NF1. Methods: Visual acuity and colour tests, visual field examination, slit lamp biomicroscopy of the anterior segment, and a detailed examination of the retina by indirect ophthalmoscopy were performed at diagnosis and follow up in 72 consecutive subjects (29 males, 43 females; aged 1–64 years; mean age 14.6 years) seen at the university departments of paediatrics in Catania and Rome, Italy, during years 1990–2003, who had in restricted body areas: (1) typical pigmentary manifestations of NF1 (café au lait spots and freckling) only (n = 48); (2) NF1 pigmentary manifestations and neurofibromas alone (n = 2); (3) neurofibromas only (n = 15); and (4) plexiform neurofibromas only (n = 7). Results: None of the 72 patients had Lisch nodules in the iris irrespective of age at eye examination or hypertelorism (a “minor” NF1 feature) and none developed typical associated ophthalmological NF1 complications. An additional child had an isolated optic pathways glioma (OPG), which behaved both biologically and radiographically as an NF1 associated OPG. Conclusions: This represents the first systematic study reporting on eye involvement in the largest series of individuals at different ages having segmental NF1. As one of the postulated mechanisms to explain segmental NF1 is somatic mosaicism for the NF1 gene (so far demonstrated only in two patients) the present findings could be explained either by the fact that the eye is too far from the mutated area with NF1 lesions in most cases or by the NF1 (or other “predisposing” or “cooperating”) gene mutation restricted to too few cellular clones or to tissues embryologically different from the eye. PMID:15489488

  3. Ophthalmological manifestations in segmental neurofibromatosis type 1.

    Science.gov (United States)

    Ruggieri, M; Pavone, P; Polizzi, A; Di Pietro, M; Scuderi, A; Gabriele, A; Spalice, A; Iannetti, P

    2004-11-01

    To study the ophthalmological manifestations in individuals with the typical features of neurofibromatosis type 1 (NF1) circumscribed to one or more body segments, usually referred to as segmental NF1. Visual acuity and colour tests, visual field examination, slit lamp biomicroscopy of the anterior segment, and a detailed examination of the retina by indirect ophthalmoscopy were performed at diagnosis and follow up in 72 consecutive subjects (29 males, 43 females; aged 1-64 years; mean age 14.6 years) seen at the university departments of paediatrics in Catania and Rome, Italy, during years 1990-2003, who had in restricted body areas: (1) typical pigmentary manifestations of NF1 (cafe au lait spots and freckling) only (n = 48); (2) NF1 pigmentary manifestations and neurofibromas alone (n = 2); (3) neurofibromas only (n = 15); and (4) plexiform neurofibromas only (n = 7). None of the 72 patients had Lisch nodules in the iris irrespective of age at eye examination or hypertelorism (a "minor" NF1 feature) and none developed typical associated ophthalmological NF1 complications. An additional child had an isolated optic pathways glioma (OPG), which behaved both biologically and radiographically as an NF1 associated OPG. This represents the first systematic study reporting on eye involvement in the largest series of individuals at different ages having segmental NF1. As one of the postulated mechanisms to explain segmental NF1 is somatic mosaicism for the NF1 gene (so far demonstrated only in two patients) the present findings could be explained either by the fact that the eye is too far from the mutated area with NF1 lesions in most cases or by the NF1 (or other "predisposing" or "cooperating") gene mutation restricted to too few cellular clones or to tissues embryologically different from the eye.

  4. Boston type 1 keratoprosthesis for failed keratoplasty.

    Science.gov (United States)

    Hager, Jonathan L; Phillips, David L; Goins, Kenneth M; Kitzmann, Anna S; Greiner, Mark A; Cohen, Alex W; Welder, Jeffrey D; Wagoner, Michael D

    2016-02-01

    The purpose of this study was to evaluate the outcomes of the Boston type 1 keratoprosthesis (Kpro-1) in eyes with failed keratoplasty. A retrospective review was performed of every patient treated with a Kpro-1 at a tertiary eye care center between January 1, 2008 and July 1, 2013. Eyes with a failed keratoplasty originally performed for corneal edema, trauma, or keratoconus were included in the statistical analysis. The main outcome measures were visual outcome, prosthesis retention, and postoperative complications. Twenty-four eyes met the inclusion criteria, including 13 eyes with corneal edema, 8 eyes with trauma, and 3 eyes with keratoconus. After a mean follow-up period of 28.9 months (range 7-63 months), the median best corrected visual acuity (BCVA) was 20/125. The BCVA was ≥ 20/40 in 4 (16.7 %) eyes, ≥ 20/70 in 9 (37.5 %) eyes, and ≥ 20/200 in 14 (58.3 %) eyes. Overall, the postoperative BCVA improved in 17 (70.9 %) eyes, was unchanged in 3 (12.5 %) eyes, and was worse in 4 (16.7 %) eyes. The initial Kpro-1 was retained in 22 (91.7 %) eyes, and was successfully repeated in the other 2 eyes. One or more serious prosthesis- or sight-threatening complications occurred in 8 (33.3 %) eyes. These included 1 case of wound dehiscence leading to prosthesis extrusion, 1 case of fungal keratitis leading to prosthesis extrusion, 4 cases of endophthalmitis, and 5 retinal detachments. The Boston Kpro-1 is associated with an excellent prognosis for prosthesis retention and satisfactory visual improvement in eyes with previous failed keratoplasty.

  5. [Neuropsychological performance in neurofibromatosis type 1].

    Science.gov (United States)

    Hernández Del Castillo, Lilia; Martínez Bermejo, Antonio; Portellano Pérez, José Antonio; Tirado Requero, Pilar; Garriz Luis, Alexandra; Velázquez Fragua, Ramón

    2017-08-01

    Neurofibromatosis type 1 (NF1) is a genetic disorder with various clinical manifestations that affect the peripheral and central nervous system, as well as the skin, bones and endocrine and vascular system. There is still insufficient knowledge of neuropsychological effects of NF1 on children, and there is some controversy about the cognitive deficits that defines the cognitive profile of patients affected by this disorder. In this study an analysis is made of the neuropsychological performance of a group of patients affected by NF1, compared with a control group of healthy children. A comparison was made between the neuropsychological performance of a group of 23 boys and girls with a mean age of 8.7 years (+/-1.39) and diagnosed with NF1, and a control group consisting of 21 healthy children, with mean age of 8.9 years (+/- 1.41) and with similar socio-demographic characteristics. The Wechsler Intelligence Scale for Children (WISC) was applied to evaluate the subjects of both groups. The group of patients affected with NF1 showed a lower performance in every primary index of WISC IV: Verbal Comprehension Index, Fluid Reasoning Index, Working Memory Index, Processing Speed Index, and full Scale IQ. Only in two subscales were no statistically significant differences observed: similarities and coding. The results show subtle and generalised neuropsychological alterations in the sample of children affected with NF1, which affect most of cognitive domains that have been evaluated. Proper specific and early neuropsychological treatment should be provided in order to prevent the high risk for these children of presenting learning difficulties and school failure. Copyright © 2016 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  6. Epilepsy surgery in Neurofibromatosis Type 1.

    Science.gov (United States)

    Barba, Carmen; Jacques, Thomas; Kahane, Philippe; Polster, Tilman; Isnard, Jean; Leijten, Frans S S; Ozkara, Cigdem; Tassi, Laura; Giordano, Flavio; Castagna, Maura; John, Alison; Oz, Buge; Salon, Caroline; Streichenberger, Nathalie; Cross, Judith Helen; Guerrini, Renzo

    2013-08-01

    Epilepsy is relatively uncommon in patients with Neurofibromatosis Type 1 (NF1) and seizures are usually well controlled with antiepileptic treatment. However, pharmacoresistance has been reported in patients with NF1 and MRI evidence of malformations of cortical development or glioneuronal tumours. Available information on epilepsy surgery in NF1 is limited to a few patients with gliomas and glioneuronal tumours who underwent lesionectomies. We conducted a survey amongst 25 European epilepsy surgery centres to collect patients with NF1 who had undergone surgery for drug-resistant seizures and identified 12 patients from eight centres. MRI abnormalities were present in all patients but one. They were unilateral temporal in eight, bilateral temporal in one and multilobar or hemispheric in two. Seizures originated from the temporal lobe in ten patients, from the temporo-parieto-occipital region in one, and were bitemporal in one. One year after surgery eight patients were seizure free, one had worthwhile improvement and the remaining three had experienced no benefit. Postoperative outcome, available at 2 years in ten patients and at 5 years in three, remained stable in all but one whose seizures reappeared. Histology revealed dysembryoplastic neuroepithelial tumour (DNET) in five patients, hippocampal sclerosis in four, mixed pathology in one and polymicrogyria in one. No histological abnormality was observed in the remaining patient. Epilepsy surgery can be performed effectively in patients with NF1 provided a single and well-delimited epileptogenic zone is recognized. The high prevalence of DNETs in this series might suggest a non-fortuitous association with NF1. Copyright © 2013 Elsevier B.V. All rights reserved.

  7. Neurofibromatosis type 1 and autism spectrum disorder.

    Science.gov (United States)

    Garg, Shruti; Green, Jonathan; Leadbitter, Kathy; Emsley, Richard; Lehtonen, Annukka; Evans, D Gareth; Huson, Susan M

    2013-12-01

    To determine the prevalence of autism spectrum disorder (ASD) in Neurofibromatosis Type 1 (NF1). Second-phase population-based epidemiologic study using an allcase NF1 registry in a defined UK 4.1 million population area. A total of 109 (52.7%) of 207 responders from the initial screening phase were grouped by using the parent-rated Social Responsiveness Scale (SRS) as significant ASD (SRS≥76; n = 32), moderate ASD (SRS ≥ 60Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Scale-Generic, and verbal IQ were combined by using standard Collaborative Program for Excellence in Autism criteria into an ASD categorization for each case (ASD, broad ASD with partial features, non-ASD). A preplanned weighted analysis was used to derive prevalence estimates for the whole population. Fourteen (29.5%) of 47 showed ASD, 13 (27.7%) broad ASD, and 20 (42.5%) non-ASD. The ASD/broad ASD group showed male predominance (1.7:1.0), but did not differ significantly from the non-ASD group on IQ, age, socioeconomic status, inheritance, physical severity, or education. The population prevalence estimate is 24.9% ASD (95% confidence interval 13.1%-42.1%) and 20.8% broad ASD (95% confidence interval 10.0%-38.1%); a total of 45.7% showing some ASD spectrum phenotype. Findings indicate high prevalence of ASD in NF1, with implications for clinical practice and further research into NF1 as a single-gene model for autism.

  8. Cannabinoids and schizophrenia: therapeutic prospects.

    Science.gov (United States)

    Robson, P J; Guy, G W; Di Marzo, V

    2014-01-01

    Approximately one third of patients diagnosed with schizophrenia do not achieve adequate symptom control with standard antipsychotic drugs (APs). Some of these may prove responsive to clozapine, but non-response to APs remains an important clinical problem and cause of increased health care costs. In a significant proportion of patients, schizophrenia is associated with natural and iatrogenic metabolic abnormalities (obesity, dyslipidaemia, impaired glucose tolerance or type 2 diabetes mellitus), hyperadrenalism and an exaggerated HPA response to stress, and chronic systemic inflammation. The endocannabinoid system (ECS) in the brain plays an important role in maintaining normal mental health. ECS modulates emotion, reward processing, sleep regulation, aversive memory extinction and HPA axis regulation. ECS overactivity contributes to visceral fat accumulation, insulin resistance and impaired energy expenditure. The cannabis plant synthesises a large number of pharmacologically active compounds unique to it known as phytocannabinoids. In contrast to the euphoric and pro-psychotic effects of delta-9-tetrahydrocannabinol (THC), certain non-intoxicating phytocannabinoids have emerged in pre-clinical and clinical models as potential APs. Since the likely mechanism of action does not rely upon dopamine D2 receptor antagonism, synergistic combinations with existing APs are plausible. The anti-inflammatory and immunomodulatory effects of the non-intoxicating phytocannabinoid cannabidiol (CBD) are well established and are summarised below. Preliminary data reviewed in this paper suggest that CBD in combination with a CB1 receptor neutral antagonist could not only augment the effects of standard APs but also target the metabolic, inflammatory and stress-related components of the schizophrenia phenotype.

  9. CB1 Cannabinoid Receptors and their Associated Proteins

    Science.gov (United States)

    Howlett, Allyn C.; Blume, Lawrence C.; Dalton, George D.

    2011-01-01

    CB1 receptors are G-protein coupled receptors (GPCRs) abundant in neurons, in which they modulate neurotransmission. The CB1 receptor influence on memory and learning is well recognized, and disease states associated with CB1 receptors are observed in addiction disorders, motor dysfunction, schizophrenia, and in bipolar, depression, and anxiety disorders. Beyond the brain, CB1 receptors also function in liver and adipose tissues, vascular as well as cardiac tissue, reproductive tissues and bone. Signal transduction by CB1 receptors occurs through interaction with Gi/o proteins to inhibit adenylyl cyclase, activate mitogen-activated protein kinases (MAPK), inhibit voltage-gated Ca2+ channels, activate K+ currents (Kir), and influence Nitric Oxide (NO) signaling. CB1 receptors are observed in internal organelles as well as plasma membrane. β-Arrestins, adaptor protein AP-3, and G-protein receptor-associated sorting protein 1 (GASP1) modulate cellular trafficking. Cannabinoid Receptor Interacting Protein 1a (CRIP1a) is an accessory protein whose function has not been delineated. Factor Associated with Neutral sphingomyelinase (FAN) regulates ceramide signaling. Such diversity in cellular signaling and modulation by interacting proteins suggests that agonists and allosteric modulators could be developed to specifically regulate unique, cell type-specific responses. PMID:20166926

  10. CB2 Cannabinoid Receptor As Potential Target against Alzheimer's Disease.

    Science.gov (United States)

    Aso, Ester; Ferrer, Isidro

    2016-01-01

    The CB2 receptor is one of the components of the endogenous cannabinoid system, a complex network of signaling molecules and receptors involved in the homeostatic control of several physiological functions. Accumulated evidence suggests a role for CB2 receptors in Alzheimer's disease (AD) and indicates their potential as a therapeutic target against this neurodegenerative disease. Levels of CB2 receptors are significantly increased in post-mortem AD brains, mainly in microglia surrounding senile plaques, and their expression levels correlate with the amounts of Aβ42 and β-amyloid plaque deposition. Moreover, several studies on animal models of AD have demonstrated that specific CB2 receptor agonists, which are devoid of psychoactive effects, reduce AD-like pathology, resulting in attenuation of the inflammation associated with the disease but also modulating Aβ and tau aberrant processing, among other effects. CB2 receptor activation also improves cognitive impairment in animal models of AD. This review discusses available data regarding the role of CB2 receptors in AD and the potential usefulness of specific agonists of these receptors against AD.

  11. Glucose Transporter Type 1 Deficiency Syndrome with Carbohydrate-Responsive Symptoms but without Epilepsy

    Science.gov (United States)

    Koy, Anne; Assmann, Birgit; Klepper, Joerg; Mayatepek, Ertan

    2011-01-01

    Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is caused by a defect in glucose transport across the blood-brain barrier. The main symptoms are epilepsy, developmental delay, movement disorders, and deceleration of head circumference. A ketogenic diet has been shown to be effective in controlling epilepsy in GLUT1-DS. We report a female…

  12. Natural and experimental infection of sheep with European bat lyssavirus type-1 of Danish bat origin

    DEFF Research Database (Denmark)

    Tjørnehøj, Kirsten; Fooks, A.R.; Agerholm, J.S.

    2006-01-01

    In 1998 and 2002, European bat lyssavirus type-1 (EBLV-1) was demonstrated in brain tissue of five Danish sheep suffering from micrological disorders. Four of the five sheep also had encephalic listeriosis. The animals originated from four flocks on pastures within a limited area of western Jutla...

  13. Established and potential therapeutic applications of cannabinoids in oncology.

    Science.gov (United States)

    Walsh, Declan; Nelson, Kristine A; Mahmoud, Fade Aziz

    2003-03-01

    Cannabis occurs naturally in the dried flowering or fruiting tops of the Cannabis sativa plant. Cannabis is most often consumed by smoking marihuana. Cannabinoids are the active compounds extracted from cannabis. Recently, there has been renewed interest in cannabinoids for medicinal purposes. The two proven indications for the use of the synthetic cannabinoid (dronabinol) are chemotherapy-induced nausea and vomiting and AIDS-related anorexia. Other possible effects that may prove beneficial in the oncology population include analgesia, antitumor effect, mood elevation, muscle relaxation, and relief of insomnia. Two types of cannabinoid receptors, CB1 and CB2, have been detected. CB1 receptors are expressed mainly in the central and peripheral nervous system. CB2 receptors are found in certain nonneuronal tissues, particularly in the immune cells. Recent discovery of both the cannabinoid receptors and endocannabinoids has opened a new era in research on the pharmaceutical applications of cannabinoids. The use of cannabinoids should be continued in the areas indicated, and further studies are needed to evaluate other potential uses in clinical oncology.

  14. Cannabinoid-based medicines for neurological disorders--clinical evidence.

    Science.gov (United States)

    Wright, Stephen

    2007-08-01

    Whereas the cannabis plant has a long history of medicinal use, it is only in recent years that a sufficient understanding of the pharmacology of the main plant constituents has allowed for a better understanding of the most rational therapeutic targets. The distribution of cannabinoid receptors, both within the nervous system and without, and the development of pharmacological tools to investigate their function has lead to a substantial increase in efforts to develop cannabinoids as therapeutic agents. Concomitant with these efforts, the understanding of the pharmacology of plant cannabinoids at receptor and other systems distinct from the cannabinoid receptors suggests that the therapeutic applications of plant-derived cannabinoids (and presumably their synthetic derivatives also) may be diverse. This review aims to discuss the clinical evidence investigating the use of medicines derived, directly or indirectly, from plant cannabinoids with special reference to neurological disorders. Published studies suggest that the oral administration of cannabinoids may not be the preferred route of administration and that plant extracts show greater evidence of efficacy than synthetic compounds. One of these, Sativex (GW Pharmaceuticals), was approved as a prescription medicine in Canada in 2005 and is currently under regulatory review in the EU.

  15. Equid herpesvirus type 1 activates platelets.

    Directory of Open Access Journals (Sweden)

    Tracy Stokol

    Full Text Available Equid herpesvirus type 1 (EHV-1 causes outbreaks of abortion and neurological disease in horses. One of the main causes of these clinical syndromes is thrombosis in placental and spinal cord vessels, however the mechanism for thrombus formation is unknown. Platelets form part of the thrombus and amplify and propagate thrombin generation. Here, we tested the hypothesis that EHV-1 activates platelets. We found that two EHV-1 strains, RacL11 and Ab4 at 0.5 or higher plaque forming unit/cell, activate platelets within 10 minutes, causing α-granule secretion (surface P-selectin expression and platelet microvesiculation (increased small events double positive for CD41 and Annexin V. Microvesiculation was more pronounced with the RacL11 strain. Virus-induced P-selectin expression required plasma and 1.0 mM exogenous calcium. P-selectin expression was abolished and microvesiculation was significantly reduced in factor VII- or X-deficient human plasma. Both P-selectin expression and microvesiculation were re-established in factor VII-deficient human plasma with added purified human factor VIIa (1 nM. A glycoprotein C-deficient mutant of the Ab4 strain activated platelets as effectively as non-mutated Ab4. P-selectin expression was abolished and microvesiculation was significantly reduced by preincubation of virus with a goat polyclonal anti-rabbit tissue factor antibody. Infectious virus could be retrieved from washed EHV-1-exposed platelets, suggesting a direct platelet-virus interaction. Our results indicate that EHV-1 activates equine platelets and that α-granule secretion is a consequence of virus-associated tissue factor triggering factor X activation and thrombin generation. Microvesiculation was only partly tissue factor and thrombin-dependent, suggesting the virus causes microvesiculation through other mechanisms, potentially through direct binding. These findings suggest that EHV-1-induced platelet activation could contribute to the thrombosis

  16. Environmental modulators of type 1 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Banshi Saboo

    2016-06-01

    Full Text Available In genetically susceptible subjects, type 1 diabetes (T1D appears to be a chronic immune- mediated disease with a subclinical prodromal period characterized by selective loss of insulin-releasing pancreatic beta cells. However, only a relatively small proportion of genetically susceptible subjects progress to clinical disease, which indicates that environmental factors are needed to trigger and drive the disease process in genetically predisposed subjects. In this article we provide a selective review on environmental factors involved in the pathogenesis of T1D. Accumulating evidence suggests that the proportion of subjects with high-risk human leukocyte antigen (HLA genotypes has decreased over the last decades among patients with newly diagnosed T1D, whereas the proportion of those with low-risk or even protective HLA genotypes has increased. These findings indicate that increased environmental pressure is responsible for progression to clinical diabetes in patients with less genetic predisposition. The birth cohort studies indicate that the first signs of beta cell autoimmunity may be induced during infancy before age 3, which implies that dietary factors for beta cell autoimmunity and T1D may be active in that time period, during which early nutrition provides essential exogenous exposure. Progression to clinical T1D typically needs the combination of genetic disease susceptibility, a diabetogenic trigger, and a high exposure to a driving antigen. The triggers appear to be enteroviruses and rotaviruses as well as components of the infant diet including cows milk and gluten, while the Mediterranean diet appears protective. The only definite enterovirus responsible for T1D is congenital rubella, which may be complicated by late development of T1D. There is a temporal association between enteroviral infection and future development of antibodies resulting in T1D. Clinical studies indicate that islet cell antibodies develop 3 months after birth

  17. The Endocannabinoid System, Cannabinoids, and Pain

    Directory of Open Access Journals (Sweden)

    Perry G. Fine

    2013-10-01

    Full Text Available The endocannabinoid system is involved in a host of homeostatic and physiologic functions, including modulation of pain and inflammation. The specific roles of currently identified endocannabinoids that act as ligands at endogenous cannabinoid receptors within the central nervous system (primarily but not exclusively CB1 receptors and in the periphery (primarily but not exclusively CB2 receptors are only partially elucidated, but they do exert an influence on nociception. Exogenous plant-based cannabinoids (phytocannabinoids and chemically related compounds, like the terpenes, commonly found in many foods, have been found to exert significant analgesic effects in various chronic pain conditions. Currently, the use of Δ9-tetrahydrocannabinol is limited by its psychoactive effects and predominant delivery route (smoking, as well as regulatory or legal constraints. However, other phytocannabinoids in combination, especially cannabidiol and β-caryophyllene, delivered by the oral route appear to be promising candidates for the treatment of chronic pain due to their high safety and low adverse effects profiles. This review will provide the reader with the foundational basic and clinical science linking the endocannabinoid system and the phytocannabinoids with their potentially therapeutic role in the management of chronic pain.

  18. Towards the use of cannabinoids as antitumour agents.

    Science.gov (United States)

    Velasco, Guillermo; Sánchez, Cristina; Guzmán, Manuel

    2012-05-04

    Various reports have shown that cannabinoids (the active components of marijuana and their derivatives) can reduce tumour growth and progression in animal models of cancer, in addition to their well-known palliative effects on some cancer-associated symptoms. This Opinion article discusses our current understanding of cannabinoids as antitumour agents, focusing on recent insights into the molecular mechanisms of action, including emerging resistance mechanisms and opportunities for combination therapy approaches. Such knowledge is required for the optimization of preclinical cannabinoid-based therapies and for the preliminary clinical testing that is currently underway.

  19. Counteractive effects of cannabinoid and nicotine-addictive behavior.

    Science.gov (United States)

    Han, Jing; Liu, Zhiqiang; Ren, Wei; Zhang, Xia

    2011-03-09

    Our recent results suggest that cannabinoid exposure induces conditioned place preference (CPP) through facilitated induction of synaptic long-term depression at dopamine circuitry of the midbrain ventral tegmental area (VTA). Here, we show that chronic nicotine exposure also induces CPP, but facilitates the induction of synaptic long-term potentiation in the VTA. Coadministration of cannabinoid and nicotine leads to a blockade of facilitated long-term depression and long-term potentiation induction in these neurons and elimination of CPP. These findings point to counteractive effects of cannabinoid and nicotine-addictive behavior through opposite changes in synaptic plasticity of dopamine circuitry of the VTA.

  20. Phase I hydroxylated metabolites of the K2 synthetic cannabinoid JWH-018 retain in vitro and in vivo cannabinoid 1 receptor affinity and activity.

    Directory of Open Access Journals (Sweden)

    Lisa K Brents

    Full Text Available K2 products are synthetic cannabinoid-laced, marijuana-like drugs of abuse, use of which is often associated with clinical symptoms atypical of marijuana use, including hypertension, agitation, hallucinations, psychosis, seizures and panic attacks. JWH-018, a prevalent K2 synthetic cannabinoid, is structurally distinct from Δ(9-THC, the main psychoactive ingredient in marijuana. Since even subtle structural differences can lead to differential metabolism, formation of novel, biologically active metabolites may be responsible for the distinct effects associated with K2 use. The present study proposes that K2's high adverse effect occurrence is due, at least in part, to distinct JWH-018 metabolite activity at the cannabinoid 1 receptor (CB1R.JWH-018, five potential monohydroxylated metabolites (M1-M5, and one carboxy metabolite (M6 were examined in mouse brain homogenates containing CB1Rs, first for CB1R affinity using a competition binding assay employing the cannabinoid receptor radioligand [(3H]CP-55,940, and then for CB1R intrinsic efficacy using an [(35S]GTPγS binding assay. JWH-018 and M1-M5 bound CB1Rs with high affinity, exhibiting K(i values that were lower than or equivalent to Δ(9-THC. These molecules also stimulated G-proteins with equal or greater efficacy relative to Δ(9-THC, a CB1R partial agonist. Most importantly, JWH-018, M2, M3, and M5 produced full CB1R agonist levels of activation. CB1R-mediated activation was demonstrated by blockade with O-2050, a CB1R-selective neutral antagonist. Similar to Δ(9-THC, JWH-018 and M1 produced a marked depression of locomotor activity and core body temperature in mice that were both blocked by the CB1R-preferring antagonist/inverse agonist AM251.Unlike metabolites of most drugs, the studied JWH-018 monohydroxylated compounds, but not the carboxy metabolite, retain in vitro and in vivo activity at CB1Rs. These observations, combined with higher CB1R affinity and activity relative to Δ(9

  1. Cannabinoids for the Treatment of Schizophrenia? A Balanced Neurochemical Framework for Both Adverse and Therapeutic Effects of Cannabis Use

    Directory of Open Access Journals (Sweden)

    Carissa M. Coulston

    2011-01-01

    Full Text Available Recent studies have found that cannabinoids may improve neuropsychological performance, ameliorate negative symptoms, and have antipsychotic properties for a subgroup of the schizophrenia population. These findings are in contrast to the longstanding history of adverse consequences of cannabis use, predominantly on the positive symptoms, and a balanced neurochemical basis for these opposing views is lacking. This paper details a review of the neurobiological substrates of schizophrenia and the neurochemical effects of cannabis use in the normal population, in both cortical (in particular prefrontal and subcortical brain regions. The aim of this paper is to provide a holistic neurochemical framework in which to understand how cannabinoids may impair, or indeed, serve to ameliorate the positive and negative symptoms as well as cognitive impairment. Directions in which future research can proceed to resolve the discrepancies are briefly discussed.

  2. Lethal high: acute disseminated encephalomyelitis (ADEM) triggered by toxic effect of synthetic cannabinoid black mamba.

    Science.gov (United States)

    Samra, Kiran; Boon, Ian S; Packer, Gregory; Jacob, Saiju

    2017-04-22

    A previously well 25-year-old man presented with agitation, double incontinence and left-sided incoordination. His symptoms started after smoking a synthetic cannabinoid (black mamba) 5 days earlier. Over 48 hours, he developed aphasia, generalised hypertonia, hyper-reflexia and dense left hemiparesis. This progressed to profuse diaphoresis, fever, tachycardia, hypertension and a possible seizure necessitating admission to the intensive care unit. CT head and cerebrospinal fluid analysis were unremarkable. MRI brain demonstrated asymmetric multifocal hyperintense lesions in white and grey matter, which raised suspicions of acute disseminated encephalomyelitis (ADEM). An electroencephalogram showed widespread brain wave slowing, indicating diffuse cerebral dysfunction. Cerebral angiogram was normal. Toxicology analysis of the substance confirmed a potent synthetic cannabinoid NM2201, technically legal at the time. The patient made a slow but significant recovery after a course of intravenous methylprednisolone, intravenous immunoglobulins and oral steroids, and was later transferred to a rehabilitation bed. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  3. Cardiorespiratory anomalies in mice lacking CB1 cannabinoid receptors.

    Directory of Open Access Journals (Sweden)

    Alessandro Silvani

    Full Text Available Cannabinoid type 1 (CB1 receptors are expressed in the nervous and cardiovascular systems. In mice, CB1 receptor deficiency protects from metabolic consequences of a high-fat diet (HFD, increases sympathetic activity to brown fat, and entails sleep anomalies. We investigated whether sleep-wake and diet-dependent cardiorespiratory control is altered in mice lacking CB1 receptors. CB1 receptor knock-out (KO and intact wild-type (WT mice were fed standard diet or a HFD for 3 months, and implanted with a telemetric arterial pressure transducer and electrodes for sleep scoring. Sleep state was assessed together with arterial pressure and heart rate (home cage, or breathing (whole-body plethysmograph. Increases in arterial pressure and heart rate on passing from the light (rest to the dark (activity period in the KO were significantly enhanced compared with the WT. These increases were unaffected by cardiac (β1 or vascular (α1 adrenergic blockade. The breathing rhythm of the KO during sleep was also more irregular than that of the WT. A HFD increased heart rate, impaired cardiac vagal modulation, and blunted the central autonomic cardiac control during sleep. A HFD also decreased cardiac baroreflex sensitivity in the KO but not in the WT. In conclusion, we performed the first systematic study of cardiovascular function in CB1 receptor deficient mice during spontaneous wake-sleep behavior, and demonstrated that CB1 receptor KO alters cardiorespiratory control particularly in the presence of a HFD. The CB1 receptor signaling may thus play a role in physiological cardiorespiratory regulation and protect from some adverse cardiovascular consequences of a HFD.

  4. Cardiorespiratory anomalies in mice lacking CB1 cannabinoid receptors.

    Science.gov (United States)

    Silvani, Alessandro; Berteotti, Chiara; Bastianini, Stefano; Cohen, Gary; Lo Martire, Viviana; Mazza, Roberta; Pagotto, Uberto; Quarta, Carmelo; Zoccoli, Giovanna

    2014-01-01

    Cannabinoid type 1 (CB1) receptors are expressed in the nervous and cardiovascular systems. In mice, CB1 receptor deficiency protects from metabolic consequences of a high-fat diet (HFD), increases sympathetic activity to brown fat, and entails sleep anomalies. We investigated whether sleep-wake and diet-dependent cardiorespiratory control is altered in mice lacking CB1 receptors. CB1 receptor knock-out (KO) and intact wild-type (WT) mice were fed standard diet or a HFD for 3 months, and implanted with a telemetric arterial pressure transducer and electrodes for sleep scoring. Sleep state was assessed together with arterial pressure and heart rate (home cage), or breathing (whole-body plethysmograph). Increases in arterial pressure and heart rate on passing from the light (rest) to the dark (activity) period in the KO were significantly enhanced compared with the WT. These increases were unaffected by cardiac (β1) or vascular (α1) adrenergic blockade. The breathing rhythm of the KO during sleep was also more irregular than that of the WT. A HFD increased heart rate, impaired cardiac vagal modulation, and blunted the central autonomic cardiac control during sleep. A HFD also decreased cardiac baroreflex sensitivity in the KO but not in the WT. In conclusion, we performed the first systematic study of cardiovascular function in CB1 receptor deficient mice during spontaneous wake-sleep behavior, and demonstrated that CB1 receptor KO alters cardiorespiratory control particularly in the presence of a HFD. The CB1 receptor signaling may thus play a role in physiological cardiorespiratory regulation and protect from some adverse cardiovascular consequences of a HFD.

  5. The application of plant in vitro cultures in cannabinoid production.

    Science.gov (United States)

    Wróbel, Tomasz; Dreger, Mariola; Wielgus, Karolina; Słomski, Ryszard

    2017-12-16

    Cannabinoids have considerable interest in the pharmaceutical industry. However, the production of medicines from hemp (Cannabis sativa L.) in most countries is restricted by law. Large-scale, field cultivation of hemp is difficult to control. Cannabinoid content in plants is variable and depends on multiple factors. Therefore, alternative methods of production have been investigated. The development of micropropagation techniques is a necessary step for genetic modification. Promising results have been obtained for certain narcotic genotypes. However, micropropagation of fibre types requires further research. Hemp can be genetically modified which may contribute to the breeding of new varieties in the future. Cell suspension cultures and hairy root cultures of hemp have been used to produce cannabinoids but obtaining cannabinoids from callus and cell suspension cultures has proved impossible. Adventitious roots can, however, deliver small amounts of these metabolites but production ceases over time and is too low for industrial applications.

  6. CB2 Cannabinoid Receptor As Potential Target against Alzheimer's Disease

    National Research Council Canada - National Science Library

    Aso, Ester; Ferrer, Isidro

    2016-01-01

    The CB2 receptor is one of the components of the endogenous cannabinoid system, a complex network of signaling molecules and receptors involved in the homeostatic control of several physiological functions...

  7. Cannabinoids and cancer: pros and cons of an antitumour strategy.

    Science.gov (United States)

    Bifulco, Maurizio; Laezza, Chiara; Pisanti, Simona; Gazzerro, Patrizia

    2006-05-01

    In the last two decades, research has dramatically increased the knowledge of cannabinoids biology and pharmacology. In mammals, compounds with properties similar to active components of Cannabis sativa, the so called 'endocannabinoids', have been shown to modulate key cell-signalling pathways involved in cancer cell growth, invasion and metastasis. To date, cannabinoids have been licensed for clinical use as palliative treatment of chemotherapy, but increased evidences showed direct antiproliferative actions of cannabinoid agonists on several tumour cells in vitro and in animal models. In this article, we will review the principal molecular pathways modulated by cannabinoids on cancer and summarize pros and cons evidence on the possible future use of endocannabinoid-based drugs in cancer therapy.

  8. Genetics Home Reference: autosomal recessive cerebellar ataxia type 1

    Science.gov (United States)

    ... Twitter Home Health Conditions ARCA1 Autosomal recessive cerebellar ataxia type 1 Printable PDF Open All Close All ... the expand/collapse boxes. Description Autosomal recessive cerebellar ataxia type 1 ( ARCA1 ) is a condition characterized by ...

  9. Pregnancy outcome in type 1 diabetic women with microalbuminuria

    DEFF Research Database (Denmark)

    Ekbom, P; Damm, P; Feldt-Rasmussen, B

    2001-01-01

    To determine the influence of microalbuminuria on pregnancy outcome in women with type 1 diabetes.......To determine the influence of microalbuminuria on pregnancy outcome in women with type 1 diabetes....

  10. Diet Treatment Glucose Transporter Type 1 Deficiency (G1D)

    Science.gov (United States)

    2017-10-17

    GLUT1DS1; Epilepsy; Glut1 Deficiency Syndrome 1, Autosomal Recessive; Glucose Metabolism Disorders; Glucose Transport Defect; Glucose Transporter Type 1 Deficiency Syndrome; Glucose Transporter Protein Type 1 Deficiency Syndrome

  11. Cannabinoid Receptors: A Novel Target for Treating Prostate Cancer

    Science.gov (United States)

    2006-02-01

    receptor agonists could be developed as novel therapeutic agents for the treatment of prostate cancer (Sarfaraz et al., 2005). To understand the...for its treatment has become a challenging issue. In recent years cannabinoids, the active components of Cannabis sativa linnaeus (marijuana) and...cannabinoid receptor agonists could be developed as novel therapeutic agents for the treatment of prostate cancer (Sarfaraz et al., 2005). To understand

  12. Cannabinoid Receptors: A Novel Target for Therapy for Prostate Cancer

    Science.gov (United States)

    2008-02-01

    targets and mechanism based agents for its treatment has become a challenging issue. In recent years, cannabinoids, the active components of Cannabis ...human prostate cancer cells. Specific aim II of the proposal was designed to investigate the therapeutic potential of cannabinoids under in vivo...for PSA by specific immunoassay. Protocol-2 This protocol was designed to assess the therapeutic potential of WIN-55,212-2. For this purpose

  13. Vascular targets for cannabinoids: animal and human studies

    Science.gov (United States)

    Stanley, Christopher; O'Sullivan, Saoirse E

    2014-01-01

    Application of cannabinoids and endocannabinoids to perfused vascular beds or individual isolated arteries results in changes in vascular resistance. In most cases, the result is vasorelaxation, although vasoconstrictor responses are also observed. Cannabinoids also modulate the actions of vasoactive compounds including acetylcholine, methoxamine, angiotensin II and U46619 (thromboxane mimetic). Numerous mechanisms of action have been proposed including receptor activation, potassium channel activation, calcium channel inhibition and the production of vasoactive mediators such as calcitonin gene-related peptide, prostanoids, NO, endothelial-derived hyperpolarizing factor and hydrogen peroxide. The purpose of this review is to examine the evidence for the range of receptors now known to be activated by cannabinoids. Direct activation by cannabinoids of CB1, CBe, TRPV1 (and potentially other TRP channels) and PPARs in the vasculature has been observed. A potential role for CB2, GPR55 and 5-HT1A has also been identified in some studies. Indirectly, activation of prostanoid receptors (TP, IP, EP1 and EP4) and the CGRP receptor is involved in the vascular responses to cannabinoids. The majority of this evidence has been obtained through animal research, but recent work has confirmed some of these targets in human arteries. Vascular responses to cannabinoids are enhanced in hypertension and cirrhosis, but are reduced in obesity and diabetes, both due to changes in the target sites of action. Much further work is required to establish the extent of vascular actions of cannabinoids and the application of this research in physiological and pathophysiological situations. Linked ArticlesThis article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6 PMID:24329566

  14. Health Risk Behaviors With Synthetic Cannabinoids Versus Marijuana.

    Science.gov (United States)

    Clayton, Heather B; Lowry, Richard; Ashley, Carmen; Wolkin, Amy; Grant, Althea M

    2017-04-01

    Data are limited on the behavioral risk correlates of synthetic cannabinoid use. The purpose of this study was to compare the behavioral risk correlates of synthetic cannabinoid use with those among marijuana users. Data from the 2015 Youth Risk Behavior Survey, a cross-sectional survey conducted in a nationally representative sample of students in grades 9 through 12 (N = 15 624), were used to examine the association between self-reported type of marijuana use (ie, never use of marijuana and synthetic cannabinoids, ever use of marijuana only, and ever use of synthetic cannabinoids) and self-report of 36 risk behaviors across 4 domains: substance use, injury/violence, mental health, and sexual health. Multivariable models were used to calculate adjusted prevalence ratios. Students who ever used synthetic cannabinoids had a significantly greater likelihood of engaging in each of the behaviors in the substance use and sexual risk domains compared with students who ever used marijuana only. Students who ever used synthetic cannabinoids were more likely than students who ever used marijuana only to have used marijuana before age 13 years, to have used marijuana ≥1 times during the past 30 days, and to have used marijuana ≥20 times during the past 30 days. Several injury/violence behaviors were more prevalent among students who ever used synthetic cannabinoids compared with students who ever used marijuana only. Health professionals and school-based substance use prevention programs should include strategies focused on the prevention of both synthetic cannabinoids and marijuana. Copyright © 2017 by the American Academy of Pediatrics.

  15. Cannabinoids and Dementia: A Review of Clinical and Preclinical Data

    OpenAIRE

    Michael Halpern; Sebastian Walther

    2010-01-01

    The endocannabinoid system has been shown to be associated with neurodegenerative diseases and dementia. We review the preclinical and clinical data on cannabinoids and four neurodegenerative diseases: Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD) and vascular dementia (VD). Numerous studies have demonstrated an involvement of the cannabinoid system in neurotransmission, neuropathology and neurobiology of dementias. In addition, several candidate compounds have...

  16. Tests for genetic interactions in type 1 diabetes

    DEFF Research Database (Denmark)

    Morahan, Grant; Mehta, Munish; James, Ian

    2011-01-01

    Interactions between genetic and environmental factors lead to immune dysregulation causing type 1 diabetes and other autoimmune disorders. Recently, many common genetic variants have been associated with type 1 diabetes risk, but each has modest individual effects. Familial clustering of type 1...

  17. IACM 2nd Conference on Cannabinoids in Medicine.

    Science.gov (United States)

    Grotenhermen, Franjo; Müller-Vahl, Kirsten

    2003-12-01

    The International Association for Cannabis as Medicine 2nd Conference on Cannabinoids in Medicine focused on new clinical research with cannabis and single cannabinoids (Delta(9)-tetrahydrocannabinol, CT-3) and on animal research with possible therapeutic implications. The meeting brought together basic researchers, clinicians and physicians to facilitate an exchange of knowledge and experience in this field. Even a talk by a patient with multiple sclerosis was included in a workshop on neurology. Current clinical research with cannabinoids focuses mainly on chronic pain and neurological disorders adding to accepted indications such as anorexia in AIDS-wasting and antiemetic effects in cancer chemotherapy. First results are promising and larger studies are underway or have recently been completed and are awaiting publication. New basic research opens further areas of possible uses for modulators of the endogenous cannabinoid system, including osteoporosis, cancer and inflammation. A workshop on psychiatry focused on effects of cannabis use on onset, incidence and the course of schizophrenia. Basic and clinical research shows that adolescents might be more vulnerable than adults to possible psychiatric effects of cannabinoids. It was concluded that possible side effects of cannabinoids should be taken into account but do not preclude a legitimate medical use.

  18. Synthetic cannabinoids: the hidden side of Spice drugs.

    Science.gov (United States)

    Pintori, Nicholas; Loi, Barbara; Mereu, Maddalena

    2017-09-01

    Spice drugs are herbal mixtures sprayed with synthetic cannabinoids designed to mimic the psychoactive ingredient in marijuana [Δ-tetrahydrocannabinol (Δ-THC)] and synthesized by introducing modifications to the chemical structure of parental compounds aiming to circumvent legal regulations. Synthetic cannabinoid use/abuse can be devastating as toxicological effects and adverse reactions cannot be entirely predicted and may vary with the dose, route of administration, individual vulnerability and concomitant intake with other drugs. The absence of validated testing procedures in the clinical field makes difficult the adoption of a therapeutic approach effective in coping with the synthetic cannabinoid phenomenon, posing a significant challenge for prevention, treatment and public health in general. The aim of this review is to gain insights into the epidemiological, pharmacological and toxicological properties of synthetic cannabinoids, aiming to provide a reliable background needed for the management of synthetic cannabinoid-related adverse effects. Consumers, competent authorities and medical care professionals should be aware of the risks associated with synthetic cannabinoid use.

  19. The influence of cannabinoids on generic traits of neurodegeneration.

    Science.gov (United States)

    Fagan, S G; Campbell, V A

    2014-03-01

    In an increasingly ageing population, the incidence of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease are rising. While the aetiologies of these disorders are different, a number of common mechanisms that underlie their neurodegenerative components have been elucidated; namely neuroinflammation, excitotoxicity, mitochondrial dysfunction and reduced trophic support. Current therapies focus on treatment of the symptoms and attempt to delay the progression of these diseases but there is currently no cure. Modulation of the endogenous cannabinoid system is emerging as a potentially viable option in the treatment of neurodegeneration. Endocannabinoid signalling has been found to be altered in many neurodegenerative disorders. To this end, pharmacological manipulation of the endogenous cannabinoid system, as well as application of phytocannabinoids and synthetic cannabinoids have been investigated. Signalling from the CB1 and CB2 receptors are known to be involved in the regulation of Ca(2+) homeostasis, mitochondrial function, trophic support and inflammatory status, respectively, while other receptors gated by cannabinoids such as PPARγ, are gaining interest in their anti-inflammatory properties. Through multiple lines of evidence, this evolutionarily conserved neurosignalling system has shown neuroprotective capabilities and is therefore a potential target for neurodegenerative disorders. This review details the mechanisms of neurodegeneration and highlights the beneficial effects of cannabinoid treatment. This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6. © 2013 The British Pharmacological Society.

  20. Differential role of cannabinoids in the pathogenesis of skin cancer.

    Science.gov (United States)

    Glodde, Nicole; Jakobs, Mira; Bald, Tobias; Tüting, Thomas; Gaffal, Evelyn

    2015-10-01

    Cannabinoids (CB) like ∆(9)-tetrahydrocannabinol (THC) can induce cancer cell apoptosis and inhibit angiogenesis. However, the use of cannabinoids for the treatment of malignant diseases is discussed controversially because of their immunomodulatory effects which can suppress anti-tumor immunity. Here we investigated the role of exogenous and endogenous cannabinoids in mouse skin cancer. First we examined the effect of THC, which binds to CB receptors (CB1, CB2), on the growth of the mouse melanoma cell lines B16 and HCmel12 in vitro and in vivo in wild type (WT) and CB1/CB2-receptor deficient mice (Cnr1/2(-/-)). Next we evaluated the role of the endogenous cannabinoid system by studying the growth of chemically induced melanomas, fibrosarcoma and papillomas in WT and Cnr1/2(-/-) mice. THC significantly inhibited tumor growth of transplanted HCmel12 melanomas in a CB receptor-dependent manner in vivo through antagonistic effects on its characteristic pro-inflammatory microenvironment. Chemically induced skin tumors developed in a similar manner in Cnr1/2(-/-) mice when compared to WT mice. Our results confirm the value of exogenous cannabinoids for the treatment of melanoma but do not support a role for the endogenous cannabinoid system in the pathogenesis of skin cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. [Different views on the association between cannabinoids and cancer].

    Science.gov (United States)

    Vidinský, B; Gál, P; Mojzis, J

    2006-01-01

    Cannabinoids are the major active components of the most widely used illegal drug - marihuana. They have a long history of the medicinal use. However, they are still a controversial topic in oncological praxis. Cannabinoids play a role in different organs of human body and they are an integral part of the newly described endocannabinoid system, which regulates several body functions. The important function of endocannabinoids which is related to cancer, is the regulation of cell cycle and cell survival pathways. Presented review gives three different views on the association between cannabinoids and cancer. First, the treatment of adverse symptoms of oncological therapy - nausea and vomiting inhibition, appetite stimulation, pain relieving, mood modulation and muscle stiffness relieving. Second, in the late 1990s, three possible mechanisms of antitumour action were identified - apoptosis induction, direct cell cycle arrest and angiogenesis and metastasis inhibition. The phase I/II of clinical trials are carrying out in Spain. They study effects of local administration of tetrahydrokanabinol on the growth of glioblastoma multiforme. Third, the results of the newest study focused on the association between cannabinoids use and cancer risk showed no significant association between increased cancer incidence and cannabinoids use and