High-Frequency Stimulation of the Subthalamic Nucleus Activates Motor Cortex Pyramidal Tract Neurons by a Process Involving Local Glutamate, GABA and Dopamine Receptors in Hemi-Parkinsonian Rats.

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Chuang, Chi-Fen; Wu, Chen-Wei; Weng, Ying; Hu, Pei-San; Yeh, Shin-Rung; Chang, Yen-Chung

2018-04-30

Deep brain stimulation (DBS) is widely used to treat advanced Parkinson’s disease (PD). Here, we investigated how DBS applied on the subthalamic nucleus (STN) influenced the neural activity in the motor cortex. Rats, which had the midbrain dopaminergic neurons partially depleted unilaterally, called the hemi-Parkinsonian rats, were used as a study model. c-Fos expression in the neurons was used as an indicator of neural activity. Application of high-frequency stimulation (HFS) upon the STN was used to mimic the DBS treatment. The motor cortices in the two hemispheres of hemi-Parkinsonian rats were found to contain unequal densities of c-Fos-positive (Fos+) cells, and STN-HFS rectified this bilateral imbalance. In addition, STN-HFS led to the intense c-Fos expression in a group of motor cortical neurons which exhibited biochemical and anatomical characteristics resembling those of the pyramidal tract (PT) neurons sending efferent projections to the STN. The number of PT neurons expressing high levels of c-Fos was significantly reduced by local application of the antagonists of non-N-methyl-D-aspartate (non-NMDA) glutamate receptors, gammaaminobutyric acid A (GABAA) receptors and dopamine receptors in the upper layers of the motor cortex. The results indicate that the coincident activations of synapses and dopamine receptors in the motor cortex during STN-HFS trigger the intense expression of c-Fos of the PT neurons. The implications of the results on the cellular mechanism underlying the therapeutic effects of STN-DBS on the movement disorders of PD are also discussed.

Fluvoxamine maleate effects on dopamine signaling in the prefrontal cortex of stressed Parkinsonian rats: Implications for learning and memory.

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Dallé, Ernest; Daniels, Willie M U; Mabandla, Musa V

2017-06-01

Parkinson's disease (PD) is also associated with cognitive impairment and reduced extrinsic supply of dopamine (DA) to the prefrontal cortex (PFC). In the present study, we looked at whether exposure to early life stress reduces DA and serotonin (5-HT) concentration in the PFC thus leading to enhanced cognitive impairment in a Parkinsonian rat model. Maternal separation was the stressor used to develop an animal model for early life stress that has chronic effects on brain and behavior. Sprague-Dawley rats were treated with the antidepressant Fluvoxamine maleate (FM) prior to a unilateral 6-hydroxydopamine (6-OHDA) lesion to model motor deficits in rats. The Morris water maze (MWM) and the forelimb use asymmetry (cylinder) tests were used to assess learning and memory impairment and motor deficits respectively. Blood plasma was used to measure corticosterone concentration and prefrontal tissue was collected for lipid peroxidation, DA, and 5-HT analysis. Our results show that animals exposed to early life stress displayed learning and memory impairment as well as elevated basal plasma corticosterone concentration which were attenuated by treatment with FM. A 6-OHDA lesion effect was evidenced by impairment in the cylinder test as well as decreased DA and 5-HT concentration in the PFC. These effects were attenuated by FM treatment resulting in higher DA concentration in the PFC of treated animals than in non-treated animals. This study suggests that DA and 5-HT signaling in the PFC are responsive to FM and may reduce stress-induced cognitive impairment in PD. Copyright © 2017. Published by Elsevier Inc.

Homologous Basal Ganglia Network Models in Physiological and Parkinsonian Conditions

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Jyotika Bahuguna

2017-08-01

Full Text Available The classical model of basal ganglia has been refined in recent years with discoveries of subpopulations within a nucleus and previously unknown projections. One such discovery is the presence of subpopulations of arkypallidal and prototypical neurons in external globus pallidus, which was previously considered to be a primarily homogeneous nucleus. Developing a computational model of these multiple interconnected nuclei is challenging, because the strengths of the connections are largely unknown. We therefore use a genetic algorithm to search for the unknown connectivity parameters in a firing rate model. We apply a binary cost function derived from empirical firing rate and phase relationship data for the physiological and Parkinsonian conditions. Our approach generates ensembles of over 1,000 configurations, or homologies, for each condition, with broad distributions for many of the parameter values and overlap between the two conditions. However, the resulting effective weights of connections from or to prototypical and arkypallidal neurons are consistent with the experimental data. We investigate the significance of the weight variability by manipulating the parameters individually and cumulatively, and conclude that the correlation observed between the parameters is necessary for generating the dynamics of the two conditions. We then investigate the response of the networks to a transient cortical stimulus, and demonstrate that networks classified as physiological effectively suppress activity in the internal globus pallidus, and are not susceptible to oscillations, whereas parkinsonian networks show the opposite tendency. Thus, we conclude that the rates and phase relationships observed in the globus pallidus are predictive of experimentally observed higher level dynamical features of the physiological and parkinsonian basal ganglia, and that the multiplicity of solutions generated by our method may well be indicative of a natural

Parkinsonian signs are a risk factor for falls.

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Dahodwala, Nabila; Nwadiogbu, Chinwe; Fitts, Whitney; Partridge, Helen; Karlawish, Jason

2017-06-01

Parkinsonian signs are common, non-specific findings in older adults and associated with increased rates of dementia and mortality. It is important to understand which motor outcomes are associated with parkinsonian signs. To determine the role of parkinsonian signs on fall rates among older adults. We conducted a longitudinal study of primary care patients from the University of Pennsylvania Health System. Adults over 55 years were assessed at baseline through surveys and a neurological examination. We recorded falls over the following 2 years. Parkinsonian signs were defined as the presence of 2 of 4 cardinal signs. Incident falls were compared between subjects with and without parkinsonian signs, and modified Poisson regression used to adjust for potential confounders in the relationship between parkinsonian signs and falls. 982 subjects with a mean age of 68 (s.d. 8.8) years participated. 29% of participants fell and 12% exhibited parkinsonian signs at baseline. The unadjusted RR for falls among individuals with parkinsonian signs was 1.36 (95% CI 1.05-1.76, p=0.02). After adjusting for age, cognitive function, urinary incontinence, depression, diabetes, stroke and arthritis, individuals with parkinsonian signs were still 38% more likely to fall than those without parkinsonian signs (RR 1.38, 95% CI 1.04-1.82; p=0.03). Falls among those with parkinsonian signs were more likely to lead to injury (53% vs 37%; p=0.04). Parkinsonian signs are a significant, independent risk factor for falls. Early detection of this clinical state is important in order to implement fall prevention programs among primary care patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Model-based iterative learning control of Parkinsonian state in thalamic relay neuron

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Liu, Chen; Wang, Jiang; Li, Huiyan; Xue, Zhiqin; Deng, Bin; Wei, Xile

2014-09-01

Although the beneficial effects of chronic deep brain stimulation on Parkinson's disease motor symptoms are now largely confirmed, the underlying mechanisms behind deep brain stimulation remain unclear and under debate. Hence, the selection of stimulation parameters is full of challenges. Additionally, due to the complexity of neural system, together with omnipresent noises, the accurate model of thalamic relay neuron is unknown. Thus, the iterative learning control of the thalamic relay neuron's Parkinsonian state based on various variables is presented. Combining the iterative learning control with typical proportional-integral control algorithm, a novel and efficient control strategy is proposed, which does not require any particular knowledge on the detailed physiological characteristics of cortico-basal ganglia-thalamocortical loop and can automatically adjust the stimulation parameters. Simulation results demonstrate the feasibility of the proposed control strategy to restore the fidelity of thalamic relay in the Parkinsonian condition. Furthermore, through changing the important parameter—the maximum ionic conductance densities of low-threshold calcium current, the dominant characteristic of the proposed method which is independent of the accurate model can be further verified.

Enkephalin and dynorphin neuropeptides are differently correlated with locomotor hypersensitivity and levodopa-induced dyskinesia in parkinsonian rats.

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Sgroi, Stefania; Capper-Loup, Christine; Paganetti, Paolo; Kaelin-Lang, Alain

2016-06-01

The opioidergic neuropeptides dynorphin (DYN) and enkephalin (ENK) and the D1 and D2 dopaminergic receptors (D1R, D2R) are involved in the striatal control of motor and behavioral function. In Parkinson's disease, motor disturbances such as "on-off" motor fluctuations and involuntary movements (dyskinesia) are severe complications that often arise after chronic l-dihydroxyphenylalanine (l-DOPA) treatment. Changes in the striatal expression of preproENK (PPENK), proDYN (PDYN), D1R, and D2R mRNA have been observed in parkinsonian animals treated with l-DOPA. Enhanced opioidergic transmission has been found in association with l-DOPA-induced dyskinesia, but the connection of PPENK, PDYN, D1R, and D2R mRNA expression with locomotor activity remains unclear. In this study, we measured PPENK, PDYN, D1R and D2R mRNA levels by in situ hybridization in the striatum of 6-OHDA hemi-parkinsonian rats treated with l-DOPA (PD+l-DOPA group), along with two control groups (PD+saline and naive+l-DOPA). We found different levels of expression of PPENK, PDYN, D1R and D2R mRNA across the experimental groups and correlated the changes in mRNA expression with dyskinesia and locomotor variables assessed by open field test during several phases of l-DOPA treatment. Both PDYN and PPENK mRNA levels were correlated with the severity of dyskinesia, while PPENK mRNA levels were also correlated with the frequency of contralateral rotational movements and with locomotor variables. Moreover, a strong correlation was found between D1R mRNA expression and D2R mRNA expression in the PD+l-DOPA group. These findings suggest that, in parkinsonian animals treated with l-DOPA, high levels of PPENK are a prerequisite for a locomotor sensitization to l-DOPA treatment, while PDYN overexpression is responsible only for the development of dyskinesia. Copyright © 2016 Elsevier Inc. All rights reserved.

Amniotic fluid stem cells with low γ-interferon response showed behavioral improvement in Parkinsonism rat model.

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Yu-Jen Chang

Full Text Available Amniotic fluid stem cells (AFSCs are multipotent stem cells that may be used in transplantation medicine. In this study, AFSCs established from amniocentesis were characterized on the basis of surface marker expression and differentiation potential. To further investigate the properties of AFSCs for translational applications, we examined the cell surface expression of human leukocyte antigens (HLA of these cells and estimated the therapeutic effect of AFSCs in parkinsonian rats. The expression profiles of HLA-II and transcription factors were compared between AFSCs and bone marrow-derived mesenchymal stem cells (BMMSCs following treatment with γ-IFN. We found that stimulation of AFSCs with γ-IFN prompted only a slight increase in the expression of HLA-Ia and HLA-E, and the rare HLA-II expression could also be observed in most AFSCs samples. Consequently, the expression of CIITA and RFX5 was weakly induced by γ-IFN stimulation of AFSCs compared to that of BMMSCs. In the transplantation test, Sprague Dawley rats with 6-hydroxydopamine lesioning of the substantia nigra were used as a parkinsonian-animal model. Following the negative γ-IFN response AFSCs injection, apomorphine-induced rotation was reduced by 75% in AFSCs engrafted parkinsonian rats but was increased by 53% in the control group after 12-weeks post-transplantation. The implanted AFSCs were viable, and were able to migrate into the brain's circuitry and express specific proteins of dopamine neurons, such as tyrosine hydroxylase and dopamine transporter. In conclusion, the relative insensitivity AFSCs to γ-IFN implies that AFSCs might have immune-tolerance in γ-IFN inflammatory conditions. Furthermore, the effective improvement of AFSCs transplantation for apomorphine-induced rotation paves the way for the clinical application in parkinsonian therapy.

The effect of anti-parkinsonian drugs on chlorpromazine-induced depression of operant behaviour.

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Székely, J I; Dunai-Kovács, Z; Borsy, J

1976-01-01

Rats were conditioned in automatic Skinner boxes on a discrete trial avoidance-escape schedule. The chlorpromazine-induced conditioned reflex inhibition could be reversed by apomorphine and amantadine, but not by atropine, trihexyphenidyl and diethazine. These findings seem to provide an additional tool for differentiating the atropine-like and dopaminergic anti-parkinsonian drugs.

From Parkinsonian thalamic activity to restoring thalamic relay using deep brain stimulation: new insights from computational modeling

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Meijer, H. G. E.; Krupa, M.; Cagnan, H.; Lourens, M. A. J.; Heida, T.; Martens, H. C. F.; Bour, L. J.; van Gils, S. A.

2011-10-01

We present a computational model of a thalamocortical relay neuron for exploring basal ganglia thalamocortical loop behavior in relation to Parkinson's disease and deep brain stimulation (DBS). Previous microelectrode, single-unit recording studies demonstrated that oscillatory interaction within and between basal ganglia nuclei is very often accompanied by synchronization at Parkinsonian rest tremor frequencies (3-10 Hz). These oscillations have a profound influence on thalamic projections and impair the thalamic relaying of cortical input by generating rebound action potentials. Our model describes convergent inhibitory input received from basal ganglia by the thalamocortical cells based on characteristics of normal activity, and/or low-frequency oscillations (activity associated with Parkinson's disease). In addition to simulated input, we also used microelectrode recordings as inputs for the model. In the resting state, and without additional sensorimotor input, pathological rebound activity is generated for even mild Parkinsonian input. We have found a specific stimulation window of amplitudes and frequencies for periodic input, which corresponds to high-frequency DBS, and which also suppresses rebound activity for mild and even more prominent Parkinsonian input. When low-frequency pathological rebound activity disables the thalamocortical cell's ability to relay excitatory cortical input, a stimulation signal with parameter settings corresponding to our stimulation window can restore the thalamocortical cell's relay functionality.

Mucuna pruriens seed extract reduces oxidative stress in nigrostriatal tissue and improves neurobehavioral activity in paraquat-induced Parkinsonian mouse model.

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Yadav, Satyndra Kumar; Prakash, Jay; Chouhan, Shikha; Singh, Surya Pratap

2013-06-01

Parkinson's disease (PD) is a neurodegenerative disease which causes rigidity, resting tremor and postural instability. Treatment for this disease is still under investigation. Mucuna pruriens (L.), is a traditional herbal medicine, used in India since 1500 B.C., as a neuroprotective agent. In this present study, we evaluated the therapeutic effects of aqueous extract of M. pruriens (Mp) seed in Parkinsonian mouse model developed by chronic exposure to paraquat (PQ). Results of our study revealed that the nigrostriatal portion of Parkinsonian mouse brain showed significantly increased levels of nitrite, malondialdehyde (MDA) and reduced levels of catalase compared to the control. In the Parkinsonian mice hanging time was decreased, whereas narrow beam walk time and foot printing errors were increased. Treatment with aqueous seed extract of Mp significantly increased the catalase activity and decreased the MDA and nitrite level, compared to untreated Parkinsonian mouse brain. Mp treatment also improved the behavioral abnormalities. It increased hanging time, whereas it decreased narrow beam walk time and foot printing error compared to untreated Parkinsonian mouse brain. Furthermore, we observed a significant reduction in tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra (SN) and striatum region of the brain, after treatment with PQ which was considerably restored by the use of Mp seed extract. Our result suggested that Mp seed extract treatment significantly reduced the PQ induced neurotoxicity as evident by decrease in oxidative damage, physiological abnormalities and immunohistochemical changes in the Parkinsonian mouse. Copyright © 2013 Elsevier Ltd. All rights reserved.

The network of causal interactions for beta oscillations in the pedunculopontine nucleus, primary motor cortex, and subthalamic nucleus of walking parkinsonian rats.

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Li, Min; Zhou, Ming; Wen, Peng; Wang, Qiang; Yang, Yong; Xiao, Hu; Xie, Zhengyuan; Li, Xing; Wang, Ning; Wang, Jinyan; Luo, Fei; Chang, Jingyu; Zhang, Wangming

2016-08-01

Oscillatory activity has been well-studied in many structures within cortico-basal ganglia circuits, but it is not well understood within the pedunculopontine nucleus (PPN), which was recently introduced as a potential target for the treatment of gait and postural impairments in advanced stages of Parkinson's disease (PD). To investigate oscillatory activity in the PPN and its relationship with oscillatory activity in cortico-basal ganglia circuits, we simultaneously recorded local field potentials in the PPN, primary motor cortex (M1), and subthalamic nucleus (STN) of 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian rats during resting and walking. After analysis of power spectral density, coherence, and partial Granger causality, three major findings emerged: 1) after 6-OHDA lesions, beta band oscillations were enhanced in all three regions during walking; 2) the direction of information flow for beta oscillations among the three structures was STN→M1, STN→PPN, and PPN→M1; 3) after the treatment of levodopa, beta activity in the three regions was reduced significantly and the flow of beta band was also abrogated. Our results suggest that beta activity in the PPN is transmitted from the basal ganglia and probably comes from the STN, and the STN plays a dominant role in the network of causal interactions for beta activity. Thus, the STN may be a potential source of aberrant beta band oscillations in PD. Levodopa can inhibit beta activity in the PPN of parkinsonian rats but cannot relieve parkinsonian patients' axial symptoms clinically. Therefore, beta oscillations may not be the major cause of axial symptoms. Copyright © 2016 Elsevier Inc. All rights reserved.

Diagnosis of Parkinsonian disorders using a channelized Hotelling observer model: Proof of principle

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Bal, H.; Bal, G.; Acton, P. D.

2007-01-01

Imaging dopamine transporters using PET and SPECT probes is a powerful technique for the early diagnosis of Parkinsonian disorders. In order to perform automated accurate diagnosis of these diseases, a channelized Hotelling observer (CHO) based model was developed and evaluated using the SPECT tracer [Tc-99m]TRODAT-1. Computer simulations were performed using a digitized striatal phantom to characterize early stages of the disease (20 lesion-present cases with varying lesion size and contrast). Projection data, modeling the effects of attenuation and geometric response function, were obtained for each case. Statistical noise levels corresponding to those observed clinically were added to the projection data to obtain 100 noise realizations for each case. All the projection data were reconstructed, and a subset of the transaxial slices containing the striatum was summed and used for further analysis. CHO models, using the Laguerre-Gaussian functions as channels, were designed for two cases: (1) By training the model using individual lesion-present samples and (2) by training the model using pooled lesion-present samples. A decision threshold obtained for each CHO model was used to classify the study population (n=40). It was observed that individual lesion trained CHO models gave high diagnostic accuracy for lesions that were larger than those used to train the model and vice-versa. On the other hand, the pooled CHO model was found to give a high diagnostic accuracy for all the lesion cases (average diagnostic accuracy=0.95±0.07; p<0.0001 Fisher's exact test). Based on our results, we conclude that a CHO model has the potential to provide early and accurate diagnosis of Parkinsonian disorders, thereby improving patient management

The phenomenology of parkinsonian tremor.

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Deuschl, Günther; Papengut, Frank; Hellriegel, Helge

2012-01-01

The definition of Parkinsonian tremor covers all different forms occurring in Parkinson's disease. The most common form is rest tremor, labelled as typical Parkinsonian tremor. Other variants cover also postural and action tremors. Data support the notion that suppression of rest tremor may be more specific for PD tremors. Several differential diagnoses like rest tremor in ET, dystonic tremor, psychogenic tremor and Holmes' tremor may be misinterpreted as PD-tremor. Tests and clinical clues to separate them are presented. Copyright © 2011 Elsevier Ltd. All rights reserved.

Analysis of glottal source parameters in Parkinsonian speech.

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Hanratty, Jane; Deegan, Catherine; Walsh, Mary; Kirkpatrick, Barry

2016-08-01

Diagnosis and monitoring of Parkinson's disease has a number of challenges as there is no definitive biomarker despite the broad range of symptoms. Research is ongoing to produce objective measures that can either diagnose Parkinson's or act as an objective decision support tool. Recent research on speech based measures have demonstrated promising results. This study aims to investigate the characteristics of the glottal source signal in Parkinsonian speech. An experiment is conducted in which a selection of glottal parameters are tested for their ability to discriminate between healthy and Parkinsonian speech. Results for each glottal parameter are presented for a database of 50 healthy speakers and a database of 16 speakers with Parkinsonian speech symptoms. Receiver operating characteristic (ROC) curves were employed to analyse the results and the area under the ROC curve (AUC) values were used to quantify the performance of each glottal parameter. The results indicate that glottal parameters can be used to discriminate between healthy and Parkinsonian speech, although results varied for each parameter tested. For the task of separating healthy and Parkinsonian speech, 2 out of the 7 glottal parameters tested produced AUC values of over 0.9.

Correlation between cortical beta power and gait speed is suppressed in a parkinsonian model, but restored by therapeutic deep brain stimulation.

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Polar, Christian A; Gupta, Rahul; Lehmkuhle, Mark J; Dorval, Alan D

2018-05-30

The motor cortex and subthalamic nucleus (STN) of patients with Parkinson's disease (PD) exhibit abnormally high levels of electrophysiological oscillations in the ~12-35 Hz beta-frequency range. Recent studies have shown that beta is partly carried forward to regulate future motor states in the healthy condition, suggesting that steady state beta power is lower when a sequence of movements occurs in a short period of time, such as during fast gait. However, whether this relationship between beta power and motor states persists upon parkinsonian onset or in response to effective therapy is unclear. Using a 6-hydroxy dopamine (6-OHDA) rat model of PD and a custom-built behavioral and neurophysiological recording system, we aimed to elucidate a better understanding of the mechanisms underlying cortical beta power and PD symptoms. In addition to elevated levels of beta oscillations, we show that parkinsonian onset was accompanied by a decoupling of movement intensity - quantified as gait speed - from cortical beta power. Although subthalamic deep brain stimulation (DBS) reduced general levels of beta oscillations in the cortex of all PD animals, the brain's capacity to regulate steady state levels of beta power as a function of movement intensity was only restored in animals with therapeutic DBS. We propose that, in addition to lowering general levels of cortical beta power, restoring the brain's ability to maintain this inverse relationship is critical for effective symptom suppression. Copyright © 2017. Published by Elsevier Inc.

Parkinsonian syndroms: Clinical phenotype, differential diagnosis and disease progression

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Storch, A.

2002-01-01

Parkinsonian syndromes include idiopathic Parkinson's disease (IPD), other neurodegenerative diseases with parkinsonism, the so-called atypical parkinsonian syndromes, and symptomatic parkinsonian syndromes, such as Wilson's disease. IPD is the most frequent disease with parkinsonism as the main clinical feature and is responsible for approx. 80% of all parkinsonian syndromes. Atypical parkinsonian syndromes are the most important differential diagnoses of IPD. The two most frequent types are multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). For clinical diagnosis it is essential to take a careful medical history and to examine the patients physically in regular intervals. However, various clinico-pathological studies have shown that approx. 25% of patients with clinical diagnosis of IPD may have other causes of parkinsonism. Selected technical investigations, in particular functional imaging of the central dopaminergic system using PET or SPECT, may help to make clinical diagnosis more secure. This paper reviews the clinical features and diagnostic findings in diseases with parkinsonism and summarises the difficulties in establishing early and differential diagnoses. (orig.) [de

Deep brain stimulation of the center median-parafascicular complex of the thalamus has efficient anti-parkinsonian action associated with widespread cellular responses in the basal ganglia network in a rat model of Parkinson's disease.

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Jouve, Loréline; Salin, Pascal; Melon, Christophe; Kerkerian-Le Goff, Lydia

2010-07-21

The thalamic centromedian-parafascicular (CM/Pf) complex, mainly represented by Pf in rodents, is proposed as an interesting target for the neurosurgical treatment of movement disorders, including Parkinson's disease. In this study, we examined the functional impact of subchronic high-frequency stimulation (HFS) of Pf in the 6-hydroxydopamine-lesioned hemiparkinsonian rat model. Pf-HFS had significant anti-akinetic action, evidenced by alleviation of limb use asymmetry (cylinder test). Whereas this anti-akinetic action was moderate, Pf-HFS totally reversed lateralized neglect (corridor task), suggesting potent action on sensorimotor integration. At the cellular level, Pf-HFS partially reversed the dopamine denervation-induced increase in striatal preproenkephalin A mRNA levels, a marker of the neurons of the indirect pathway, without interfering with the markers of the direct pathway (preprotachykinin and preprodynorphin). Pf-HFS totally reversed the lesion-induced changes in the gene expression of cytochrome oxidase subunit I in the subthalamic nucleus, the globus pallidus, and the substantia nigra pars reticulata, and partially in the entopeduncular nucleus. Unlike HFS of the subthalamic nucleus, Pf-HFS did not induce per se dyskinesias and directly, although partially, alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced forelimb dyskinesia. Conversely, L-DOPA treatment negatively interfered with the anti-parkinsonian effect of Pf-HFS. Altogether, these data show that Pf-DBS, by recruiting a large basal ganglia circuitry, provides moderate to strong anti-parkinsonian benefits that might, however, be affected by L-DOPA. The widespread behavioral and cellular outcomes of Pf-HFS evidenced here demonstrate that CM/Pf is an important node for modulating the pathophysiological functioning of basal ganglia and related disorders.

Dopamine receptors in the Parkinsonian brain

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Rinne, U K; Loennberg, P; Koskinen, V [Turku Univ. (Finland). Dept. of Neurology

1981-01-01

Striatal dopamine receptors were studied in 44 patients with Parkinson disease by the radioligand-binding technique using /sup 3/H-spiroperidol. The specific binding of /sup 3/H-spiroperidol was either significantly increased or reduced in the caudate nucleus and putamen of parkinsonian patients without levodopa therapy. Scatchard analysis showed that there were corresponding changes in the receptor number, but no significant changes in the mean dissociation constant. The increased binding of /sup 3/H-spiroperidol in the basal ganglia was also found in parkinsonian patients suffering from psychotic episodes and treated with neuroleptic drugs. Normal and low binding of /sup 3/H-spiroperidol was found in patients treated with levodopa. Clinically, the patient with low binding were more disabled and had lost the beneficial response to levodopa. Thus in Parkinson disease in some patients a denervation supersensitivity seemed to develop and in some others a loss of postsynaptic dopamine receptor sites in the neostriatium. The latter alteration may contribute to the decreased response of parkinsonian patients to chronic levodopa therapy.

Dopamine receptors in the Parkinsonian brain

International Nuclear Information System (INIS)

Rinne, U.K.; Loennberg, P.; Koskinen, V.

1981-01-01

Striatal dopamine receptors were studied in 44 patients with Parkinson disease by the radioligand-binding technique using 3 H-spiroperidol. The specific binding of 3 H-spiroperidol was either significantly increased or reduced in the caudate nucleus and putamen of parkinsonian patients without levodopa therapy. Scatchard analysis showed that there were corresponding changes in the receptor number, but no significant changes in the mean dissociation constant. The increased binding of 3 H-spiroperidol in the basal ganglia was also found in parkinsonian patients suffering from psychotic episodes and treated with neuroleptic drugs. Normal and low binding of 3 H-spiroperidol was found in patients treated with levodopa. Clinically, the patient with low binding were more disabled and had lost the beneficial response to levodopa. Thus in Parkinson disease in some patients a denervation supersensitivity seemed to develop and in some others a loss of postsynaptic dopamine receptor sites in the neostriatium. The latter alteration may contribute to the decreased response of parkinsonian patients to chronic levodopa therapy. (author)

Associations between quantitative mobility measures derived from components of conventional mobility testing and Parkinsonian gait in older adults.

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Aron S Buchman

Full Text Available OBJECTIVE: To provide objective measures which characterize mobility in older adults assessed in the community setting and to examine the extent to which these measures are associated with parkinsonian gait. METHODS: During conventional mobility testing in the community-setting, 351 ambulatory non-demented Memory and Aging Project participants wore a belt with a whole body sensor that recorded both acceleration and angular velocity in 3 directions. We used measures derived from these recordings to quantify 5 subtasks including a walking, b transition from sit to stand, c transition from stand to sit, d turning and e standing posture. Parkinsonian gait and other mild parkinsonian signs were assessed with a modified version of the original Unified Parkinson's Disease Rating Scale (mUPDRS. RESULTS: In a series of separate regression models which adjusted for age and sex, all 5 mobility subtask measures were associated with parkinsonian gait and accounted for 2% to 32% of its variance. When all 5 subtask measures were considered in a single model, backward elimination showed that measures of walking sit to stand and turning showed independent associations with parkinsonian gait and together accounted for more than 35% of its variance. Cross-validation using data from a 2(nd group of 258 older adults showed similar results. In similar analyses, only walking was associated with bradykinesia and sway with tremor. INTERPRETATION: Quantitative mobility subtask measures vary in their associations with parkinsonian gait scores and other parkinsonian signs in older adults. Quantifying the different facets of mobility has the potential to facilitate the clinical characterization and understanding the biologic basis for impaired mobility in older adults.

Associations between Quantitative Mobility Measures Derived from Components of Conventional Mobility Testing and Parkinsonian Gait in Older Adults

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Buchman, Aron S.; Leurgans, Sue E.; Weiss, Aner; VanderHorst, Veronique; Mirelman, Anat; Dawe, Robert; Barnes, Lisa L.; Wilson, Robert S.; Hausdorff, Jeffrey M.; Bennett, David A.

2014-01-01

Objective To provide objective measures which characterize mobility in older adults assessed in the community setting and to examine the extent to which these measures are associated with parkinsonian gait. Methods During conventional mobility testing in the community-setting, 351 ambulatory non-demented Memory and Aging Project participants wore a belt with a whole body sensor that recorded both acceleration and angular velocity in 3 directions. We used measures derived from these recordings to quantify 5 subtasks including a) walking, b) transition from sit to stand, c) transition from stand to sit, d) turning and e) standing posture. Parkinsonian gait and other mild parkinsonian signs were assessed with a modified version of the original Unified Parkinson’s Disease Rating Scale (mUPDRS). Results In a series of separate regression models which adjusted for age and sex, all 5 mobility subtask measures were associated with parkinsonian gait and accounted for 2% to 32% of its variance. When all 5 subtask measures were considered in a single model, backward elimination showed that measures of walking sit to stand and turning showed independent associations with parkinsonian gait and together accounted for more than 35% of its variance. Cross-validation using data from a 2nd group of 258 older adults showed similar results. In similar analyses, only walking was associated with bradykinesia and sway with tremor. Interpretation Quantitative mobility subtask measures vary in their associations with parkinsonian gait scores and other parkinsonian signs in older adults. Quantifying the different facets of mobility has the potential to facilitate the clinical characterization and understanding the biologic basis for impaired mobility in older adults. PMID:24465997

Modulating basal ganglia and cerebellar activity to suppress parkinsonian tremor

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Heida, Tjitske; Zhao, Yan; van Wezel, Richard Jack Anton

2013-01-01

Despite extensive research, the detailed pathophysiology of the parkinsonian tremor is still unknown. It has been hypothesized that the generation of parkinsonian tremor is related to abnormal activity within the basal ganglia. The cerebello-thalamic-cortical loop has been suggested to indirectly

Iron and cell death in Parkinson's disease: a nuclear microscopic study into iron-rich granules in the parkinsonian substantia nigra of primate models

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Thong, P.S.P.; Watt, F. E-mail: phywattf@nus.edu.sg; Ponraj, D.; Leong, S.K.; He, Y.; Lee, T.K.Y

1999-09-02

Parkinson's disease is a degenerative brain disease characterised by a loss of cells in the substantia nigra (SN) region of the brain and accompanying biochemical changes such as inhibition of mitochondrial function, increased iron concentrations and decreased glutathione levels in the parkinsonian SN. Though the aetiology of the disease is still unknown, the observed biochemical changes point to the involvement of oxidative stress. In particular, iron is suspected to play a role by promoting free radical production, leading to oxidative stress and cell death. The increase in iron in the parkinsonian SN has been confirmed by several research groups, both in human post-mortem brains and in brain tissue from parkinsonian animal models. However, the question remains as to whether the observed increase in iron is a cause or a consequence of the SN cell death process. Our previous study using unilaterally 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)-lesioned monkeys in a time sequence experiment has shown that the increase in bulk iron concentrations follow rather than precede dopaminergic cell death. However, changes in the localised iron concentrations, which may play a more direct role in SN cell death, may not be reflected at the bulk level. Indeed, we have observed iron-rich granules in parkinsonian SNs. From this time sequence study into the iron content of iron-rich granules in the SNs of an untreated control and unilaterally MPTP-lesioned parkinsonian models, we present the following observations: (1) Iron-rich granules are found in both control and parkinsonian SNs and are variable in size and iron content in any one model. (2) These iron-rich granules may be associated with neuromelanin granules found in the SN and are known to accumulate transition metal ions such as iron. (3) The early onset of bulk SN cell loss (35%) was accompanied by a significant elevation of iron in granules found in the MPTP-injected SN compared to the contra-lateral SN

Differential Diagnosis Tool for Parkinsonian Syndrome Using Multiple Structural Brain Measures

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Miho Ota

2013-01-01

Full Text Available Clinical differentiation of parkinsonian syndromes such as the Parkinson variant of multiple system atrophy (MSA-P and cerebellar subtype (MSA-C from Parkinson's disease is difficult in the early stage of the disease. To identify the correlative pattern of brain changes for differentiating parkinsonian syndromes, we applied discriminant analysis techniques by magnetic resonance imaging (MRI. T1-weighted volume data and diffusion tensor images were obtained by MRI in eighteen patients with MSA-C, 12 patients with MSA-P, 21 patients with Parkinson’s disease, and 21 healthy controls. They were evaluated using voxel-based morphometry and tract-based spatial statistics, respectively. Discriminant functions derived by step wise methods resulted in correct classification rates of 0.89. When differentiating these diseases with the use of three independent variables together, the correct classification rate was the same as that obtained with step wise methods. These findings support the view that each parkinsonian syndrome has structural deviations in multiple brain areas and that a combination of structural brain measures can help to distinguish parkinsonian syndromes.

Neuronal Entropy-Rate Feature of Entopeduncular Nucleus in Rat Model of Parkinson's Disease.

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Darbin, Olivier; Jin, Xingxing; Von Wrangel, Christof; Schwabe, Kerstin; Nambu, Atsushi; Naritoku, Dean K; Krauss, Joachim K; Alam, Mesbah

2016-03-01

The function of the nigro-striatal pathway on neuronal entropy in the basal ganglia (BG) output nucleus, i.e. the entopeduncular nucleus (EPN) was investigated in the unilaterally 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD). In both control subjects and subjects with 6-OHDA lesion of dopamine (DA) the nigro-striatal pathway, a histological hallmark for parkinsonism, neuronal entropy in EPN was maximal in neurons with firing rates ranging between 15 and 25 Hz. In 6-OHDA lesioned rats, neuronal entropy in the EPN was specifically higher in neurons with firing rates above 25 Hz. Our data establishes that the nigro-striatal pathway controls neuronal entropy in motor circuitry and that the parkinsonian condition is associated with abnormal relationship between firing rate and neuronal entropy in BG output nuclei. The neuronal firing rates and entropy relationship provide putative relevant electrophysiological information to investigate the sensory-motor processing in normal condition and conditions such as movement disorders.

Assessing bradykinesia in Parkinsonian disorders

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Gian ePal

2013-06-01

Full Text Available Objective: Bradykinesia is one of the clinical hallmarks of Parkinson’s disease (PD and atypical Parkinsonian syndromes. Clinical ratings scales and technology based assessments have been developed to measure bradykinesia. We review the different tools that exist for measurement of bradykinesia and analyze their reliability and applicability to PD and atypical Parkinsonian syndromes.Methods: We summarize data on the factor structure of the two primary scales used to assess PD, the Unified Parkinson’s Disease Rating Scale (UPDRS and Movement Disorder Society revision of the UPDRS, the MDS-UPDRS. We review how these scales have been used in atypical Parkinsonian syndromes, specifically Progressive Supranuclear Palsy (PSP. Finally, we report on the different technology based tools being used to assess bradykinesia. Results: The UPDRS is a useful measure of PD function and disability with 6 clinically distinct factors, 3 of which pertain to bradykinesia. The MDS-UPDRS has shown high internal consistency and correlation with the original UPDRS. Factor analysis of the UPDRS in PSP reveals 5 clinically distinct factors, 2 of which are independent bradykinesia factors. Thus the UPDRS and MDS-UPDRS are reliable and applicable scales for PD and the UPDRS can be used to assess bradykinesia in PSP. Technology based tools for measuring bradykinesia include gyrosensors, Coordination Ability Test System, Brain Test, quantitative digitography, Motus motion analysis system, PRIMAS, and the At-Home Testing Device. These tools have been compared to the UPDRS motor subscale and are effective in assessing bradykinesia.Conclusion: The UPDRS and MDS-UPDRS are well-established measures of bradykinesia that are applicable and useful in PD. The UPDRS is also been shown to be applicable to PSP. Different technologies exist to measure bradykinesia, though further work is needed to validate these assessment tools and bring them to clinical practice.

Effects of glutamate and α2-noradrenergic receptor antagonists on the development of neurotoxicity produced by chronic rotenone in rats

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Alam, Mesbah; Danysz, Wojciech; Schmidt, Werner Juergen; Dekundy, Andrzej

2009-01-01

Systemic inhibition of complex I by rotenone in rats represents a model of Parkinson's disease (PD). The aim of this study was to elucidate whether neramexane (NMDA, nicotinic α9/α10 and 5-HT 3 receptor antagonist), idazoxan (α 2 -adrenoceptor antagonist) or 2-methyl-6-(phenyl-ethyl)-pyrimidine (MPEP, metabotropic glutamate receptor 5 antagonist) prevents rotenone-induced parkinsonian-like behaviours and neurochemical changes in rats. Rotenone (2.5 mg/kg i.p. daily) was administered over 60 days together with saline, neramexane (5 mg/kg i.p., b.i.d.), idazoxan (2.5 mg/kg i.p., b.i.d.) or MPEP (2.5 mg/kg i.p., b.i.d.). The same doses of neramexane, idazoxan and MPEP were administered to rats treated with vehicle instead of rotenone. Treatment-related effects on parkinsonian-like behaviours, such as hypokinesia/rigidity and locomotor activity, were evaluated. Moreover, concentrations of dopamine, serotonin and their metabolites were measured in rats from each experimental group. Over the 60-day treatment period, the rotenone + saline treated animals developed hypokinesia, expressed as an increase in the bar and grid descent latencies in the catalepsy test, and a decrease in locomotor activity. Neramexane and idazoxan partially prevented the development of catalepsy in rotenone-treated rats. Co-administration of MPEP with rotenone resulted only in a decrease in descent latency in the grid test on day 60. Chronic rotenone treatment reduced concentrations of dopamine and serotonin in the anterior striatum, which was blocked by co-treatment with neramexane or idazoxan but not with MPEP. Only neramexane treatment blocked the rotenone-induced decrease in dopamine levels in the substantia nigra pars compacta. In conclusion, neramexane and idazoxan counteracted to some extent the development of parkinsonian symptoms and neurochemical alterations in the rotenone model of Parkinson's disease.

Pneumophonic coordination impairments in parkinsonian dysarthria: importance of aerodynamic parameters measurements.

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Moustapha, S M; Alain, G; Robert, E; Bernard, T; Mourtalla, Kâ M; Lamine, G; François, V

2012-01-01

Among Parkinsonian axial signs, dysarthria represents an important disabling symptom able to lead towards a significant reduction of oral communication. Several methods of dysarthria assessment have been used but aerodynamic evaluation is rare in the literature. To highlight the importance of aerodynamic parameters measurements in assessment of parkinsonian dysarthria. Using a dedicated system (EVA2), 24 parkinsonian patients were recorded after withdrawal of L-dopa for at least 12 h (condition called OFF DOPA) in order to evaluate intra-oral pressure (IOP), mean oral air flow (MOAF) and laryngeal resistance (LR) on six /p/ during realization of the sentence "Papa ne m'a pas parle' de beau-papa" ("Daddy did not speak to me about daddy-in-law") which corresponds to a breath group. 50 control subjects were recorded in parallel in order to define reference measurements. It appeared that there is in Parkinson's disease aerodynamic impairments which were evidenced by the fall in IOP and that of MOAF in patients compared with control subjects. The difference between the two groups was statistically significant. In addition a greater instability of LR in patients compared with control subjects was also noted. Our results show that measurements of aerodynamics parameters, by reflecting the dysfunction induced by disease, may well be relevant factors in parkinsonian dysarthria evaluation.

A subpopulation of dopaminergic neurons co-expresses serotonin in ventral mesencephalic cultures but not after intrastriatal transplantation in a rat model of Parkinsons disease

DEFF Research Database (Denmark)

Di Santo, Stefano; Seiler, Stefanie; Ducray, Angélique

2017-01-01

Cell replacement therapy is a promising avenue into the investigation and treatment of Parkinson’s disease (PD) and in some cases significant long-term motor improvements have been demonstrated. The main source of donor tissue is the human fetal ventral mesencephalon (VM), which consists...... 30% of the dopaminergic neurons in the donor tissue co-expressed serotonin, no co-localization could be detected in grafts one month after intrastriatal transplantation into hemi-parkinsonian rats. In conclusion, a significant and susceptible sub-population of dopaminergic neurons in fetal VM tissues...... both fetal rat and human dissociated, organotypic and neurosphere VM cultures as well as an animal model of PD were investigated. In dissociated rat VM cultures approximately 30% of the TH positive neurons co-expressed serotonin, while no co-localization with GABA was observed. Interestingly, co...

Effect of speech therapy and pharmacological treatment in prosody of parkinsonians

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Luciana Lemos de Azevedo

2015-01-01

Full Text Available Objective Parkinsonian patients usually present speech impairment. The aim of this study was to verify the influence of levodopa and of the adapted Lee Silverman Vocal Treatment® method on prosodic parameters employed by parkinsonian patients. Method Ten patients with idiopathic Parkinson's disease using levodopa underwent recording of utterances produced in four stages: expressing attitudes of certainty and doubt and declarative and interrogative modalities. The sentences were recorded under the effect of levodopa (on, without the effect of levodopa (off; before and after speech therapy during the on and off periods. Results The speech therapy and its association with drug treatment promoted the improvement of prosodic parameters: increase of fundamental frequency measures, reduction of measures of duration and greater intensity. Conclusion The association of speech therapy to medication treatment is of great value in improving the communication of parkinsonian patients.

The nature of tremor circuits in parkinsonian and essential tremor

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Cagnan, Hayriye; Little, Simon; Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic; Hariz, Marwan; Cheeran, Binith; Fitzgerald, James; Green, Alexander L.; Aziz, Tipu

2014-01-01

Tremor is a cardinal feature of Parkinson’s disease and essential tremor, the two most common movement disorders. Yet, the mechanisms underlying tremor generation remain largely unknown. We hypothesized that driving deep brain stimulation electrodes at a frequency closely matching the patient’s own tremor frequency should interact with neural activity responsible for tremor, and that the effect of stimulation on tremor should reveal the role of different deep brain stimulation targets in tremor generation. Moreover, tremor responses to stimulation might reveal pathophysiological differences between parkinsonian and essential tremor circuits. Accordingly, we stimulated 15 patients with Parkinson’s disease with either thalamic or subthalamic electrodes (13 male and two female patients, age: 50–77 years) and 10 patients with essential tremor with thalamic electrodes (nine male and one female patients, age: 34–74 years). Stimulation at near-to tremor frequency entrained tremor in all three patient groups (ventrolateral thalamic stimulation in Parkinson’s disease, P = 0.0078, subthalamic stimulation in Parkinson’s disease, P = 0.0312; ventrolateral thalamic stimulation in essential tremor, P = 0.0137; two-tailed paired Wilcoxon signed-rank tests). However, only ventrolateral thalamic stimulation in essential tremor modulated postural tremor amplitude according to the timing of stimulation pulses with respect to the tremor cycle (e.g. P = 0.0002 for tremor amplification, two-tailed Wilcoxon rank sum test). Parkinsonian rest and essential postural tremor severity (i.e. tremor amplitude) differed in their relative tolerance to spontaneous changes in tremor frequency when stimulation was not applied. Specifically, the amplitude of parkinsonian rest tremor remained unchanged despite spontaneous changes in tremor frequency, whereas that of essential postural tremor reduced when tremor frequency departed from median values. Based on these results we conclude that

The emergence of two anti-phase oscillatory neural populations in a computational model of the Parkinsonian globus pallidus

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Robert John Merrison-Hort

2013-12-01

Full Text Available Experiments in rodent models of Parkinson's Disease have demonstrated a prominent increase of oscillatory firing patterns in neurons within the Parkinsonian globus pallidus (GP which may underlie some of the motor symptoms of the disease. There are two main pathways from the cortex to GP: via the striatum and via the subthalamic nucleus (STN, but it is not known how these inputs sculpt the pathological pallidal firing patterns. To study this we developed a novel neural network model of conductance-based spiking pallidal neurons with cortex-modulated input from STN neurons. Our results support the hypothesis that entrainment occurs primarily via the subthalamic pathway. We find that as a result of the interplay between excitatory input from the STN and mutual inhibitory coupling between GP neurons, a homogeneous population of GP neurons demonstrates a self-organising dynamical behaviour where two groups of neurons emerge: one spiking in-phase with the cortical rhythm and the other in anti-phase. This finding mirrors what is seen in recordings from the GP of rodents that have had Parkinsonism induced via brain lesions. Our model also includes downregulation of Hyperpolarization-activated Cyclic Nucleotide-gated (HCN channels in response to burst firing of GP neurons, since this has been suggested as a possible mechanism for the emergence of Parkinsonian activity. We found that the downregulation of HCN channels provides even better correspondence with experimental data but that it is not essential in order for the two groups of oscillatory neurons to appear. We discuss how the influence of inhibitory striatal input will strengthen our results.

Pneumophonic Coordination Impairments in Parkinsonian Dysarthria

African Journals Online (AJOL)

Patients and Methods: Using a dedicated system (EVA2), 24 parkinsonian patients were recorded after withdrawal of Ldopa for at least 12 h (condition called OFF DOPA) in order to evaluate intra-oral pressure (IOP), mean oral air flow (MOAF) and laryngeal resistance (LR) on six /p/ during realization of the sentence ''Papa ...

Development of a unilaterally-lesioned 6-OHDA mouse model of Parkinson's disease.

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Thiele, Sherri L; Warre, Ruth; Nash, Joanne E

2012-02-14

The unilaterally lesioned 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD) has proved to be invaluable in advancing our understanding of the mechanisms underlying parkinsonian symptoms, since it recapitulates the changes in basal ganglia circuitry and pharmacology observed in parkinsonian patients(1-4). However, the precise cellular and molecular changes occurring at cortico-striatal synapses of the output pathways within the striatum, which is the major input region of the basal ganglia remain elusive, and this is believed to be site where pathological abnormalities underlying parkinsonian symptoms arise(3,5). In PD, understanding the mechanisms underlying changes in basal ganglia circuitry following degeneration of the nigro-striatal pathway has been greatly advanced by the development of bacterial artificial chromosome (BAC) mice over-expressing green fluorescent proteins driven by promoters specific for the two striatal output pathways (direct pathway: eGFP-D1; indirect pathway: eGFP-D2 and eGFP-A2a)(8), allowing them to be studied in isolation. For example, recent studies have suggested that there are pathological changes in synaptic plasticity in parkinsonian mice(9,10). However, these studies utilised juvenile mice and acute models of parkinsonism. It is unclear whether the changes described in adult rats with stable 6-OHDA lesions also occur in these models. Other groups have attempted to generate a stable unilaterally-lesioned 6-OHDA adult mouse model of PD by lesioning the medial forebrain bundle (MFB), unfortunately, the mortality rate in this study was extremely high, with only 14% surviving the surgery for 21 days or longer(11). More recent studies have generated intra-nigral lesions with both a low mortality rate >80% loss of dopaminergic neurons, however expression of L-DOPA induced dyskinesia(11,12,13,14) was variable in these studies. Another well established mouse model of PD is the MPTP-lesioned mouse(15). Whilst this

A biophysical model of the cortex-basal ganglia-thalamus network in the 6-OHDA lesioned rat model of Parkinson's disease.

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Kumaravelu, Karthik; Brocker, David T; Grill, Warren M

2016-04-01

Electrical stimulation of sub-cortical brain regions (the basal ganglia), known as deep brain stimulation (DBS), is an effective treatment for Parkinson's disease (PD). Chronic high frequency (HF) DBS in the subthalamic nucleus (STN) or globus pallidus interna (GPi) reduces motor symptoms including bradykinesia and tremor in patients with PD, but the therapeutic mechanisms of DBS are not fully understood. We developed a biophysical network model comprising of the closed loop cortical-basal ganglia-thalamus circuit representing the healthy and parkinsonian rat brain. The network properties of the model were validated by comparing responses evoked in basal ganglia (BG) nuclei by cortical (CTX) stimulation to published experimental results. A key emergent property of the model was generation of low-frequency network oscillations. Consistent with their putative pathological role, low-frequency oscillations in model BG neurons were exaggerated in the parkinsonian state compared to the healthy condition. We used the model to quantify the effectiveness of STN DBS at different frequencies in suppressing low-frequency oscillatory activity in GPi. Frequencies less than 40 Hz were ineffective, low-frequency oscillatory power decreased gradually for frequencies between 50 Hz and 130 Hz, and saturated at frequencies higher than 150 Hz. HF STN DBS suppressed pathological oscillations in GPe/GPi both by exciting and inhibiting the firing in GPe/GPi neurons, and the number of GPe/GPi neurons influenced was greater for HF stimulation than low-frequency stimulation. Similar to the frequency dependent suppression of pathological oscillations, STN DBS also normalized the abnormal GPi spiking activity evoked by CTX stimulation in a frequency dependent fashion with HF being the most effective. Therefore, therapeutic HF STN DBS effectively suppresses pathological activity by influencing the activity of a greater proportion of neurons in the output nucleus of the BG.

Imaging biomarkers in Parkinson?s disease and Parkinsonian syndromes: current and emerging concepts

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Saeed, Usman; Compagnone, Jordana; Aviv, Richard I.; Strafella, Antonio P.; Black, Sandra E.; Lang, Anthony E.; Masellis, Mario

2017-01-01

Two centuries ago in 1817, James Parkinson provided the first medical description of Parkinson?s disease, later refined by Jean-Martin Charcot in the mid-to-late 19th century to include the atypical parkinsonian variants (also termed, Parkinson-plus syndromes). Today, Parkinson?s disease represents the second most common neurodegenerative disorder with an estimated global prevalence of over 10 million. Conversely, atypical parkinsonian syndromes encompass a group of relatively heterogeneous d...

How Parkinsonian Toxins Dysregulate the Autophagy Machinery

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Ruben K. Dagda

2013-11-01

Full Text Available Since their discovery, Parkinsonian toxins (6-hydroxydopamine, MPP+, paraquat, and rotenone have been widely employed as in vivo and in vitro chemical models of Parkinson’s disease (PD. Alterations in mitochondrial homeostasis, protein quality control pathways, and more recently, autophagy/mitophagy have been implicated in neurotoxin models of PD. Here, we highlight the molecular mechanisms by which different PD toxins dysregulate autophagy/mitophagy and how alterations of these pathways play beneficial or detrimental roles in dopamine neurons. The convergent and divergent effects of PD toxins on mitochondrial function and autophagy/mitophagy are also discussed in this review. Furthermore, we propose new diagnostic tools and discuss how pharmacological modulators of autophagy/mitophagy can be developed as disease-modifying treatments for PD. Finally, we discuss the critical need to identify endogenous and synthetic forms of PD toxins and develop efficient health preventive programs to mitigate the risk of developing PD.

Cognition In Parkinsonian Syndromes : A Review

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Das Sujata

2004-01-01

Full Text Available Parkinson′s disease is a distinctive progressive disorder characterised clinically by tremor, rigidity, bradykinesia and postural imbalance. Although James Parkinson himself denied the presence of intellectual changes in the parkinsonian Disease, thorough exploration has revealed behavioural and cognitive changes to be explicit in the patients. India, along with its demographic shift and its overwhelming population growth, falls a victim to all old-age degenerative diseases. A large percentage of the elderly Indian population today suffers from Parkinsonian and related disorders. Disturbed cognition and neurobehavioral abnormalities are enough reasons for a falling ADL (activities of daily living curve, and consequent distress to families of PD patients. Spontaneous involvement of one and all is required to not only intervene with the right pharmacological therapy, but also to empathize and develop the right attitude towards the affected person. Cognitive dysfunction in Parkinson′s disease is well established and its affection in the early stage has been reported. In this article. We attempt to review and update the various cognitive impairments that occur in all the Parkinson related disorders which necessitates diagnosis, management and rehabilitation to alleviate patients′ suffering. It also reviews the role of frontal lobe, dementia and depression with respect to these patients.

Parkinsonian phenotype in Machado-Joseph disease (MJD/SCA3: a two-case report

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Vasconcelos João

2011-10-01

Full Text Available Abstract Background Machado-Joseph disease (MJD, or spinocerebellar ataxia type 3 (SCA3, is an autosomal dominant neurodegenerative disorder of late onset, which is caused by a CAG repeat expansion in the coding region of the ATXN3 gene. This disease presents clinical heterogeneity, which cannot be completely explained by the size of the repeat tract. MJD presents extrapyramidal motor signs, namely Parkinsonism, more frequently than the other subtypes of autosomal dominant cerebellar ataxias. Although Parkinsonism seems to segregate within MJD families, only a few MJD patients develop parkinsonian features and, therefore, the clinical and genetic aspects of these rare presentations remain poorly investigated. The main goal of this work was to describe two MJD patients displaying the parkinsonian triad (tremor, bradykinesia and rigidity, namely on what concerns genetic variation in Parkinson's disease (PD associated loci (PARK2, LRRK2, PINK1, DJ-1, SNCA, MAPT, APOE, and mtDNA tRNAGln T4336C. Case presentation Patient 1 is a 40 year-old female (onset at 30 years of age, initially with a pure parkinsonian phenotype (similar to the phenotype previously reported for her mother. Patient 2 is a 38 year-old male (onset at 33 years of age, presenting an ataxic phenotype with parkinsonian features (not seen either in other affected siblings or in his father. Both patients presented an expanded ATXN3 allele with 72 CAG repeats. No PD mutations were found in the analyzed loci. However, allelic variants previously associated with PD were observed in DJ-1 and APOE genes, for both patients. Conclusions The present report adds clinical and genetic information on this particular and rare MJD presentation, and raises the hypothesis that DJ-1 and APOE polymorphisms may confer susceptibility to the parkinsonian phenotype in MJD.

Electro-acupuncture stimulation acts on the basal ganglia output pathway to ameliorate motor impairment in Parkinsonian model rats.

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Jia, Jun; Li, Bo; Sun, Zuo-Li; Yu, Fen; Wang, Xuan; Wang, Xiao-Min

2010-04-01

The role of electro-acupuncture (EA) stimulation on motor symptoms in Parkinson's disease (PD) has not been well studied. In a rat hemiparkinsonian model induced by unilateral transection of the medial forebrain bundle (MFB), EA stimulation improved motor impairment in a frequency-dependent manner. Whereas EA stimulation at a low frequency (2 Hz) had no effect, EA stimulation at a high frequency (100 Hz) significantly improved motor coordination. However, neither low nor high EA stimulation could significantly enhance dopamine levels in the striatum. EA stimulation at 100 Hz normalized the MFB lesion-induced increase in midbrain GABA content, but it had no effect on GABA content in the globus pallidus. These results suggest that high-frequency EA stimulation improves motor impairment in MFB-lesioned rats by increasing GABAergic inhibition in the output structure of the basal ganglia.

Subthalamic deep brain stimulation reduces pathological information transmission to the thalamus in a rat model of parkinsonism

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Collin James Anderson

2015-07-01

Full Text Available The degeneration of dopaminergic neurons in the substantia nigra pars compacta leads to parkinsonian motor symptoms via changes in electrophysiological activity throughout the basal ganglia. High-frequency deep brain stimulation (DBS partially treats these symptoms, but the mechanisms are unclear. We hypothesize that motor symptoms of Parkinson's disease are associated with increased information transmission from basal ganglia output neurons to motor thalamus input neurons, and that therapeutic DBS of the subthalamic nucleus (STN treats these symptoms by reducing this extraneous information transmission. We tested these hypotheses in a unilateral, 6-hydroxydopamine-lesioned rodent model of hemiparkinsonism. Information transfer between basal ganglia output neurons and motor thalamus input neurons increased in both the orthodromic and antidromic directions with hemiparkinsonian onset, and these changes were reversed by behaviorally therapeutic STN-DBS. Omnidirectional information increases in the parkinsonian state underscore the detrimental nature of that pathological information, and suggest a loss of information channel independence. Therapeutic STN-DBS reduced that pathological information, suggesting an effective increase in the number of independent information channels. We interpret these data with a model in which pathological information and fewer information channels diminishes the scope of possible motor activities, driving parkinsonian symptoms. In this model, STN-DBS restores information-channel independence by eliminating or masking the parkinsonism-associated information, and thus enlarges the scope of possible motor activities, alleviating parkinsonian symptoms.

Gypenosides attenuate the development of L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rat model of Parkinson's disease.

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Shin, Keon Sung; Zhao, Ting Ting; Park, Keun Hong; Park, Hyun Jin; Hwang, Bang Yeon; Lee, Chong Kil; Lee, Myung Koo

2015-04-21

Gypenosides (GPS) and ethanol extract of Gynostemma pentaphyllum (GP-EX) show anxiolytic effects on affective disorders in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of Parkinson's disease (PD). Long-term administration of L-3,4-dihydroxyphenylalanine (L-DOPA) leads to the development of severe motor side effects such as L-DOPA-induced-dyskinesia (LID) in PD. The present study investigated the effects of GPS and GP-EX on LID in a 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD. Daily administration of L-DOPA (25 mg/kg) in the 6-OHDA-lesioned rat model of PD for 22 days induced expression of LID, which was determined by the body and locomotive AIMs scores and contralateral rotational behaviors. However, co-treatments of GPS (25 and 50 mg/kg) or GP-EX (50 mg/kg) with L-DOPA significantly attenuated the development of LID without compromising the anti-parkinsonian effects of L-DOPA. In addition, the increases in ∆FosB expression and ERK1/2 phosphorylation in 6-OHDA-lesioned rats induced by L-DOPA administration were significantly reduced by co-treatment with GPS (25 and 50 mg/kg) or GP-EX (50 mg/kg). These results suggest that GPS (25 and 50 mg/kg) and GP-EX (50 mg/kg) effectively attenuate the development of LID by modulating the biomarker activities of ∆FosB expression and ERK1/2 phosphorylation in the 6-OHDA-lesioned rat model of PD. GPS and GP-EX will be useful adjuvant therapeutics for LID in PD.

The beneficial effect of the flavonoid quercetin on behavioral changes in hemi-Parkinsonian rats

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Mehdi Mehdizadeh

2010-01-01

Full Text Available   Abstract   Introduction: A large body of experimental evidence supports a role for oxidative stress as a mediator of nerve cell death in Parkinson's disease (PD. Flavonoids like quercetin have been reported to prevent neuronal degeneration caused by increased oxidative burden, therefore, this study examined whether quercetin administration at a high dose would attenuate behavioral abnormalities in experimental model of PD in rat.   Methods: For this purpose, unilateral intrastriatal 6-hydroxydopamine (6-OHDA-lesioned rats were pretreated with quercetin (20 mg/kg; i.p. 1 hour before surgery and treated once a day for one month. After one month, apomorphine-induced rotational behavior was measured postlesion.   Results: Apomorphine-induced rotations were counted after 4 weeks. Quercetin administration could attenuate the rotational behavior in treated lesioned rats as compared to untreated ones.   Discussion: Flavonoid quercetin administration for one month could attenuate behavioral abnormalities in 6-OHDA model of PD.

The beneficial effect of the flavonoid quercetin on behavioral changes in hemi-Parkinsonian rats

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Mehdi Mehdizadeh

2010-01-01

Full Text Available Introduction: A large body of experimental evidence supports a role for oxidative stress as a mediator of nerve cell death in Parkinson's disease (PD. Flavonoids like quercetin have been reported to prevent neuronal degeneration caused by increased oxidative burden, therefore, this study examined whether quercetin administration at a high dose would attenuate behavioral abnormalities in experimental model of PD in rat. Methods: For this purpose, unilateral intrastriatal 6-hydroxydopamine (6-OHDA-lesioned rats were pretreated with quercetin (20 mg/kg i.p. 1 hour before surgery and treated once a day for one month. After one month, apomorphine-induced rotational behavior was measured postlesion. Results: Apomorphine-induced rotations were counted after 4 weeks. Quercetin administration could attenuate the rotational behavior in treated lesioned rats as compared to untreated ones. Discussion: Flavonoid quercetin administration for one month could attenuate behavioral abnormalities in 6-OHDA model of PD.

Diffusion tensor imaging differentiates vascular parkinsonism from parkinsonian syndromes of degenerative origin in elderly subjects

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Deverdun, Jérémy [Department of Neuroradiology, Montpellier University Hospital Center, Gui de Chauliac Hospital, Montpellier (France); Laboratoire Charles Coulomb, CNRS UMR 5221 - Université Montpellier II, Montpellier (France); I2FH, Institut d’Imagerie Fonctionnelle Humaine, Hôpital Gui de Chauliac, CHRU de, Montpellier (France); Menjot de Champfleur, Sophie [Department of Neuroradiology, Montpellier University Hospital Center, Gui de Chauliac Hospital, Montpellier (France); Clinique du Parc, Castelnau-le-Lez (France); Cabello-Aguilar, Simon [Department of Neuroradiology, Montpellier University Hospital Center, Gui de Chauliac Hospital, Montpellier (France); I2FH, Institut d’Imagerie Fonctionnelle Humaine, Hôpital Gui de Chauliac, CHRU de, Montpellier (France); Maury, Florence [Department of Neurology, Montpellier University Hospital Center, Gui de Chauliac Hospital, Montpellier (France); Molino, François [Laboratoire Charles Coulomb, CNRS UMR 5221 - Université Montpellier II, Montpellier (France); Institut de Génomique Fonctionnelle, UMR 5203 - INSERM U661 - Université Montpellier II - Université, Montpellier I (France); Charif, Mahmoud [Department of Neurology, Montpellier University Hospital Center, Gui de Chauliac Hospital, Montpellier (France); Leboucq, Nicolas [Department of Neuroradiology, Montpellier University Hospital Center, Gui de Chauliac Hospital, Montpellier (France); Ayrignac, Xavier; Labauge, Pierre [Department of Neurology, Montpellier University Hospital Center, Gui de Chauliac Hospital, Montpellier (France); and others

2014-11-15

Background and Purpose: The etiologic diagnosis of parkinsonian syndromes is of particular importance when considering syndromes of vascular or degenerative origin. The purpose of this study is to find differences in the white-matter architecture between those two groups in elderly patients. Materials and Methods: Thirty-five patients were prospectively included (multiple-system atrophy, n = 5; Parkinson's disease, n = 15; progressive supranuclear palsy, n = 9; vascular parkinsonism, n = 6), with a mean age of 76 years. Patients with multiple-system atrophy, progressive supranuclear palsy and Parkinson's disease were grouped as having parkinsonian syndromes of degenerative origin. Brain MRIs included diffusion tensor imaging. Fractional anisotropy and mean-diffusivity maps were spatially normalized, and group analyses between parkinsonian syndromes of degenerative origin and vascular parkinsonism were performed using a voxel-based approach. Results: Statistical parametric-mapping analysis of diffusion tensor imaging data showed decreased fractional anisotropy value in internal capsules bilaterally in patients with vascular parkinsonism compared to parkinsonian syndromes of degenerative origin (p = 0.001) and showed a lower mean diffusivity in the white matter of the left superior parietal lobule (p = 0.01). Fractional anisotropy values were found decreased in the middle cerebellar peduncles in multiple-system atrophy compared to Parkinson's disease and progressive supranuclear palsy. The mean diffusivity was increased in those regions for these subgroups. Conclusion: Clinically defined vascular parkinsonism was associated with decreased fractional anisotropy in the deep white matter (internal capsules) compared to parkinsonian syndromes of degenerative origin. These findings are consistent with previously published neuropathological data.

Diffusion tensor imaging differentiates vascular parkinsonism from parkinsonian syndromes of degenerative origin in elderly subjects

International Nuclear Information System (INIS)

Deverdun, Jérémy; Menjot de Champfleur, Sophie; Cabello-Aguilar, Simon; Maury, Florence; Molino, François; Charif, Mahmoud; Leboucq, Nicolas; Ayrignac, Xavier; Labauge, Pierre

2014-01-01

Background and Purpose: The etiologic diagnosis of parkinsonian syndromes is of particular importance when considering syndromes of vascular or degenerative origin. The purpose of this study is to find differences in the white-matter architecture between those two groups in elderly patients. Materials and Methods: Thirty-five patients were prospectively included (multiple-system atrophy, n = 5; Parkinson's disease, n = 15; progressive supranuclear palsy, n = 9; vascular parkinsonism, n = 6), with a mean age of 76 years. Patients with multiple-system atrophy, progressive supranuclear palsy and Parkinson's disease were grouped as having parkinsonian syndromes of degenerative origin. Brain MRIs included diffusion tensor imaging. Fractional anisotropy and mean-diffusivity maps were spatially normalized, and group analyses between parkinsonian syndromes of degenerative origin and vascular parkinsonism were performed using a voxel-based approach. Results: Statistical parametric-mapping analysis of diffusion tensor imaging data showed decreased fractional anisotropy value in internal capsules bilaterally in patients with vascular parkinsonism compared to parkinsonian syndromes of degenerative origin (p = 0.001) and showed a lower mean diffusivity in the white matter of the left superior parietal lobule (p = 0.01). Fractional anisotropy values were found decreased in the middle cerebellar peduncles in multiple-system atrophy compared to Parkinson's disease and progressive supranuclear palsy. The mean diffusivity was increased in those regions for these subgroups. Conclusion: Clinically defined vascular parkinsonism was associated with decreased fractional anisotropy in the deep white matter (internal capsules) compared to parkinsonian syndromes of degenerative origin. These findings are consistent with previously published neuropathological data

Therapeutic cloning in individual parkinsonian mice

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Tabar, Viviane; Tomishima, Mark; Panagiotakos, Georgia; Wakayama, Sayaka; Menon, Jayanthi; Chan, Bill; Mizutani, Eiji; Al-Shamy, George; Ohta, Hiroshi; Wakayama, Teruhiko; Studer, Lorenz

2009-01-01

Cell transplantation with embryonic stem (ES) cell progeny requires immunological compatibility with host tissue. ‘Therapeutic cloning’ is a strategy to overcome this limitation by generating nuclear transfer (nt)ES cells that are genetically matched to an individual. Here we establish the feasibility of treating individual mice via therapeutic cloning. Derivation of 187 ntES cell lines from 24 parkinsonian mice, dopaminergic differentiation, and transplantation into individually matched host mice showed therapeutic efficacy and lack of immunological response. PMID:18376409

Neural dynamics in Parkinsonian brain: The boundary between synchronized and nonsynchronized dynamics

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Park, Choongseok; Worth, Robert M.; Rubchinsky, Leonid L.

2011-04-01

Synchronous oscillatory dynamics is frequently observed in the human brain. We analyze the fine temporal structure of phase-locking in a realistic network model and match it with the experimental data from Parkinsonian patients. We show that the experimentally observed intermittent synchrony can be generated just by moderately increased coupling strength in the basal ganglia circuits due to the lack of dopamine. Comparison of the experimental and modeling data suggest that brain activity in Parkinson's disease resides in the large boundary region between synchronized and nonsynchronized dynamics. Being on the edge of synchrony may allow for easy formation of transient neuronal assemblies.

Effects of electroacupuncture on metabolic changes in motor cortex and striatum of 6-hydroxydopamine-induced Parkinsonian rats.

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Li, Min; Wang, Ke; Su, Wen-Ting; Jia, Jun; Wang, Xiao-Min

2017-10-06

To explore the possible underlying mechanism by investigating the effect of electroacupuncture (EA) treatment on the primary motor cortex and striatum in a unilateral 6-hydroxydopamine (6-OHDA) induced rat Parkinson's disease (PD) model. Male Sprague-Dawley rats were randomly divided into sham group (n=16), model group (n=14), and EA group (n=14). EA stimulation at Dazhui (GV 14) and Baihui (GV20) was applied to PD rats in the EA group for 4 weeks. Behavioral tests were conducted to evaluate the effectiveness of EA treatment. Metabolites were detected by 7.0 T proton nuclear magnetic resonance. Following 4 weeks of EA treatment in PD model rats, the abnormal behavioral impairment induced by 6-OHDA was alleviated. In monitoring changes in metabolic activity, ratios of myoinositol/creatine (Cr) and N-acetyl aspartate (NAA)/Cr in the primary motor cortex were significantly lower at the injected side than the non-injected side in PD rats (P=0.024 and 0.020). The ratios of glutamate + glutamine (Glx)/Cr and NAA/Cr in the striatum were higher and lower, respectively, at the injected side than the non-injected side (P=0.046 and 0.008). EA treatment restored the balance of metabolic activity in the primary motor cortex and striatum. In addition, the taurine/Cr ratio and Glx/Cr ratio were elevated in the striatum of PD model rats compared to sham-lesioned rats (P=0.026 and 0.000). EA treatment alleviated the excessive glutamatergic transmission by down-regulating the striatal Glx/Cr ratio (P=0.001). The Glx/Cr ratio was negatively correlated with floor plane spontaneous locomotion in PD rats (P=0.027 and P=0.0007). EA treatment is able to normalize the metabolic balance in the primary motor cortex and striatum of PD rats, which may contribute to its therapeutic effect on motor deficits. The striatal Glx/Cr ratio may serve as a potential indicator of PD and a therapeutic target of EA treatment.

Amyloid-related biomarkers and axonal damage proteins in parkinsonian syndromes

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Bech, Sara; Hjermind, Lena E; Salvesen, Lisette

2012-01-01

Clinical differentiation between parkinsonian syndromes (PS) remains a challenge despite well-established clinical diagnostic criteria. Specific diagnostic biomarkers have yet to be identified, though in recent years, studies have been published on the aid of certain brain related proteins (BRP) ...

Brain MR Contribution to the Differential Diagnosis of Parkinsonian Syndromes: An Update

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Giovanni Rizzo

2016-01-01

Full Text Available Brain magnetic resonance (MR represents a useful and feasible tool for the differential diagnosis of Parkinson’s disease. Conventional MR may reveal secondary forms of parkinsonism and may show peculiar brain alterations of atypical parkinsonian syndromes. Furthermore, advanced MR techniques, such as morphometric-volumetric analyses, diffusion-weighted imaging, diffusion tensor imaging, tractography, proton MR spectroscopy, and iron-content sensitive imaging, have been used to obtain quantitative parameters useful to increase the diagnostic accuracy. Currently, many MR studies have provided both qualitative and quantitative findings, reflecting the underlying neuropathological pattern of the different degenerative parkinsonian syndromes. Although the variability in the methods and results across the studies limits the conclusion about which technique is the best, specific radiologic phenotypes may be identified. Qualitative/quantitative MR changes in the substantia nigra do not discriminate between different parkinsonisms. In the absence of extranigral abnormalities, the diagnosis of PD is more probable, whereas basal ganglia changes (mainly in the putamen suggest the diagnosis of an atypical parkinsonian syndrome. In this context, changes in pons, middle cerebellar peduncles, and cerebellum suggest the diagnosis of MSA, in midbrain and superior cerebellar peduncles the diagnosis of PSP, and in whole cerebral hemispheres (mainly in frontoparietal cortex with asymmetric distribution the diagnosis of Corticobasal Syndrome.

Focused and Sustained Attention Is Modified by a Goal-Based Rehabilitation in Parkinsonian Patients.

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Ferrazzoli, Davide; Ortelli, Paola; Maestri, Roberto; Bera, Rossana; Gargantini, Roberto; Palamara, Grazia; Zarucchi, Marianna; Giladi, Nir; Frazzitta, Giuseppe

2017-01-01

Rehabilitation for patients with Parkinson's disease (PD) is based on cognitive strategies that exploit attention. Parkinsonians exhibit impairments in divided attention and interference control. Nevertheless, the effectiveness of specific rehabilitation treatments based on attention suggests that other attentional functions are preserved. Data about attention are conflicting in PD, and it is not clear whether rehabilitative treatments that entail attentional strategies affect attention itself. Reaction times (RTs) represent an instrument to explore attention and investigate whether changes in attentional performances parallel rehabilitation induced-gains. RTs of 103 parkinsonian patients in "on" state, without cognitive deficits, were compared with those of a population of 34 healthy controls. We studied those attentional networks that subtend the use of cognitive strategies in motor rehabilitation: alertness and focused and sustained attention, which is a component of the executive system. We used visual and auditory RTs to evaluate alertness and multiple choices RTs (MC RTs) to explore focused and sustained attention. Parkinsonian patients underwent these tasks before and after a 4-week multidisciplinary, intensive and goal-based rehabilitation treatment (MIRT). Unified Parkinson's Disease Rating Scale (UPDRS) III and Timed Up and Go test (TUG) were assessed at the enrollment and at the end of MIRT to evaluate the motor-functional effectiveness of treatment. We did not find differences in RTs between parkinsonian patients and controls. Further, we found that improvements in motor-functional outcome measures after MIRT ( p attention, are preserved in "on" state. This explains why Parkinsonians benefit from a goal-based rehabilitation that entails the use of attention. The reduction in MC RTs suggests a positive effect of MIRT on the executive component of attention and indicates that this type of rehabilitation provides benefits by exploiting executive functions

Characterization of the porcine FBX07 gene: the first step towards generation of a pig model for Parkinsonian pyramidal syndrome

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Larsen, Knud; Bendixen, Christian

2012-01-01

Parkinsonian pyramidal syndrome, also named pallido-pyramidal syndrome (PKPS), is the combination of early-onset progressive Parkinsonism with pyramidal tract signs. FBXO7, an F-box protein, is a component of modular E3 ubiquitin protein ligases called SCFs (SKP1, cullin, F-box proteins), which...

Human olfactory bulb neural stem cells mitigate movement disorders in a rat model of Parkinson's disease.

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Marei, Hany E S; Lashen, Samah; Farag, Amany; Althani, Asmaa; Afifi, Nahla; A, Abd-Elmaksoud; Rezk, Shaymaa; Pallini, Roberto; Casalbore, Patrizia; Cenciarelli, Carlo

2015-07-01

Parkinson's disease (PD) is a neurological disorder characterized by the loss of midbrain dopaminergic (DA) neurons. Neural stem cells (NSCs) are multipotent stem cells that are capable of differentiating into different neuronal and glial elements. The production of DA neurons from NSCs could potentially alleviate behavioral deficits in Parkinsonian patients; timely intervention with NSCs might provide a therapeutic strategy for PD. We have isolated and generated highly enriched cultures of neural stem/progenitor cells from the human olfactory bulb (OB). If NSCs can be obtained from OB, it would alleviate ethical concerns associated with the use of embryonic tissue, and provide an easily accessible cell source that would preclude the need for invasive brain surgery. Following isolation and culture, olfactory bulb neural stem cells (OBNSCs) were genetically engineered to express hNGF and GFP. The hNFG-GFP-OBNSCs were transplanted into the striatum of 6-hydroxydopamin (6-OHDA) Parkinsonian rats. The grafted cells survived in the lesion environment for more than eight weeks after implantation with no tumor formation. The grafted cells differentiated in vivo into oligodendrocyte-like (25 ± 2.88%), neuron-like (52.63 ± 4.16%), and astrocyte -like (22.36 ± 1.56%) lineages, which we differentiated based on morphological and immunohistochemical criteria. Transplanted rats exhibited a significant partial correction in stepping and placing in non-pharmacological behavioral tests, pole and rotarod tests. Taken together, our data encourage further investigations of the possible use of OBNSCs as a promising cell-based therapeutic strategy for Parkinson's disease. © 2014 Wiley Periodicals, Inc.

Bee Venom Alleviates Motor Deficits and Modulates the Transfer of Cortical Information through the Basal Ganglia in Rat Models of Parkinson's Disease.

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Maurice, Nicolas; Deltheil, Thierry; Melon, Christophe; Degos, Bertrand; Mourre, Christiane; Amalric, Marianne; Kerkerian-Le Goff, Lydia

2015-01-01

Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson's disease (PD). Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure) in pharmacological (neuroleptic treatment) and lesional (unilateral intranigral 6-hydroxydopamine injection) PD models. In the hemi-parkinsonian 6-hydroxydopamine lesion model, subchronic bee venom treatment significantly alleviates contralateral forelimb akinesia and apomorphine-induced rotations. Moreover, a single injection of bee venom reverses haloperidol-induced catalepsy, a pharmacological model reminiscent of parkinsonian akinetic deficit. This effect is mimicked by apamin, a blocker of small conductance Ca2+-activated K+ (SK) channels, and blocked by CyPPA, a positive modulator of these channels, suggesting the involvement of SK channels in the bee venom antiparkinsonian action. In vivo electrophysiological recordings in the substantia nigra pars reticulata (basal ganglia output structure) showed no significant effect of BV on the mean neuronal discharge frequency or pathological bursting activity. In contrast, analyses of the neuronal responses evoked by motor cortex stimulation show that bee venom reverses the 6-OHDA- and neuroleptic-induced biases in the influence exerted by the direct inhibitory and indirect excitatory striatonigral circuits. These data provide the first evidence for a beneficial action of bee venom on the pathological functioning of the cortico-basal ganglia circuits underlying motor PD symptoms with potential relevance to the symptomatic treatment of this disease.

Postsynaptic density protein 95-regulated NR2B tyrosine phosphorylation and interactions of Fyn with NR2B in levodopa-induced dyskinesia rat models

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Ba M

2014-12-01

Full Text Available Maowen Ba,1,* Min Kong,2,* Guozhao Ma3 1Department of Neurology, Yuhuangding Hospital, Yantai City, Shandong, People’s Republic of China; 2Department of Neurology, Yantaishan Hospital, Yantai City, Shandong, People’s Republic of China; 3Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Shandong, People’s Republic of China *These authors contributed equally to this work Context: Abnormality in interactions between N-methyl-d-aspartate (NMDA receptor and its signaling molecules occurs in the lesioned striatum in Parkinson’s disease (PD and levodopa-induced dyskinesia (LID. It was reported that Fyn-mediated NR2B tyrosine phosphorylation, can enhance NMDA receptor function. Postsynaptic density protein 95 (PSD-95, one of the synapse-associated proteins, regulates interactions between receptor and downstream-signaling molecules. In light of the relationship between PSD-95, NR2B, and Fyn kinases, does PSD-95 contribute to the overactivity of NMDA receptor function induced by dopaminergic treatment? To further prove the possibility, the effects of regulating the PSD-95 expression on the augmented NR2B tyrosine phosphorylation and on the interactions of Fyn and NR2B in LID rat models were evaluated.Methods: In the present study, parkinsonian rat models were established by injecting 6-hydroxydopamine. Subsequently, valid PD rats were treated with levodopa (50 mg/kg/day with benserazide 12.5 mg/kg/day, twice daily intraperitoneally for 22 days to create LID rat models. Then, the effect of pretreatment with an intrastriatal injection of the PSD-95mRNA antisense oligonucleotides (PSD-95 ASO on the rotational response to levodopa challenge was assessed. The effects of pretreatment with an intrastriatal injection of PSD-95 ASO on the augmented NR2B tyrosine phosphorylation and interactions of Fyn with NR2B in the LID rat models were detected by immunoblotting and immunoprecipitation. Results: Levodopa

Intrathecal application of autologous bone marrow cell preparations in parkinsonian syndromes

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Storch, Alexander; Csoti, Ilona; Eggert, Karla

2012-01-01

A growing number of patients is treated with intrathecal application of autologous bone marrow cells (aBMCs), but clinical data are completely lacking in movement disorders. We provide first clinical data on efficacy and safety of this highly experimental treatment approach in parkinsonian...

Potential mechanisms for imperfect synchronization in parkinsonian basal ganglia.

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Choongseok Park

Full Text Available Neural activity in the brain of parkinsonian patients is characterized by the intermittently synchronized oscillatory dynamics. This imperfect synchronization, observed in the beta frequency band, is believed to be related to the hypokinetic motor symptoms of the disorder. Our study explores potential mechanisms behind this intermittent synchrony. We study the response of a bursting pallidal neuron to different patterns of synaptic input from subthalamic nucleus (STN neuron. We show how external globus pallidus (GPe neuron is sensitive to the phase of the input from the STN cell and can exhibit intermittent phase-locking with the input in the beta band. The temporal properties of this intermittent phase-locking show similarities to the intermittent synchronization observed in experiments. We also study the synchronization of GPe cells to synaptic input from the STN cell with dependence on the dopamine-modulated parameters. Earlier studies showed how the strengthening of dopamine-modulated coupling may lead to transitions from non-synchronized to partially synchronized dynamics, typical in Parkinson's disease. However, dopamine also affects the cellular properties of neurons. We show how the changes in firing patterns of STN neuron due to the lack of dopamine may lead to transition from a lower to a higher coherent state, roughly matching the synchrony levels observed in basal ganglia in normal and parkinsonian states. The intermittent nature of the neural beta band synchrony in Parkinson's disease is achieved in the model due to the interplay of the timing of STN input to pallidum and pallidal neuronal dynamics, resulting in sensitivity of pallidal output to the phase of the arriving STN input. Thus the mechanism considered here (the change in firing pattern of subthalamic neurons through the dopamine-induced change of membrane properties may be one of the potential mechanisms responsible for the generation of the intermittent synchronization

Multicentre European study of thalamic stimulation in parkinsonian and essential tremor

NARCIS (Netherlands)

Limousin, P.; Speelman, J. D.; Gielen, F.; Janssens, M.

1999-01-01

Thalamic stimulation has been proposed to treat disabling tremor. The aims of this multicentre study were to evaluate the efficacy and the morbidity of thalamic stimulation in a large number of patients with parkinsonian or essential tremor. One hundred and eleven patients were included in the study

The cardioprotective efficacy of TVP1022 in a rat model of ischaemia/reperfusion.

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Ertracht, Offir; Liani, Esti; Bachner-Hinenzon, Noa; Bar-Am, Orit; Frolov, Luba; Ovcharenko, Elena; Awad, Huda; Blum, Shany; Barac, Yaron; Amit, Tamar; Adam, Dan; Youdim, Moussa; Binah, Ofer

2011-06-01

Because myocardial infarction is a major cause of morbidity and mortality worldwide, protecting the heart from the ischaemia and reperfusion (I/R) damage is the focus of intense research. Based on our in vitro findings showing that TVP1022 (the S-enantiomer of rasagiline, an anti-Parkinsonian drug) possesses cardioprotective effects, in the present study we investigated the hypothesis that TVP1022 can attenuate myocardial damage in an I/R model in rats. The model consisted of 30-min occlusion of the left anterior descending artery followed by 4 or 24 h reperfusion. In addition, we investigated the possible mechanisms of cardioprotection in H9c2 cells and neonatal rat ventricular myocytes (NRVM) exposed to oxidative stress induced by H(2) O(2) . TVP1022 (20 and 40 mg·kg(-1) ) administered 5 min before reperfusion followed by an additional dose 4 h after reperfusion reduced the infarct size and attenuated the decline in ventricular function. TVP1022 also attenuated I/R-induced deterioration in cardiac mitochondrial integrity evaluated by mitochondrial swelling capacity. In vitro, using H9c2 cells and NRVM, TVP1022 attenuated both serum free- and H(2) O(2) -induced damage, preserved mitochondrial membrane potential and Bcl-2 levels, inhibited mitochondrial cytochrome c release and the increase in cleaved caspase 9 and 3 levels, and enhanced the phosphorylation of protein kinase C and glycogen synthase kinase-3β. TVP1022 provided cardioprotection in a model of myocardial infarction, and therefore should be considered as a novel adjunctive therapy for attenuating myocardial damage resulting from I/R injuries. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Estimation of the phase response curve from Parkinsonian tremor.

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Saifee, Tabish A; Edwards, Mark J; Kassavetis, Panagiotis; Gilbertson, Tom

2016-01-01

Phase response curves (PRCs), characterizing the response of an oscillator to weak external perturbation, have been estimated from a broad range of biological oscillators, including single neurons in vivo. PRC estimates, in turn, provide an intuitive insight into how oscillatory systems become entrained and how they can be desynchronized. Here, we explore the application of PRC theory to the case of Parkinsonian tremor. Initial attempts to establish a causal effect of subthreshold transcranial magnetic stimulation applied to primary motor cortex on the filtered tremor phase were unsuccessful. We explored the possible explanations of this and demonstrate that assumptions made when estimating the PRC in a traditional setting, such as a single neuron, are not arbitrary when applied to the case of tremor PRC estimation. We go on to extract the PRC of Parkinsonian tremor using an iterative method that requires varying the definition of the tremor cycle and estimating the PRC at multiple peristimulus time samples. Justification for this method is supported by estimates of PRC from simulated single neuron data. We provide an approach to estimating confidence limits for tremor PRC and discuss the interpretational caveats introduced by tremor harmonics and the intrinsic variability of the tremor's period. Copyright © 2016 the American Physiological Society.

Elevated homocysteine by levodopa is detrimental to neurogenesis in parkinsonian model.

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Jin Young Shin

Full Text Available BACKGROUND: Modulation of neurogenesis that acts as an endogenous repair mechanism would have a significant impact on future therapeutic strategies for Parkinson's disease (PD. Several studies demonstrated dopaminergic modulation of neurogenesis in the subventricular zone (SVZ of the adult brain. Levodopa, the gold standard therapy for PD, causes an increase in homocysteine levels that induces neuronal death via N-methyl-D-aspartate (NMDA receptor. The present study investigated whether elevated homocysteine by levodopa treatment in a parkinsonian model would modulate neurogenesis via NMDA receptor signal cascade and compared the effect of levodopa and pramipexol (PPX on neurogenic activity. METHODOLOGY/PRINCIPAL FINDINGS: Neurogenesis was assessed in vitro using neural progenitor cells (NPCs isolated from the SVZ and in vivo with the BrdU-injected animal model of PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Modulation of homocysteine levels was evaluated using co-cultures of NPCs and astrocytes and PD animals. Immunochemical and Western blot analyses were used to measure neurogenesis and determine the cell death signaling. Levodopa treatment increased release of homocysteine on astrocytes culture media as well as in plasma and brain of PD animals. Increased homocysteine by levodopa led to increased apoptosis of NPCs through the NMDA receptor-dependent the extracellular signal-regulated kinase (ERK signaling pathways. The administration of a NMDA antagonist significantly attenuated apoptotic cell death in levodopa-treated NPCs and markedly increased the number of BrdU-positive cells in the SVZ of levodopa-treated PD animals. Comparative analysis revealed that PPX treatment significantly increased the number of NPCs and BrdU-positive cells in the SVZ of PD animals compared to levodopa treatment. Our present study demonstrated that increased homocysteine by levodopa has a detrimental effect on neurogenesis through NMDA receptor

Simultaneous Transplantation of Fetal Ventral Mesencephalic Tissue and Encapsulated Genetically Modified Cells Releasing GDNF in a Hemi-Parkinsonian Rat Model of Parkinson’s Disease

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Perez-Bouza, Alberto; Di Santo, Stefano; Seiler, Stefanie

2017-01-01

Transplantation of fetal ventral mesencephalic (VM) neurons for Parkinson's disease (PD) is limited by poor survival and suboptimal integration of grafted tissue into the host brain. In a 6-OHDA rat model of PD we investigated the feasibility of simultaneous transplantation of rat fetal VM tissue...... between groups were observed for the number of surviving TH-ir neurons or graft volume. In conclusion, our findings demonstrate that simultaneous transplantation of fetal VM tissue and encapsulated GDNF-releasing cells is feasible and support the graft survival and function. Pre-treatment of donor tissue...

18F FDG PET/CT in differential diagnosis of Parkinsonian disorders

International Nuclear Information System (INIS)

Deepa; Moon, S.; Mahajan, S.; Thapa, P.; Gupta, P.; Sahana; Tripathi, M.; Sharma, R.; Mondal, A.; Batla, A.; Nehru, R.; Kushwaha, S.; Mishra, A.K.

2010-01-01

Full text: Differential diagnosis of Parkinsonian disorders can be challenging in the early phase of disease course. Positron Emission Tomography (PET) imaging with 18 F Fluorodeoxyglucose (FDG) has been used to identify characteristic patterns of glucose metabolism in patients with idiopathic Parkinson's Disease (PD) as well as variant forms of Parkinsonism such as Multisystem Atrophy (MSA), Progressive Supranuclear Palsy (PSP) and cortico basal ganglionic degeneration (CBGD). In this study we assessed the utility of 18 F FDG PET/CT in the differential diagnosis Parkinsonian syndromes. 66 Parkinsonian patients with a mean age of 59.6 ± 11.50 years, male: female ratio of 3.12:1, age range of 35-84 years with a disease duration of 2.6 ± .68 years were referred for FDG PET to determine whether their scan patterns could distinguish idiopathic Parkinsons from the Parkinson plus syndromes. Approximately 60 minutes following intravenous injection of 370 MBq of 18 F-FDG, PET/CT scan of the brain was acquired in a whole-body Full Ring PET/CT scanner (Discovery STE16 camera). A low dose CT was obtained on the same area without IV contrast for attenuation correction and coregistration. Images were reconstructed using a 3D VUE algorithm and slices were reformatted into transaxial, coronal and sagittal views. Subsequently the images were processed and visually analyzed on Xeleris workstation. Images were classified by visual analysis into the various subgroups, those with normal to increased basal ganglia uptake were classified into Idiopathic Parkinson's (40/45) and when basal ganglia uptake was decreased they were Parkinsons Plus (19/21). The study demonstrates that 18 F FDG PET performed at the time of initial referral for parkinsonism could accurately classify patients into Parkinson's disease and Parkinson plus subtypes

Differential Diagnosis of Patients with Inconclusive Parkinsonian Features Using [{sup 18}F]FP-CIT PET/CT

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Park, Eunkyung; Hwang, Yu Mi; Lee, Channyoung; Oh, Sun Young; Kim, Young Chul; Choe, Jae Gol; Park, Kun Woo [Korea Univ., Seoul (Korea, Republic of); Kim, Sujin [Seoul National Univ. College of Medicine, Seoul (Korea, Republic of)

2014-06-15

It is often difficult to differentiate parkinsonism, especially when patients show uncertain parkinsonian features. We investigated the usefulness of dopamine transporter (DAT) imaging for the differential diagnosis of inconclusive parkinsonism using [{sup 18}F]FP-CIT PET. Twenty-four patients with inconclusive parkinsonian features at initial clinical evaluation and nine healthy controls were studied. Patients consisted of three subgroups: nine patients whose diagnoses were unclear concerning whether they had idiopathic Parkinson's disease or drug-induced parkinsonism ('PD/DIP'), nine patients who fulfilled neither the diagnostic criteria of PD nor of essential tremor ('PD/ET'), and six patients who were alleged to have either PD or atypical parkinsonian syndrome ('PD/APS'). Brain PET images were obtained 120 min after injection of 185 MBq [{sup 18}F]FP-CIT. Imaging results were quantified and compared with follow-up clinical diagnoses. Overall, 11 of 24 patients demonstrated abnormally decreased DAT availability on the PET scans, whereas 13 were normal. PET results could diagnose PD/DIP and PD/ET patients as having PD in six patients, DIP in seven, and ET in five; however, the diagnoses of all six PD/APS patients remained inconclusive. Among 15 patients who obtained a final follow-up diagnosis, the image-based diagnosis was congruent with the follow-up diagnosis in 11 patients. Four unsolved cases had normal DAT availability, but clinically progressed to PD during the follow-up period. [{sup 18}F]FP-CIT PET imaging is useful in the differential diagnosis of patients with inconclusive parkinsonian features, except in patients who show atypical features or who eventually progress to PD.

The Addenbrooke's Cognitive Examination for the differential diagnosis and longitudinal assessment of patients with parkinsonian disorders.

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Rittman, Timothy; Ghosh, Boyd C; McColgan, Peter; Breen, David P; Evans, Jonathan; Williams-Gray, Caroline H; Barker, Roger A; Rowe, James B

2013-05-01

Differentiating idiopathic Parkinson's disease from atypical parkinsonian syndromes is challenging, especially in the early stages. We assessed whether the Revised Addenbrooke's Cognitive Examination (ACE-R) could differentiate between parkinsonian syndromes and reflect longitudinal changes in cognition in these disorders. The ACE-R was administered at baseline and after approximately 18 months to 135 patients with parkinsonian disorders: 86 with idiopathic Parkinson's disease (PD), 30 with progressive supranuclear palsy (PSP), 19 with corticobasal degeneration (CBD). We assessed differences between groups for ACE-R, ACE-R subscores and Mini Mental State Examination (MMSE) scores at baseline (analyses of variance, receiver operating characteristics curves), and the interaction between diagnosis and change in ACE-R scores between visits (analyses of variance). The ACE-R verbal fluency subscore distinguished between PSP and PD with a high sensitivity (0.92) and specificity (0.87); total ACE-R score and the visuospatial subscore were less specific (0.87 and 0.84 respectively) and sensitive (0.70 and 0.73). Significant group level differences were found between PD and PSP for MMSE and ACE-R (total score and subscores for attention and concentration, fluency, language, and visuospatial function), and between PD and CBD for the ACE-R visuospatial subscore. Performance worsened between visits for ACE-R score in PD (p=0.001) and CBD (p=0.001); visuospatial subscore in PD (p=0.003), PSP (p=0.022) and CBD (p=0.0002); and MMSE in CBD (p=0.004). We propose the ACE-R, particularly the verbal fluency subscore, as a valuable contributor to the differential diagnosis of parkinsonian syndromes in the correct clinical context. The ACE-R may reflect disease progression in PD and CBD.

Modulation of attentional processing by deep brain stimulation of the pedunculopontine nucleus region in patients with parkinsonian disorders.

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Fischer, Julia; Schwiecker, Kati; Bittner, Verena; Heinze, Hans-Jochen; Voges, Jürgen; Galazky, Imke; Zaehle, Tino

2015-07-01

Low-frequency electrical stimulation of the pedunculopontine nucleus (PPN) is a therapeutic approach aiming to improve motor symptoms such as freezing of gate and postural instability in parkinsonian disorders. Because the PPN is a component of the reticular activating system, we tested whether PPN stimulation directly affects attention and consciousness. Eight patients with parkinsonian disorders and implanted with electrodes in the bilateral PPN underwent computerized assessment of attention. Performance in 3 standard reaction time (RT) tasks was assessed at 5 different stimulation frequencies in 5 consecutive sessions. Stimulation of the PPN at low (8 Hz) and therapeutic (20 Hz) frequencies led to a significant improvement of performance in a simple RT task. Patients' RTs were significantly faster at stimulation frequencies of 8 Hz and 20 Hz relative to no stimulation. Stimulation did not affect patients' performance in more complex attentional tasks. Low-frequent stimulation of PPN improves basal attentional processing in patients with parkinsonian disorders, leading to an improved tonic alertness. As successful performance in this task requires the intrinsic ability to build up and keep a certain level of attention, this might be interpreted as attentional augmentation related to stimulation features. Stimulation had no effect on more complex attentional processing. Our results suggest an influence of the PPN on certain aspects of attention, supporting attentional augmentation as one possible mechanism to improve motor action and gait in patients with parkinsonian disorders. (c) 2015 APA, all rights reserved).

The beneficial effect of the flavonoid quercetin on behavioral changes in hemi-Parkinsonian rats

OpenAIRE

Mehdi Mehdizadeh; Mohammad Taghi Joghataei; Maliheh Nobakht; Roya Aryanpour

2010-01-01

  Abstract   Introduction: A large body of experimental evidence supports a role for oxidative stress as a mediator of nerve cell death in Parkinson's disease (PD). Flavonoids like quercetin have been reported to prevent neuronal degeneration caused by increased oxidative burden, therefore, this study examined whether quercetin administration at a high dose would attenuate behavioral abnormalities in experimental model of PD in rat.   Methods: For this purpose, unilateral intrastriatal 6-hydr...

Treatment with subthreshold doses of caffeine plus trihexyphenidyl fully restores locomotion and exploratory activity in reserpinized rats.

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Moo-Puc, Rosa E; Villanueva-Toledo, Jairo; Arankowsky-Sandoval, Gloria; Alvarez-Cervera, Fernando; Góngora-Alfaro, José L

2004-09-09

Trihexyphenidyl (THP) is a drug commonly used to reduce parkinsonian symptoms. An important side effect of this agent is memory impairment. Since caffeine enhances the potency of THP to inhibit haloperidol-induced catalepsy, caffeine may be used as an adjuvant of lower doses of THP, in order to improve its antiparkinsonian effects without causing memory disruption. To further assess the synergism between caffeine and THP, both drugs were tested in reserpinized rats, another preclinical model of Parkinson's disease. Four groups of rats (n = 7) were treated with reserpine (5 mg/kg, i.p.). A control group (n = 7) was treated only with the vehicle for reserpine (dimethylsulphoxide). The spontaneous locomotor behavior was tested 24 h later in a box with infrared sensors, 30 min after receiving one of the following treatments: distilled water (1 ml/kg), caffeine (1 mg/kg), THP (0.1 mg/kg) or caffeine plus THP. The levels of horizontal locomotion (14 +/- 5%) and vertical exploration (15 +/- 10%) were significantly lower in reserpinized rats treated with distilled water, compared with the mean activity values (100%) recorded in animals pretreated only with the vehicle for reserpine. The reserpine-induced hypokinesia was neither reversed by caffeine alone nor by THP alone. However, the combination of caffeine plus THP restored locomotion (141 +/- 19%) and vertical exploration (82 +/- 17%) to levels not significantly different to those of non-reserpinized rats. Moreover, the time-course of locomotion and exploration displayed the characteristic habituation over time, in which short-term memory processes are involved. Also, the thigmotaxis index indicated that the combined treatment did not induce anxiety-like behavior. Hence, these results support the proposal that low, subthreshold doses of caffeine plus THP have the potential to alleviate the motor disabilities in parkinsonian patients, with a low risk of causing anxiety or memory impairment.

Predictive value of dopamine transporter SPECT imaging with [123I]PE2I in patients with subtle parkinsonian symptoms

International Nuclear Information System (INIS)

Ziebell, Morten; Thomsen, Gerda; Knudsen, Gitte M.; Andersen, Birgitte B.; Pinborg, Lars H.; Karlsborg, Merete; Hasselbalch, Steen G.

2012-01-01

To examine the diagnostic sensitivity and specificity of dopamine transporter SPECT imaging with a highly dopamine transporter selective radioligand. The study included consecutively enrolled, drug-naive patients with an average short history of parkinsonian motor symptoms, referred for diagnostic scanning. The study group comprised 288 patients naive to antiparkinson treatment who were enrolled as they were admitted for a diagnostic SPECT scan with the radioligand [ 123 I]-N-(3-iodoprop-2E-enyl)-2-β-carbomethoxy-3β-(4-methylphenyl)n ortropane ( 123 I-PE2I). After the diagnostic scanning, patients were followed clinically with an average follow-up of 19.7 ± 12.5 months. A diagnosis could be clinically settled in 189 patients and among these patients, a dopamine transporter scan had a sensitivity of 88% and a specificity of 91% for discrimination between patients with and without striatal neurodegeneration. In cognitively impaired patients (Mini Mental State Examination 2 differentiated between idiopathic Parkinson's disease and atypical parkinsonian syndromes with a specificity of 84% and a sensitivity of 63%. In drug-naive patients with subtle clinical parkinsonian motor symptoms, dopamine transporter scan using 123 I-PE21 has a high sensitivity and specificity in distinguishing between patients with and without striatal neurodegeneration. The specificity is lower in patients who are also cognitively impaired. Calculation of the striatal APR can assist in differentiating between idiopathic Parkinson's disease and atypical parkinsonian syndromes. (orig.)

Alterations in primary motor cortex neurotransmission and gene expression in hemi-parkinsonian rats with drug-induced dyskinesia.

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Lindenbach, D; Conti, M M; Ostock, C Y; Dupre, K B; Bishop, C

2015-12-03

Treatment of Parkinson's disease (PD) with dopamine replacement relieves symptoms of poverty of movement, but often causes drug-induced dyskinesias. Accumulating clinical and pre-clinical evidence suggests that the primary motor cortex (M1) is involved in the pathophysiology of PD and that modulating cortical activity may be a therapeutic target in PD and dyskinesia. However, surprisingly little is known about how M1 neurotransmitter tone or gene expression is altered in PD, dyskinesia or associated animal models. The present study utilized the rat unilateral 6-hydroxydopamine (6-OHDA) model of PD/dyskinesia to characterize structural and functional changes taking place in M1 monoamine innervation and gene expression. 6-OHDA caused dopamine pathology in M1, although the lesion was less severe than in the striatum. Rats with 6-OHDA lesions showed a PD motor impairment and developed dyskinesia when given L-DOPA or the D1 receptor agonist, SKF81297. M1 expression of two immediate-early genes (c-Fos and ARC) was strongly enhanced by either L-DOPA or SKF81297. At the same time, expression of genes specifically involved in glutamate and GABA signaling were either modestly affected or unchanged by lesion and/or treatment. We conclude that M1 neurotransmission and signal transduction in the rat 6-OHDA model of PD/dyskinesia mirror features of human PD, supporting the utility of the model to study M1 dysfunction in PD and the elucidation of novel pathophysiological mechanisms and therapeutic targets. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Mean-field modeling of the basal ganglia-thalamocortical system. II Dynamics of parkinsonian oscillations.

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van Albada, S J; Gray, R T; Drysdale, P M; Robinson, P A

2009-04-21

Neuronal correlates of Parkinson's disease (PD) include a shift to lower frequencies in the electroencephalogram (EEG) and enhanced synchronized oscillations at 3-7 and 7-30 Hz in the basal ganglia, thalamus, and cortex. This study describes the dynamics of a recent physiologically based mean-field model of the basal ganglia-thalamocortical system, and shows how it accounts for many key electrophysiological correlates of PD. Its detailed functional connectivity comprises partially segregated direct and indirect pathways through two populations of striatal neurons, a hyperdirect pathway involving a corticosubthalamic projection, thalamostriatal feedback, and local inhibition in striatum and external pallidum (GPe). In a companion paper, realistic steady-state firing rates were obtained for the healthy state, and after dopamine loss modeled by weaker direct and stronger indirect pathways, reduced intrapallidal inhibition, lower firing thresholds of the GPe and subthalamic nucleus (STN), a stronger projection from striatum to GPe, and weaker cortical interactions. Here it is shown that oscillations around 5 and 20 Hz can arise with a strong indirect pathway, which also causes increased synchronization throughout the basal ganglia. Furthermore, increased theta power with progressive nigrostriatal degeneration is correlated with reduced alpha power and peak frequency, in agreement with empirical results. Unlike the hyperdirect pathway, the indirect pathway sustains oscillations with phase relationships that coincide with those found experimentally. Alterations in the responses of basal ganglia to transient stimuli accord with experimental observations. Reduced cortical gains due to both nigrostriatal and mesocortical dopamine loss lead to slower changes in cortical activity and may be related to bradykinesia. Finally, increased EEG power found in some studies may be partly explained by a lower effective GPe firing threshold, reduced GPe-GPe inhibition, and/or weaker

The Progressive BSSG Rat Model of Parkinson's: Recapitulating Multiple Key Features of the Human Disease.

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Jackalina M Van Kampen

Full Text Available The development of effective neuroprotective therapies for Parkinson's disease (PD has been severely hindered by the notable lack of an appropriate animal model for preclinical screening. Indeed, most models currently available are either acute in nature or fail to recapitulate all characteristic features of the disease. Here, we present a novel progressive model of PD, with behavioural and cellular features that closely approximate those observed in patients. Chronic exposure to dietary phytosterol glucosides has been found to be neurotoxic. When fed to rats, β-sitosterol β-d-glucoside (BSSG triggers the progressive development of parkinsonism, with clinical signs and histopathology beginning to appear following cessation of exposure to the neurotoxic insult and continuing to develop over several months. Here, we characterize the progressive nature of this model, its non-motor features, the anatomical spread of synucleinopathy, and response to levodopa administration. In Sprague Dawley rats, chronic BSSG feeding for 4 months triggered the progressive development of a parkinsonian phenotype and pathological events that evolved slowly over time, with neuronal loss beginning only after toxin exposure was terminated. At approximately 3 months following initiation of BSSG exposure, animals displayed the early emergence of an olfactory deficit, in the absence of significant dopaminergic nigral cell loss or locomotor deficits. Locomotor deficits developed gradually over time, initially appearing as locomotor asymmetry and developing into akinesia/bradykinesia, which was reversed by levodopa treatment. Late-stage cognitive impairment was observed in the form of spatial working memory deficits, as assessed by the radial arm maze. In addition to the progressive loss of TH+ cells in the substantia nigra, the appearance of proteinase K-resistant intracellular α-synuclein aggregates was also observed to develop progressively, appearing first in the

The effect of electroacupuncture on proteomic changes in the motor cortex of 6-OHDA Parkinsonian rats.

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Li, Min; Li, Lijuan; Wang, Ke; Su, Wenting; Jia, Jun; Wang, Xiaomin

2017-10-15

Electroacupuncture (EA) has been reported to alleviate motor deficits in Parkinson's disease (PD) patients, and PD animal models. However, the mechanisms by which EA improves motor function have not been investigated. We have employed a 6-hydroxydopamine (6-OHDA) unilateral injection induced PD model to investigate whether EA alters protein expression in the motor cortex. We found that 4weeks of EA treatment significantly improved spontaneous floor plane locomotion and rotarod performance. High-throughput proteomic analysis in the motor cortex was employed. The expression of 54 proteins were altered in the unlesioned motor cortex, and 102 protein expressions were altered in the lesioned motor cortex of 6-OHDA rats compared to sham rats. Compared to non-treatment PD control, EA treatment reversed 6 proteins in unlesioned and 19 proteins in lesioned motor cortex. The present study demonstrated that PD induces proteomic changes in the motor cortex, some of which are rescued by EA treatment. These targeted proteins were mainly involved in increasing autophagy, mRNA processing and ATP binding and maintaining the balance of neurotransmitters. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of Electrical and Optogenetic Deep Brain Stimulation on Synchronized Oscillatory Activity in Parkinsonian Basal Ganglia.

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Ratnadurai-Giridharan, Shivakeshavan; Cheung, Chung C; Rubchinsky, Leonid L

2017-11-01

Conventional deep brain stimulation of basal ganglia uses high-frequency regular electrical pulses to treat Parkinsonian motor symptoms but has a series of limitations. Relatively new and not yet clinically tested, optogenetic stimulation is an effective experimental stimulation technique to affect pathological network dynamics. We compared the effects of electrical and optogenetic stimulation of the basal gangliaon the pathologicalParkinsonian rhythmic neural activity. We studied the network response to electrical stimulation and excitatory and inhibitory optogenetic stimulations. Different stimulations exhibit different interactions with pathological activity in the network. We studied these interactions for different network and stimulation parameter values. Optogenetic stimulation was found to be more efficient than electrical stimulation in suppressing pathological rhythmicity. Our findings indicate that optogenetic control of neural synchrony may be more efficacious than electrical control because of the different ways of how stimulations interact with network dynamics.

Fetal porcine ventral mesencephalon graft. Determination of the optimal gestational age for implantation in Parkinsonian patients

NARCIS (Netherlands)

HogenEsch, RI; Koopmans, J; Copray, JCVM; van Roon, WMC; Kema, [No Value; Molenaar, G; Go, KG; Staal, MJ

Human fetal ventral mesencephalon tissue has been used as dopaminergic striatal implants in Parkinsonian patients, so far with variable effects. Fetuses from animals that breed in large litters, e.g., pigs, have been considered as alternative donors of dopaminergic tissue. The optimal gestational

Primary motor cortex of the parkinsonian monkey: altered encoding of active movement

Science.gov (United States)

Pasquereau, Benjamin; DeLong, Mahlon R.

2016-01-01

Abnormalities in the movement-related activation of the primary motor cortex (M1) are thought to be a major contributor to the motor signs of Parkinson’s disease. The existing evidence, however, variably indicates that M1 is under-activated with movement, overactivated (due to a loss of functional specificity) or activated with abnormal timing. In addition, few models consider the possibility that distinct cortical neuron subtypes may be affected differently. Those gaps in knowledge were addressed by studying the extracellular activity of antidromically-identified lamina 5b pyramidal-tract type neurons (n = 153) and intratelencephalic-type corticostriatal neurons (n = 126) in the M1 of two monkeys as they performed a step-tracking arm movement task. We compared movement-related discharge before and after the induction of parkinsonism by administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and quantified the spike rate encoding of specific kinematic parameters of movement using a generalized linear model. The fraction of M1 neurons with movement-related activity declined following MPTP but only marginally. The strength of neuronal encoding of parameters of movement was reduced markedly (mean 29% reduction in the coefficients from the generalized linear model). This relative decoupling of M1 activity from kinematics was attributable to reductions in the coefficients that estimated the spike rate encoding of movement direction (−22%), speed (−40%), acceleration (−49%) and hand position (−33%). After controlling for MPTP-induced changes in motor performance, M1 activity related to movement itself was reduced markedly (mean 36% hypoactivation). This reduced activation was strong in pyramidal tract-type neurons (−50%) but essentially absent in corticostriatal neurons. The timing of M1 activation was also abnormal, with earlier onset times, prolonged response durations, and a 43% reduction in the prevalence of movement-related changes

[Deep brain stimulation in parkinsonian patients with dopa intolerance].

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García-Ruiz, Pedro J; Feliz-Feliz, Cici; Ayerbe Gracia, Joaquín; Matías Arbelo, José; Salvador, Carlos; Val Fernández, Javier Del; García-Caldentey, Juan

2017-10-28

Deep brain stimulation (DBS) is at present, a useful treatment for patients with advanced Parkinson's disease and motor complications. The crucial step toward consistent DBS outcomes remains careful patient selection; several conditions must be fulfilled including excellent levo dopa response. We report two cases of early onset Parkinson's disease with severe intolerance to levo dopa but excellent and sustained response to DBS. DBS can be a useful alternative for parkinsonian patients with severe intolerance to levo dopa, provided a positive acute response to levo dopa or apomorphine is obtained. Copyright © 2017 Sociedad Española de Neurocirugía. Publicado por Elsevier España, S.L.U. All rights reserved.

Parkinsonian Symptomatology May Correlate with CT Findings before and after Shunting in Idiopathic Normal Pressure Hydrocephalus

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Mitsuaki Ishii

2010-01-01

Full Text Available We aimed to investigate the characteristics of Parkinsonian features assessed by the unified Parkinson's disease rating scale (UPDRS and determine their correlations with the computed tomography (CT findings in patients with idiopathic normal pressure hydrocephalus (iNPH. The total score and the scores for arising from chair, gait, postural stability, and body hypokinesia in the motor examination section of UPDRS were significantly improved after shunt operations. Stepwise multiple regression analysis revealed that postural stability was the determinant of the gait domain score of the iNPH grading scale. The canonical correlation analysis between the CT findings and the shunt-responsive Parkinsonian features indicated that Evans index rather than midbrain diameters had a large influence on the postural stability. Thus, the pathophysiology of postural instability as a cardinal feature of gait disturbance may be associated with impaired frontal projections close to the frontal horns of the lateral ventricles in the iNPH patients.

Piribedil and pathological gambling in six parkinsonian patients.

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Micheli, Federico E; Giugni, Juan C; Espinosa, Micke E De Arco; Calvo, Daniela S; Raina, Gabriela B

2015-02-01

Impulse control disorders (ICD) in Parkinson's disease (PD) have attracted increasing interest. They are characterized by the inability to control the impulse to perform an act that can be detrimental to them or to others. Although dopamine agonists (DA), as a group, have been associated with impulse control disorders (ICD), piribedil has rarely been reported to cause them. Case reports of six parkinsonian patients on piribedil presenting pathological gambling (PG). All of the patients presented ICD associated with piribedil use. Two of them received this medication as first treatment and four of them who had developed ICDs secondary to other DA that reappeared with piribedil. Despite piribedil is commercially available in only a few countries, it should be considered in the differential diagnosis of PG in patients with PD.

Piribedil and Pathological Gambling in six Parkinsonian patients

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Federico E. Micheli

2015-02-01

Full Text Available Impulse control disorders (ICD in Parkinson's disease (PD have attracted increasing interest. They are characterized by the inability to control the impulse to perform an act that can be detrimental to them or to others. Although dopamine agonists (DA, as a group, have been associated with impulse control disorders (ICD, piribedil has rarely been reported to cause them. Method Case reports of six parkinsonian patients on piribedil presenting pathological gambling (PG. Results All of the patients presented ICD associated with piribedil use. Two of them received this medication as first treatment and four of them who had developed ICDs secondary to other DA that reappeared with piribedil. Conclusion Despite piribedil is commercially available in only a few countries, it should be considered in the differential diagnosis of PG in patients with PD.

Optimized temporal pattern of brain stimulation designed by computational evolution.

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Brocker, David T; Swan, Brandon D; So, Rosa Q; Turner, Dennis A; Gross, Robert E; Grill, Warren M

2017-01-04

Brain stimulation is a promising therapy for several neurological disorders, including Parkinson's disease. Stimulation parameters are selected empirically and are limited to the frequency and intensity of stimulation. We varied the temporal pattern of deep brain stimulation to ameliorate symptoms in a parkinsonian animal model and in humans with Parkinson's disease. We used model-based computational evolution to optimize the stimulation pattern. The optimized pattern produced symptom relief comparable to that from standard high-frequency stimulation (a constant rate of 130 or 185 Hz) and outperformed frequency-matched standard stimulation in a parkinsonian rat model and in patients. Both optimized and standard high-frequency stimulation suppressed abnormal oscillatory activity in the basal ganglia of rats and humans. The results illustrate the utility of model-based computational evolution of temporal patterns to increase the efficiency of brain stimulation in treating Parkinson's disease and thereby reduce the energy required for successful treatment below that of current brain stimulation paradigms. Copyright © 2017, American Association for the Advancement of Science.

A Population of Indirect Pathway Striatal Projection Neurons Is Selectively Entrained to Parkinsonian Beta Oscillations.

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Sharott, Andrew; Vinciati, Federica; Nakamura, Kouichi C; Magill, Peter J

2017-10-11

Classical schemes of basal ganglia organization posit that parkinsonian movement difficulties presenting after striatal dopamine depletion stem from the disproportionate firing rates of spiny projection neurons (SPNs) therein. There remains, however, a pressing need to elucidate striatal SPN firing in the context of the synchronized network oscillations that are abnormally exaggerated in cortical-basal ganglia circuits in parkinsonism. To address this, we recorded unit activities in the dorsal striatum of dopamine-intact and dopamine-depleted rats during two brain states, respectively defined by cortical slow-wave activity (SWA) and activation. Dopamine depletion escalated striatal net output but had contrasting effects on "direct pathway" SPNs (dSPNs) and "indirect pathway" SPNs (iSPNs); their firing rates became imbalanced, and they disparately engaged in network oscillations. Disturbed striatal activity dynamics relating to the slow (∼1 Hz) oscillations prevalent during SWA partly generalized to the exaggerated beta-frequency (15-30 Hz) oscillations arising during cortical activation. In both cases, SPNs exhibited higher incidences of phase-locked firing to ongoing cortical oscillations, and SPN ensembles showed higher levels of rhythmic correlated firing, after dopamine depletion. Importantly, in dopamine-depleted striatum, a widespread population of iSPNs, which often displayed excessive firing rates and aberrant phase-locked firing to cortical beta oscillations, preferentially and excessively synchronized their firing at beta frequencies. Conversely, dSPNs were neither hyperactive nor synchronized to a large extent during cortical activation. These data collectively demonstrate a cell type-selective entrainment of SPN firing to parkinsonian beta oscillations. We conclude that a population of overactive, excessively synchronized iSPNs could orchestrate these pathological rhythms in basal ganglia circuits. SIGNIFICANCE STATEMENT Chronic depletion of dopamine

Association of heart rate variability with clinical outcome in Parkinsonian patients after subthalamic deep brain stimulation: A retrospective cohort study

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Shin-Yuan Chen

2011-09-01

Conclusion: Our study showed an improvement in autonomic cardiovascular regulation in Parkinsonian patients with >50% improvement in rating scale after STN-DBS, which implied morbidity reduction in nonmotor symptoms among such patients.

Effect of rhythmic auditory cueing on parkinsonian gait: A systematic review and meta-analysis.

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Ghai, Shashank; Ghai, Ishan; Schmitz, Gerd; Effenberg, Alfred O

2018-01-11

The use of rhythmic auditory cueing to enhance gait performance in parkinsonian patients' is an emerging area of interest. Different theories and underlying neurophysiological mechanisms have been suggested for ascertaining the enhancement in motor performance. However, a consensus as to its effects based on characteristics of effective stimuli, and training dosage is still not reached. A systematic review and meta-analysis was carried out to analyze the effects of different auditory feedbacks on gait and postural performance in patients affected by Parkinson's disease. Systematic identification of published literature was performed adhering to PRISMA guidelines, from inception until May 2017, on online databases; Web of science, PEDro, EBSCO, MEDLINE, Cochrane, EMBASE and PROQUEST. Of 4204 records, 50 studies, involving 1892 participants met our inclusion criteria. The analysis revealed an overall positive effect on gait velocity, stride length, and a negative effect on cadence with application of auditory cueing. Neurophysiological mechanisms, training dosage, effects of higher information processing constraints, and use of cueing as an adjunct with medications are thoroughly discussed. This present review bridges the gaps in literature by suggesting application of rhythmic auditory cueing in conventional rehabilitation approaches to enhance motor performance and quality of life in the parkinsonian community.

Model-based analysis and control of a network of basal ganglia spiking neurons in the normal and Parkinsonian states

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Liu, Jianbo; Khalil, Hassan K.; Oweiss, Karim G.

2011-08-01

Controlling the spatiotemporal firing pattern of an intricately connected network of neurons through microstimulation is highly desirable in many applications. We investigated in this paper the feasibility of using a model-based approach to the analysis and control of a basal ganglia (BG) network model of Hodgkin-Huxley (HH) spiking neurons through microstimulation. Detailed analysis of this network model suggests that it can reproduce the experimentally observed characteristics of BG neurons under a normal and a pathological Parkinsonian state. A simplified neuronal firing rate model, identified from the detailed HH network model, is shown to capture the essential network dynamics. Mathematical analysis of the simplified model reveals the presence of a systematic relationship between the network's structure and its dynamic response to spatiotemporally patterned microstimulation. We show that both the network synaptic organization and the local mechanism of microstimulation can impose tight constraints on the possible spatiotemporal firing patterns that can be generated by the microstimulated network, which may hinder the effectiveness of microstimulation to achieve a desired objective under certain conditions. Finally, we demonstrate that the feedback control design aided by the mathematical analysis of the simplified model is indeed effective in driving the BG network in the normal and Parskinsonian states to follow a prescribed spatiotemporal firing pattern. We further show that the rhythmic/oscillatory patterns that characterize a dopamine-depleted BG network can be suppressed as a direct consequence of controlling the spatiotemporal pattern of a subpopulation of the output Globus Pallidus internalis (GPi) neurons in the network. This work may provide plausible explanations for the mechanisms underlying the therapeutic effects of deep brain stimulation (DBS) in Parkinson's disease and pave the way towards a model-based, network level analysis and closed

[Establishment of rat model of psychical erectile dysfunction].

Science.gov (United States)

Wang, Qiu-lin; Wang, Shu-ren; Duan, Jin

2006-01-01

To set up a method of establishing the animal model of psychical erectile dysfunction with emotional stress. All thirty-six male rats with normal sexual function were divided into three groups, i. e. normal group, model group and demasculinized group randomly according to their weights. The rats in the model group were suspended upside down in midair over the water and irritated repeatedly. Two weeks later, the sexual abilities of all rats, i. e. the times of mounting and intromitting the estrus female rats, the latent period of mounting, intromission and ejaculation, were recorded, and the number of rats that had sexual activities was also counted. And the hemorheology indices of the rats were measured. Compared with the normal rats, the latency of mounting [(152.5 +/- 24.6) s vs (42.4 +/- 9.6) s] and intromission [(437.0 +/- 67.7) s vs (130.8 +/- 39.1) s] of the model rats were longer (P 0.05). The hemorheology indices, e. g. blood viscosity, hematocrit (Hct) and red cell aggregation (RCA), of the model rats was significant higher than that of the normal and demasculinized rats (P erectile dysfunction can be made ideally with psychical stress.

Parkinsonian syndromes presenting with circadian rhythm sleep disorder- advanced sleep-phase type.

Science.gov (United States)

Shukla, Garima; Kaul, Bhavna; Gupta, Anupama; Goyal, Vinay; Behari, Madhuri

2015-01-01

Circadian rhythm sleep disorder-advanced sleep-phase type is a relatively uncommon disorder, mostly seen among the elderly population. Impaired circadian rhythms have been reported in neurodegenerative conditions; however, there are no reports of any circadian rhythm sleep disorder among patients with Parkinsonian syndromes. We report two patients who presented with this circadian rhythm disorder, and were then diagnosed with a Parkinsonian syndrome. The cases. A 65-year-old retired man presented with history of abrupt change in sleep schedules, sleeping around 6.30-7 p.m. and waking up around 3-4 a.m. for the last 2 months. On detailed examination, the patient was observed to have symmetrical bradykinesia and cogwheel rigidity of limbs. A diagnosis of multiple system atrophy was made, supported by MRI findings and evidence of autonomic dysfunction. Symptoms of change in sleep-wake cycles resolved over the next 1 year, while the patient was treated with dopaminergic therapy. A 47-year-old man, who was being evaluated for presurgical investigation for refractory temporal lobe epilepsy, presented with complaints suggestive of dysarthria, bradykinesia of limbs and frequent falls for 5 months. Simultaneously, he began to sleep around 7 p.m. and wake up at about 2-3 a.m. Examination revealed severe axial rigidity, restricted vertical gaze and bradykinesia of limbs. A diagnosis of progressive supranuclear palsy was made. This is the first report of Parkinson's plus syndromes presenting with a circadian rhythm sleep disorder-advanced sleep-phase type. More prospective assessment for circadian sleep disorders may introduce useful insights into similar associations. Copyright 2015, NMJI.

Adenosine A2A Receptor Modulates the Activity of Globus Pallidus Neurons in Rats

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Hui-Ling Diao

2017-11-01

Full Text Available The globus pallidus is a central nucleus in the basal ganglia motor control circuit. Morphological studies have revealed the expression of adenosine A2A receptors in the globus pallidus. To determine the modulation of adenosine A2A receptors on the activity of pallidal neurons in both normal and parkinsonian rats, in vivo electrophysiological and behavioral tests were performed in the present study. The extracellular single unit recordings showed that micro-pressure administration of adenosine A2A receptor agonist, CGS21680, regulated the pallidal firing activity. GABAergic neurotransmission was involved in CGS21680-induced modulation of pallidal neurons via a PKA pathway. Furthermore, application of two adenosine A2A receptor antagonists, KW6002 or SCH442416, mainly increased the spontaneous firing of pallidal neurons, suggesting that endogenous adenosine system modulates the activity of pallidal neurons through adenosine A2A receptors. Finally, elevated body swing test (EBST showed that intrapallidal microinjection of adenosine A2A receptor agonist/antagonist induced ipsilateral/contralateral-biased swing, respectively. In addition, the electrophysiological and behavioral findings also revealed that activation of dopamine D2 receptors by quinpirole strengthened KW6002/SCH442416-induced excitation of pallidal activity. Co-application of quinpirole with KW6002 or SCH442416 alleviated biased swing in hemi-parkinsonian rats. Based on the present findings, we concluded that pallidal adenosine A2A receptors may be potentially useful in the treatment of Parkinson's disease.

IBZM SPECT and FDG PET in the differential diagnosis of Parkinsonian syndromes. Comparison with respect to inter-rater agreement

DEFF Research Database (Denmark)

Derlin, T; Afzal, W; Wilke, F

2010-01-01

Aim: Both IBZM SPECT and FDG PET may be used for differentiation between Parkinson's disease (PD) and atypical neurodegenerative parkinsonian syndromes (APS). However, there are only very limited data of both modalities in the same subjects. The present study compared both modalities with respect...

Brain monoamine oxidase B and A in human parkinsonian dopamine deficiency disorders.

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Tong, Junchao; Rathitharan, Gausiha; Meyer, Jeffrey H; Furukawa, Yoshiaki; Ang, Lee-Cyn; Boileau, Isabelle; Guttman, Mark; Hornykiewicz, Oleh; Kish, Stephen J

2017-09-01

See Jellinger (doi:10.1093/awx190) for a scientific commentary on this article. The enzyme monoamine oxidases (B and A subtypes, encoded by MAOB and MAOA, respectively) are drug targets in the treatment of Parkinson's disease. Inhibitors of MAOB are used clinically in Parkinson's disease for symptomatic purposes whereas the potential disease-modifying effect of monoamine oxidase inhibitors is debated. As astroglial cells express high levels of MAOB, the enzyme has been proposed as a brain imaging marker of astrogliosis, a cellular process possibly involved in Parkinson's disease pathogenesis as elevation of MAOB in astrocytes might be harmful. Since brain monoamine oxidase status in Parkinson's disease is uncertain, our objective was to measure, by quantitative immunoblotting in autopsied brain homogenates, protein levels of both monoamine oxidases in three different degenerative parkinsonian disorders: Parkinson's disease (n = 11), multiple system atrophy (n = 11), and progressive supranuclear palsy (n = 16) and in matched controls (n = 16). We hypothesized that if MAOB is 'substantially' localized to astroglial cells, MAOB levels should be generally associated with standard astroglial protein measures (e.g. glial fibrillary acidic protein). MAOB levels were increased in degenerating putamen (+83%) and substantia nigra (+10%, non-significant) in multiple system atrophy; in caudate (+26%), putamen (+27%), frontal cortex (+31%) and substantia nigra (+23%) of progressive supranuclear palsy; and in frontal cortex (+33%), but not in substantia nigra of Parkinson's disease, a region we previously reported no increase in astrocyte protein markers. Although the magnitude of MAOB increase was less than those of standard astrocytic markers, significant positive correlations were observed amongst the astrocyte proteins and MAOB. Despite suggestions that MAOA (versus MAOB) is primarily responsible for metabolism of dopamine in dopamine neurons, there was no loss of the

The neurogenetics of atypical parkinsonian disorders.

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Fogel, Brent L; Clark, Mary C; Geschwind, Daniel H

2014-04-01

Although classic Parkinson disease is the disorder most commonly associated with the clinical feature of parkinsonism, there is in fact a broader spectrum of disease represented by a collection of phenotypically similar neurodegenerative conditions that mimic many of its core features. These atypical parkinsonian disorders most commonly include progressive supranuclear palsy and corticobasal degeneration, disorders both associated with frontotemporal dementia, as well as multiple system atrophy and dementia with Lewy bodies. Although the clinical distinction of these disorders still remains a challenge to physicians, recent advances in genetics are poised to tease apart the differences. Insights into the molecular etiologies underlying these conditions will improve diagnosis, yield a better understanding of the underlying disease pathology, and ultimately lend stimulation to the development of potential treatments. At the same time, the wide range of phenotypes observed from mutations in a single gene warrants broad testing facilitated by advances in DNA sequencing. These expanding genomic approaches, ranging from the use of next-generation sequencing to identify causative or risk-associated gene variations to the study of epigenetic modification linking human genetics to environmental factors, are poised to lead the field into a new age of discovery. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Cortical stimulation evokes abnormal responses in the dopamine-depleted rat basal ganglia.

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Kita, Hitoshi; Kita, Takako

2011-07-13

The motor cortex (MC) sends massive projections to the basal ganglia. Motor disabilities in patients and animal models of Parkinson's disease (PD) may be caused by dopamine (DA)-depleted basal ganglia that abnormally process the information originating from MC. To study how DA depletion alters signal transfer in the basal ganglia, MC stimulation-induced (MC-induced) unitary responses were recorded from the basal ganglia of control and 6-hydroxydopamine-treated hemi-parkinsonian rats anesthetized with isoflurane. This report describes new findings about how DA depletion alters MC-induced responses. MC stimulation evokes an excitation in normally quiescent striatal (Str) neurons projecting to the globus pallidus external segment (GPe). After DA-depletion, the spontaneous firing of Str-GPe neurons increases, and MC stimulation evokes a shorter latency excitation followed by a long-lasting inhibition that was invisible under normal conditions. The increased firing activity and the newly exposed long inhibition generate tonic inhibition and a disfacilitation in GPe. The disfacilitation in GPe is then amplified in basal ganglia circuitry and generates a powerful long inhibition in the basal ganglia output nucleus, the globus pallidus internal segment. Intra-Str injections of a behaviorally effective dose of DA precursor l-3,4-dihydroxyphenylalanine effectively reversed these changes. These newly observed mechanisms also support the generation of pauses and burst activity commonly observed in the basal ganglia of parkinsonian subjects. These results suggest that the generation of abnormal response sequences in the basal ganglia contributes to the development of motor disabilities in PD and that intra-Str DA supplements effectively suppress abnormal signal transfer.

Parkinsonian Rest Tremor Is Associated With Modulations of Subthalamic High-Frequency Oscillations.

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Hirschmann, Jan; Butz, Markus; Hartmann, Christian J; Hoogenboom, Nienke; Özkurt, Tolga E; Vesper, Jan; Wojtecki, Lars; Schnitzler, Alfons

2016-10-01

High frequency oscillations (>200 Hz) have been observed in the basal ganglia of PD patients and were shown to be modulated by the administration of levodopa and voluntary movement. The objective of this study was to test whether the power of high-frequency oscillations in the STN is associated with spontaneous manifestation of parkinsonian rest tremor. The electromyogram of both forearms and local field potentials from the STN were recorded in 11 PD patients (10 men, age 58 [9.4] years, disease duration 9.2 [6.3] years). Patients were recorded at rest and while performing repetitive hand movements before and after levodopa intake. High-frequency oscillation power was compared across epochs containing rest tremor, tremor-free rest, or voluntary movement and related to the tremor cycle. We observed prominent slow (200-300 Hz) and fast (300-400 Hz) high-frequency oscillations. The ratio between slow and fast high-frequency oscillation power increased when tremor became manifest. This increase was consistent across nuclei (94%) and occurred in medication ON and OFF. The ratio outperformed other potential markers of tremor, such as power at individual tremor frequency, beta power, or low gamma power. For voluntary movement, we did not observe a significant difference when compared with rest or rest tremor. Finally, rhythmic modulations of high-frequency oscillation power occurred within the tremor cycle. Subthalamic high-frequency oscillation power is closely linked to the occurrence of parkinsonian rest tremor. The balance between slow and fast high-frequency oscillation power combines information on motor and medication state. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

Paraquat induces oxidative stress, neuronal loss in substantia nigra region and Parkinsonism in adult rats: Neuroprotection and amelioration of symptoms by water-soluble formulation of Coenzyme Q10

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Sridhar TS

2009-07-01

Full Text Available Abstract Background Parkinson's disease, for which currently there is no cure, develops as a result of progressive loss of dopamine neurons in the brain; thus, identification of any potential therapeutic intervention for disease management is of a great importance. Results Here we report that prophylactic application of water-soluble formulation of coenzyme Q10 could effectively offset the effects of environmental neurotoxin paraquat, believed to be a contributing factor in the development of familial PD. In this study we utilized a model of paraquat-induced dopaminergic neurodegeneration in adult rats that received three weekly intra-peritoneal injections of the herbicide paraquat. Histological and biochemical analyses of rat brains revealed increased levels of oxidative stress markers and a loss of approximately 65% of dopamine neurons in the substantia nigra region. The paraquat-exposed rats also displayed impaired balancing skills on a slowly rotating drum (rotorod evidenced by their reduced spontaneity in gait performance. In contrast, paraquat exposed rats receiving a water-soluble formulation of coenzyme Q10 in their drinking water prior to and during the paraquat treatment neither developed neurodegeneration nor reduced rotorod performance and were indistinguishable from the control paraquat-untreated rats. Conclusion Our data confirmed that paraquat-induced neurotoxicity represents a convenient rat model of Parkinsonian neurodegeneration suitable for mechanistic and neuroprotective studies. This is the first preclinical evaluation of a water-soluble coenzyme Q10 formulation showing the evidence of prophylactic neuroprotection at clinically relevant doses.

Rethinking Energy in Parkinsonian Motor Symptoms: A Potential Role for Neural Metabolic Deficits

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Shinichi eAmano

2015-01-01

Full Text Available Parkinson’s disease (PD is characterized as a chronic and progressive neurodegenerative disorder that results in a variety of debilitating symptoms, including bradykinesia, resting tremor, rigidity, and postural instability. Research spanning several decades has emphasized basal ganglia dysfunction, predominantly resulting from dopaminergic cell loss, as the primarily cause of the aforementioned parkinsonian features. But, why those particular features manifest themselves remains an enigma. The goal of this paper is to develop a theoretical framework that parkinsonian motor features are behavioral consequence of a long-term adaptation to their inability (inflexibility or lack of capacity to meet energetic demands, due to neural metabolic deficits arising from mitochondrial dysfunction associated with PD. Here, we discuss neurophysiological changes that are generally associated with PD, such as selective degeneration of dopaminergic neurons in the substantia nigra pars compacta, in conjunction with metabolic and mitochondrial dysfunction. We then characterize the cardinal motor symptoms of PD, bradykinesia, resting tremor, rigidity and gait disturbance, reviewing literature to demonstrate how these motor patterns are actually energy efficient from a metabolic perspective. We will also develop three testable hypotheses: (1 neural metabolic deficits precede the increased rate of neurodegeneration and onset of behavioral symptoms in PD, (2 motor behavior of persons with PD are more sensitive to changes in metabolic/bioenergetic state, and (3 improvement of metabolic function could lead to better motor performance in persons with PD. These hypotheses are designed to introduce a novel viewpoint that can elucidate the connections between metabolic, neural and motor function in PD.

Effects of crocin on brain oxidative damage and aversive memory in a 6-OHDA model of Parkinson's disease.

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Rajaei, Z; Hosseini, M; Alaei, H

2016-09-01

The purpose of the present study was to investigate the effect of crocin on brain oxidative damage and memory deficits in a 6-hydroxydopamine (6-OHDA) model of Parkinson's disease. Male Wistar rats were subjected to unilateral injection of 6-OHDA (16 µg) into the medial forebrain bundle and treated with crocin (30 and 60 mg/kg) for six weeks. The rats were tested for memory performance at six weeks after 6-OHDA infusion, and then were killed for the estimation of biochemical parameters. The increase in thiobarbituric acid reactive substances (TBARS) and nitrite levels in the hippocampus were observed in the 6-OHDA lesioned rats, which was accompanied by memory deficits in a passive avoidance test at the end of week 6. Moreover, treatment with crocin decreased TBARS and nitrite levels in the hippocampus, and improved aversive memory. The present study conclusively demonstrated that crocin acts as an antioxidant and anti-inflammatory agent in the hippocampus of parkinsonian rats and could improve aversive memory through its properties.

Alterations in energy metabolism, neuroprotection and visual signal transduction in the retina of Parkinsonian, MPTP-treated monkeys.

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Laura Campello

Full Text Available Parkinson disease is mainly characterized by the degeneration of dopaminergic neurons in the central nervous system, including the retina. Different interrelated molecular mechanisms underlying Parkinson disease-associated neuronal death have been put forward in the brain, including oxidative stress and mitochondrial dysfunction. Systemic injection of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP to monkeys elicits the appearance of a parkinsonian syndrome, including morphological and functional impairments in the retina. However, the intracellular events leading to derangement of dopaminergic and other retinal neurons in MPTP-treated animal models have not been so far investigated. Here we have used a comparative proteomics approach to identify proteins differentially expressed in the retina of MPTP-treated monkeys. Proteins were solubilized from the neural retinas of control and MPTP-treated animals, labelled separately with two different cyanine fluorophores and run pairwise on 2D DIGE gels. Out of >700 protein spots resolved and quantified, 36 were found to exhibit statistically significant differences in their expression levels, of at least ± 1.4-fold, in the parkinsonian monkey retina compared with controls. Most of these spots were excised from preparative 2D gels, trypsinized and subjected to MALDI-TOF MS and LC-MS/MS analyses. Data obtained were used for protein sequence database interrogation, and 15 different proteins were successfully identified, of which 13 were underexpressed and 2 overexpressed. These proteins were involved in key cellular functional pathways such as glycolysis and mitochondrial electron transport, neuronal protection against stress and survival, and phototransduction processes. These functional categories underscore that alterations in energy metabolism, neuroprotective mechanisms and signal transduction are involved in MPTP-induced neuronal degeneration in the retina, in similarity to

Histamine Potentiates Cyclosomatostatin-Induced Catalepsy in Old Rats

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Ionov

2015-05-01

Full Text Available Background The decreased level of somatostatin and increased level of histamine are detected in the Parkinsonian brain. In old Wistar rats, the brain somatostatin deficiency can initiate catalepsy that suggests the pathogenic significance of this abnormality in Parkinson’s disease (PD. The ability of histamine to affect the somatostatin deficiency action is not studied. Objectives The current study aimed to examine if histamine alters the cataleptogenic activity of the brain somatostatin deficiency in Wistar rats. Materials and Methods The animals used in the study were 100 - 110 and 736 - 767 days old. Catalepsy was evaluated by the bar test. The inhibition of the brain somatostatin activity was simulated by I.C.V. administration of cyclosomatostatin (cycloSOM, a somatostatin receptor antagonist. Results CycloSOM (0.2, 1.0, and 5.0 µg and histamine (1.0 and 10.0 µg alone were ineffective in both young and old animals. In combination, however, cycloSOM and histamine initiated cataleptic response in old rats. Effect of the combination was inhibited by H1 and H2 but not H3 antagonists. Conclusions CycloSOM and histamine synergistically exert catalepsy in old rats. In light of these data, the combination of the decreased brain level of somatostatin and increased brain level of histamine may be of pathogenic relevance for extrapyramidal signs in PD.

Neuroprotective potential of curcumin in combination with piperine against 6-hydroxy dopamine induced motor deficit and neurochemical alterations in rats.

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Singh, Shamsher; Kumar, Puneet

2017-02-01

6-hydroxy dopamine (6-OHDA) is a neurotoxin which on intranigral administration produces severe nigrostriatal damage with motor and cognitive deficit in animals. Curcumin (CMN) in combination with bioenhancer piperine (PP) in 6-hydroxydopamine-induced Parkinsonian rats was used to investigate the antioxidant, neuromodulatory and neuroprotective mechanisms. Hemi-Parkinson's rat model was developed with intranigral infusion of 6-OHDA (8 μg/2 μl, once, unilaterally), treatment with CMN (25 and 50 mg/kg) and combination of PP (2.5 mg/kg) with CMN (25 mg/kg) was given daily for 21 days starting from the 7th day after 6-OHDA infusion. The behavioral (locomotor, grip strength, and narrow beam walk) parameters were studied on weekly basis. On 22nd day, isolated brain preparations were subjected to biochemical (lipid peroxidation, glutathione, and nitrite), neuroinflammatory (IL-1β, IL-6, and TNF- α), and neurochemical (DA, NE, 5- HT, GABA, Glutamate, DOPAC, HVA, and 5-HIAA) analysis. Oral administration of CMN had significantly prevented behavioral, neuroinflammatory, and neurochemical changes and preserved the antioxidant potential of the nigrostriatum in rats treated with 6-OHDA. In the present study, PP and CMN had afforded a better neuroprotective effect compared to alone treatment on behavior, biochemical, neuroinflammatory, and neurochemical parameters in rats.

ENU mutagenesis to generate genetically modified rat models.

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van Boxtel, Ruben; Gould, Michael N; Cuppen, Edwin; Smits, Bart M G

2010-01-01

The rat is one of the most preferred model organisms in biomedical research and has been extremely useful for linking physiology and pathology to the genome. However, approaches to genetically modify specific genes in the rat germ line remain relatively scarce. To date, the most efficient approach for generating genetically modified rats has been the target-selected N-ethyl-N-nitrosourea (ENU) mutagenesis-based technology. Here, we describe the detailed protocols for ENU mutagenesis and mutant retrieval in the rat model organism.

Multi-class parkinsonian disorders classification with quantitative MR markers and graph-based features using support vector machines.

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Morisi, Rita; Manners, David Neil; Gnecco, Giorgio; Lanconelli, Nico; Testa, Claudia; Evangelisti, Stefania; Talozzi, Lia; Gramegna, Laura Ludovica; Bianchini, Claudio; Calandra-Buonaura, Giovanna; Sambati, Luisa; Giannini, Giulia; Cortelli, Pietro; Tonon, Caterina; Lodi, Raffaele

2018-02-01

In this study we attempt to automatically classify individual patients with different parkinsonian disorders, making use of pattern recognition techniques to distinguish among several forms of parkinsonisms (multi-class classification), based on a set of binary classifiers that discriminate each disorder from all others. We combine diffusion tensor imaging, proton spectroscopy and morphometric-volumetric data to obtain MR quantitative markers, which are provided to support vector machines with the aim of recognizing the different parkinsonian disorders. Feature selection is used to find the most important features for classification. We also exploit a graph-based technique on the set of quantitative markers to extract additional features from the dataset, and increase classification accuracy. When graph-based features are not used, the MR markers that are most frequently automatically extracted by the feature selection procedure reflect alterations in brain regions that are also usually considered to discriminate parkinsonisms in routine clinical practice. Graph-derived features typically increase the diagnostic accuracy, and reduce the number of features required. The results obtained in the work demonstrate that support vector machines applied to multimodal brain MR imaging and using graph-based features represent a novel and highly accurate approach to discriminate parkinsonisms, and a useful tool to assist the diagnosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Oxidative stress of crystalline lens in rat menopausal model

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Acer, Semra; Pekel, Gökhan; Küçükatay, Vural; Karabulut, Aysun; Yağcı, Ramazan; Çetin, Ebru Nevin; Akyer, Şahika Pınar; Şahin, Barbaros

2016-01-01

ABSTRACT Purpose: To evaluate lenticular oxidative stress in rat menopausal models. Methods: Forty Wistar female albino rats were included in this study. A total of thirty rats underwent oophorectomy to generate a menopausal model. Ten rats that did not undergo oophorectomy formed the control group (Group 1). From the rats that underwent oophorectomy, 10 formed the menopause control group (Group 2), 10 were administered a daily injection of methylprednisolone until the end of the study (Gro...

Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: Focusing on neuroprotective effects of stromal cell-derived factor-1α

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Tayra Judith

2010-04-01

Full Text Available Abstract Background Mesenchymal stem cells (MSCs are pluripotent stem cells derived from bone marrow with secretory functions of various neurotrophic factors. Stromal cell-derived factor-1α (SDF-1α is also reported as one of chemokines released from MSCs. In this research, the therapeutic effects of MSCs through SDF-1α were explored. 6-hydroxydopamine (6-OHDA, 20 μg was injected into the right striatum of female SD rats with subsequent administration of GFP-labeled MSCs, fibroblasts, (i.v., 1 × 107 cells, respectively or PBS at 2 hours after 6-OHDA injection. All rats were evaluated behaviorally with cylinder test and amphetamine-induced rotation test for 1 month with consequent euthanasia for immunohistochemical evaluations. Additionally, to explore the underlying mechanisms, neuroprotective effects of SDF-1α were explored using 6-OHDA-exposed PC12 cells by using dopamine (DA assay and TdT-mediated dUTP-biotin nick-end labeling (TUNEL staining. Results Rats receiving MSC transplantation significantly ameliorated behaviorally both in cylinder test and amphetamine-induced rotation test compared with the control groups. Correspondingly, rats with MSCs displayed significant preservation in the density of tyrosine hydroxylase (TH-positive fibers in the striatum and the number of TH-positive neurons in the substantia nigra pars compacta (SNc compared to that of control rats. In the in vitro study, SDF-1α treatment increased DA release and suppressed cell death induced by 6-OHDA administration compared with the control groups. Conclusions Consequently, MSC transplantation might exert neuroprotection on 6-OHDA-exposed dopaminergic neurons at least partly through anti-apoptotic effects of SDF-1α. The results demonstrate the potentials of intravenous MSC administration for clinical applications, although further explorations are required.

Reversal of haloperidol induced motor deficits in rats exposed to repeated immobilization stress.

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Shireen, Erum; Pervez, Sidra; Masroor, Maria; Ali, Wafa Binte; Rais, Qudsia; Khalil, Samira; Tariq, Anum; Haleem, Darakshan Jabeen

2014-09-01

Stress is defined as a non specific response of body to any physiological and psychological demand. Preclinical studies have shown that an uncontrollable stress condition produces neurochemical and behavioral deficits. The present study was conducted to test the hypothesis that a decrease in the responsiveness of somatodendritic 5-hydroxytryptamine (5-HT)-1A receptors following adaptation to stress could attenuate haloperidol induced acute parkinsonian like effect. Results showed that single exposure (2h) to immobilization stress markedly decreased food intake, growth rate and locomotor activity but these stress-induced behavioral deficits were not observed following repeated (2h/day for 5 days) exposure of immobilization stress suggesting behavioral tolerance occurs to similar stress. An important finding of present study is a reversal of haloperidol-induced motor deficits in animals exposed to repeated immobilization stress than respective control animals. It is suggested that stress induced possible desensitization of somatodendritic 5-HT-1A as well as 5-HT-2C receptors could release dopamine system from the inhibitory influence of serotonin. On the other hand, an increase in the effectiveness of postsynaptic 5-HT-1A receptors elicits a direct stimulatory influence on the activity of dopaminergic neuron and is possibly involved in the reversal of haloperidol-induced parkinsonian like symptoms in repeatedly immobilized rats.

A monoclonal antibody-GDNF fusion protein is not neuroprotective and is associated with proliferative pancreatic lesions in parkinsonian monkeys.

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Sachiko Ohshima-Hosoyama

Full Text Available Glial cell line derived neurotrophic factor (GDNF is a neurotrophic factor that has neuroprotective effects in animal models of Parkinson's disease (PD and has been proposed as a PD therapy. GDNF does not cross the blood brain barrier (BBB, and requires direct intracerebral delivery to be effective. Trojan horse technology, in which GDNF is coupled to a monoclonal antibody (mAb against the human insulin receptor (HIR, has been proposed to allow GDNF BBB transport (ArmaGen Technologies Inc.. In this study we tested the feasibility of HIRMAb-GDNF to induce neuroprotection in parkinsonian monkeys, as well as its tolerability and safety. Adult rhesus macaques were assessed throughout the study with a clinical rating scale, a computerized fine motor skills task and general health evaluations. Following baseline measurements, the animals received a unilateral intracarotid artery MPTP injection. Seven days later the animals were evaluated, matched according to disability and blindly assigned to receive twice a week i.v. treatments (vehicle, 1 or 5 mg/kg HIRmAb-GDNF for a period of three months. HIRmAb-GDNF did not improve parkinsonian motor symptoms and induced a dose-dependent hypersensitivity reaction. Quantification of dopaminergic striatal optical density and stereological nigral cell counts did not demonstrate differences between treatment groups. Focal pancreatic acinar to ductular metaplasia (ADM was noted in four of seven animals treated with 1 mg/kg HIRmAb-GDNF; two of four with ADM also had focal pancreatic intraepithelial neoplasia 1B (PanIN-1B lesions. Minimal to mild, focal to multifocal, nonsuppurative myocarditis was noted in all animals in the 5 mg/kg treatment group. Our results demonstrate that HIRmAb-GDNF dosing in a monkey model of PD is not an effective neuroprotective strategy and may present serious health risks that should be considered when planning future use of the IR antibody as a carrier, or of any systemic treatment of a

A Smart Tool for the Diagnosis of Parkinsonian Syndromes using Wireless Watches

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Andreas Goll

2014-11-01

Full Text Available Early detection and diagnosis of Parkinson disease will provide a good chance for patients to take early actions and prevent its further development. In this paper, a smart tool for the diagnosis of Parkinsonian syndromes is designed and developed using low–cost Texas Instruments eZ430-Chronos wireless watches. With this smart tool, Parkinson Bradykinesia is detected based on the cycle of a human gait, with the watch worn on the foot, and Parkinson Tremor shaking is detected and differed by frequency 0 to 8 Hz on the arm in real-time with a developed statistical diagnosis chart. It can be used in small clinics as well as home environment due to its low-cost and easy-use property.

[123I]FP-CIT (DaTSCAN) and SPET in the diagnostics of Parkinson's disease and Parkinsonian syndromes

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Chmielowski, K.; Szalus, B.; Pietrzykowski, J.; Brodacki, B.; Kotowicz, J.; Skrobowska, E.

2003-01-01

The aim of study was to verify the diagnostic value of the radiopharmaceutic [ 123I ]FP-CIT (DaTSCAN) in functional imaging of the presynaptical dopaminergic system in patients with Parkison's disease and parkinsonian syndromes: multiple system atrophy, orthostatic hypotonia Shy-Drager, essential tremor. That pilot study group consisted of 8 patients in which either preliminary diagnosis or suspicion of Parkinson's disease, parkinsonian syndrome or multiple system atrophy was set. Imaging of the brain with SPET (dual head detector Varicam Elscint) and MRI were performed. The radiopharmaceutic [ 123I ] FP-CIT (DaTSCAN) was administered intravenously in the dose 145 -148 MBq. SPET images were reconstructed by filtered backprojection with the use of Butterworth filter. The images were inspected visually. Images from SPET and MRI were superimposed by means of the workstation Hermes (Nucklear Diagnostic) with designatad regions interest (ROI) in the striatum and occipital cortex in order to assess semiquantitatively the binding of dopamine transporter. In the group of 8 patients evaluated with the use of [ 123I ]FP-CIT DaTSCAN four had normal results, and four - abnormal. The preliminary diagnosis was sustained in 3/8 of patients (including Parkinson's disease in two patients and multiple system atrophy in one patient). In the remainig 5 patients the preliminary diagnosis was changed, namely: in 2 cases the essential tremor was diagnosed, in 1 case - Parkinson's disease, in 1 case - orthostaic Sky-Drager, and in 1 case - despite the tremor of the upper limbs - results were normal. In all 8 patients the tracer proved to be useful in the confirmation of clinical diagnosis, especially in the differentiation between the essential tremor and Parkinson's disease. In the case of multiple system atrophy the imaging revealed significant loss of nigrostriatal dopaminergic neurons. Such loss was observed also in the cases of Parkinson's disease affecting the posterior parts of the

Histaminergic activity in a rodent model of Parkinson's disease.

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Nowak, Przemysław; Noras, Lukasz; Jochem, Jerzy; Szkilnik, Ryszard; Brus, Halina; Körossy, Eva; Drab, Jacek; Kostrzewa, Richard M; Brus, Ryszard

2009-04-01

Rats lesioned shortly after birth with 6-OHDA have been proposed to be a near-ideal model of severe Parkinson's disease, because of non-lethality of the procedure, near-total destruction of nigrostriatal dopaminergic fibers, and near-total dopamine (DA) denervation of striatum. There are scarce data that in Parkinson's disease, activity of the central histaminergic system is increased. Therefore, the aim of this study was to determine histamine content in the brain and the effect of histamine receptor antagonists on behavior of adult rats. At 3 days after birth, Wistar rats were pretreated with desipramine (20.0 mg/kg ip) 1 h before bilateral icv administration of the catecholaminergic neurotoxin 6-OHDA (67 microg base, on each side) or saline-ascorbic acid (0.1%) vehicle (control). At 8 weeks levels of DA and its metabolites L: -3,4-dihydroxyphenylalanine (DOPAC) and homovanillic acid (HVA) were estimated in the striatum and frontal cortex by HPCL/ED technique. In the hypothalamus, hippocampus, frontal cortex, and medulla oblongata, the level of histamine was analyzed by immunoenzymatic method. Behavioral observations (locomotion, exploratory-, oral-, and stereotyped-activity) were additionally made on control and 6-OHDA neonatally lesioned rats. Effects of DA receptor agonists (SKF 38393, apomorphine) and histamine receptor antagonists (e.g., S(+)chlorpheniramine, H(1); cimetidine, H(2); thioperamide, H(3) agonist) were determined. We confirmed that 6-OHDA significantly reduced contents of DA and its metabolites in the brain in adulthood. Histamine content was significantly increased in the hypothalamus, hipocampus, and medulla oblongata. Moreover, in 6-OHDA-lesioned rats behavioral response was altered mainly by thioperamide (H(3) antagonist). These findings indicate that histamine and the central histaminergic system are altered in the brain of rats lesioned to model Parkinson's disease, and that histaminergic neurons exert a modulating role in Parkinsonian 6

Steroid-associated osteonecrosis animal model in rats

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Li-Zhen Zheng

2018-04-01

Full Text Available Summary: Objective: Established preclinical disease models are essential for not only studying aetiology and/or pathophysiology of the relevant diseases but more importantly also for testing prevention and/or treatment concept(s. The present study proposed and established a detailed induction and assessment protocol for a unique and cost-effective preclinical steroid-associated osteonecrosis (SAON in rats with pulsed injections of lipopolysaccharide (LPS and methylprednisolone (MPS. Methods: Sixteen 24-week-old male Sprague–Dawley rats were used to induce SAON by one intravenous injection of LPS (0.2 mg/kg and three intraperitoneal injections of MPS (100 mg/kg with a time interval of 24 hour, and then, MPS (40 mg/kg was intraperitoneally injected three times a week from week 2 until sacrifice. Additional 12 rats were used as normal controls. Two and six weeks after induction, animals were scanned by metabolic dual energy X-ray absorptiometry for evaluation of tissue composition; serum was collected for bone turnover markers, Microfil perfusion was performed for angiography, the liver was collected for histopathology and bilateral femora and bilateral tibiae were collected for histological examination. Results: Three rats died after LPS injection, i.e., with 15.8% (3/19 mortality. Histological evaluation showed 100% incidence of SAON at week 2. Dual energy X-ray absorptiometry showed significantly higher fat percent and lower lean mass in SAON group at week 6. Micro-computed tomography (Micro-CT showed significant bone degradation at proximal tibia 6 weeks after SAON induction. Angiography illustrated significantly less blood vessels in the proximal tibia and significantly more leakage particles in the distal tibia 2 weeks after SAON induction. Serum amino-terminal propeptide of type I collagen and osteocalcin were significantly lower at both 2 and 6 weeks after SAON induction, and serum carboxy-terminal telopeptide was significantly

Carbidopa-based modulation of the functional effect of the AAV2-hAADC gene therapy in 6-OHDA lesioned rats.

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Agnieszka Ciesielska

Full Text Available Progressively blunted response to L-DOPA in Parkinson's disease (PD is a critical factor that complicates long-term pharmacotherapy in view of the central importance of this drug in management of the PD-related motor disturbance. This phenomenon is likely due to progressive loss of one of the key enzymes involved in the biosynthetic pathway for dopamine in the basal ganglia: aromatic L-amino acid decarboxylase (AADC. We have developed a gene therapy based on an adeno-associated virus encoding human AADC (AAV2-hAADC infused into the Parkinsonian striatum. Although no adverse clinical effects of the AAV2-hAADC gene therapy have been observed so far, the ability to more precisely regulate transgene expression or transgene product activity could be an important long-term safety feature. The present study was designed to define pharmacological regulation of the functional activity of AAV2-hAADC transgene product by manipulating L-DOPA and carbidopa (AADC inhibitor administration in hemi-parkinsonian rats. Thirty days after unilateral striatal infusion of AAV2-hAADC, animals displayed circling behavior and acceleration of dopamine metabolism in the lesioned striatum after administration of a low dose of L-DOPA (5 mg/kg co-administered with 1.25 mg/kg of carbidopa. This phenomenon was not observed in control AAV2-GFP-treated rats. Withdrawal of carbidopa from a daily L-DOPA regimen decreased the peripheral L-DOPA pool, resulting in almost total loss of L-DOPA-induced behavioral response in AAV2-hAADC rats and a significant decline in striatal dopamine turnover. The serum L-DOPA level correlated with the magnitude of circling behavior in AAV2-hAADC rats. Additionally, AADC activity in homogenates of lesioned striata transduced by AAV2-AADC was 10-fold higher when compared with AAV2-GFP-treated control striata, confirming functional transduction. Our data suggests that the pharmacological regulation of circulating L-DOPA might be effective in the

Glutamatergic Tuning of Hyperactive Striatal Projection Neurons Controls the Motor Response to Dopamine Replacement in Parkinsonian Primates.

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Singh, Arun; Jenkins, Meagan A; Burke, Kenneth J; Beck, Goichi; Jenkins, Andrew; Scimemi, Annalisa; Traynelis, Stephen F; Papa, Stella M

2018-01-23

Dopamine (DA) loss in Parkinson's disease (PD) alters the function of striatal projection neurons (SPNs) and causes motor deficits, but DA replacement can induce further abnormalities. A key pathological change in animal models and patients is SPN hyperactivity; however, the role of glutamate in altered DA responses remains elusive. We tested the effect of locally applied AMPAR or NMDAR antagonists on glutamatergic signaling in SPNs of parkinsonian primates. Following a reduction in basal hyperactivity by antagonists at either receptor, DA inputs induced SPN firing changes that were stable during the entire motor response, in clear contrast with the typically unstable effects. The SPN activity reduction over an extended putamenal area controlled the release of involuntary movements in the "on" state and therefore improved motor responses to DA replacement. These results demonstrate the pathophysiological role of upregulated SPN activity and support strategies to reduce striatal glutamate signaling for PD therapy. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Implementation of the European multicentre database of healthy controls for [(123)I]FP-CIT SPECT increases diagnostic accuracy in patients with clinically uncertain parkinsonian syndromes

DEFF Research Database (Denmark)

Albert, Nathalie L; Unterrainer, Marcus; Diemling, Markus

2016-01-01

PURPOSE: Even though [(123)I]FP-CIT SPECT provides high accuracy in detecting nigrostriatal cell loss in neurodegenerative parkinsonian syndromes (PS), some patients with an inconclusive diagnosis remain. We investigated whether the diagnostic accuracy in patients with clinically uncertain PS wit...

Distributed neural actions of anti-parkinsonian therapies as revealed by PET

International Nuclear Information System (INIS)

Goerendt, I.K.; Mehta, M.A; Stern, J.S.; Brooks, D.J.; Lawrence, A.D.; Odin, P.

2006-01-01

There is a limited understanding of how different anti-parkinsonian treatments act at the neuronal systems level. Using positron emission tomography we examined the effects of levodopa and deep brain stimulation of the subthalamic nucleus on patterns of regional cerebral blood flow in patients with Parkinson's disease during a homogenous cognitive-behavioral state rather than during an unspecified resting state. We found that when medicated precuneus, frontal, parietal, cerebellar and midbrain areas were relatively more activated than when stimulated, whereas when stimulated the precentral gyrus, caudate and thalamus were relatively more activated than when medicated. Areas that were activated by both treatments included the temporal gyri, anterior thalamus, and midbrain. Regions of prefrontal cortex showed relatively greater activation in the 'off treatment' conditions of both the medicated and stimulated groups. Our findings suggest that the two treatment methods may lead to symptomatic relief via both common and different sites of action. (author)

Effect of the MK 801 and (-) nicotine intracerebral administration on Glu and Gaba extracellular concentration in the pedunculopontine nucleus from rats

International Nuclear Information System (INIS)

Blanco Lezcano, Lisette; Lorigados Pedre, Lourdes del Carmen; Gonzalez Fraguela, Maria Elena and others

2011-01-01

Although the pharmacological manipulation of the glutamatergic and cholinergic systems have been studied in animal models of Parkinson's Disease (PD), only some authors have done work on this topic at the pedunculopontine nucleus (PPN). The present work studied the changes in glutamate (Glu) and δ-aminobutyric acid (GABA) extracellular concentrations (EC) in the PPN from hemiparkinsonian rats by 6hydroxydopamine injection. The rats were locally perfused by MK-801 (10 μ mol/l) or (-) nicotine (10 mm) solutions by cerebral microdialysis. The biochemical studies were carried out through high performance liquid chromatography coupled to fluorescence detection. Mk-801 infusion induced a significant decrease of Glu (p< 0.01) and GABA (p< 0.01) EC in PPN. On the other hand (-) nicotine infusion induced a significant increase of Glu (p< 0.001) and GABA (p< 0.001) EC in PPN from hemiparkinsonian rats. The local blockade of NMDA receptors by MK-801 infusion facilitates the interaction between Glu and their metabotropic receptors that take part in presynaptic inhibition mechanisms and interfere with neurotransmitters release. Meanwhile, the nicotine infusion sums the effects of nicotinic receptor activation with the glutamatergic and gabaergic neurotransmission changes produced in the PPN in the parkinsonian condition. The cholinergic and glutamergic drug infusion in PPN impose a new adjustment to the neurotransmission at this level that is added to the neurochemical changes associated to dopaminergic denervation.

The physiological response of obese rat model with rambutan peel extract treatment

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Sri Rahayu Lestari

2014-09-01

Full Text Available Objective: To determine body weight gain, expression of Igf-1 and Igf-1 receptor on obese rat model treated with rambutan peel extract (RPE as a physiological response. Methods: Normal and obese rat feed with normal and high calorie diet around 1 2 weeks and continued to treat with ellagic acid, RPE 15, 30 and 60 mg/kg body weight respectively. Physiological responses observed were weight gain and expression of Igf-1 with its receptor. Body weight of rat was weighed once per week. Expression of Igf-1 and igf-1R observed with fluorescence immunohistochemistry. The intensity of Igf-1 and Igf-1R expression was analysis using FSX-BSW software. Results: The lowest weight gain was obtained on obese rat model treated with RPE 30 mg/kg body weight. The expression of Igf-1 and Igf-1R were reduced on obese rat model treated with RPE compared with obese rat model of non treatment (P<0.05. The low expression of Igf-1 and Igf-1R was found on obese rat model treated with ellagic acid and RPE 30 mg/kg body weight. Conclusions: The RPE was effecting to the physiological response on obese rat model. The RPE 30 mg/kg body weight inhibited body weight gain and decreased the expression of Igf-1 and Igf- 1R of obese rat model.

Imaging biomarkers in Parkinson's disease and Parkinsonian syndromes: current and emerging concepts.

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Saeed, Usman; Compagnone, Jordana; Aviv, Richard I; Strafella, Antonio P; Black, Sandra E; Lang, Anthony E; Masellis, Mario

2017-01-01

Two centuries ago in 1817, James Parkinson provided the first medical description of Parkinson's disease, later refined by Jean-Martin Charcot in the mid-to-late 19th century to include the atypical parkinsonian variants (also termed, Parkinson-plus syndromes). Today, Parkinson's disease represents the second most common neurodegenerative disorder with an estimated global prevalence of over 10 million. Conversely, atypical parkinsonian syndromes encompass a group of relatively heterogeneous disorders that may share some clinical features with Parkinson's disease, but are uncommon distinct clinicopathological diseases. Decades of scientific advancements have vastly improved our understanding of these disorders, including improvements in in vivo imaging for biomarker identification. Multimodal imaging for the visualization of structural and functional brain changes is especially important, as it allows a 'window' into the underlying pathophysiological abnormalities. In this article, we first present an overview of the cardinal clinical and neuropathological features of, 1) synucleinopathies: Parkinson's disease and other Lewy body spectrum disorders, as well as multiple system atrophy, and 2) tauopathies: progressive supranuclear palsy, and corticobasal degeneration. A comprehensive presentation of well-established and emerging imaging biomarkers for each disorder are then discussed. Biomarkers for the following imaging modalities are reviewed: 1) structural magnetic resonance imaging (MRI) using T1, T2, and susceptibility-weighted sequences for volumetric and voxel-based morphometric analyses, as well as MRI derived visual signatures, 2) diffusion tensor MRI for the assessment of white matter tract injury and microstructural integrity, 3) proton magnetic resonance spectroscopy for quantifying proton-containing brain metabolites, 4) single photon emission computed tomography for the evaluation of nigrostriatal integrity (as assessed by presynaptic dopamine

Acoustic noise improves motor learning in spontaneously hypertensive rats, a rat model of attention deficit hyperactivity disorder.

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Söderlund, Göran B W; Eckernäs, Daniel; Holmblad, Olof; Bergquist, Filip

2015-03-01

The spontaneously hypertensive (SH) rat model of ADHD displays impaired motor learning. We used this characteristic to study if the recently described acoustic noise benefit in learning in children with ADHD is also observed in the SH rat model. SH rats and a Wistar control strain were trained in skilled reach and rotarod running under either ambient noise or in 75 dBA white noise. In other animals the effect of methylphenidate (MPH) on motor learning was assessed with the same paradigms. To determine if acoustic noise influenced spontaneous motor activity, the effect of acoustic noise was also determined in the open field activity paradigm. We confirm impaired motor learning in the SH rat compared to Wistar SCA controls. Acoustic noise restored motor learning in SH rats learning the Montoya reach test and the rotarod test, but had no influence on learning in Wistar rats. Noise had no effect on open field activity in SH rats, but increased corner time in Wistar. MPH completely restored rotarod learning and performance but did not improve skilled reach in the SH rat. It is suggested that the acoustic noise benefit previously reported in children with ADHD is shared by the SH rat model of ADHD, and the effect is in the same range as that of stimulant treatment. Acoustic noise may be useful as a non-pharmacological alternative to stimulant medication in the treatment of ADHD. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Interaction between subclinical doses of the Parkinson's disease associated gene, α-synuclein, and the pesticide, rotenone, precipitates motor dysfunction and nigrostriatal neurodegeneration in rats.

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Naughton, Carol; O'Toole, Daniel; Kirik, Deniz; Dowd, Eilís

2017-01-01

In most patients, Parkinson's disease is thought to emerge after a lifetime of exposure to, and interaction between, various genetic and environmental risk factors. One of the key genetic factors linked to this condition is α-synuclein, and the α-synuclein protein is pathologically associated with idiopathic cases. However, α-synuclein pathology is also present in presymptomatic, clinically "normal" individuals suggesting that environmental factors, such as Parkinson's disease-linked agricultural pesticides, may be required to precipitate Parkinson's disease in these individuals. In this context, the aim of this study was to assess the behavioural and neuropathological impact of exposing rats with a subclinical load of α-synuclein to subclinical doses of the organic pesticide, rotenone. Rats were randomly assigned to two groups for intra-nigral infusion of AAV 2/5- GFP or AAV 2/5 -α-synuclein. Post viral motor function was assessed at 8, 10 and 12 weeks in the Corridor, Stepping and Whisker tests of lateralised motor function. At week 12, animals were performance-matched to receive a subsequent intra-striatal challenge of the organic pesticide rotenone (or its vehicle) to yield four final groups (Control, Rotenone, AAV 2/5 -α-synuclein and Combined). Behavioural testing resumed one week after rotenone surgery and continued for 5 weeks. We found that, when administered alone, neither intra-nigral AAV-α-synuclein nor intra-striatal rotenone caused sufficient nigrostriatal neurodegeneration to induce a significant motor impairment in their own right. However, when these were administered sequentially to the same rats, the interaction between the two Parkinsonian challenges significantly exacerbated nigrostriatal neurodegeneration which precipitated a pronounced impairment in motor function. These results indicate that exposing rats with a subclinical α-synuclein-induced pathology to the pesticide, rotenone, profoundly exacerbates their Parkinsonian

Efficacy of rasagiline in patients with the parkinsonian variant of multiple system atrophy: a randomised, placebo-controlled trial.

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Poewe, Werner; Seppi, Klaus; Fitzer-Attas, Cheryl J; Wenning, Gregor K; Gilman, Sid; Low, Phillip A; Giladi, Nir; Barone, Paolo; Sampaio, Cristina; Eyal, Eli; Rascol, Olivier

2015-02-01

Multiple system atrophy is a complex neurodegenerative disorder for which no effective treatment exists. We aimed to assess the effect of rasagiline on symptoms and progression of the parkinsonian variant of multiple system atrophy. We did this randomised, double-blind, placebo-controlled trial between Dec 15, 2009, and Oct 20, 2011, at 40 academic sites specialised in the care of patients with multiple systemic atrophy across 12 countries. Eligible participants aged 30 years or older with possible or probable parkinsonian variant multiple system atrophy were randomly assigned (1:1), via computer-generated block randomisation (block size of four), to receive either rasagiline 1 mg per day or placebo. Randomisation was stratified by study centre. The investigators, study funder, and personnel involved in patient assessment, monitoring, analysis and data management were masked to group assignment. The primary endpoint was change from baseline to study end in total Unified Multiple System Atrophy Rating Scale (UMSARS) score (parts I and II). Analysis was by modified intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00977665. We randomly assigned 174 participants to the rasagiline group (n=84) or the placebo group (n=90); 21 (25%) patients in the rasagiline group and 15 (17%) in the placebo group withdrew from the study early. At week 48, patients in the rasagiline group had progressed by an adjusted mean of 7·2 (SE 1·2) total UMSARS units versus 7·8 (1·1) units in those in the placebo group. This treatment difference of -0·60 (95% CI -3·68 to 2·47; p=0·70) was not significant. 68 (81%) patients in the rasagiline group and 67 (74%) patients in the placebo group reported adverse events, and we recorded serious adverse events in 29 (35%) versus 23 (26%) patients. The most common adverse events in the rasagiline group were dizziness (n=10 [12%]), peripheral oedema (n=9 [11%]), urinary tract infections (n=9 [11%]), and orthostatic

Structure-Activity Relationship Models for Rat Carcinogenesis and Assessing the Role Mutagens Play in Model Predictivity

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Carrasquer, C. Alex; Batey, Kaylind; Qamar, Shahid; Cunningham, Albert R.; Cunningham, Suzanne L.

2016-01-01

We previously demonstrated that fragment based cat-SAR carcinogenesis models consisting solely of mutagenic or non-mutagenic carcinogens varied greatly in terms of their predictive accuracy. This led us to investigate how well the rat cancer cat-SAR model predicted mutagens and non-mutagens in their learning set. Four rat cancer cat-SAR models were developed: Complete Rat, Transgender Rat, Male Rat, and Female Rat, with leave-one-out (LOO) validation concordance values of 69%, 74%, 67%, and 73%, respectively. The mutagenic carcinogens produced concordance values in the range of 69–76% as compared to only 47–53% for non-mutagenic carcinogens. As a surrogate for mutagenicity comparisons between single site and multiple site carcinogen SAR models was analyzed. The LOO concordance values for models consisting of 1-site, 2-site, and 4+-site carcinogens were 66%, 71%, and 79%, respectively. As expected, the proportion of mutagens to non-mutagens also increased, rising from 54% for 1-site to 80% for 4+-site carcinogens. This study demonstrates that mutagenic chemicals, in both SAR learning sets and test sets, are influential in assessing model accuracy. This suggests that SAR models for carcinogens may require a two-step process in which mutagenicity is first determined before carcinogenicity can be accurately predicted. PMID:24697549

Oxidative stress of crystalline lens in rat menopausal model.

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Acer, Semra; Pekel, Gökhan; Küçükatay, Vural; Karabulut, Aysun; Yağcı, Ramazan; Çetin, Ebru Nevin; Akyer, Şahika Pınar; Şahin, Barbaros

2016-01-01

To evaluate lenticular oxidative stress in rat menopausal models. Forty Wistar female albino rats were included in this study. A total of thirty rats underwent oophorectomy to generate a menopausal model. Ten rats that did not undergo oophorectomy formed the control group (Group 1). From the rats that underwent oophorectomy, 10 formed the menopause control group (Group 2), 10 were administered a daily injection of methylprednisolone until the end of the study (Group 3), and the remaining 10 rats were administered intraperitoneal streptozocin to induce diabetes mellitus (Group 4). Total oxidant status (TOS), total antioxidant capacity (TAC), and oxidative stress index (OSI) measurements of the crystalline lenses were analyzed. The mean OSI was the lowest in group 1 and highest in group 4. Nevertheless, the difference between the groups was not statistically significant in terms of OSI (p >0.05). The mean TOS values were similar between the groups (p >0.05), whereas the mean TAC of group 1 was significantly higher than that of the other groups (p <0.001). Our results indicate that menopause may not promote cataract formation.

Thrombolytic and anticoagulation treatment in a rat embolic stroke model

DEFF Research Database (Denmark)

Rasmussen, Rune Skovgaard; Overgaard, K; Meden, P

2003-01-01

OBJECTIVES: The effects of pentasaccharide (PENTA), given alone or combined with thrombolysis using recombinant tissue plasminogen activator (rt-PA), on infarct size and clinical outcome were evaluated in a rat embolic stroke model. MATERIALS AND METHODS: Ninety-two rats were embolized unilateral...... alone or combined with rt-PA did not significantly increase mortality or tendency for hemorrhage.......OBJECTIVES: The effects of pentasaccharide (PENTA), given alone or combined with thrombolysis using recombinant tissue plasminogen activator (rt-PA), on infarct size and clinical outcome were evaluated in a rat embolic stroke model. MATERIALS AND METHODS: Ninety-two rats were embolized unilaterally...

ENU mutagenesis to generate genetically modified rat models

NARCIS (Netherlands)

van Boxtel, R.; Gould, M.; Cuppen, E.; Smits, B.M.

2010-01-01

The rat is one of the most preferred model organisms in biomedical research and has been extremely useful for linking physiology and pathology to the genome. However, approaches to genetically modify specific genes in the rat germ line remain relatively scarce. To date, the most efficient approach

Evidence for hydroxyl radical scavenging action of nitric oxide donors in the protection against 1-methyl-4-phenylpyridinium-induced neurotoxicity in rats.

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Banerjee, Rebecca; Saravanan, Karuppagounder S; Thomas, Bobby; Sindhu, Kizhake M; Mohanakumar, Kochupurackal P

2008-06-01

In the present study we provide evidence for hydroxyl radical (*OH) scavenging action of nitric oxide (NO*), and subsequent dopaminergic neuroprotection in a hemiparkinsonian rat model. Reactive oxygen species are strongly implicated in the nigrostriatal dopaminergic neurotoxicity caused by the parkinsonian neurotoxin, 1-methyl-4-phenylpyridinium (MPP+). Since the role of this free radical as a neurotoxicant or neuroprotectant is debatable, we investigated the effects of some of the NO* donors such as S-nitroso-N-acetylpenicillamine (SNAP), 3-morpholinosydnonimine hydrochloride (SIN-1), sodium nitroprusside (SNP) and nitroglycerin (NG) on in vitro *OH generation in a Fenton-like reaction involving ferrous citrate, as well as in MPP+-induced *OH production in the mitochondria. We also tested whether co-administration of NO* donor and MPP+ could protect against MPP+-induced dopaminergic neurotoxicity in rats. While NG, SNAP and SIN-1 attenuated MPP+-induced *OH generation in the mitochondria, and in a Fenton-like reaction, SNP caused up to 18-fold increase in *OH production in the latter reaction. Striatal dopaminergic depletion following intranigral infusion of MPP+ in rats was significantly attenuated by NG, SNAP and SIN-1, but not by SNP. Solutions of NG, SNAP and SIN-1, exposed to air for 48 h to remove NO*, when administered similarly failed to attenuate MPP+-induced neurotoxicity in vivo. Conversely, long-time air-exposed SNP solution when administered in rats intranigrally, caused a dose-dependent depletion of the striatal dopamine. These results confirm the involvement of *OH in the nigrostriatal degeneration caused by MPP+, indicate the *OH scavenging ability of NO*, and demonstrate protection by NO* donors against MPP+-induced dopaminergic neurotoxicity in rats.

Classification of Parkinsonian syndromes from FDG-PET brain data using decision trees with SSM/PCA features.

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Mudali, D; Teune, L K; Renken, R J; Leenders, K L; Roerdink, J B T M

2015-01-01

Medical imaging techniques like fluorodeoxyglucose positron emission tomography (FDG-PET) have been used to aid in the differential diagnosis of neurodegenerative brain diseases. In this study, the objective is to classify FDG-PET brain scans of subjects with Parkinsonian syndromes (Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy) compared to healthy controls. The scaled subprofile model/principal component analysis (SSM/PCA) method was applied to FDG-PET brain image data to obtain covariance patterns and corresponding subject scores. The latter were used as features for supervised classification by the C4.5 decision tree method. Leave-one-out cross validation was applied to determine classifier performance. We carried out a comparison with other types of classifiers. The big advantage of decision tree classification is that the results are easy to understand by humans. A visual representation of decision trees strongly supports the interpretation process, which is very important in the context of medical diagnosis. Further improvements are suggested based on enlarging the number of the training data, enhancing the decision tree method by bagging, and adding additional features based on (f)MRI data.

The characterization of obese polycystic ovary syndrome rat model suitable for exercise intervention.

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Chuyan Wu

Full Text Available To develop a new polycystic ovary syndrome (PCOS rat model suitable for exercise intervention.Thirty six rats were randomly divided into three experimental groups: PCOS rats with high-fat diet (PF, n = 24, PCOS rats with ordinary diet (PO, n = 6, and control rats with ordinary diet (CO, n = 6. Two kinds of PCOS rat model were made by adjustment diet structure and testosterone injection for 28 days. After a successful animal model, PF model rats were randomly assigned to three groups: exercise with a continuation of high-fat diet (PF-EF, n = 6, sedentary with a continuation of high-fat diet (PF-SF, n = 6, exercise with an ordinary diet (PF-EO, n = 6. Fasting blood glucose (FBG and insulin (FINS, estrogen (E2, progesterone (P, and testosterone (T in serum were determined by RIA, and ovarian morphology was evaluated by Image-Pro plus 6.0.Body weight, Lee index, FINS increased significantly in PF rat model. Serum levels of E2 and T were significantly higher in PF and PO than in CO. Ovary organ index and ovarian areas were significant lower in PF than in CO. After intervention for 2 weeks, the levels of 1 h postprandial blood glucose (PBG1, 2 h postprandial blood glucose (PBG2, FINS and the serum levels of T decreased significantly in PF-EF rats and PF-EO rats. The ratio of FBG/FINS was significant higher in PF-EO rats than in PF-SF rats. Ovarian morphology showed that the numbers of preantral follicles and atretic follicles decreased significantly, and the numbers of antral follicles and corpora lutea increased significantly in the rats of PF-EF and PF-EO.By combination of high-fat diet and testosterone injection, the obese PCOS rat model is conformable with the lifestyle habits of fatty foods and insufficient exercise, and has metabolic and reproductive characteristics of human PCOS. This model can be applied to study exercise intervention.

Treadmill Exercise Improves Motor Dysfunction and Hyperactivity of the Corticostriatal Glutamatergic Pathway in Rats with 6-OHDA-Induced Parkinson’s Disease

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Wei Chen

2017-01-01

Full Text Available Hyperactivity in the corticostriatal glutamatergic pathway (CGP induces basal ganglia dysfunction, contributing to parkinsonian syndrome (PS. Physical exercise can improve PS. However, the effect of exercise on the CGP, and whether this pathway is involved in the improvement of PS, remains unclear. Parkinson’s disease (PD was induced in rats by 6-hydroxydopamine injection into the right medial forebrain bundle. Motor function was assessed using the cylinder test. Striatal neuron (SN spontaneous and evoked firing activity was recorded, and the expression levels of Cav1.3 and CaMKII in the striatum were measured after 4 weeks of treadmill exercise. The motor function in PD rats was improved by treadmill exercise. SN showed significantly enhanced excitability, and treadmill exercise reduced SN excitability in PD rats. In addition, firing activity was evoked in SNs by stimulation of the primary motor cortex, and SNs exhibited significantly decreased stimulus threshold, increased firing rates, and reduced latency. The expression of Cav1.3 and p-CaMKII (Thr286 in the striatum were enhanced in PD rats. However, these effects were reversed by treadmill exercise. These findings suggest that treadmill exercise inhibits CGP hyperactivity in PD rats, which may be related to improvement of PS.

Oxidative stress of crystalline lens in rat menopausal model

Directory of Open Access Journals (Sweden)

Semra Acer

Full Text Available ABSTRACT Purpose: To evaluate lenticular oxidative stress in rat menopausal models. Methods: Forty Wistar female albino rats were included in this study. A total of thirty rats underwent oophorectomy to generate a menopausal model. Ten rats that did not undergo oophorectomy formed the control group (Group 1. From the rats that underwent oophorectomy, 10 formed the menopause control group (Group 2, 10 were administered a daily injection of methylprednisolone until the end of the study (Group 3, and the remaining 10 rats were administered intraperitoneal streptozocin to induce diabetes mellitus (Group 4. Total oxidant status (TOS, total antioxidant capacity (TAC, and oxidative stress index (OSI measurements of the crystalline lenses were analyzed. Results: The mean OSI was the lowest in group 1 and highest in group 4. Nevertheless, the difference between the groups was not statistically significant in terms of OSI (p >0.05. The mean TOS values were similar between the groups (p >0.05, whereas the mean TAC of group 1 was significantly higher than that of the other groups (p <0.001. Conclusions: Our results indicate that menopause may not promote cataract formation.

A novel model of invasive fungal rhinosinusitis in rats.

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Zhang, Fang; An, Yunfang; Li, Zeqing; Zhao, Changqing

2013-01-01

Invasive fungal rhinosinusitis (IFRS) is a life-threatening inflammatory disease that affects immunocompromised patients, but animal models of the disease are scarce. This study aimed to develop an IFRS model in neutropenic rats. The model was established in three consecutive steps: unilateral nasal obstruction with Merocel sponges, followed by administration of cyclophosphamide (CPA), and, finally, nasal inoculation with Aspergillus fumigatus. Fifty healthy Wistar rats were randomly divided into five groups, with group I as the controls, group II undergoing unilateral nasal obstruction alone, group III undergoing nasal obstruction with fungal inoculation, group IV undergoing nasal obstruction with administration of CPA, and group V undergoing nasal obstruction with administration of CPA and fungal inoculation. Hematology, histology, and mycology investigations were performed. The changes in the rat absolute neutrophil counts (ANCs) were statistically different across the groups. The administration of CPA decreased the ANCs, whereas nasal obstruction with fungal inoculation increased the ANCs, and nasal obstruction did not change them. Histological examination of the rats in group V revealed the hyphal invasion of sinus mucosa and bone, thrombosis, and tissue infarction. No pathology indicative of IFRS was observed in the remaining groups. Positive rates of fungal culture in tissue homogenates from the maxillary sinus (62.5%) and lung (25%) were found in group V, whereas groups I, II, III, and IV showed no fungal culture in the homogenates. A rat IFRS model was successfully developed through nasal obstruction, CPA-induced neutropenia, and fungal inoculation. The disease model closely mimics the pathophysiology of anthropic IFRS.

Rat models of spinal cord injury: from pathology to potential therapies

Science.gov (United States)

2016-01-01

ABSTRACT A long-standing goal of spinal cord injury research is to develop effective spinal cord repair strategies for the clinic. Rat models of spinal cord injury provide an important mammalian model in which to evaluate treatment strategies and to understand the pathological basis of spinal cord injuries. These models have facilitated the development of robust tests for assessing the recovery of locomotor and sensory functions. Rat models have also allowed us to understand how neuronal circuitry changes following spinal cord injury and how recovery could be promoted by enhancing spontaneous regenerative mechanisms and by counteracting intrinsic inhibitory factors. Rat studies have also revealed possible routes to rescuing circuitry and cells in the acute stage of injury. Spatiotemporal and functional studies in these models highlight the therapeutic potential of manipulating inflammation, scarring and myelination. In addition, potential replacement therapies for spinal cord injury, including grafts and bridges, stem primarily from rat studies. Here, we discuss advantages and disadvantages of rat experimental spinal cord injury models and summarize knowledge gained from these models. We also discuss how an emerging understanding of different forms of injury, their pathology and degree of recovery has inspired numerous treatment strategies, some of which have led to clinical trials. PMID:27736748

Optimal control of directional deep brain stimulation in the parkinsonian neuronal network

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Fan, Denggui; Wang, Zhihui; Wang, Qingyun

2016-07-01

The effect of conventional deep brain stimulation (DBS) on debilitating symptoms of Parkinson's disease can be limited because it can only yield the spherical field. And, some side effects are clearly induced with influencing their adjacent ganglia. Recent experimental evidence for patients with Parkinson's disease has shown that a novel DBS electrode with 32 independent stimulation source contacts can effectively optimize the clinical therapy by enlarging the therapeutic windows, when it is applied on the subthalamic nucleus (STN). This is due to the selective activation in clusters of various stimulation contacts which can be steered directionally and accurately on the targeted regions of interest. In addition, because of the serious damage to the neural tissues, the charge-unbalanced stimulation is not typically indicated and the real DBS utilizes charge-balanced bi-phasic (CBBP) pulses. Inspired by this, we computationally investigate the optimal control of directional CBBP-DBS from the proposed parkinsonian neuronal network of basal ganglia-thalamocortical circuit. By appropriately tuning stimulation for different neuronal populations, it can be found that directional steering CBBP-DBS paradigms are superior to the spherical case in improving parkinsonian dynamical properties including the synchronization of neuronal populations and the reliability of thalamus relaying the information from cortex, which is in a good agreement with the physiological experiments. Furthermore, it can be found that directional steering stimulations can increase the optimal stimulation intensity of desynchronization by more than 1 mA compared to the spherical case. This is consistent with the experimental result with showing that there exists at least one steering direction that can allow increasing the threshold of side effects by 1 mA. In addition, we also simulate the local field potential (LFP) and dominant frequency (DF) of the STN neuronal population induced by the activation

Cannabis exacerbates depressive symptoms in rat model induced by reserpine.

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Khadrawy, Yasser A; Sawie, Hussein G; Abdel-Salam, Omar M E; Hosny, Eman N

2017-05-01

Cannabis sativa is one of the most widely recreational drugs and its use is more prevalent among depressed patients. Some studies reported that Cannabis has antidepressant effects while others showed increased depressive symptoms in Cannabis users. Therefore, the present study aims to investigate the effect of Cannabis extract on the depressive-like rats. Twenty four rats were divided into: control, rat model of depression induced by reserpine and depressive-like rats treated with Cannabis sativa extract (10mg/kg expressed as Δ9-tetrahydrocannabinol). The depressive-like rats showed a severe decrease in motor activity as assessed by open field test (OFT). This was accompanied by a decrease in monoamine levels and a significant increase in acetylcholinesterase activity in the cortex and hippocampus. Na + ,K + -ATPase activity increased in the cortex and decreased in the hippocampus of rat model. In addition, a state of oxidative stress was evident in the two brain regions. This was indicated from the significant increase in the levels of lipid peroxidation and nitric oxide. No signs of improvement were observed in the behavioral and neurochemical analyses in the depressive-like rats treated with Cannabis extract. Furthermore, Cannabis extract exacerbated the lipid peroxidation in the cortex and hippocampus. According to the present findings, it could be concluded that Cannabis sativa aggravates the motor deficits and neurochemical changes induced in the cortex and hippocampus of rat model of depression. Therefore, the obtained results could explain the reported increase in the depressive symptoms and memory impairment among Cannabis users. Copyright © 2017 Elsevier B.V. All rights reserved.

Gut Microbial Diversity in Rat Model Induced by Rhubarb

Science.gov (United States)

Peng, Ying; Wu, Chunfu; Yang, Jingyu; Li, Xiaobo

2014-01-01

Rhubarb is often used to establish chronic diarrhea and spleen (Pi)-deficiency syndrome animal models in China. In this study, we utilized the enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR) method to detect changes in bacterial diversity in feces and the bowel mucosa associated with this model. Total microbial genomic DNA from the small bowel (duodenum, jejunum, and ileum), large bowel (proximal colon, distal colon, and rectum), cecum, and feces of normal and rhubarb-exposed rats were used as templates for the ERIC-PCR analysis. We found that the fecal microbial composition did not correspond to the bowel bacteria mix. More bacterial diversity was observed in the ileum of rhubarb-exposed rats (Panalysis with the SPSS software, the Canonical Discriminant Function Formulae for model rats was established. PMID:25048267

Generation and characterization of rat liver stem cell lines and their engraftment in a rat model of liver failure

Science.gov (United States)

Kuijk, Ewart W.; Rasmussen, Shauna; Blokzijl, Francis; Huch, Meritxell; Gehart, Helmuth; Toonen, Pim; Begthel, Harry; Clevers, Hans; Geurts, Aron M.; Cuppen, Edwin

2016-01-01

The rat is an important model for liver regeneration. However, there is no in vitro culture system that can capture the massive proliferation that can be observed after partial hepatectomy in rats. We here describe the generation of rat liver stem cell lines. Rat liver stem cells, which grow as cystic organoids, were characterized by high expression of the stem cell marker Lgr5, by the expression of liver progenitor and duct markers, and by low expression of hepatocyte markers, oval cell markers, and stellate cell markers. Prolonged cultures of rat liver organoids depended on high levels of WNT-signalling and the inhibition of BMP-signaling. Upon transplantation of clonal lines to a Fah−/− Il2rg−/− rat model of liver failure, the rat liver stem cells engrafted into the host liver where they differentiated into areas with FAH and Albumin positive hepatocytes. Rat liver stem cell lines hold potential as consistent reliable cell sources for pharmacological, toxicological or metabolic studies. In addition, rat liver stem cell lines may contribute to the development of regenerative medicine in liver disease. To our knowledge, the here described liver stem cell lines represent the first organoid culture system in the rat. PMID:26915950

Wendan decoction improves learning and memory deficits in a rat model of schizophrenia

Institute of Scientific and Technical Information of China (English)

Cuiping Yang; Changchun Cai; Xiaojin Yang; Yanping Yang; Zhigang Zhou; Jianhua Liu; Heping Ye; Hongjiao Wan

2012-01-01

An experimental model of schizophrenia was established using dizocilpine (MK-801). Rats were intragastrically administered with Wendan decoction or clozapine for 21 days prior to establishing the model. The results revealed that the latency of schizophrenia model rats to escape from the hidden platform in the Morris water maze was significantly shortened after administration of Wendan decoction or clozapine. In addition, the treated rats crossed the platform significantly more times than the untreated model rats. Moreover, the rate of successful long-term potentiation induction in the Wendan decoction group and clozapine group were also obviously increased compared with the model group, and the population spike peak latency was significantly shortened. These experimental findings suggest that Wendan decoction can improve the learning and memory ability of schizophrenic rats to the same extent as clozapine treatment.

Impact of surgery targeting the caudal intralaminar thalamic nuclei on the pathophysiological functioning of basal ganglia in a rat model of Parkinson's disease.

Science.gov (United States)

Kerkerian-Le Goff, Lydia; Bacci, Jean-Jacques; Jouve, Loreline; Melon, Christophe; Salin, Pascal

2009-02-16

There is accumulating evidence that the centre median-parafascicular (CM/Pf) complex of the thalamus is implicated in basal ganglia-related movement disorders and notably in Parkinson's disease. However, the impact of the changes affecting CM/Pf on the pathophysiological functioning of basal ganglia in parkinsonian state remains poorly understood. To address this issue, we have examined the effects of excitotoxic lesion of CM/Pf and of 6-hydroxydopamine-induced lesion of nigral dopamine neurons, separately or in association, on gene expression of markers of neuronal activity in the rat basal ganglia (striatal neuropeptide precursors, GAD67, cytochrome oxidase subunit I) by quantitative in situ hybridization histochemistry. CM/Pf lesion prevented the changes produced by the dopamine denervation in the components of the indirect pathway connecting the striatum to the output structures (striatopallidal neurons, globus pallidus, subthalamic nucleus), and among the output structures, in the entopeduncular nucleus. Preliminary data on the effects of deep brain stimulation of CM/Pf in rats with nigral dopamine lesion show that this surgical approach produces efficient anti-akinetic effect associated with partial reversal of the dopamine lesion-induced increase in striatal preproenkephalin A mRNA levels, a marker of the striatopallidal neurons. These data, which provide substrates for the potential of CM/Pf surgery in the treatment of movement disorders, are discussed in comparison with the effects of lesion or deep brain stimulation of the subthalamic nucleus, the currently preferred target for the surgical treatment of PD.

Phenotypic Characterization of LEA Rat: A New Rat Model of Nonobese Type 2 Diabetes

Directory of Open Access Journals (Sweden)

Tadashi Okamura

2013-01-01

Full Text Available Animal models have provided important information for the genetics and pathophysiology of diabetes. Here we have established a novel, nonobese rat strain with spontaneous diabetes, Long-Evans Agouti (LEA rat derived from Long-Evans (LE strain. The incidence of diabetes in the males was 10% at 6 months of age and 86% at 14 months, while none of the females developed diabetes. The blood glucose level in LEA male rats was between 200 and 300 mg/dl at 120 min according to OGTT. The glucose intolerance in correspondence with the impairment of insulin secretion was observed in male rats, which was the main cause of diabetes in LEA rats. Histological examination revealed that the reduction of β-cell mass was caused by progressive fibrosis in pancreatic islets in age-dependent manner. The intracytoplasmic hyaline droplet accumulation and the disappearance of tubular epithelial cell layer associated with thickening of basement membrane were evident in renal proximal tubules. The body mass index and glycaemic response to exogenous insulin were comparable to those of control rats. The unique characteristics of LEA rat are a great advantage not only to analyze the progression of diabetes, but also to disclose the genes involved in type 2 diabetes mellitus.

Persistent estrus rat models of polycystic ovary disease: an update.

Science.gov (United States)

Singh, Krishna B

2005-10-01

To critically review published articles on polycystic ovary (PCO) disease in rat models, with a focus on delineating its pathophysiology. Review of the English-language literature published from 1966 to March 2005 was performed through PubMed search. Keywords or phrases used were persistent estrus, chronic anovulation, polycystic ovary, polycystic ovary disease, and polycystic ovary syndrome. Articles were also located via bibliographies of published literature. University Health Sciences Center. Articles on persistent estrus and PCO in rats were selected and reviewed regarding the methods for induction of PCO disease. Changes in the reproductive cycle, ovarian morphology, hormonal parameters, and factors associated with the development of PCO disease in rat models were analyzed. Principal methods for inducing PCO in the rat include exposure to constant light, anterior hypothalamic and amygdaloidal lesions, and the use of androgens, estrogens, antiprogestin, and mifepristone. The validated rat PCO models provide useful information on morphologic and hormonal disturbances in the pathogenesis of chronic anovulation in this condition. These studies have aimed to replicate the morphologic and hormonal characteristics observed in the human PCO syndrome. The implications of these studies to human condition are discussed.

MRI and morphological observation in C6 glioma model rats and significance

International Nuclear Information System (INIS)

Zhou Ying; Yuan Bo; Wang Hao; Lu Jin; Yuan Changji; Ma Yue; Tong Dan; Zhang Kun; Gao Feng; Wu Xiaogang

2013-01-01

Objective: To establish stable and reliable rat C6 glioma model, and to perform MRI dynamic observation and pathomorphological observation in model animal brain, and to provide experimental basis for pharmaceutical research on anti-glioma drugs. Methods: The C6 glioma cells were cultured and 20 μL cultural fluid containing 1×10 6 C6 cells was sterotactically implanted into the left caudate nuclei in 10 male Wistar rats, respectively. The changes in the behavior of the rats after implantation were observed and recorded. MRI dynamic scanning was performed in 10 rats 2, 3 and 4 weeks after implantation and the brain tissues were taken for general and pathological examination when the 10 rats were naturally dead. The survival period of tumor-bearing rats was calculated. Results: 2 weeks after implantation the rats showed decreased activities and food intake, fur lackluster, and conjunctival congestion and so on; 3 weeks later, some rats appeared nerve symptoms such as body twitch, body hemiplegy, body distortion, rotation and so on. All the 10 rats died in 8-30 d. The median survival period of the tumor-bearing rats was 18 d, the average survival period was (18.3±7.3) d. The pathological examination showed that the tumor cells were arranged irregularly closely and karyokinesis was easy to see; tumor vascular tissue proliferation and tumor invasive growth into surrounding normal tissues were found. The expression of glial fibrillary acidic protein (GFAP) was positive in the tumors. Conclusion: A stable animal model of intracranial glioma is successfully established by stereotactic implantation of C6 cells into the rat caudate nucleus. The results of MRI dynamic observation and pathohistological observation on the model animal brain tissue. Can provide experimental basis for selecting the appropriate time window to perform the pharmaceutical research on anti-glioma drugs. (authors)

Hormone-induced rat model of polycystic ovary syndrome: A systematic review.

Science.gov (United States)

Noroozzadeh, Mahsa; Behboudi-Gandevani, Samira; Zadeh-Vakili, Azita; Ramezani Tehrani, Fahimeh

2017-12-15

Despite polycystic ovary syndrome (PCOS) being one of the most common endocrine disorders affecting reproductive-aged women, the etiopathogenesis and mechanisms of this syndrome remain unclear. Considering the ethical limitations in human studies, animal models that reflect many features of PCOS are crucial resources to investigate this syndrome. We aimed to introduce the most suitable rat model of PCOS that closely mimics the endocrine, ovarian and metabolic disturbances of human PCOS phenotype, while maintaining normal reproductive system morphology in adulthood, in order to further more detailed investigations about PCOS. We searched Pubmed, Science direct, and Web of science between 1990 and 2016, for relevant English manuscripts, using keywords including the "Polycystic Ovary Syndrome AND Rat Model" to generate a subset of citations relevant to our research. Included were those articles that compared at least both ovarian histology or estrous cycle and reproductive hormonal profiles in hormone-induced rat model of PCOS and controls. Differences in the findings between hormone-induced PCOS rats appear to be a result of the degree of transplacental transfer of the steroid administered into the fetus, dose and type of hormone, route of administration and timing and duration of exposure. We conclude that prenatal hormone-induced rat model with a lower dose and shorter time of exposure during the critical period of fetal development that exhibits endocrine, ovarian and metabolic disturbances similar to PCOS in women, while maintaining normal reproductive system morphology in adulthood is more suitable than postnatal hormone-induced rat model to facilitate studies regarding PCOS. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of the hook of Uncaria rhynchophylla on neurotoxicity in the 6-hydroxydopamine model of Parkinson's disease.

Science.gov (United States)

Shim, Jin Sup; Kim, Hyo Geun; Ju, Mi Sun; Choi, Jin Gyu; Jeong, Seo Young; Oh, Myung Sook

2009-11-12

While the hook of Uncaria rhynchophylla (URH) is a traditional herb used in northeast Asia for the treatment of Parkinson's disease (PD)-like symptoms such as tremor, it has not been experimentally evaluated in a PD model. We investigated the effects of URH on 6-hydroxydapamine (6-OHDA)-induced neurotoxicity in in vitro and in vivo models of PD. The cell viability, anti-oxidative activity, and anti-apoptotic activity of a water extract of URH (URE) were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide, reactive oxygen species (ROS), total glutathione (GSH), and caspase-3 assays in PC12 cells stressed by 6-OHDA. We also investigated the behavioral recovery and dopaminergic neuron protection of URE using an apomorphine-induced rotation test and tyrosine hydroxylase immunohistochemistry in the hemi-parkinsonian rat model of the unilateral 6-OHDA lesion of the medial forebrain bundle. In PC12 cells, URE significantly reduced cell death and the generation of ROS, increased GSH levels, and inhibited caspase-3 activity induced by 6-OHDA. In 6-OHDA-lesioned rats, posttreatment with URE (5 mg/kg/day for 14 days) significantly reduced apomorphine-induced rotation, and it lowered dopaminergic neuronal loss in substantia nigra pars compacta. URE possesses neuroprotective activity against 6-OHDA-induced toxicity through anti-oxidative and anti-apoptotic activities in PD models.

Generation of muscular dystrophy model rats with a CRISPR/Cas system.

Science.gov (United States)

Nakamura, Katsuyuki; Fujii, Wataru; Tsuboi, Masaya; Tanihata, Jun; Teramoto, Naomi; Takeuchi, Shiho; Naito, Kunihiko; Yamanouchi, Keitaro; Nishihara, Masugi

2014-07-09

Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disorder caused by mutations in the Dmd gene encoding Dystrophin. DMD model animals, such as mdx mice and canine X-linked muscular dystrophy dogs, have been widely utilized in the development of a treatment for DMD. Here, we demonstrate the generation of Dmd-mutated rats using a clustered interspaced short palindromic repeats (CRISPR)/Cas system, an RNA-based genome engineering technique that is also adaptive to rats. We simultaneously targeted two exons in the rat Dmd gene, which resulted in the absence of Dystrophin expression in the F0 generation. Dmd-mutated rats exhibited a decline in muscle strength, and the emergence of degenerative/regenerative phenotypes in the skeletal muscle, heart, and diaphragm. These mutations were heritable by the next generation, and F1 male rats exhibited similar phenotypes in their skeletal muscles. These model rats should prove to be useful for developing therapeutic methods to treat DMD.

Long-term BPA infusions. Evaluation in the rat brain tumor and rat spinal cord models

International Nuclear Information System (INIS)

Coderre, J.A.; Micca, P.L.; Nawrocky, M.M.; Joel, D.D.; Morris, G.M.

2000-01-01

In the BPA-based dose escalation clinical trial, the observations of tumor recurrence in areas of extremely high calculated tumor doses suggest that the BPA distribution is non-uniform. Longer (6-hour) i.v. infusions of BPA are evaluated in the rat brain tumor and spinal cord models to address the questions of whether long-term infusions are more effective against the tumor and whether long-term infusions are detrimental in the central nervous system. In the rat spinal cord, the 50% effective doses (ED 50 ) for myeloparesis were not significantly different after a single i.p. injection of BPA-fructose or a 6 hour i.v. infusion. In the rat 9L gliosarcoma brain tumor model, BNCT following 2-hr or 6-hr infusions of BPA-F produced similar levels of long term survival. (author)

Striatal grafts in a rat model of Huntington's disease

DEFF Research Database (Denmark)

Guzman, R; Meyer, M; Lövblad, K O

1999-01-01

Survival and integration into the host brain of grafted tissue are crucial factors in neurotransplantation approaches. The present study explored the feasibility of using a clinical MR scanner to study striatal graft development in a rat model of Huntington's disease. Rat fetal lateral ganglionic...... time-points graft location could not be further verified. Measures for graft size and ventricle size obtained from MR images highly correlated with measures obtained from histologically processed sections (R = 0.8, P fetal rat lateral ganglionic...

[Establishment of rat model with diabetes mellitus and concomitant periodontitis and the carotid artery lesions in the model rats].

Science.gov (United States)

Ren, X Y; Wang, C; Liu, X; Li, H; Gao, J H; Ge, X J

2017-12-09

Objectives: To establish SD rat model with type 2 diabetes mellitus (DM) and concomitant chronic periodontitis (CP) and to evaluate the influence of periodontitis on the vascular lesions of type 2 diabetes rats. Methods: Totally 241 clean level SD rats were randomly divided into four groups, group A (normal control, NC, n= 27), group B (DM, n= 34), group C (CP, n= 90) and group D (DM+CP, n= 90). The rats of DM group were fed with high-fat and high-sugar diet for 8 to 10 weeks, and then were multiply injected with small dose streptozotocin under the condition of ice bath. Blood sugar levels after the injection were dynamically monitored at 72 h, 1 week, 2 weeks and 4 weeks, respectively. The CP model was established by means of ligation. Bilateral maxillary first and second molars were selected and ligated using 0.2 mm orthodontic wires binding with 4-0 surgical suture soaked with Porphyromonas gingivalis (Pg) suspension. After a period of 14 weeks, all the rats were put to death. Maxillary samples were subjected to methylene blue staining to observe alveolar bone loss. Bilateral carotid artery specimens were collected. The left carotid artery specimens were used to detect the prevalence of Pg using quantitative real-time PCR. The right carotid artery specimens were used to observe pathological changes. Results: Blood sugar levels of rats in group B and D increased and changed sharply after Streptozotocin injection with in 1 week. Symptoms of 'more drink, more food and body weight loss' appeared. The fasting blood glucose (FBG) was more than 7.8 mmol/L and (or) the random blood glucose (RBG) was more than 17.8 mmol/L. Both FBG and RBG became stable after 2 to 3 weeks. Levels of HbA1C in group B and D ([7.32±0.45]%, [9.41±0.45]%) were significantly higher than that of group A ([4.02±0.45]%) ( Pdiabetes vascular lesions.

Validation of infrared thermography in serotonin-induced itch model in rats

DEFF Research Database (Denmark)

Dagnæs-Hansen, Frederik; Jasemian, Yousef; Gazerani, Parisa

The number of scratching bouts is generally used as a standard method in animal models of itch. The aim of the present study was to validate the application of infrared thermography (IR-Th) in a serotonin-induced itch model in rats. Adult Sprague-Dawley male rats (n = 24) were used in 3 consecuti...

A common optimization principle for motor execution in healthy subjects and parkinsonian patients.

Science.gov (United States)

Baraduc, Pierre; Thobois, Stéphane; Gan, Jing; Broussolle, Emmanuel; Desmurget, Michel

2013-01-09

Recent research on Parkinson's disease (PD) has emphasized that parkinsonian movement, although bradykinetic, shares many attributes with healthy behavior. This observation led to the suggestion that bradykinesia in PD could be due to a reduction in motor motivation. This hypothesis can be tested in the framework of optimal control theory, which accounts for many characteristics of healthy human movement while providing a link between the motor behavior and a cost/benefit trade-off. This approach offers the opportunity to interpret movement deficits of PD patients in the light of a computational theory of normal motor control. We studied 14 PD patients with bilateral subthalamic nucleus (STN) stimulation and 16 age-matched healthy controls, and tested whether reaching movements were governed by similar rules in these two groups. A single optimal control model accounted for the reaching movements of healthy subjects and PD patients, whatever the condition of STN stimulation (on or off). The choice of movement speed was explained in all subjects by the existence of a preset dynamic range for the motor signals. This range was idiosyncratic and applied to all movements regardless of their amplitude. In PD patients this dynamic range was abnormally narrow and correlated with bradykinesia. STN stimulation reduced bradykinesia and widened this range in all patients, but did not restore it to a normal value. These results, consistent with the motor motivation hypothesis, suggest that constrained optimization of motor effort is the main determinant of movement planning (choice of speed) and movement production, in both healthy and PD subjects.

A Rat Excised Larynx Model of Vocal Fold Scar

Science.gov (United States)

Welham, Nathan V.; Montequin, Douglas W.; Tateya, Ichiro; Tateya, Tomoko; Choi, Seong Hee; Bless, Diane M.

2009-01-01

Purpose: To develop and evaluate a rat excised larynx model for the measurement of acoustic, aerodynamic, and vocal fold vibratory changes resulting from vocal fold scar. Method: Twenty-four 4-month-old male Sprague-Dawley rats were assigned to 1 of 4 experimental groups: chronic vocal fold scar, chronic vocal fold scar treated with 100-ng basic…

Lodenafil treatment in the monocrotaline model of pulmonary hypertension in rats

OpenAIRE

Polonio, Igor Bastos; Acencio, Milena Marques Pagliareli; Pazetti, Rogério; Almeida, Francine Maria de; Silva, Bárbara Soares da; Pereira, Karina Aparecida Bonifácio; Souza, Rogério

2014-01-01

We assessed the effects of lodenafil on hemodynamics and inflammation in the rat model of monocrotaline-induced pulmonary hypertension (PH). Thirty male Sprague-Dawley rats were randomly divided into three groups: control; monocrotaline (experimental model); and lodenafil (experimental model followed by lodenafil treatment, p.o., 5 mg/kg daily for 28 days) Mean pulmonary artery pressure (mPAP) was obtained by right heart catheterization. We investigated right ventricular hypertrophy (RVH) and...

Improvement of insulin secretion in rat models of diabetes after ACEI/ARB therapy

International Nuclear Information System (INIS)

Tian Jingyan; Li Fengying; Liu Yun; Long Hongmei; Li Weiyi; Wang Xiao; Zhang Hongli; Li Guo; Luo Min

2009-01-01

Objective To study the effect of ACEI/ARB therapy on the secretion of insulin and glucagon as well as serum lipid peroxidation marker 8-iso PGF-2α levels in streptozoticin (STZ) induced diabetic rat models.Methods Twenty-four rat models of STZ induced diabetes were prepared (random blood sugar>16.7 mmol/L). Of which, 8 models were fed enalaprial 5mg/kg/d, 8 models were fed losartan 10μg/kg/d and 8 models left unterated. Fasting serum insulin,glucagon (with RIA) and 8-iso PGF-2α (with ELISA) levels were measured in these models and 8 control rats three weeks later. Intravenous glucose tolerance test (IVGTT) were performed in 12 rats (3 animals in each group) six weeks later. Results: Serum levels of insulin in the treated models were higher than those in the non-treated models but without significance (P>0.05). Serum levels of glucagon and 8-iso PGF-2α levels in the treated models were significantly lower than those in the non-treated models (P 6 x ) in the treated models. Conclusion: ACEI/ARB treatment could improve the secretion of insulin in rat models of diabetes, which might be beneficial for controlling the progression of the disease. This phenomenon is consistent with the result of clinical study. (authors)

Using a hybrid neuron in physiologically inspired models of the basal ganglia

Directory of Open Access Journals (Sweden)

Corey Michael Thibeault

2013-07-01

Full Text Available Our current understanding of the basal ganglia has facilitated the creation of computational models that have contributed novel theories, explored new functional anatomy and demonstrated results complementing physiological experiments. However, the utility of these models extends beyond these applications. Particularly in neuromorphic engineering, where the basal ganglia's role in computation is important for applications such as power efficient autonomous agents and model-based control strategies. The neurons used in existing computational models of the basal ganglia however, are not amenable for many low-power hardware implementations. Motivated by a need for more hardware accessible networks, we replicate four published models of the basal ganglia, spanning single neuron and small networks, replacing the more computationally expensive neuron models with an Izhikevich hybrid neuron. This begins with a network modeling action-selection, where the basal activity levels and the ability to appropriately select the most salient input is reproduced. A Parkinson's disease model is then explored under normal conditions, Parkinsonian conditions and during subthalamic nucleus deep brain stimulation. The resulting network is capable of replicating the loss of thalamic relay capabilities in the Parkinsonian state and its return under deep brain stimulation. This is also demonstrated using a network capable of action-selection. Finally, a study of correlation transfer under different patterns of Parkinsonian activity is presented. These networks successfully captured the significant results of the originals studies. This not only creates a foundation for neuromorphic hardware implementations but may also support the development of large-scale biophysical models. The former potentially providing a way of improving the efficacy of deep brain stimulation and the latter allowing for the efficient simulation of larger more comprehensive networks.

Infrared Thermography in Serotonin-Induced Itch Model in Rats

DEFF Research Database (Denmark)

Jasemian, Yousef; Gazerani, Parisa; Dagnæs-Hansen, Frederik

2012-01-01

The study validated the application of infrared thermography in a serotonin-induced itch model in rats since the only available method in animal models of itch is the count of scratching bouts. Twenty four adult Sprague-Dawley male rats were used in 3 experiments: 1) local vasomotor response...... with no scratching reflex was investigated. Serotonin elicited significant scratching and lowered the local temperature at the site of injection. A negative dose-temperature relationship of serotonin was found by thermography. Vasoregulation at the site of serotonin injection took place in the absence of scratching...

Effects of high-frequency stimulation of the internal pallidal segment on neuronal activity in the thalamus in parkinsonian monkeys

Science.gov (United States)

Kammermeier, Stefan; Pittard, Damien; Hamada, Ikuma

2016-01-01

Deep brain stimulation of the internal globus pallidus (GPi) is a major treatment for advanced Parkinson's disease. The effects of this intervention on electrical activity patterns in targets of GPi output, specifically in the thalamus, are poorly understood. The experiments described here examined these effects using electrophysiological recordings in two Rhesus monkeys rendered moderately parkinsonian through treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), after sampling control data in the same animals. Analysis of spontaneous spiking activity of neurons in the basal ganglia-receiving areas of the ventral thalamus showed that MPTP-induced parkinsonism is associated with a reduction of firing rates of segments of the data that contained neither bursts nor decelerations, and with increased burst firing. Spectral analyses revealed an increase of power in the 3- to 13-Hz band and a reduction in the γ-range in the spiking activity of these neurons. Electrical stimulation of the ventrolateral motor territory of GPi with macroelectrodes, mimicking deep brain stimulation in parkinsonian patients (bipolar electrodes, 0.5 mm intercontact distance, biphasic stimuli, 120 Hz, 100 μs/phase, 200 μA), had antiparkinsonian effects. The stimulation markedly reduced oscillations in thalamic firing in the 13- to 30-Hz range and uncoupled the spiking activity of recorded neurons from simultaneously recorded local field potential (LFP) activity. These results confirm that oscillatory and nonoscillatory characteristics of spontaneous activity in the basal ganglia receiving ventral thalamus are altered in MPTP-induced parkinsonism. Electrical stimulation of GPi did not entrain thalamic activity but changed oscillatory activity in the ventral thalamus and altered the relationship between spikes and simultaneously recorded LFPs. PMID:27683881

Efficacy of Polaprezinc for Acute Radiation Proctitis in a Rat Model

International Nuclear Information System (INIS)

Doi, Hiroshi; Kamikonya, Norihiko; Takada, Yasuhiro; Fujiwara, Masayuki; Tsuboi, Keita; Inoue, Hiroyuki; Tanooka, Masao; Nakamura, Takeshi; Shikata, Toshiyuki; Tsujimura, Tohru; Hirota, Shozo

2011-01-01

Purpose: The purpose of the present study was to standardize the experimental rat model of radiation proctitis and to examine the efficacy of polaprezinc on radiation proctitis. Methods and Materials: A total of 54 female Wistar rats (5 weeks old) were used. The rats were divided into three groups: those treated with polaprezinc (PZ+), those treated with base alone, exclusive of polaprezinc (PZ-), and those treated without any medication (control). All the rats were irradiated to the rectum. Polaprezinc was prepared as an ointment. The ointment was administered rectally each day after irradiation. All rats were killed on the 10th day after irradiation. The mucosal changes were evaluated endoscopically and pathologically. The results were graded from 0 to 4 and compared according to milder or more severe status, as applicable. Results: According to the endoscopic findings, the proportion of mild changes in the PZ+, PZ-, and control group was 71.4%, 25.0%, and 14.3% respectively. On pathologic examination, the proportion of low-grade findings in the PZ+, PZ-, and control group was 80.0%, 58.3%, and 42.9% for mucosal damage, 85.0%, 41.7%, and 42.9% for a mild degree of inflammation, and 50.0%, 33.3%, and 4.8% for a shallow depth of inflammation, respectively. The PZ+ group tended to have milder mucosal damage than the other groups, according to all criteria used. In addition, significant differences were observed between the PZ+ and control groups regarding the endoscopic findings, degree of inflammation, and depth of inflammation. Conclusions: This model was confirmed to be a useful experimental rat model for radiation proctitis. The results of the present study have demonstrated the efficacy of polaprezinc against acute radiation-induced rectal disorders using the rat model.

Ideal Experimental Rat Models for Liver Diseases.

Science.gov (United States)

Lee, Sang Woo; Kim, Sung Hoon; Min, Seon Ok; Kim, Kyung Sik

2011-05-01

There are many limitations for conducting liver disease research in human beings due to the high cost and potential ethical issues. For this reason, conducting a study that is difficult to perform in humans using appropriate animal models, can be beneficial in ascertaining the pathological physiology, and in developing new treatment modalities. However, it is difficult to determine the appropriate animal model which is suitable for research purposes, since every patient has different and diverse clinical symptoms, adverse reactions, and complications due to the pathological physiology. Also, it is not easy to reproduce identically various clinical situations in animal models. Recently, the Guide for the Care and Use of Laboratory Animals has tightened up the regulations, and therefore it is advisable to select the appropriate animals and decide upon the appropriate quantities through scientific and systemic considerations before conducting animal testing. Therefore, in this review article the authors examined various white rat animal testing models and determined the appropriate usable rat model, and the pros and cons of its application in liver disease research. The authors believe that this review will be beneficial in selecting proper laboratory animals for research purposes.

Effects of aspirin and enoxaparin in a rat model of liver fibrosis.

Science.gov (United States)

Li, Chen-Jie; Yang, Zhi-Hui; Shi, Xiao-Liu; Liu, De-Liang

2017-09-21

To examine the effects of aspirin and enoxaparin on liver function, coagulation index and histopathology in a rat model of liver fibrosis. METHODS Forty-five male Sprague-Dawley rats were randomly divided into the control group (n = 5) and model group (n = 40). Thioacetamide (TAA) was used to induce liver fibrosis in the model group. TAA-induced fibrotic rats received TAA continuously (n = 9), TAA + low-dose aspirin (n = 9), TAA + high-dose aspirin (n = 9) or TAA + enoxaparin (n = 9) for 4 wk. All rats were euthanized after 4 wk, and both hematoxylin-eosin and Masson staining were performed to observe pathological changes in liver tissue. Liver fibrosis was assessed according to the METAVIR score. Compared with untreated cirrhotic controls, a significant improvement in fibrosis grade was observed in the low-dose aspirin, high-dose aspirin and enoxaparin treated groups, especially in the high-dose aspirin treated group. Alanine aminotransferase and total bilirubin were higher, albumin was lower and both prothrombin time and international normalized ratio were prolonged in the four treatment groups compared to controls. No significant differences among the four groups were observed. Aspirin and enoxaparin can alleviate liver fibrosis in this rat model.

Trace element mapping in Parkinsonian brain by quantitative ion beam microscopy

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Barapatre, Nirav; Morawski, Markus; Butz, Tilman; Reinert, Tilo

2010-06-01

The role of iron in the pathogenesis of the Parkinson's disease (PD) is a current subject of research in Neurochemistry, since an abnormal increase in iron is reported in the substantia nigra (SN) of Parkinsonian patients. A severe loss of the cells containing dopamine in the SN in the PD has also drawn attention towards the function of a browny-black pigment called neuromelanin, which accumulates predominantly in these dopaminergic neurons. The neuromelanin has an ability to chelate metal ions, which, in free state, may cause considerable damage to cells by reacting with their lipid-rich membranes. However, it could also potentiate free radical production if it releases the bound metal ions. The highly sensitive and non-destructive micro-PIXE method suits best to quantify and map the trace elements in the SN. The accuracy in charge measurement for such microanalysis studies is of utmost importance for quantitative analysis. Since a Faraday cup is usually placed behind the thin biological sample to measure the charge, the primary and the secondary electrons, knocked out from the sample by traversing ion beam, hamper an exact charge determination. Hence, a new non-interceptive technique was developed for precise charge measurement and for continuous monitoring of beam current.

Trace element mapping in Parkinsonian brain by quantitative ion beam microscopy

International Nuclear Information System (INIS)

Barapatre, Nirav; Morawski, Markus; Butz, Tilman; Reinert, Tilo

2010-01-01

The role of iron in the pathogenesis of the Parkinson's disease (PD) is a current subject of research in Neurochemistry, since an abnormal increase in iron is reported in the substantia nigra (SN) of Parkinsonian patients. A severe loss of the cells containing dopamine in the SN in the PD has also drawn attention towards the function of a browny-black pigment called neuromelanin, which accumulates predominantly in these dopaminergic neurons. The neuromelanin has an ability to chelate metal ions, which, in free state, may cause considerable damage to cells by reacting with their lipid-rich membranes. However, it could also potentiate free radical production if it releases the bound metal ions. The highly sensitive and non-destructive micro-PIXE method suits best to quantify and map the trace elements in the SN. The accuracy in charge measurement for such microanalysis studies is of utmost importance for quantitative analysis. Since a Faraday cup is usually placed behind the thin biological sample to measure the charge, the primary and the secondary electrons, knocked out from the sample by traversing ion beam, hamper an exact charge determination. Hence, a new non-interceptive technique was developed for precise charge measurement and for continuous monitoring of beam current.

Trace element mapping in Parkinsonian brain by quantitative ion beam microscopy

Energy Technology Data Exchange (ETDEWEB)

Barapatre, Nirav, E-mail: barapatre@physik.uni-leipzig.d [Nukleare Festkoerperphysik, Universitaet Leipzig, Linnestr. 5, 04103 Leipzig (Germany); Morawski, Markus [Paul-Flechsig-Institut fuer Hirnforschung, Universitaet Leipzig, Jahnalle 59, 04109 Leipzig (Germany); Butz, Tilman; Reinert, Tilo [Nukleare Festkoerperphysik, Universitaet Leipzig, Linnestr. 5, 04103 Leipzig (Germany)

2010-06-15

The role of iron in the pathogenesis of the Parkinson's disease (PD) is a current subject of research in Neurochemistry, since an abnormal increase in iron is reported in the substantia nigra (SN) of Parkinsonian patients. A severe loss of the cells containing dopamine in the SN in the PD has also drawn attention towards the function of a browny-black pigment called neuromelanin, which accumulates predominantly in these dopaminergic neurons. The neuromelanin has an ability to chelate metal ions, which, in free state, may cause considerable damage to cells by reacting with their lipid-rich membranes. However, it could also potentiate free radical production if it releases the bound metal ions. The highly sensitive and non-destructive micro-PIXE method suits best to quantify and map the trace elements in the SN. The accuracy in charge measurement for such microanalysis studies is of utmost importance for quantitative analysis. Since a Faraday cup is usually placed behind the thin biological sample to measure the charge, the primary and the secondary electrons, knocked out from the sample by traversing ion beam, hamper an exact charge determination. Hence, a new non-interceptive technique was developed for precise charge measurement and for continuous monitoring of beam current.

Comparison of blood biochemics between acute myocardial infarction models with blood stasis and simple acute myocardial infarction models in rats

International Nuclear Information System (INIS)

Qu Shaochun; Yu Xiaofeng; Wang Jia; Zhou Jinying; Xie Haolin; Sui Dayun

2010-01-01

Objective: To construct the acute myocardial infarction models in rats with blood stasis and study the difference on blood biochemics between the acute myocardial infarction models with blood stasis and the simple acute myocardial infarction models. Methods: Wistar rats were randomly divided into control group, acute blood stasis model group, acute myocardial infarction sham operation group, acute myocardial infarction model group and of acute myocardial infarction model with blood stasis group. The acute myocardial infarction models under the status of the acute blood stasis in rats were set up. The serum malondialdehyde (MDA), nitric oxide (NO), free fatty acid (FFA), tumor necrosis factor-α (TNF-α) levels were detected, the activities of serum superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and the levels of prostacycline (PGI2), thromboxane A 2 (TXA 2 ) and endothelin (ET) in plasma were determined. Results: There were not obvious differences in MDA, SOD, GSH-Px and FFA between the acute myocardial infarction models with blood stasis in rats and the simple acute myocardial infarction models (P 2 and NO, and the increase extents of TXA 2 , ET and TNF-α in the acute myocardial infarction models in rats with blood stasis were higher than those in the simple acute myocardial infarction models (P 2 and NO, are significant when the acute myocardial infarction models in rats with blood stasis and the simple acute myocardial infarction models are compared. The results show that it is defective to evaluate pharmacodynamics of traditional Chinese drug with only simple acute myocardial infarction models. (authors)

An improved experimental model for peripheral neuropathy in rats

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Q.M. Dias

2013-03-01

Full Text Available A modification of the Bennett and Xie chronic constriction injury model of peripheral painful neuropathy was developed in rats. Under tribromoethanol anesthesia, a single ligature with 100% cotton glace thread was placed around the right sciatic nerve proximal to its trifurcation. The change in the hind paw reflex threshold after mechanical stimulation observed with this modified model was compared to the change in threshold observed in rats subjected to the Bennett and Xie or the Kim and Chung spinal ligation models. The mechanical threshold was measured with an automated electronic von Frey apparatus 0, 2, 7, and 14 days after surgery, and this threshold was compared to that measured in sham rats. All injury models produced significant hyperalgesia in the operated hind limb. The modified model produced mean ± SD thresholds in g (19.98 ± 3.08, 14.98 ± 1.86, and 13.80 ± 1.00 at 2, 7, and 14 days after surgery, respectively similar to those obtained with the spinal ligation model (20.03 ± 1.99, 13.46 ± 2.55, and 12.46 ± 2.38 at 2, 7, and 14 days after surgery, respectively, but less variable when compared to the Bennett and Xie model (21.20 ± 8.06, 18.61 ± 7.69, and 18.76 ± 6.46 at 2, 7, and 14 days after surgery, respectively. The modified method required less surgical skill than the spinal nerve ligation model.

An improved experimental model for peripheral neuropathy in rats

International Nuclear Information System (INIS)

Dias, Q.M.; Rossaneis, A.C.; Fais, R.S.; Prado, W.A.

2013-01-01

A modification of the Bennett and Xie chronic constriction injury model of peripheral painful neuropathy was developed in rats. Under tribromoethanol anesthesia, a single ligature with 100% cotton glace thread was placed around the right sciatic nerve proximal to its trifurcation. The change in the hind paw reflex threshold after mechanical stimulation observed with this modified model was compared to the change in threshold observed in rats subjected to the Bennett and Xie or the Kim and Chung spinal ligation models. The mechanical threshold was measured with an automated electronic von Frey apparatus 0, 2, 7, and 14 days after surgery, and this threshold was compared to that measured in sham rats. All injury models produced significant hyperalgesia in the operated hind limb. The modified model produced mean ± SD thresholds in g (19.98 ± 3.08, 14.98 ± 1.86, and 13.80 ± 1.00 at 2, 7, and 14 days after surgery, respectively) similar to those obtained with the spinal ligation model (20.03 ± 1.99, 13.46 ± 2.55, and 12.46 ± 2.38 at 2, 7, and 14 days after surgery, respectively), but less variable when compared to the Bennett and Xie model (21.20 ± 8.06, 18.61 ± 7.69, and 18.76 ± 6.46 at 2, 7, and 14 days after surgery, respectively). The modified method required less surgical skill than the spinal nerve ligation model

An improved experimental model for peripheral neuropathy in rats

Directory of Open Access Journals (Sweden)

Q.M. Dias

Full Text Available A modification of the Bennett and Xie chronic constriction injury model of peripheral painful neuropathy was developed in rats. Under tribromoethanol anesthesia, a single ligature with 100% cotton glace thread was placed around the right sciatic nerve proximal to its trifurcation. The change in the hind paw reflex threshold after mechanical stimulation observed with this modified model was compared to the change in threshold observed in rats subjected to the Bennett and Xie or the Kim and Chung spinal ligation models. The mechanical threshold was measured with an automated electronic von Frey apparatus 0, 2, 7, and 14 days after surgery, and this threshold was compared to that measured in sham rats. All injury models produced significant hyperalgesia in the operated hind limb. The modified model produced mean ± SD thresholds in g (19.98 ± 3.08, 14.98 ± 1.86, and 13.80 ± 1.00 at 2, 7, and 14 days after surgery, respectively similar to those obtained with the spinal ligation model (20.03 ± 1.99, 13.46 ± 2.55, and 12.46 ± 2.38 at 2, 7, and 14 days after surgery, respectively, but less variable when compared to the Bennett and Xie model (21.20 ± 8.06, 18.61 ± 7.69, and 18.76 ± 6.46 at 2, 7, and 14 days after surgery, respectively. The modified method required less surgical skill than the spinal nerve ligation model.

An improved experimental model for peripheral neuropathy in rats

Energy Technology Data Exchange (ETDEWEB)

Dias, Q.M.; Rossaneis, A.C.; Fais, R.S.; Prado, W.A. [Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil)

2013-03-15

A modification of the Bennett and Xie chronic constriction injury model of peripheral painful neuropathy was developed in rats. Under tribromoethanol anesthesia, a single ligature with 100% cotton glace thread was placed around the right sciatic nerve proximal to its trifurcation. The change in the hind paw reflex threshold after mechanical stimulation observed with this modified model was compared to the change in threshold observed in rats subjected to the Bennett and Xie or the Kim and Chung spinal ligation models. The mechanical threshold was measured with an automated electronic von Frey apparatus 0, 2, 7, and 14 days after surgery, and this threshold was compared to that measured in sham rats. All injury models produced significant hyperalgesia in the operated hind limb. The modified model produced mean ± SD thresholds in g (19.98 ± 3.08, 14.98 ± 1.86, and 13.80 ± 1.00 at 2, 7, and 14 days after surgery, respectively) similar to those obtained with the spinal ligation model (20.03 ± 1.99, 13.46 ± 2.55, and 12.46 ± 2.38 at 2, 7, and 14 days after surgery, respectively), but less variable when compared to the Bennett and Xie model (21.20 ± 8.06, 18.61 ± 7.69, and 18.76 ± 6.46 at 2, 7, and 14 days after surgery, respectively). The modified method required less surgical skill than the spinal nerve ligation model.

Long-term detection of Parkinsonian tremor activity from subthalamic nucleus local field potentials.

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Houston, Brady; Blumenfeld, Zack; Quinn, Emma; Bronte-Stewart, Helen; Chizeck, Howard

2015-01-01

Current deep brain stimulation paradigms deliver continuous stimulation to deep brain structures to ameliorate the symptoms of Parkinson's disease. This continuous stimulation has undesirable side effects and decreases the lifespan of the unit's battery, necessitating earlier replacement. A closed-loop deep brain stimulator that uses brain signals to determine when to deliver stimulation based on the occurrence of symptoms could potentially address these drawbacks of current technology. Attempts to detect Parkinsonian tremor using brain signals recorded during the implantation procedure have been successful. However, the ability of these methods to accurately detect tremor over extended periods of time is unknown. Here we use local field potentials recorded during a deep brain stimulation clinical follow-up visit 1 month after initial programming to build a tremor detection algorithm and use this algorithm to detect tremor in subsequent visits up to 8 months later. Using this method, we detected the occurrence of tremor with accuracies between 68-93%. These results demonstrate the potential of tremor detection methods for efficacious closed-loop deep brain stimulation over extended periods of time.

Step training in a rat model for complex aneurysmal vascular microsurgery

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Martin Dan

2015-12-01

Full Text Available Introduction: Microsurgery training is a key step for the young neurosurgeons. Both in vascular and peripheral nerve pathology, microsurgical techniques are useful tools for the proper treatment. Many training models have been described, including ex vivo (chicken wings and in vivo (rat, rabbit ones. Complex microsurgery training include termino-terminal vessel anastomosis and nerve repair. The aim of this study was to describe a reproducible complex microsurgery training model in rats. Materials and methods: The experimental animals were Brown Norway male rats between 10-16 weeks (average 13 and weighing between 250-400g (average 320g. We performed n=10 rat hind limb replantations. The surgical steps and preoperative management are carefully described. We evaluated the vascular patency by clinical assessment-color, temperature, capillary refill. The rats were daily inspected for any signs of infections. The nerve regeneration was assessed by foot print method. Results: There were no case of vascular compromise or autophagia. All rats had long term survival (>90 days. The nerve regeneration was clinically completed at 6 months postoperative. The mean operative time was 183 minutes, and ischemia time was 25 minutes.

The JCR:LA-cp rat: a novel rodent model of cystic medial necrosis.

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Pung, Yuh Fen; Chilian, William M; Bennett, Martin R; Figg, Nichola; Kamarulzaman, Mohd Hamzah

2017-03-01

Although there are multiple rodent models of the metabolic syndrome, very few develop vascular complications. In contrast, the JCR:LA-cp rat develops both metabolic syndrome and early atherosclerosis in predisposed areas. However, the pathology of the normal vessel wall has not been described. We examined JCR:LA control (+/+) or cp/cp rats fed normal chow diet for 6 or 18 mo. JCR:LA-cp rats developed multiple features of advanced cystic medial necrosis including "cysts," increased collagen formation and proteoglycan deposition around cysts, apoptosis of vascular smooth muscle cells, and spotty medial calcification. These appearances began within 6 mo and were extensive by 18 mo. JCR:LA-cp rats had reduced medial cellularity, increased medial thickness, and vessel hypoxia that was most marked in the adventitia. In conclusion, the normal chow-fed JCR:LA-cp rat represents a novel rodent model of cystic medial necrosis, associated with multiple metabolic abnormalities, vascular smooth muscle cell apoptosis, and vessel hypoxia. NEW & NOTEWORTHY Triggers for cystic medial necrosis (CMN) have been difficult to study due to lack of animal models to recapitulate the pathologies seen in humans. Our study is the first description of CMN in the rat. Thus the JCR:LA-cp rat represents a useful model to investigate the underlying molecular changes leading to the development of CMN. Copyright © 2017 the American Physiological Society.

BDNF levels are increased by aminoindan and rasagiline in a double lesion model of Parkinson׳s disease.

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Ledreux, Aurélie; Boger, Heather A; Hinson, Vanessa K; Cantwell, Kelsey; Granholm, Ann-Charlotte

2016-01-15

The anti-Parkinsonian drug rasagiline is a selective, irreversible inhibitor of monoamine oxidase and is used in the treatment of Parkinson׳s disease (PD). Its postulated neuroprotective effects may be attributed to MAO inhibition, or to its propargylamine moiety. The major metabolite of rasagiline, aminoindan, has shown promising neuroprotective properties in vitro but there is a paucity of studies investigating in vivo effects of this compound. Therefore, we examined neuroprotective effects of rasagiline and its metabolite aminoindan in a double lesion model of PD. Male Fisher 344 rats received i.p. injections of the noradrenergic neurotoxin DSP-4 and intra-striatal stereotaxic microinjections of the dopamine neurotoxin 6-OHDA. Saline, rasagiline or aminoindan (3mg/kg/day s.c.) were delivered via Alzet minipumps for 4 weeks. Rats were then tested for spontaneous locomotion and a novel object recognition task. Following behavioral testing, brain tissue was processed for ELISA measurements of growth factors and immunohistochemistry. Double-lesioned rats treated with rasagiline or aminoindan had reduced behavioral deficits, both in motor and cognitive tasks compared to saline-treated double-lesioned rats. BDNF levels were significantly increased in the hippocampus and striatum of the rasagiline- and aminoindan-lesioned groups compared to the saline-treated lesioned group. Double-lesioned rats treated with rasagiline or aminoindan exhibited a sparing in the mitochondrial marker Hsp60, suggesting mitochondrial involvement in neuroprotection. Tyrosine hydroxylase (TH) immunohistochemistry revealed a sparing of TH-immunoreactive terminals in double-lesioned rats treated with rasagiline or aminoindan in the striatum, hippocampus, and substantia nigra. These data provide evidence of neuroprotection by aminoindan and rasagiline via their ability to enhance BDNF levels. Published by Elsevier B.V.

PET imaging of dopamine transporters with [18F]FE-PE2I: Effects of anti-Parkinsonian drugs

International Nuclear Information System (INIS)

Bang, Ji-In; Jung, In Soon; Song, Yoo Sung; Park, Hyun Soo; Moon, Byung Seok; Lee, Byung Chul; Kim, Sang Eun

2016-01-01

Purpose: This study aimed to assess the striatal [ 18 F]FE-PE2I binding and the immunohistochemical stain of tyrosine hydroxylase (TH) in the striatum, and to evaluate the effects of therapeutic drugs on [ 18 F]FE-PE2I binding. Methods: Dynamic PET/CT of [ 18 F]FE-PE2I was performed in Parkinson’s disease (PD) rat models, induced by the unilateral injection of 6-OHDA into the striatum. A simplified reference tissue model method was used to calculate the striatal binding potential (striatal BP ND ). Each of the four normal rats was pretreated with pramipexole, amantadine, and escitalopram 30 min before [ 18 F]FE-PE2I injection. The effect of L-DOPA combined with benserazide was assessed in the normal and PD rats. Results: The BP ND was significantly lower in the lesioned striatum than in the striatum of the normal rats. After the pretreatment with pramipexole, amantadine, and escitalopram, the values of the striatal BP ND did not differ from those of the controls. The pretreatment with L-DOPA/benserazide, however, significantly reduced the striatal BP ND . The striatal BP ND of the PD rats with L-DOPA/benserazide pretreatment was not different from that of the same PD rats with placebo treatment. Conclusion: [ 18 F]FE-PE2I may be used as a radioligand for the in-vivo imaging of the DAT. In the normal rats, [ 18 F]FE-PE2I binding is unaffected by pramipexole, amantadine, and escitalopram. L-DOPA/benserazide does not affect the striatal [ 18 F]FE-PE2I binding in PD rats

Creation of Consistent Burn Wounds: A Rat Model

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Elijah Zhengyang Cai

2014-07-01

Full Text Available Background Burn infliction techniques are poorly described in rat models. An accurate study can only be achieved with wounds that are uniform in size and depth. We describe a simple reproducible method for creating consistent burn wounds in rats. Methods Ten male Sprague-Dawley rats were anesthetized and dorsum shaved. A 100 g cylindrical stainless-steel rod (1 cm diameter was heated to 100℃ in boiling water. Temperature was monitored using a thermocouple. We performed two consecutive toe-pinch tests on different limbs to assess the depth of sedation. Burn infliction was limited to the loin. The skin was pulled upwards, away from the underlying viscera, creating a flat surface. The rod rested on its own weight for 5, 10, and 20 seconds at three different sites on each rat. Wounds were evaluated for size, morphology and depth. Results Average wound size was 0.9957 cm2 (standard deviation [SD] 0.1845 (n=30. Wounds created with duration of 5 seconds were pale, with an indistinct margin of erythema. Wounds of 10 and 20 seconds were well-defined, uniformly brown with a rim of erythema. Average depths of tissue damage were 1.30 mm (SD 0.424, 2.35 mm (SD 0.071, and 2.60 mm (SD 0.283 for duration of 5, 10, 20 seconds respectively. Burn duration of 5 seconds resulted in full-thickness damage. Burn duration of 10 seconds and 20 seconds resulted in full-thickness damage, involving subjacent skeletal muscle. Conclusions This is a simple reproducible method for creating burn wounds consistent in size and depth in a rat burn model.

Characterization of dystrophin deficient rats: a new model for Duchenne muscular dystrophy.

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Larcher, Thibaut; Lafoux, Aude; Tesson, Laurent; Remy, Séverine; Thepenier, Virginie; François, Virginie; Le Guiner, Caroline; Goubin, Helicia; Dutilleul, Maéva; Guigand, Lydie; Toumaniantz, Gilles; De Cian, Anne; Boix, Charlotte; Renaud, Jean-Baptiste; Cherel, Yan; Giovannangeli, Carine; Concordet, Jean-Paul; Anegon, Ignacio; Huchet, Corinne

2014-01-01

A few animal models of Duchenne muscular dystrophy (DMD) are available, large ones such as pigs or dogs being expensive and difficult to handle. Mdx (X-linked muscular dystrophy) mice only partially mimic the human disease, with limited chronic muscular lesions and muscle weakness. Their small size also imposes limitations on analyses. A rat model could represent a useful alternative since rats are small animals but 10 times bigger than mice and could better reflect the lesions and functional abnormalities observed in DMD patients. Two lines of Dmd mutated-rats (Dmdmdx) were generated using TALENs targeting exon 23. Muscles of animals of both lines showed undetectable levels of dystrophin by western blot and less than 5% of dystrophin positive fibers by immunohistochemistry. At 3 months, limb and diaphragm muscles from Dmdmdx rats displayed severe necrosis and regeneration. At 7 months, these muscles also showed severe fibrosis and some adipose tissue infiltration. Dmdmdx rats showed significant reduction in muscle strength and a decrease in spontaneous motor activity. Furthermore, heart morphology was indicative of dilated cardiomyopathy associated histologically with necrotic and fibrotic changes. Echocardiography showed significant concentric remodeling and alteration of diastolic function. In conclusion, Dmdmdx rats represent a new faithful small animal model of DMD.

Postictal in situ MRS brain lactate in the rat kindling model.

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Maton, B M; Najm, I M; Wang, Y; Lüders, H O; Ng, T C

1999-12-10

To determine the temporal and spatial extent of the lactate (Lact) changes as correlated with seizure characteristics and EEG changes in the rat kindling model. Prior studies using MRS have detected cerebral Lact postictally in animal models of seizures and in patients with intractable focal epilepsy. We performed MRS in sham control rats (n = 4) and in rats stimulated in the right hippocampus at two different stages of the kindling and at three time points after the seizures: 3 hours (n = 4 and 2). Lact/creatine (Cr) and N-acetylaspartate (NAA)/Cr ratios were measured in six contiguous voxels (three left, three right) covering the hippocampi, anterior and posterior regions, and compared with EEG and ictal behavior. Lact/Cr ratios were measured at a very low level in the sham control rats and in the >3-hour group. In the epilepsy.

Lowered iPLA2γ activity causes increased mitochondrial lipid peroxidation and mitochondrial dysfunction in a rotenone-induced model of Parkinson's disease.

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Chao, Honglu; Liu, Yinlong; Fu, Xian; Xu, Xiupeng; Bao, Zhongyuan; Lin, Chao; Li, Zheng; Liu, Yan; Wang, Xiaoming; You, Yongping; Liu, Ning; Ji, Jing

2018-02-01

iPLA 2 γ, calcium-independent phospholipase A 2 γ, discerningly hydrolyses glycerophospholipids to liberate free fatty acids. iPLA 2 γ-deficiency has been associated with abnormal mitochondrial function. More importantly, the iPLA 2 family is causative proteins in mitochondrial neurodegenerative disorders such as parkinsonian disorders. However, the mechanisms by which iPLA 2 γ affects Parkinson's disease (PD) remain unknown. Mitochondrion stress has a key part in rotenone-induced dopaminergic neuronal degeneration. The present evaluation revealed that lowered iPLA 2 γ function provokes the parkinsonian phenotype and leads to the reduction of dopamine and its metabolites, lowered survival, locomotor deficiencies, and organismal hypersensitivity to rotenone-induced oxidative stress. In addition, lowered iPLA 2 γ function escalated the amount of mitochondrial irregularities, including mitochondrial reactive oxygen species (ROS) regeneration, reduced ATP synthesis, reduced glutathione levels, and abnormal mitochondrial morphology. Further, lowered iPLA 2 γ function was tightly linked with strengthened lipid peroxidation and mitochondrial membrane flaws following rotenone treatment, which can cause cytochrome c release and eventually apoptosis. These results confirmed the important role of iPLA 2 γ, whereby decreasing iPLA 2 γ activity aggravates mitochondrial degeneration to induce neurodegenerative disorders in a rotenone rat model of Parkinson's disease. These findings may be useful in the design of rational approaches for the prevention and treatment of PD-associated symptoms. Copyright © 2017 Elsevier Inc. All rights reserved.

Ibuprofen or piroxicam protects nigral neurons and delays the development of l-dopa induced dyskinesia in rats with experimental Parkinsonism: Influence on angiogenesis.

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Teema, Asmaa M; Zaitone, Sawsan A; Moustafa, Yasser M

2016-08-01

Neuroinflammation and angiogenesis have been involved in the pathogenesis of Parkinson's disease (PD). This study investigated the effect of ibuprofen or piroxicam on the motor response to l-dopa and development of dyskinesia in Parkinsonian rats focusing on the anti-angiogenic role of the two non-steroidal anti-inflammatory drugs (NSAIDs). Rats were divided into nine groups as follows: Group I: the vehicle group, Group II: rotenone group, rats were injected with nine doses of rotenone (1 mg/kg/48 h), group III&IV: rats received rotenone + ibuprofen (10 or 30 mg/kg), Group V-VI: rats received rotenone + piroxicam (1 or 3 mg/kg), Group VII: rats received rotenone + l-dopa/carbidopa (100/10 mg/kg), Group VIII-IX: rats received rotenone + l-dopa/carbidopa + ibuprofen (30 mg/kg) or piroxicam (3 mg/kg). In general, drugs were administered daily for ten weeks. Rotenone-treated rats showed motor dysfunction, lower striatal dopamine, lower staining for nigral tyrosine hydroxylase but higher level of striatal cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) compared to vehicle-treated rats (P piroxicam in combination with l-dopa preserved the effect of l-dopa at the end of week 10, delayed the development of dyskinesia and decreased striatal COX-2 and VEGF levels. In conclusion, the current study suggests that ibuprofen and piroxicam are promising candidates for neuroprotection in PD and may have utility in conjunction with l-dopa in order to ensure the longevity of its action and to delay the development of dyskinesia. Copyright © 2016 Elsevier Ltd. All rights reserved.

Monte Carlo-based dose reconstruction in a rat model for scattered ionizing radiation investigations.

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Kirkby, Charles; Ghasroddashti, Esmaeel; Kovalchuk, Anna; Kolb, Bryan; Kovalchuk, Olga

2013-09-01

In radiation biology, rats are often irradiated, but the precise dose distributions are often lacking, particularly in areas that receive scatter radiation. We used a non-dedicated set of resources to calculate detailed dose distributions, including doses to peripheral organs well outside of the primary field, in common rat exposure settings. We conducted a detailed dose reconstruction in a rat through an analog to the conventional human treatment planning process. The process consisted of: (i) Characterizing source properties of an X-ray irradiator system, (ii) acquiring a computed tomography (CT) scan of a rat model, and (iii) using a Monte Carlo (MC) dose calculation engine to generate the dose distribution within the rat model. We considered cranial and liver irradiation scenarios where the rest of the body was protected by a lead shield. Organs of interest were the brain, liver and gonads. The study also included paired scenarios where the dose to adjacent, shielded rats was determined as a potential control for analysis of bystander effects. We established the precise doses and dose distributions delivered to the peripheral organs in single and paired rats. Mean doses to non-targeted organs in irradiated rats ranged from 0.03-0.1% of the reference platform dose. Mean doses to the adjacent rat peripheral organs were consistent to within 10% those of the directly irradiated rat. This work provided details of dose distributions in rat models under common irradiation conditions and established an effective scenario for delivering only scattered radiation consistent with that in a directly irradiated rat.

Physiologically Based Pharmacokinetic Model for Terbinafine in Rats and Humans

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Hosseini-Yeganeh, Mahboubeh; McLachlan, Andrew J.

2002-01-01

The aim of this study was to develop a physiologically based pharmacokinetic (PB-PK) model capable of describing and predicting terbinafine concentrations in plasma and tissues in rats and humans. A PB-PK model consisting of 12 tissue and 2 blood compartments was developed using concentration-time data for tissues from rats (n = 33) after intravenous bolus administration of terbinafine (6 mg/kg of body weight). It was assumed that all tissues except skin and testis tissues were well-stirred compartments with perfusion rate limitations. The uptake of terbinafine into skin and testis tissues was described by a PB-PK model which incorporates a membrane permeability rate limitation. The concentration-time data for terbinafine in human plasma and tissues were predicted by use of a scaled-up PB-PK model, which took oral absorption into consideration. The predictions obtained from the global PB-PK model for the concentration-time profile of terbinafine in human plasma and tissues were in close agreement with the observed concentration data for rats. The scaled-up PB-PK model provided an excellent prediction of published terbinafine concentration-time data obtained after the administration of single and multiple oral doses in humans. The estimated volume of distribution at steady state (Vss) obtained from the PB-PK model agreed with the reported value of 11 liters/kg. The apparent volume of distribution of terbinafine in skin and adipose tissues accounted for 41 and 52%, respectively, of the Vss for humans, indicating that uptake into and redistribution from these tissues dominate the pharmacokinetic profile of terbinafine. The PB-PK model developed in this study was capable of accurately predicting the plasma and tissue terbinafine concentrations in both rats and humans and provides insight into the physiological factors that determine terbinafine disposition. PMID:12069977

Modeling the distribution of Norway rats (Rattus norvegicus on offshore islands in the Falkland Islands

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Michael A. Tabak

2015-01-01

Full Text Available Non-native rats (Rattus spp. threaten native island species worldwide. Efforts to eradicate them from islands have increased in frequency and become more ambitious in recent years. However, the long-term success of some eradication efforts has been compromised by the ability of rats, particularly Norway rats (Rattus norvegicus which are good swimmers, to recolonize islands following eradications. In the Falkland Islands, an archipelago in the South Atlantic Ocean, the distance of 250 m between islands (once suggested as the minimum separation distance for an effective barrier to recolonization has shown to be insufficient. Norway rats are present on about half of the 503 islands in the Falklands. Bird diversity is lower on islands with rats and two vulnerable passerine species, Troglodytes cobbi (the only endemic Falkland Islands passerine and Cinclodes antarcticus, have greatly reduced abundances and/or are absent on islands with rats. We used logistic regression models to investigate the potential factors that may determine the presence of Norway rats on 158 islands in the Falkland Islands. Our models included island area, distance to the nearest rat-infested island, island location, and the history of island use by humans as driving variables. Models best supported by data included only distance to the nearest potential source of rats and island area, but the relative magnitude of the effect of distance and area on the presence of rats varied depending on whether islands were in the eastern or western sector of the archipelago. The human use of an island was not a significant parameter in any models. A very large fraction (72% of islands within 500 m of the nearest potential rat source had rats, but 97% of islands farther than 1,000 m away from potential rat sources were free of rats.

Radiation-induced hydronephrosis in the rat: a new experimental model

International Nuclear Information System (INIS)

Knowles, J.F.

1985-01-01

An experimental model for investigating the effects of localized X-irradiation on a single ureter or the bladder trigone in rats is described. Obstruction of the urinary tract in the irradiated region gives rise to hydroureter and hydronephrosis and the development of these, as detected urographically, gives a clear-cut end point. After irradiation of the ureter with a single dose of 37.4 gy many rats died of gut lesions but after 23.4 Gy only one such death occurred while 14 of 16 rats developed hydronephrosis. Irradiation of the bladder trigone was not associated with intercurrent deaths, even after 40 Gy, and after 25 Gy 9 of 11 rats developed hydronephrosis. (author)

Heterogeneous stock rat: a unique animal model for mapping genes influencing bone fragility.

Science.gov (United States)

Alam, Imranul; Koller, Daniel L; Sun, Qiwei; Roeder, Ryan K; Cañete, Toni; Blázquez, Gloria; López-Aumatell, Regina; Martínez-Membrives, Esther; Vicens-Costa, Elia; Mont, Carme; Díaz, Sira; Tobeña, Adolf; Fernández-Teruel, Alberto; Whitley, Adam; Strid, Pernilla; Diez, Margarita; Johannesson, Martina; Flint, Jonathan; Econs, Michael J; Turner, Charles H; Foroud, Tatiana

2011-05-01

Previously, we demonstrated that skeletal mass, structure and biomechanical properties vary considerably among 11 different inbred rat strains. Subsequently, we performed quantitative trait loci (QTL) analysis in four inbred rat strains (F344, LEW, COP and DA) for different bone phenotypes and identified several candidate genes influencing various bone traits. The standard approach to narrowing QTL intervals down to a few candidate genes typically employs the generation of congenic lines, which is time consuming and often not successful. A potential alternative approach is to use a highly genetically informative animal model resource capable of delivering very high resolution gene mapping such as Heterogeneous stock (HS) rat. HS rat was derived from eight inbred progenitors: ACI/N, BN/SsN, BUF/N, F344/N, M520/N, MR/N, WKY/N and WN/N. The genetic recombination pattern generated across 50 generations in these rats has been shown to deliver ultra-high even gene-level resolution for complex genetic studies. The purpose of this study is to investigate the usefulness of the HS rat model for fine mapping and identification of genes underlying bone fragility phenotypes. We compared bone geometry, density and strength phenotypes at multiple skeletal sites in HS rats with those obtained from five of the eight progenitor inbred strains. In addition, we estimated the heritability for different bone phenotypes in these rats and employed principal component analysis to explore relationships among bone phenotypes in the HS rats. Our study demonstrates that significant variability exists for different skeletal phenotypes in HS rats compared with their inbred progenitors. In addition, we estimated high heritability for several bone phenotypes and biologically interpretable factors explaining significant overall variability, suggesting that the HS rat model could be a unique genetic resource for rapid and efficient discovery of the genetic determinants of bone fragility. Copyright �

General developmental health in the VPA-rat model of autism

DEFF Research Database (Denmark)

Favre, Mônica R; Rinaldi Barkat, Tania; Lamendola, Deborah

2013-01-01

Autism is a neurodevelopmental condition diagnosed by impaired social interaction, abnormal communication and, stereotyped behaviors. While post-mortem and imaging studies have provided good insights into the neurobiological symptomology of autism, animal models can be used to study...... with VPA during early pregnancy show an increased risk for giving birth to an autistic child. In rats, early embryonic exposure, around the time of neural tube closure, leads to autism-like anatomical and behavioral abnormalities in the offspring. Considering the increasing use of the VPA rat model, we...

Depressive-like symptoms in a reserpine-induced model of fibromyalgia in rats.

Science.gov (United States)

Blasco-Serra, Arantxa; Escrihuela-Vidal, Francesc; González-Soler, Eva M; Martínez-Expósito, Fernando; Blasco-Ausina, M Carmen; Martínez-Bellver, Sergio; Cervera-Ferri, Ana; Teruel-Martí, Vicent; Valverde-Navarro, Alfonso A

2015-11-01

Since the pathogenesis of fibromyalgia is unknown, treatment options are limited, ineffective and in fact based on symptom relief. A recently proposed rat model of fibromyalgia is based on central depletion of monamines caused by reserpine administration. This model showed widespread musculoskeletal pain and depressive-like symptoms, but the methodology used to measure such symptoms has been criticized. Evidence relates the high prevalence of pain and depression in fibromyalgia to common pathogenic pathways, most probably focused on the monoaminergic system. The present study aims at a validation of the reserpine model of fibromyalgia. For this purpose, rats undergoing this model have been tested for depressive-like symptoms with a Novelty-Suppressed Feeding Test adaptation. Animals administered with reserpine and subjected to forced food deprivation performed a smaller number of incursions to the center of the open field, evidenced by a decrease in the per-minute rate of the rats' approaching, smelling or touching the food. They also took more time to eat from the central food than control rats. These NSFT findings suggest the presence of depressive-like disorders in this animal model of fibromyalgia. Copyright © 2015 Elsevier Inc. All rights reserved.

Protective effects of Naringin in a rat model of spinal cord ischemia ...

African Journals Online (AJOL)

generation and downregulating inflammatory markers in an SCI rat model. Keywords: Naringin ... intestinal microflora to yield a metabolite called naringenin ... disease (PD). Moreover .... CAT was significantly reduced in SCII rats compared ...

Characterization of a frozen shoulder model using immobilization in rats.

Science.gov (United States)

Kim, Du Hwan; Lee, Kil-Ho; Lho, Yun-Mee; Ha, Eunyoung; Hwang, Ilseon; Song, Kwang-Soon; Cho, Chul-Hyun

2016-12-08

The objective of this study was to investigate serial changes for histology of joint capsule and range of motion of the glenohumeral joint after immobilization in rats. We hypothesized that a rat shoulder contracture model using immobilization would be capable of producing effects on the glenohumeral joint similar to those seen in patients with frozen shoulder. Sixty-four Sprague-Dawley rats were randomly divided into one control group (n = 8) and seven immobilization groups (n = 8 per group) that were immobilized with molding plaster for 3 days, or for 1, 2, 3, 4, 5, or 6 weeks. At each time point, eight rats were euthanized for histologic evaluation of the axillary recess and for measurement of the abduction angle. Infiltration of inflammatory cells was found in the synovial tissue until 2 weeks after immobilization. However, inflammatory cells were diminished and fibrosis was dominantly observed in the synovium and subsynovial tissue 3 weeks after immobilization. From 1 week after immobilization, the abduction angle of all immobilization groups at each time point was significantly lower than that of the control group. Our study demonstrated that a rat frozen shoulder model using immobilization generates the pathophysiologic process of inflammation leading to fibrosis on the glenohumeral joint similar to that seen in patients with frozen shoulder. This model was attained within 3 weeks after immobilization. It may serve as a useful tool to investigate pathogenesis at the molecular level and identify potential target genes that are involved in the development of frozen shoulder.

Aerosol Infection Model of Tuberculosis in Wistar Rats

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Sheshagiri Gaonkar

2010-01-01

Full Text Available We explored suitability of a rat tuberculosis aerosol infection model for investigating the pharmacodynamics of new antimycobacterial agents. Infection of rats via the aerosol route led to a reproducible course of M. tuberculosis infection in the lungs. The pulmonary bacterial load increased logarithmically during the first six weeks, thereafter, the infection stabilized for the next 12 weeks. We observed macroscopically visible granulomas in the lungs with demonstrable acid-fast bacilli and associated histopathology. Rifampicin (RIF at a dose range of 30 to 270 mg/kg exhibited a sharp dose response while isoniazid (INH at a dose range of 10 to 90 mg/kg and ethambutol (EMB at 100 to 1000 mg/kg showed shallow dose responses. Pyrazinamide (PZA had no dose response between 300 and 1000 mg/kg dose range. In a separate time kill study at fixed drug doses (RIF 90 mg/kg, INH 30 mg/kg, EMB 300 mg/kg, and PZA 300 mg/kg the bactericidal effect of all the four drugs increased with longer duration of treatment from two weeks to four weeks. The observed infection profile and therapeutic outcomes in this rat model suggest that it can be used as an additional, pharmacologically relevant efficacy model to develop novel antitubercular compounds at the interface of discovery and development.

Establishment of an induced rat model of malignant pleural mesothelioma

International Nuclear Information System (INIS)

Han Dan; Wu Beihai; Yang Hongsheng; Song Guangyi

2004-01-01

Objective: To establish a convenient and practical malignant pleural mesothelioma (MPM) model induced by crocidolite in Da Yao, which has a high induction rate and can be used for imaging and multiple experimental studies and is similar to human MPM. Methods 40 mg of crocidolite suspension was injected into the right chest cavity in 100 Wistar rats in the test group, while same amount of sterilized saline water was injected in 20 rats in the control group. The animals were observed daily , and weighted once a month. CT scanning was performed regularly. When the rats were dead or dying, they were dissected immediately and pathological changes were recorded after CT examination. The experiment lasted for 2 years. Results: The overall induction rate was 71.6%. The survival time of the first MPM rat was 285 days. The mean living span of rats with MPM was (469 ± 21) days. The pathological features of the induced MPMs were multiple morphologically and there were some CT features in different periods. CT imaging could show some MPM features and find the tumour earlier. Conclusion: The cause, positions, tissues and clinical condition of induced tumors were the same as humans. The model had a higher similarity with human MPM in differentiation degree and histological type, and the model can be used to study the mechanism of MPM, to discuss the measures of prevention, and to guide clinical diagnosis and treatment. Multi-morphology of the history from the induced tumors could make up the shortage, which was the difficulty in getting all periods of tissue samples in clinical research and being used in imaging and many kinds of researches. It was a valuable animal model to study MPM. (authors)

Absence of “Warm-Up” during Active Avoidance Learning in a Rat Model of Anxiety Vulnerability: Insights from Computational Modeling

Science.gov (United States)

Myers, Catherine E.; Smith, Ian M.; Servatius, Richard J.; Beck, Kevin D.

2014-01-01

Avoidance behaviors, in which a learned response causes omission of an upcoming punisher, are a core feature of many psychiatric disorders. While reinforcement learning (RL) models have been widely used to study the development of appetitive behaviors, less attention has been paid to avoidance. Here, we present a RL model of lever-press avoidance learning in Sprague-Dawley (SD) rats and in the inbred Wistar Kyoto (WKY) rat, which has been proposed as a model of anxiety vulnerability. We focus on “warm-up,” transiently decreased avoidance responding at the start of a testing session, which is shown by SD but not WKY rats. We first show that a RL model can correctly simulate key aspects of acquisition, extinction, and warm-up in SD rats; we then show that WKY behavior can be simulated by altering three model parameters, which respectively govern the tendency to explore new behaviors vs. exploit previously reinforced ones, the tendency to repeat previous behaviors regardless of reinforcement, and the learning rate for predicting future outcomes. This suggests that several, dissociable mechanisms may contribute independently to strain differences in behavior. The model predicts that, if the “standard” inter-session interval is shortened from 48 to 24 h, SD rats (but not WKY) will continue to show warm-up; we confirm this prediction in an empirical study with SD and WKY rats. The model further predicts that SD rats will continue to show warm-up with inter-session intervals as short as a few minutes, while WKY rats will not show warm-up, even with inter-session intervals as long as a month. Together, the modeling and empirical data indicate that strain differences in warm-up are qualitative rather than just the result of differential sensitivity to task variables. Understanding the mechanisms that govern expression of warm-up behavior in avoidance may lead to better understanding of pathological avoidance, and potential pathways to modify these processes. PMID

Continuous real-time in vivo measurement of cerebral nitric oxide supports theoretical predictions of an irreversible switching in cerebral ROS after sufficient exposure to external toxins.

Science.gov (United States)

Finnerty, Niall J; O'Riordan, Saidhbhe L; Lowry, John P; Cloutier, Mathieu; Wellstead, Peter

2013-01-01

Mathematical models of the interactions between alphasynuclein (αS) and reactive oxygen species (ROS) predict a systematic and irreversible switching to damagingly high levels of ROS after sufficient exposure to risk factors associated with Parkinson's disease (PD). We tested this prediction by continuously monitoring real-time changes in neurochemical levels over periods of several days in animals exposed to a toxin known to cause Parkinsonian symptoms. Nitric oxide (NO) sensors were implanted in the brains of freely moving rats and the NO levels continuously recorded while the animals were exposed to paraquat (PQ) injections of various amounts and frequencies. Long-term, real-time measurement of NO in a cohort of animals showed systematic switching in levels when PQ injections of sufficient size and frequency were administered. The experimental observations of changes in NO imply a corresponding switching in endogenous ROS levels and support theoretical predictions of an irreversible change to damagingly high levels of endogenous ROS when PD risks are sufficiently large. Our current results only consider one form of PD risk, however, we are sufficiently confident in them to conclude that: (i) continuous long-term measurement of neurochemical dynamics provide a novel way to measure the temporal change and system dynamics which determine Parkinsonian damage, and (ii) the bistable feedback switching predicted by mathematical modelling seems to exist and that a deeper analysis of its characteristics would provide a way of understanding the pathogenic mechanisms that initiate Parkinsonian cell damage.

Morphofunctional analysis of experimental model of esophageal achalasia in rats.

Science.gov (United States)

Sabirov, A G; Raginov, I S; Burmistrov, M V; Chelyshev, Y A; Khasanov, R Sh; Moroshek, A A; Grigoriev, P N; Zefirov, A L; Mukhamedyarov, M A

2010-10-01

We carried out a detailed analysis of rat model of esophageal achalasia previously developed by us. Manifest morphological and functional disorders were observed in experimental achalasia: hyperplasia of the squamous epithelium, reduced number of nerve fibers, excessive growth of fibrous connective tissue in the esophageal wall, high contractile activity of the lower esophageal sphincter, and reduced motility of the longitudinal muscle layer. Changes in rat esophagus observed in experimental achalasia largely correlate with those in esophageal achalasia in humans. Hence, our experimental model can be used for the development of new methods of disease treatment.

Therapeutic effects of arotinolol, a beta-adrenergic blocker, on tremor in MPTP-induced parkinsonian monkeys.

Science.gov (United States)

Kuno, S; Mizuta, E; Nishida, J; Takechi, M

1992-10-01

The effect of arotinolol, a peripherally acting beta-adrenergic-blocking agent, on postural or kinetic tremor was studied in monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. Male cynomolgus monkeys (Macaca fascicularis) were treated with three injections of MPTP hydrochloride (0.3 mg/kg, i.v.) at an interval of 3-4 days, followed by several injections of the same dose every 7 days. Four monkeys with persistent parkinsonian symptoms manifested for greater than 1 year were used. The animals developed mild to moderate degrees of postural or kinetic tremor, and their motor activity was reduced. Arotinolol (20-30 mg/kg, s.c.) significantly suppressed postural tremor in a dose-dependent manner. Propranolol (20-30 mg/kg) was also effective in suppressing the tremor. However, the application of propranolol induced emesis, whereas arotinolol had no adverse effects. These results suggest that arotinolol is a useful adjunct to dopaminergic therapy for tremor in Parkinson's disease.

Sex and laterality differences in parkinsonian impairment and transcranial ultrasound in never-treated schizophrenics and their first degree relatives in an Andean population.

Science.gov (United States)

Kamis, Danielle; Stratton, Lee; Calvó, María; Padilla, Eduardo; Florenzano, Néstor; Guerrero, Gonzalo; Molina Rangeon, Beatriz; Molina, Juan; de Erausquin, Gabriel A

2015-05-01

We tested the hypothesis that loss of substantia nigra neurons in subjects at risk of schizophrenia (1), as reflected by midbrain hyperechogenicity (2) and parkinsonian motor impairment (3), is asymmetric and influenced by sex. We evaluated 62 subjects with never-treated chronic schizophrenia, 80 of their adult, unaffected first degree relatives and 62 healthy controls (matched by sex and age to the cases), part of an Andean population of Northern Argentina. Parkinsonism was scored blindly using UPDRS-3 (Unified Parkinson's Disease Rating Scale) on videotaped exams by 2 independent raters. Transcranial ultrasound was performed by an expert sonographist blind to subject condition with a 2.5 MHz transducer through a temporal bone window. Quantification of echogenic area was carried out on saved images by a different evaluator. We found a significant difference in parkinsonian motor impairment between patients, their relatives as well as controls. All three groups showed worse parkinsonism on the left side than the right, corresponding with increased echogenicity on the right substantia nigra compared with the left. Females had significantly more right echogenicity than males, and patients and unaffected relatives were significantly more echogenic than controls on that side. On the left, only female patients had significant echogenicity. Our data supports the notion that unaffected relatives of schizophrenic subjects have increased parkinsonism and concomitant brainstem abnormalities which may represent a vulnerability to the disease. Both motor and brainstem abnormalities are asymmetric and influenced by sex. Copyright © 2015 Elsevier B.V. All rights reserved.

Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

Science.gov (United States)

Zhang, Jing; Li, Pei; Guo, Hai-fang; Liu, Li; Liu, Xiao-dong

2012-01-01

Aim: To characterize pharmacokinetic-pharmacodynamic modeling of diclofenac in Freund's complete adjuvant (FCA)-induced arthritic rats using prostaglandin E2 (PGE2) as a biomarker. Methods: The pharmacokinetics of diclofenac was investigated using 20-day-old arthritic rats. PGE2 level in the rats was measured using an enzyme immunoassay. A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to illustrate the relationship between the plasma concentration of diclofenac and the inhibition of PGE2 production. The inhibition of diclofenac on lipopolysaccharide (LPS)-induced PGE2 production in blood cells was investigated in vitro. Results: Similar pharmacokinetic behavior of diclofenac was found both in normal and FCA-induced arthritic rats. Diclofenac significantly decreased the plasma levels of PGE2 in both normal and arthritic rats. The inhibitory effect on PGE2 levels in the plasma was in proportion to the plasma concentration of diclofenac. No delay in the onset of inhibition was observed, suggesting that the effect compartment was located in the central compartment. An inhibitory effect sigmoid Imax model was selected to characterize the relationship between the plasma concentration of diclofenac and the inhibition of PGE2 production in vivo. The Imax model was also used to illustrate the inhibition of diclofenac on LPS-induced PGE2 production in blood cells in vitro. Conclusion: Arthritis induced by FCA does not alter the pharmacokinetic behaviors of diclofenac in rats, but the pharmacodynamics of diclofenac is slightly affected. A PK-PD model characterizing an inhibitory effect sigmoid Imax can be used to fit the relationship between the plasma PGE2 and diclofenac levels in both normal rats and FCA-induced arthritic rats. PMID:22842736

Royal Jelly Prevents Osteoporosis in Rats: Beneficial Effects in Ovariectomy Model and in Bone Tissue Culture Model

Directory of Open Access Journals (Sweden)

Saburo Hidaka

2006-01-01

Full Text Available Royal jelly (RJ has been used worldwide for many years as medical products, health foods and cosmetics. Since RJ contains testosterone and has steroid hormone-type activities, we hypothesized that it may have beneficial effects on osteoporosis. We used both an ovariectomized rat model and a tissue culture model. Rats were divided into eight groups as follows: sham-operated (Sham, ovariectomized (OVX, OVX given 0.5% (w/w raw RJ, OVX given 2.0% (w/w RJ, OVX given 0.5% (w/w protease-treated RJ (pRJ, OVX given 2.0% (w/w pRJ, OVX given 17β-estradiol and OVX given its vehicle, respectively. The Ovariectomy decreased tibial bone mineral density (BMD by 24%. Administration of 17β-estradiol to OVX rats recovered the tibial BMD decrease by 100%. Administration of 2.0% (w/w RJ and 0.5–2.0% (w/w pRJ to OVX rats recovered it by 85% or more. These results indicate that both RJ and pRJ are almost as effective as 17β-estradiol in preventing the development of bone loss induced by ovariectomy in rats. In tissue culture models, both RJ and pRJ increased calcium contents in femoral-diaphyseal and femoral-metaphyseal tissue cultures obtained from normal male rats. However, in a mouse marrow culture model, they neither inhibited the parathyroid hormone (PTH-induced calcium loss nor affected the formation of osteoclast-like cells induced by PTH in mouse marrow culture system. Therefore, our results suggest that both RJ and pRJ may prevent osteoporosis by enhancing intestinal calcium absorption, but not by directly antagonizing the action of PTH.

Characterization of SV-40 Tag rats as a model to study prostate cancer

International Nuclear Information System (INIS)

Harper, Curt E; Patel, Brijesh B; Cook, Leah M; Wang, Jun; Shirai, Tomoyuki; Eltoum, Isam A; Lamartiniere, Coral A

2009-01-01

Prostate cancer is the second most frequently diagnosed cancer in men. Animal models that closely mimic clinical disease in humans are invaluable tools in the fight against prostate cancer. Recently, a Simian Virus-40 T-antigen (SV-40 Tag) targeted probasin promoter rat model was developed. This model, however, has not been extensively characterized; hence we have investigated the ontogeny of prostate cancer and determined the role of sex steroid receptor and insulin-like growth factor-1 (IGF-1) signaling proteins in the novel SV-40 Tag rat. The SV-40 Tag rat was histopathologically characterized for time to tumor development, incidence and multiplicity and in the ventral, dorsal, lateral and anterior lobes of the prostate. Immunoassay techniques were employed to measure cell proliferation, apoptosis, and sex steroid receptor and growth factor signaling-related proteins. Steroid hormone concentrations were measured via coated well enzyme linked immunosorbent assay (ELISA) kits. Prostatic intraepithelial neoplasia (PIN) and well-differentiated prostate cancer developed as early as 2 and 10 weeks of age, respectively in the ventral prostate (VP) followed by in the dorsolateral (DLP). At 8 weeks of age, testosterone and dihydrotestosterone (DHT) concentrations in SV-40 Tag rats were increased when compared to non-transgenic rats. High cell proliferation and apoptotic indices were found in VP and DLP of transgenic rats. Furthermore, we observed increased protein expression of androgen receptor, IGF-1, IGF-1 receptor, and extracellular signal-regulated kinases in the prostates of SV-40 Tag rats. The rapid development of PIN and prostate cancer in conjunction with the large prostate size makes the SV-40 Tag rat a useful model for studying prostate cancer. This study provides evidence of the role of sex steroid and growth factor proteins in prostate cancer development and defines appropriate windows of opportunity for preclinical trials and aids in the rational design of

Radiation-induced cognitive dysfunction: an experimental model in the old rat

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Lamproglou, Ioannis; Chen, QI Ming; Boisserie, Gilbert; Mazeron, Jean-Jacques; Poisson, Michel; Baillet, Francois; Le Poncin, Monique; Delattre, Jean-Yves

1995-01-01

Purpose: To develop a model of radiation-induced behavioral dysfunction. Methods and Materials: A course of whole brain radiation therapy (30 Gy/10 fractions/12 days) was administered to 26 Wistar rats ages 16-27 months, while 26 control rats received sham irradiation. Sequential behavioral studies including one-way avoidance, two-way avoidance, and a standard operant conditioning method (press-lever avoidance) were undertaken. In addition, rats were studied in a water maze 7 months postradiation therapy. Results: Prior to radiation therapy, both groups were similar. No difference was found 1 and 3 months postradiation therapy. At 6-7 months postradiation therapy, irradiated rats had a much lower percentage of avoidance than controls for one-way avoidance (23% vs. 55%, p {<=} 0.001) and two-way avoidance (18% vs. 40%, p {<=} 0.01). Seven months postradiation therapy the reaction time was increased (press-lever avoidance, 11.20 s vs. 8.43 s, p {<=} 0.05) and the percentage of correct response was lower (water maze, 53% vs. 82%) in irradiated rats compared with controls. Pathological examination did not demonstrate abnormalities of the irradiated brains at the light microscopic level. Conclusion: Behavioral dysfunction affecting mainly memory can be demonstrated following conventional radiation therapy in old rats. This model can be used to study the pathogenesis of radiation-induced cognitive changes.

Radiation-induced cognitive dysfunction: an experimental model in the old rat

International Nuclear Information System (INIS)

Lamproglou, Ioannis; Chen, QI Ming; Boisserie, Gilbert; Mazeron, Jean-Jacques; Poisson, Michel; Baillet, Francois; Le Poncin, Monique; Delattre, Jean-Yves

1995-01-01

Purpose: To develop a model of radiation-induced behavioral dysfunction. Methods and Materials: A course of whole brain radiation therapy (30 Gy/10 fractions/12 days) was administered to 26 Wistar rats ages 16-27 months, while 26 control rats received sham irradiation. Sequential behavioral studies including one-way avoidance, two-way avoidance, and a standard operant conditioning method (press-lever avoidance) were undertaken. In addition, rats were studied in a water maze 7 months postradiation therapy. Results: Prior to radiation therapy, both groups were similar. No difference was found 1 and 3 months postradiation therapy. At 6-7 months postradiation therapy, irradiated rats had a much lower percentage of avoidance than controls for one-way avoidance (23% vs. 55%, p ≤ 0.001) and two-way avoidance (18% vs. 40%, p ≤ 0.01). Seven months postradiation therapy the reaction time was increased (press-lever avoidance, 11.20 s vs. 8.43 s, p ≤ 0.05) and the percentage of correct response was lower (water maze, 53% vs. 82%) in irradiated rats compared with controls. Pathological examination did not demonstrate abnormalities of the irradiated brains at the light microscopic level. Conclusion: Behavioral dysfunction affecting mainly memory can be demonstrated following conventional radiation therapy in old rats. This model can be used to study the pathogenesis of radiation-induced cognitive changes

Radiation-induced cognitive dysfunction: An experimental model in the old rat

International Nuclear Information System (INIS)

Lamproglou, I.; Chen, Q.M.; Poisson, M.

1995-01-01

To develop a model of radiation-induced behavioral dysfunction. A course of whole brain radiation therapy (30 Gy/10 fractions/12 days) was administered to 26 Wistar rats ages 16-27 months, while 26 control rats received sham irradiation. Sequential behavioral studies including one-way avoidance, two-way avoidance, and a standard operant conditioning method (press-lever avoidance) were undertaken. In addition, rats were studied in a water maze 7 months postradiation therapy. Prior to radiation therapy, both groups were similar. No difference was found 1 and 3 months postradiation therapy. At 6-7 months postradiation therapy, irradiated rats had a much lower percentage of avoidance than controls for one-way avoidance (23% vs. 55%, p ≤ 0.001) and two-way avoidance (18% vs. 40%, p ≤ 0.01). Seven months postradiation therapy the reaction time was increased (press-lever avoidance, 11.20 s vs. 8.43 s, p ≤ 0.05) and the percentage of correct response was lower (water maze, 53% vs. 82%) in irradiated rats compared with controls. Pathological examination did not demonstrate abnormalities of the irradiated brains at the light microscopic level. Behavioral dysfunction affecting mainly memory can be demonstrated following conventional radiation therapy in old rats. This model can be used to study the pathogenesis of radiation-induced cognitive changes. 15 refs., 3 figs., 1 tab

Prevention of injury by resveratrol in a rat model of adenine-induced ...

African Journals Online (AJOL)

phosphorous, and fibroblast growth factor-23 (FGF-23) in rat urine samples after 2 months of adenine ... parathyroid hormone, phosphorous and FGF-23 levels (p < 0.002). In rats ... cartilage degradation in animal models of arthritis. [11].

Parkinsonian Balance Deficits Quantified Using a Game Industry Board and a Specific Battery of Four Paradigms.

Science.gov (United States)

Darbin, Olivier; Gubler, Coral; Naritoku, Dean; Dees, Daniel; Martino, Anthony; Adams, Elizabeth

2016-01-01

This study describes a cost-effective screening protocol for parkinsonism based on combined objective and subjective monitoring of balance function. Objective evaluation of balance function was performed using a game industry balance board and an automated analyses of the dynamic of the center of pressure in time, frequency, and non-linear domains collected during short series of stand up tests with different modalities and severity of sensorial deprivation. The subjective measurement of balance function was performed using the Dizziness Handicap Inventory questionnaire. Principal component analyses on both objective and subjective measurements of balance function allowed to obtained a specificity and selectivity for parkinsonian patients (vs. healthy subjects) of 0.67 and 0.71 respectively. The findings are discussed regarding the relevance of cost-effective balance-based screening system as strategy to meet the needs of broader and earlier screening for parkinsonism in communities with limited access to healthcare.

Attention and executive functions in a rat model of chronic epilepsy.

Science.gov (United States)

Faure, Jean-Baptiste; Marques-Carneiro, José E; Akimana, Gladys; Cosquer, Brigitte; Ferrandon, Arielle; Herbeaux, Karine; Koning, Estelle; Barbelivien, Alexandra; Nehlig, Astrid; Cassel, Jean-Christophe

2014-05-01

Temporal lobe epilepsy is a relatively frequent, invalidating, and often refractory neurologic disorder. It is associated with cognitive impairments that affect memory and executive functions. In the rat lithium-pilocarpine temporal lobe epilepsy model, memory impairment and anxiety disorder are classically reported. Here we evaluated sustained visual attention in this model of epilepsy, a function not frequently explored. Thirty-five Sprague-Dawley rats were subjected to lithium-pilocarpine status epilepticus. Twenty of them received a carisbamate treatment for 7 days, starting 1 h after status epilepticus onset. Twelve controls received lithium and saline. Five months later, attention was assessed in the five-choice serial reaction time task, a task that tests visual attention and inhibitory control (impulsivity/compulsivity). Neuronal counting was performed in brain regions of interest to the functions studied (hippocampus, prefrontal cortex, nucleus basalis magnocellularis, and pedunculopontine tegmental nucleus). Lithium-pilocarpine rats developed motor seizures. When they were able to learn the task, they exhibited attention impairment and a tendency toward impulsivity and compulsivity. These disturbances occurred in the absence of neuronal loss in structures classically related to attentional performance, although they seemed to better correlate with neuronal loss in hippocampus. Globally, rats that received carisbamate and developed motor seizures were as impaired as untreated rats, whereas those that did not develop overt motor seizures performed like controls, despite evidence for hippocampal damage. This study shows that attention deficits reported by patients with temporal lobe epilepsy can be observed in the lithium-pilocarpine model. Carisbamate prevents the occurrence of motor seizures, attention impairment, impulsivity, and compulsivity in a subpopulation of neuroprotected rats. Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.

Cardioprotective Effect of the Compound Yangshen Granule in Rat Models with Acute Myocardial Infarction

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Xie Ming

2012-01-01

Full Text Available The protective effect of Compound Yangshen Granules was observed in myocardial infarction rat model. Rats were randomly divided into 6 groups: the model group, the control group (sham operated, the positive drug group, and small, medium, and large dosage of the Yangshen granule groups, respectively. The rats in the 3 Yangshen granule groups were orally administrated with 0.7 g/kg, 1.4 g/kg, and 2.8 g/kg for 7 consecutive days, whereas the rats of the positive drug group treated with 0.14 g/kg of Danshen Dropping Pills, and rats in the control and model groups orally administrated with saline. The rat model of acute myocardial infarction was established with ligation of coronary artery. Electrocardiograms at different time points, the blood rheology, myocardial enzymes, infarct size, and myocardial morphologic changes were measured. The results demonstrated that the granules could improve blood rheology, decrease st-segment of electrocardiograms and the activities of LDH and CK in serum, reduce myocardial infarction size, and alleviate myocardial histopathologic changes. In addition, the effect of the granules depended on the dose administrated orally. The results suggest that the Yangshen granules could produce cardioprotection effect and have potential benefits in the prevention of ischemic heart disease.

Establishment of reproducible osteosarcoma rat model using orthotopic implantation technique.

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Yu, Zhe; Sun, Honghui; Fan, Qingyu; Long, Hua; Yang, Tongtao; Ma, Bao'an

2009-05-01

In experimental musculoskeletal oncology, there remains a need for animal models that can be used to assess the efficacy of new and innovative treatment methodologies for bone tumors. Rat plays a very important role in the bone field especially in the evaluation of metabolic bone diseases. The objective of this study was to develop a rat osteosarcoma model for evaluation of new surgical and molecular methods of treatment for extremity sarcoma. One hundred male SD rats weighing 125.45+/-8.19 g were divided into 5 groups and anesthetized intraperitoneally with 10% chloral hydrate. Orthotopic implantation models of rat osteosarcoma were performed by injecting directly into the SD rat femur with a needle for inoculation with SD tumor cells. In the first step of the experiment, 2x10(5) to 1x10(6) UMR106 cells in 50 microl were injected intraosseously into median or distal part of the femoral shaft and the tumor take rate was determined. The second stage consisted of determining tumor volume, correlating findings from ultrasound with findings from necropsia and determining time of survival. In the third stage, the orthotopically implanted tumors and lung nodules were resected entirely, sectioned, and then counter stained with hematoxylin and eosin for histopathologic evaluation. The tumor take rate was 100% for implants with 8x10(5) tumor cells or more, which was much less than the amount required for subcutaneous implantation, with a high lung metastasis rate of 93.0%. Ultrasound and necropsia findings matched closely (r=0.942; p<0.01), which demonstrated that Doppler ultrasonography is a convenient and reliable technique for measuring cancer at any stage. Tumor growth curve showed that orthotopically implanted tumors expanded vigorously with time-lapse, especially in the first 3 weeks. The median time of survival was 38 days and surgical mortality was 0%. The UMR106 cell line has strong carcinogenic capability and high lung metastasis frequency. The present rat

Acetyl-L-Carnitine via Upegulating Dopamine D1 Receptor and Attenuating Microglial Activation Prevents Neuronal Loss and Improves Memory Functions in Parkinsonian Rats.

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Singh, Sonu; Mishra, Akanksha; Srivastava, Neha; Shukla, Rakesh; Shukla, Shubha

2018-01-01

Parkinson's disease is accompanied by nonmotor symptoms including cognitive impairment, which precede the onset of motor symptoms in patients and are regulated by dopamine (DA) receptors and the mesocorticolimbic pathway. The relative contribution of DA receptors and astrocytic glutamate transporter (GLT-1) in cognitive functions is largely unexplored. Similarly, whether microglia-derived increased immune response affects cognitive functions and neuronal survival is not yet understood. We have investigated the effect of acetyl-L-carnitine (ALCAR) on cognitive functions and its possible underlying mechanism of action in 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian rats. ALCAR treatment in 6-OHDA-lesioned rats improved memory functions as confirmed by decreased latency time and path length in the Morris water maze test. ALCAR further enhanced D1 receptor levels without altering D2 receptor levels in the hippocampus and prefrontal cortex (PFC) regions, suggesting that the D1 receptor is preferentially involved in the regulation of cognitive functions. ALCAR attenuated microglial activation and release of inflammatory mediators through balancing proinflammatory and anti-inflammatory cytokines, which subsequently enhanced the survival of mature neurons in the CA1, CA3, and PFC regions and improved cognitive functions in hemiparkinsonian rats. ALCAR treatment also improved glutathione (GSH) content, while decreasing oxidative stress indices, inducible nitrogen oxide synthase (iNOS) levels, and astrogliosis resulting in the upregulation of GLT-1 levels. Additionally, ALCAR prevented the loss of dopaminergic (DAergic) neurons in ventral tagmental area (VTA)/substantia nigra pars compacta (SNpc) regions of 6-OHDA-lesioned rats, thus maintaining the integrity of the nigrostriatal pathway. Together, these results demonstrate that ALCAR treatment in hemiparkinsonian rats ameliorates neurodegeneration and cognitive deficits, hence suggesting its therapeutic potential in

Volumetric abnormalities of the brain in a rat model of recurrent headache.

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Jia, Zhihua; Tang, Wenjing; Zhao, Dengfa; Hu, Guanqun; Li, Ruisheng; Yu, Shengyuan

2018-01-01

Voxel-based morphometry is used to detect structural brain changes in patients with migraine. However, the relevance of migraine and structural changes is not clear. This study investigated structural brain abnormalities based on voxel-based morphometry using a rat model of recurrent headache. The rat model was established by infusing an inflammatory soup through supradural catheters in conscious male rats. Rats were subgrouped according to the frequency and duration of the inflammatory soup infusion. Tactile sensory testing was conducted prior to infusion of the inflammatory soup or saline. The periorbital tactile thresholds in the high-frequency inflammatory soup stimulation group declined persistently from day 5. Increased white matter volume was observed in the rats three weeks after inflammatory soup stimulation, brainstem in the in the low-frequency inflammatory soup-infusion group and cortex in the high-frequency inflammatory soup-infusion group. After six weeks' stimulation, rats showed gray matter volume changes. The brain structural abnormalities recovered after the stimulation was stopped in the low-frequency inflammatory soup-infused rats and persisted even after the high-frequency inflammatory soup stimulus stopped. The changes of voxel-based morphometry in migraineurs may be the result of recurrent headache. Cognition, memory, and learning may play an important role in the chronification of migraines. Reducing migraine attacks has the promise of preventing chronicity of migraine.

Genital mycoplasmosis in rats: a model for intrauterine infection.

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Brown, M B; Peltier, M; Hillier, M; Crenshaw, B; Reyes, L

2001-09-01

Microbial infections of the chorioamnion and amniotic fluid have devastating effects on pregnancy outcome and neonatal morbidity and mortality. The mechanisms by which bacterial pathogens cause adverse effects are best addressed by an animal model of the disease with a naturally-occurring pathogen. Intrauterine infection in humans as well as genital mycoplasmosis in humans and rodents is reviewed. We describe a genital infection in rats, which provides a model for the role of infection in pregnancy, pregnancy wastage, low birth weight, and fetal infection. Infection of Sprague-Dawley rats with Mycoplasma pulmonis either vaginally or intravenously resulted in decreased litter size, increased adverse pregnancy outcome, and in utero transmission of the microorganism to the fetus. Mycoplasma pulmonis is an ideal model to study maternal genital infection during pregnancy, the impact of infections on pregnancy outcome, fetal infection, and maternal-fetal immune interactions.

Altered explorative strategies and reactive coping style in the FSL rat model of depression

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Salvatore eMagara

2015-04-01

Full Text Available Modeling depression in animals is based on the observation of behaviors interpreted as analogue to human symptoms. Typical tests used in experimental depression research are designed to evoke an either-or outcome. It is known that explorative and coping strategies are relevant for depression, however these aspects are generally not considered in animal behavioral testing. Here we investigate the Flinders Sensitive Line (FSL, a rat model of depression, compared to the Sprague-Dawley (SD rat in three independent tests where the animals are allowed to express a more extensive behavioral repertoire. The multivariate concentric square field™ (MCSF and the novel cage tests evoke exploratory behaviors in a novel environment and the home cage change test evokes social behaviors in the re-establishment of a social hierarchy. In the MCSF test, FSL rats exhibited less exploratory drive and more risk-assessment behavior compared to SD rats. When re-exposed to the arena, FSL, but not SD rats, increased their exploratory behavior compared to the first trial and displayed risk-assessment behavior to the same extent as SD rats. Thus, the behavior of FSL rats was more similar to that of SDs when the rats were familiar with the arena. In the novel cage test FSL rats exhibited a reactive coping style, consistent with the reduced exploration observed in the MCSF. Reactive coping is associated with less aggressive behavior. Accordingly, FSL rats displayed less aggressive behavior in the home cage change test. Taken together, our data show that FSL rats express altered explorative behavior and reactive coping style. Reduced interest is a core symptom of depression, and individuals with a reactive coping style are more vulnerable to the disease. Our results support the use of FSL rats as an animal model of depression and increase our understanding of the FSL rat beyond the behavioral dimensions targeted by the traditional depression-related tests.

Establishment of a rat model of early-stage liver failure and Th17/Treg imbalance

OpenAIRE

LI Dong; LU Zhonghua; GAN Jianhe

2016-01-01

ObjectiveTo investigate the methods for establishing a rat model of early-stage liver failure and the changes in Th17, Treg, and Th17/Treg after dexamethasone and thymosin interventions. MethodsA total of 64 rats were randomly divided into carbon tetrachloride (CCl4) group and endotoxin ［lipopolysaccharide (LPS)］/D-galactosamine (D-GalN) combination group to establish the rat model of early-stage liver failure. The activities of the rats and changes in liver function and whole blood Th17 and ...

A Novel Newborn Rat Kernicterus Model Created by Injecting a Bilirubin Solution into the Cisterna Magna

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Song, Sijie; Hu, Ying; Gu, Xianfang; Si, Feifei; Hua, Ziyu

2014-01-01

Background Kernicterus still occurs around the world; however, the mechanism of bilirubin neurotoxicity remains unclear, and effective treatment strategies are lacking. To solve these problems, several kernicterus (or acute bilirubin encephalopathy) animal models have been established, but these models are difficult and expensive. Therefore, the present study was performed to establish a novel kernicterus model that is simple and affordable by injecting unconjugated bilirubin solution into the cisterna magna (CM) of ordinary newborn Sprague-Dawley (SD) rats. Methods On postnatal day 5, SD rat pups were randomly divided into bilirubin and control groups. Then, either bilirubin solution or ddH2O (pH = 8.5) was injected into the CM at 10 µg/g (bodyweight). For model characterization, neurobehavioral outcomes were observed, mortality was calculated, and bodyweight was recorded after bilirubin injection and weaning. Apoptosis in the hippocampus was detected by H&E staining, TUNEL, flow cytometry and Western blotting. When the rats were 28 days old, learning and memory ability were evaluated using the Morris water maze test. Results The bilirubin-treated rats showed apparently abnormal neurological manifestations, such as clenched fists, opisthotonos and torsion spasms. Bodyweight gain in the bilirubin-treated rats was significantly lower than that in the controls (Pbilirubin-treated rats were both dramatically higher than those of the controls (P = 0.004 and 0.017, respectively). Apoptosis and necrosis in the hippocampal nerve cells in the bilirubin-treated rats were observed. The bilirubin-treated rats performed worse than the controls on the Morris water maze test. Conclusion By injecting bilirubin into the CM, we successfully created a new kernicterus model using ordinary SD rats; the model mimics both the acute clinical manifestations and the chronic sequelae. In particular, CM injection is easy to perform; thus, more stable models for follow-up study are

Establishment of a rat and guinea pig aortic interposition graft model reveals model-specific patterns of intimal hyperplasia.

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Gregory, Elaine K; Vercammen, Janet M; Flynn, Megan E; Kibbe, Melina R

2016-12-01

Although the aortic interposition bypass model has been widely used to evaluate biomaterials for bypass grafting, there is no comprehensive description of the procedure or of the distribution of intimal hyperplasia that results. The objectives of this study were to (1) review and summarize approaches of aortic interposition grafting in animal models, (2) determine the pertinent anatomy for this procedure, (3) validate this model in the rat and guinea pig, and (4) compare the distribution of intimal hyperplasia that develops in each species. A literature search was performed in PubMed from 1980 to the present to analyze the use of anesthesia, anticoagulation, antiplatelet agents, graft material, suture, and anastomotic techniques. Using 10-week-old male Sprague-Dawley rats and Hartley guinea pigs, we established pertinent aortic anatomy, developed comparable models, and assessed complications for each model. At 30 days, the graft and associated aorta were explanted, intimal formation was assessed morphometrically, and cellularity was assessed via nuclear counting. We reviewed 30 articles and summarized the pertinent procedural findings. Upon establishing both animal models, key anatomic differences between the species that affect this model were noted. Guinea pigs have a much larger cecum, increased retroperitoneal fat, and lack the iliolumbar vessels compared with the rat. Surgical outcomes for the rat model included a 53% technical success rate and a 32% technical error rate. Surgical outcomes for the guinea pig model included a 69% technical success rate and a 31% technical error rate. These two species demonstrated unique distribution of intimal hyperplasia at 30 days. Intimal hyperplasia in the rat model was greatest at two areas, the proximal graft (5400 μm 2 ; P guinea pig model developed similar intimal hyperplasia throughout the graft (4500-5100 μm 2 ; P guinea pig, and describe a unique distribution of intimal formation that results in both species

Modeling the systemic retention of beryllium in rat. Extrapolation to human

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Montero Prieto, M.; Vidania Munoz, R. de

1994-01-01

In this work, we analyzed different approaches, assayed in order to numerically describe the systemic behaviour of Beryllium. The experimental results used in this work, were previously obtained by Furchner et al. (1973), using Sprague-Dawley rats, and others animal species. Furchner's work includes the obtained model for whole body retention in rats, but not for each target organ. In this work we present the results obtained by modeling the kinetic behaviour of Beryllium in several target organs. The results of this kind of models were used in order to establish correlations among the estimated kinetic constants. The parameters of the model were extrapolated to humans and, finally, compared with others previously published. (Author) 12 refs

Modeling of systematic retention of beryllium in rats. Extrapolation to humans

International Nuclear Information System (INIS)

Montero Prieto, M.; Vidania Munoz, R. de.

1994-01-01

In this work, we analyzed different approaches, assayed in order to numerically describe the systemic behaviour of Beryllium. The experimental results used in this work, were previously obtained by Furchner et al. (1973), using Sprague-Dawley rats, and other animal species. Furchner's work includes the obtained model for whole body retention in rats but not for each target organ. In this work we present the results obtained by modeling the kinetic behaviour of Beryllium in several target organs. The results of this kind of models were used in order to establish correlations among the estimated kinetic constants. The parameters of the model were extrapolated to humans and, finally, compared with other previously published

Characterization of the Prediabetic State in a Novel Rat Model of Type 2 Diabetes, the ZFDM Rat.

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Gheni, Ghupurjan; Yokoi, Norihide; Beppu, Masayuki; Yamaguchi, Takuro; Hidaka, Shihomi; Kawabata, Ayako; Hoshino, Yoshikazu; Hoshino, Masayuki; Seino, Susumu

2015-01-01

We recently established a novel animal model of obese type 2 diabetes (T2D), the Zucker fatty diabetes mellitus (ZFDM) rat strain harboring the fatty mutation (fa) in the leptin receptor gene. Here we performed a phenotypic characterization of the strain, focusing mainly on the prediabetic state. At 6-8 weeks of age, fa/fa male rats exhibited mild glucose intolerance and severe insulin resistance. Although basal insulin secretion was remarkably high in the isolated pancreatic islets, the responses to both glucose stimulation and the incretin GLP-1 were retained. At 10-12 weeks of age, fa/fa male rats exhibited marked glucose intolerance as well as severe insulin resistance similar to that at the earlier age. In the pancreatic islets, the insulin secretory response to glucose stimulation was maintained but the response to the incretin was diminished. In nondiabetic Zucker fatty (ZF) rats, the insulin secretory responses to both glucose stimulation and the incretin in the pancreatic islets were similar to those of ZFDM rats. As islet architecture was destroyed with age in ZFDM rats, a combination of severe insulin resistance, diminished insulin secretory response to incretin, and intrinsic fragility of the islets may cause the development of T2D in this strain.

WNIN/GR-Ob - an insulin-resistant obese rat model from inbred WNIN strain.

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Harishankar, N; Vajreswari, A; Giridharan, N V

2011-09-01

WNIN/GR-Ob is a mutant obese rat strain with impaired glucose tolerance (IGT) developed at the National Institute of Nutrition (NIN), Hyderabad, India, from the existing 80 year old Wistar rat (WNIN) stock colony. The data presented here pertain to its obese nature along with IGT trait as evidenced by physical, physiological and biochemical parameters. The study also explains its existence, in three phenotypes: homozygous lean (+/+), heterozygous carrier (+/-) and homozygous obese (-/-). Thirty animals (15 males and 15 females) from each phenotype (+/+, +/-, -/-) and 24 lean and obese (6 males and 6 females) rats were taken for growth and food intake studies respectively. Twelve adult rats from each phenotype were taken for body composition measurement by total body electrical conductivity (TOBEC); 12 rats of both genders from each phenotype at different ages were taken for clinical chemistry parameters. Physiological indices of insulin resistance were calculated according to the homeostasis model assessment for insulin resistance (HOMA-IR) and also by studying U¹⁴C 2-deoxy glucose uptake (2DG). WNINGR-Ob mutants had high growth, hyperphagia, polydipsia, polyurea, glycosuria, and significantly lower lean body mass, higher fat mass as compared with carrier and lean rats. These mutants, at 50 days of age displayed abnormal response to glucose load (IGT), hyperinsulinaemia, hypertriglyceridaemia, hypercholesterolaemia and hyperleptinaemia. Basal and insulin-stimulated glucose uptakes by diaphragm were significantly decreased in obese rats as compared with lean rats. Obese rats of the designated WNIN/GR-Ob strain showed obesity with IGT, as adjudged by physical, physiological and biochemical indices. These indices varied among the three phenotypes, being lowest in lean, highest in obese and intermediate in carrier phenotypes thereby suggesting that obesity is inherited as autosomal incomplete dominant trait in this strain. This mutant obese rat model is easy to

Topiramate as a neuroprotective agent in a rat model of spinal cord injury

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Firat Narin

2017-01-01

Full Text Available Topiramate (TPM is a widely used antiepileptic and antimigraine agent which has been shown to exert neuroprotective effects in various experimental traumatic brain injury and stroke models. However, its utility in spinal cord injury has not been studied extensively. Thus, we evaluated effects of TPM on secondary cellular injury mechanisms in an experimental rat model of traumatic spinal cord injury (SCI. After rat models of thoracic contusive SCI were established by free weight-drop method, TPM (40 mg/kg was given at 12-hour intervals for four times orally. Post TPM treatment, malondialdehyde and protein carbonyl levels were significantly reduced and reduced glutathione levels were increased, while immunoreactivity for endothelial nitric oxide synthase, inducible nitric oxide synthase, and apoptotic peptidase activating factor 1 was diminished in SCI rats. In addition, TPM treatment improved the functional recovery of SCI rats. This study suggests that administration of TPM exerts neuroprotective effects on SCI.

Establishment of SHG-44 human glioma model in brain of wistar rat with stereotactic technique

International Nuclear Information System (INIS)

Hong Xinyu; Luo Yi'nan; Fu Shuanglin; Wang Zhanfeng; Bie Li; Cui Jiale

2004-01-01

Objective: To establish solid intracerebral human glioma model in Wistar rat with xenograft methods. Methods: The SHG-44 cells were injected into brain right caudate nucleus of previous immuno-inhibitory Wistar rats with stereotactic technique. The MRI scans were performed at 1 week and 2 weeks later after implantation. After 2 weeks the rats were killed and pathological examination and immunohistologic stain for human GFAP were used. Results: The MRI scan after 1 week of implantation showed the glioma was growing, pathological histochemical examination demonstrated the tumor was glioma. Human GFAP stain was positive. The growth rate of glioma model was about 60%. Conclusion: Solid intracerebral human glioma model in previous immuno-inhibitory Wistar rat is successfully established

Orthotopic model of canine osteosarcoma in athymic rats for evaluation of stereotactic radiotherapy.

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Schwartz, Anthony L; Custis, James T; Harmon, Joseph F; Powers, Barbara E; Chubb, Laura S; LaRue, Susan M; Ehrhart, Nicole P; Ryan, Stewart D

2013-03-01

To develop an orthotopic model of canine osteosarcoma in athymic rats as a model for evaluating the effects of stereotactic radiotherapy (SRT) on osteosarcoma cells. 26 athymic nude rats. 3 experiments were performed. In the first 2 experiments, rats were injected with 1 × 10(6) Abrams canine osteosarcoma cells into the proximal aspect of the tibia (n = 12) or distal aspect of the femur (6). Tumor engraftment and progression were monitored weekly via radiography, luciferase imaging, and measurement of urine pyridinoline concentration for 5 weeks and histologic evaluation after euthanasia. In the third experiment, 8 rats underwent canine osteosarcoma cell injection into the distal aspect of the femur and SRT was administered to the affected area in three 12-Gy fractions delivered on consecutive days (total radiation dose, 36 Gy). Percentage tumor necrosis and urinary pyridinoline concentrations were used to assess local tumor control. The short-term effect of SRT on skin was also evaluated. Tumors developed in 10 of 12 tibial sites and all 14 femoral sites. Administration of SRT to rats with femoral osteosarcoma was feasible and successful. Mean tumor necrosis of 95% was achieved histologically, and minimal adverse skin effects were observed. The orthotopic model of canine osteosarcoma in rats developed in this study was suitable for evaluating the effects of local tumor control and can be used in future studies to evaluate optimization of SRT duration, dose, and fractionation schemes. The model could also allow evaluation of other treatments in combination with SRT, such as chemotherapy or bisphosphonate, radioprotectant, or parathyroid hormone treatment.

Vascularized anal autotransplantation model in rats: preliminary report.

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Araki, J; Mihara, M; Narushima, M; Iida, T; Sato, T; Koshima, I

2011-11-01

Ostomy has served as an effective surgery for various anorectal disfunctions. However, it must also be noted that those patients suffered greatly from stresses caused by their stoma. Many alternative therapies have been developed, but none have solved this critical issue. Meanwhile, due to the improvements in operative methods and immunosuppressive therapy, allotranplantation has gained great popularity in recent years. Therefore, we began development of an anal transplantation model. The operation was performed in six adult Wistar rats that were divided into two groups. Group 1 underwent vascular anastomoses, while group 2 did not Group 1 grafts survived, fully recovering anal function. However, many of the group 2 grafts did not survive; those that did survive showed major defects in their anus, never recovering anal function. We succeeded in establishing the rat anal transplantation model utilizing super-microsurgery. While research in anal transplantation was behind compared to that in other fields, we hope that this model will bring significant possibilities for the future. Copyright © 2011 Elsevier Inc. All rights reserved.

Parkinsonian balance deficits quantified using a game industry board and a specific battery of four paradigms.

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Olivier Darbin

2016-08-01

Full Text Available This study describes a cost-effective screening protocol for parkinsonism based on combined objective and subjective monitoring of balance function. Objective evaluation of balance function was performed using a game industry balance board and an automated analyses of the dynamic of the center of pressure in time, frequency and non-linear domains collected during short series of stand up tests with different modalities and severity of sensorial deprivation. The subjective measurement of balance function was performed using the Dizziness Handicap Inventory questionnaire. Principal component analyses on both objective and subjective measurements of balance function allowed to obtained a specificity and selectivity for parkinsonian patients (v.s. healthy subjects of 0.67 and 0.71 respectively. The findings are discussed regarding the relevance of cost-effective balance-based screening system as strategy to meet the needs of broader and earlier screening for parkinsonism in communities with limited access to healthcare.

Do basal Ganglia amplify willed action by stochastic resonance? A model.

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V Srinivasa Chakravarthy

Full Text Available Basal ganglia are usually attributed a role in facilitating willed action, which is found to be impaired in Parkinson's disease, a pathology of basal ganglia. We hypothesize that basal ganglia possess the machinery to amplify will signals, presumably weak, by stochastic resonance. Recently we proposed a computational model of Parkinsonian reaching, in which the contributions from basal ganglia aid the motor cortex in learning to reach. The model was cast in reinforcement learning framework. We now show that the above basal ganglia computational model has all the ingredients of stochastic resonance process. In the proposed computational model, we consider the problem of moving an arm from a rest position to a target position: the two positions correspond to two extrema of the value function. A single kick (a half-wave of sinusoid, of sufficiently low amplitude given to the system in resting position, succeeds in taking the system to the target position, with high probability, only at a critical noise level. But for suboptimal noise levels, the model arm's movements resemble Parkinsonian movement symptoms like akinetic rigidity (low noise and dyskinesias (high noise.

Assessment of efficacy of polaprezinc suppositories against radiation-induced rectal disorders using an experimental rat model

International Nuclear Information System (INIS)

Doi, Hiroshi; Kamikonya, Norihiko; Takada, Yasuhiro

2009-01-01

The purpose/objective of this study was to establish an experimental rat model and examine the efficacy of polaprezinc suppositories against radiation-induced rectal disorders. Female Wister rats (6 weeks old) were used in the present study. The rats were divided into three groups. Group A was irradiated and medicated with polaprezinc suppositories. Group B was irradiated without any medication. Group C had no irradiation or medication. The rat was taped by the tail in the vertical position under anesthesia. Lead shielding was used to cover the rats except the area of the lower pelvis. They were irradiated at 22 Gy by a single fraction. Polaprezinc suppositories were inserted daily into the rat anus for 7 days after irradiation. All rats were evaluated by colonoscopy on the 7th day after irradiation, sacrificed on the 10th day, and evaluated for mucosal damage. In the clinical findings, the endoscopic findings, and the histological findings, the rats not administered polaprezinc suppositories tended to show more severe mucosal damage but there were no significant differences. Our study showed that this model was a useful experimental rat model for radiation-induced rectal disorders and polaprezinc suppositories demonstrated good efficacy against radiation proctitis. (author)

Influence of manual therapy on functional mobility after joint injury in a rat model.

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Ruhlen, Rachel L; Snider, Eric J; Sargentini, Neil J; Worthington, Bart D; Singh, Vineet K; Pazdernik, Vanessa K; Johnson, Jane C; Degenhardt, Brian F

2013-10-01

Animal models can be used to investigate manual therapy mechanisms, but testing manipulation in animal models is problematic because animals cannot directly report their pain. To develop a rat model of inflammatory joint injury to test the efficacy of manual therapy in reducing nociception and restoring function. The authors induced acute inflammatory joint injury in rats by injecting carrageenan into the ankle and then measured voluntary running wheel activity in treated and untreated rats. Treatments included manual therapy applied to the ankle and knee of the injured limb and several analgesic medications (eg, morphine, ketorolac, prednisone). Intra-articular injection of carrageenan to the ankle produced significant swelling (diameter of the ankle increased by 64% after injection; P=.004) and a robust reduction in voluntary running wheel activity (running distance reduced by 91% compared with controls; Pmanual therapy nor analgesic medications increased running wheel activity relative to untreated rats. Voluntary running wheel activity appears to be an appropriate functional measure to evaluate the impact of an acute inflammatory joint injury. However, efforts to treat the injury did not restore running relative to untreated rats.

Comparison of Allogeneic and Syngeneic Rat Glioma Models by Using MRI and Histopathologic Evaluation.

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Biasibetti, Elena; Valazza, Alberto; Capucchio, Maria T; Annovazzi, Laura; Battaglia, Luigi; Chirio, Daniela; Gallarate, Marina; Mellai, Marta; Muntoni, Elisabetta; Peira, Elena; Riganti, Chiara; Schiffer, Davide; Panciani, Pierpaolo; Lanotte, Michele

2017-03-01

Research in neurooncology traditionally requires appropriate in vivo animal models, on which therapeutic strategies are tested before human trials are designed and proceed. Several reproducible animal experimental models, in which human physiologic conditions can be mimicked, are available for studying glioblastoma multiforme. In an ideal rat model, the tumor is of glial origin, grows in predictable and reproducible patterns, closely resembles human gliomas histopathologically, and is weakly or nonimmunogenic. In the current study, we used MRI and histopathologic evaluation to compare the most widely used allogeneic rat glioma model, C6-Wistar, with the F98-Fischer syngeneic rat glioma model in terms of percentage tumor growth or regression and growth rate. In vivo MRI demonstrated considerable variation in tumor volume and frequency between the 2 rat models despite the same stereotactic implantation technique. Faster and more reproducible glioma growth occurred in the immunoresponsive environment of the F98-Fischer model, because the immune response is minimized toward syngeneic cells. The marked inability of the C6-Wistar allogeneic system to generate a reproducible model and the episodes of spontaneous tumor regression with this system may have been due to the increased humoral and cellular immune responses after tumor implantation.

Novel Rat Model of Repetitive Portal Venous Embolization Mimicking Human Non-Cirrhotic Idiopathic Portal Hypertension

DEFF Research Database (Denmark)

Klein, Sabine; Hinüber, Christian; Hittatiya, Kanishka

2016-01-01

BACKGROUND: Non-cirrhotic idiopathic portal hypertension (NCIPH) is characterized by splenomegaly, anemia and portal hypertension, while liver function is preserved. However, no animal models have been established yet. This study assessed a rat model of NCIPH and characterized the hemodynamics......, and compared it to human NCIPH. METHODS: Portal pressure (PP) was measured invasively and coloured microspheres were injected in the ileocecal vein in rats. This procedure was performed weekly for 3 weeks (weekly embolization). Rats without and with single embolization served as controls. After four weeks (one...... in the weekly embolization group. Fibrotic markers αSMA and Desmin were upregulated in weekly embolized rats. DISCUSSION: This study establishes a model using repetitive embolization via portal veins, comparable with human NCIPH and may serve to test new therapies....

The Effects of Methylphenidate on Goal-Directed Behavior in a Rat Model of ADHD

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Joman Y. Natsheh

2015-11-01

Full Text Available Although attentional and motor alterations in Attention Deficit Hyperactivity Disorder (ADHD have been well characterized, less is known about how this disorder impacts goal-directed behavior. To investigate whether there is a misbalance between goal-directed and habitual behaviors in an animal model of ADHD, we tested adult [P75-P105] Spontaneously Hypertensive Rats (SHR (ADHD rat model and Wistar-Kyoto rats (WKY, the normotensive control strain, on an instrumental conditioning paradigm with two phases: a free-operant training phase in which rats separately acquired two distinct action-outcome contingencies, and a choice test conducted in extinction prior to which one of the food outcomes was devalued through specific satiety. To assess the effects of Methylphenidate, a commonly used ADHD medication, on goal-directed behavior, we injected rats with either Methylphenidate or saline prior to the choice test. Both rat strains acquired an instrumental response, with SHR responding at greater rates over the course of training. During the choice test WKY demonstrated goal-directed behavior, responding more frequently on the lever that delivered, during training, the still-valued outcome. In contrast, SHR showed no goal-directed behavior, responding equally on both levers. However, methylphenidate administration prior to the choice test restored goal-directed behavior in SHR, and disrupted this behavior in WKY rats. This study provides the first experimental evidence for selective impairment in goal-directed behavior in rat models of ADHD, and how methylphenidate acts differently on SHR and WKY animals to restore or impair this behavior, respectively.

[The replacement therapy of rPTH(1-84) in established rat model of hypothyroidism].

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Ding, Zhiwei; Li, Tiancheng; Liu, Yuhe; Xiao, Shuifang

2015-12-01

To investigate the replacement therapy of rPTH(1-84) (recombinant human parathyroid hormone (1-84)) to hypothyroidism in established rat model. Rat model of hypothyroidism was established by resecting parathyroids. A total of 30 rats with removal of parathyroids were divided into 6 groups randomly, 5 in each group, and applied respectively with saline injection (negative control group), calcitriol treatment (positive control group) and quadripartite PTH administration with dose of 20, 40, 80 and 160 µg/kg (experimental groups). Saline and rPTH(1-84) were injected subcutaneously daily. Calcitriol was gavaged once a day. Sham-operation was conducted in 5 rats of negative control group. To verify the authenticity of the rat model with hypothyroidism, the serum was insolated centrifugally from rat blood that was obtained from angular vein at specific time to measure calcium and phosphorus concentration. Urine in 12 hours was collected by metabolic cages and the calcium concentration was measured. After 10-week drug treatment, the experiment was terminated and bilateral femoral bone and L2-5 lumbar vertebra were removed from rats. Bone mineral density (BMD)of bilateral femoral bone and lumbar vertebra was analyzed by dual X-ray absorptiometry (DXA). The concentration of bone alkaline phosphatase (BALP) in serum was determined by radioimmunoassay. The rat model with hypothyroidism was obtained by excising parathyroid gland and was verified by monitoring calcium and phosphorus concentration subsequently. Administration of rPTH(1-84) in the dose of 80 or 160 µg/kg made serum calcium and phosphorus back to normal levels, with no significant difference between the doses (P>0.05). The BMD in each group of rats with rPTH(1-84) administration was increased significantly (P0.05). Calcium and phosphorus return to normal level by administration of rPTH(1-84) in the dose of 80 µg/kg or 160 µg/kg, with increase in BMD. Calcitriol can return the level of calcium to normal and

Effects of Astragalus polysaccharides on memory impairment in a diabetic rat model

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Dun C

2016-07-01

Full Text Available Changping Dun,1 Junqian Liu,1 Fucheng Qiu,1 Xueda Wu,2 Yakun Wang,3 Yongyan Zhao,4 Ping Gu1 1Department of Neurology, the First Hospital of Hebei Medical University, 2Department of Cardiac Surgery, the Second Hospital of Hebei Medical University, 3Department of Endocrinology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, 4Department of Nursing, Maternal and Child Health Hospital of Tangshan City, Tangshan, People’s Republic of China Objective: Astragalus polysaccharides (APS are active constituents of Astragalus membranaceus. In this study, we aimed to investigate the effects of APS on memory impairment in a diabetic rat model and their mechanisms. Methods: A diabetic model was established in 50 male Wistar rats with streptozotocin intraperitoneal injection. A blood glucose level higher than 16.7 mmol/L obtained 72 hours after the injection was regarded as a successful diabetic model. The modeled rats were divided into model group, high, medium, and low doses of APS, and piracetam groups (positive control. A group of ten rats without streptozotocin-induced diabetes were used as a normal control. After respective consecutive 8-week treatments, the levels of blood fasting plasma glucose, insulin, hemoglobin A1c, memory performance, hippocampal malondialdehyde, and superoxide dismutase were determined. Results: After the 8-week APS treatment, serum fasting plasma glucose, hemoglobin A1c, and insulin levels were decreased compared with those of the model group (P<0.05. Importantly, memory impairment in the diabetic model was reversed by APS treatments. In addition, hippocampal malondialdehyde concentration was lowered, whereas that of superoxide dismutase was higher after APS treatments. Conclusion: APS are important active components responsible for memory improvement in rats with streptozotocin-induced diabetes. The potential mechanism of action is associated with the effects of APS on glucose and lipid metabolism, and

Transcriptional alterations in the left ventricle of three hypertensive rat models.

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Cerutti, Catherine; Kurdi, Mazen; Bricca, Giampiero; Hodroj, Wassim; Paultre, Christian; Randon, Jacques; Gustin, Marie-Paule

2006-11-27

Left ventricular hypertrophy (LVH) is commonly associated with hypertension and represents an independent cardiovascular risk factor. The aim of this study was to test the hypothesis that the cardiac overload related to hypertension is associated to a specific gene expression pattern independently of genetic background. Gene expression levels were obtained with microarrays for 15,866 transcripts from RNA of left ventricles from 12-wk-old rats of three hypertensive models [spontaneously hypertensive rat (SHR), Lyon hypertensive rat (LH), and heterozygous TGR(mRen2)27 rat] and their respective controls. More than 60% of the detected transcripts displayed significant changes between the three groups of normotensive rats, showing large interstrain variability. Expression data were analyzed with respect to hypertension, LVH, and chromosomal distribution. Only four genes had significantly modified expression in the three hypertensive models among which a single gene, coding for sialyltransferase 7A, was consistently overexpressed. Correlation analysis between expression data and left ventricular mass index (LVMI) over all rats identified a larger set of genes whose expression was continuously related with LVMI, including known genes associated with cardiac remodeling. Positioning the detected transcripts along the chromosomes pointed out high-density regions mostly located within blood pressure and cardiac mass quantitative trait loci. Although our study could not detect a unique reprogramming of cardiac cells involving specific genes at early stage of LVH, it allowed the identification of some genes associated with LVH regardless of genetic background. This study thus provides a set of potentially important genes contained within restricted chromosomal regions involved in cardiovascular diseases.

Effect of sodium aescinate treatment on PCOS rat model with insulin resistance.

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Chen, L; Hu, L M; Wang, Y F; Yang, H Y; Huang, X Y; Zhou, W; Sun, H X

2017-01-01

Recent studies indicated that insulin resistance may contribute to the pathogenesis of polycystic ovary syndrome (PCOS); however, the specific mechanism is still unclear. To investigate the effect of sodium aescinate (SA) on PCOS-IR rat models. Sixty rats were randomly divided into the five groups: un-treated rats (n = 12), PCOS-IR group (n = 12), PCOS-IR group plus 50 mg/kg SA (n = 12), PCOS-IR group plus 10 mg/kg SA (n = 12), PCOS-IR group plus 150 mg/kg metformin (n = 12). On day 21, rats were sacrificed, and H(and)E staining was performed for histopathologic examination of the ovaries; moreover, the serum level of follicle-stimulating hormone (FSH), testosterone, and luteotropic hormone (LH) were measured, and the expression as well as phosphorylation of PI3K, Akt and Gsk-3β were examined using western blot assay. High dosage of SA treatment improved the morphological features of the ovaries in PCOS rats, and also induced significant decrease in serum expression of testosterone and LH/FSH ratio and significant decrease in the expression of p-PI3K, p-Akt and p-Gsk-3β. Our results demonstrated that SA treatment could alleviate the symptom of PCOS in rat model through regulating the PI3K/Akt/GSK3-β pathway (Fig. 4, Ref. 22).

Anti-inflammatory activity of methyl palmitate and ethyl palmitate in different experimental rat models

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Saeed, Noha M. [Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo (Egypt); El-Demerdash, Ebtehal [Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo (Egypt); Abdel-Rahman, Hanaa M. [Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo (Egypt); Algandaby, Mardi M. [Department of Biology (Botany), Faculty of Science, King Abdulaziz University, Jeddah (Saudi Arabia); Al-Abbasi, Fahad A. [Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah (Saudi Arabia); Abdel-Naim, Ashraf B., E-mail: abnaim@pharma.asu.edu.eg [Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo (Egypt)

2012-10-01

Methyl palmitate (MP) and ethyl palmitate (EP) are naturally occurring fatty acid esters reported as inflammatory cell inhibitors. In the current study, the potential anti-inflammatory activity of MP and EP was evaluated in different experimental rat models. Results showed that MP and EP caused reduction of carrageenan-induced rat paw edema in addition to diminishing prostaglandin E2 (PGE2) level in the inflammatory exudates. In lipopolysaccharide (LPS)-induced endotoxemia in rats, MP and EP reduced plasma levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). MP and EP decreased NF-κB expression in liver and lung tissues and ameliorated histopathological changes caused by LPS. Topical application of MP and EP reduced ear edema induced by croton oil in rats. In the same animal model, MP and EP reduced neutrophil infiltration, as indicated by decreased myeloperoxidase (MPO) activity. In conclusion, this study demonstrates the effectiveness of MP and EP in combating inflammation in several experimental models. -- Highlights: ► Efficacy of MP and EP in combating inflammation was displayed in several models. ► MP and EP reduced carrageenan-induced rat paw edema and prostaglandin E2 level. ► MP and EP decreased TNF-α and IL-6 levels in experimental endotoxemia. ► MP and EP reduced NF-κB expression and histological changes in rat liver and lung. ► MP and EP reduced croton oil-induced ear edema and neutrophil infiltration.

Combating Combination of Hypertension and Diabetes in Different Rat Models

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Talma Rosenthal

2010-03-01

Full Text Available Rat experimental models are used extensively for studying physiological mechanisms and treatments of hypertension and diabetes co-existence. Each one of these conditions is a major risk factor for cardiovascular disease (CVD, and the combination of the two conditions is a potent enhancer of CVD. Five major animal models that advanced our understanding of the mechanisms and therapeutic approaches in humans are discussed in this review: Zucker, Goto-Kakizaki, SHROB, SHR/NDmcr-cp and Cohen Rosenthal diabetic hypertensive (CRDH rats. The use of various drugs, such as angiotensin-converting enzyme (ACE inhibitors (ACEIs, various angiotensin receptor blockers (ARBs, and calcium channel blockers (CCBs, to combat the effects of concomitant pathologies on the combination of diabetes and hypertension, as well as the non-pharmacological approach are reviewed in detail for each rat model. Results from experiments on these models indicate that classical factors contributing to the pathology of hypertension and diabetes combination—Including hypertension, hyperglycemia, hyperinsulinemia and hyperlipidemia—can now be treated, although these treatments do not completely prevent renal complications. Animal studies have focused on several mechanisms involved in hypertension/diabetes that remain to be translated into clinical medicine, including hypoxia, oxidative stress, and advanced glycation. Several target molecules have been identified that need to be incorporated into a treatment modality. The challenge continues to be the identification and interpretation of the clinical evidence from the animal models and their application to human treatment.

[Experimental study on establishment of a simple model of rats crush injury-crush syndrome].

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Chen, Xi; Liu, Yuehong; Xu, Wei; Qin, Tingwu; Zhao, Luping; Liu, Shuping; Zhang, Yi; Tan, Hong; Zhou, Yu

2013-01-01

To establish a repeatable, simple, and effective model of rat crush injury and crush syndrome. A total of 42 female Sprague Dawley rats (2-month-old, (CS) so as to lay a foundation for further study on CS. weighing 160-180 g) were divided randomly into the control group (n=6) and experimental group (n=36). The rats of the experimental group were used to establish the crush injury and CS model in both lower limbs by self-made crush injury mould. The survival rate and hematuria rate were observed after decompression. The biochemical indexes of blood were measured at 2, 4, 8, 12, 24, and 48 hours after decompression. The samples of muscle, kidney, and heart were harvested for morphological observation. There was no treatment in the control group, and the same tests were performed. Seven rats died and 15 rats had hematuria during compression in the experimental group. Swelling of the lower limb and muscle tissue was observed in the survival rats after reperfusion. The liver function test results showed that the levels of alanine transaminase and aspartate aminotransferase in the experimental group were significantly higher than those in the control group (P congestion and swelling, renal tubular epithelial cell degeneration, edema, necrosis, and myoglobin tube type were found in the kidneys; and myocardial structure had no obvious changes. The method of the crush injury and CS model by self-made crush injury mould is a simple and effective procedure and the experimental result is stable. It is a simple method to establish an effective model of rats crush injury and CS.

Lodenafil treatment in the monocrotaline model of pulmonary hypertension in rats.

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Polonio, Igor Bastos; Acencio, Milena Marques Pagliareli; Pazetti, Rogério; Almeida, Francine Maria de; Silva, Bárbara Soares da; Pereira, Karina Aparecida Bonifácio; Souza, Rogério

2014-01-01

We assessed the effects of lodenafil on hemodynamics and inflammation in the rat model of monocrotaline-induced pulmonary hypertension (PH). Thirty male Sprague-Dawley rats were randomly divided into three groups: control; monocrotaline (experimental model); and lodenafil (experimental model followed by lodenafil treatment, p.o., 5 mg/kg daily for 28 days) Mean pulmonary artery pressure (mPAP) was obtained by right heart catheterization. We investigated right ventricular hypertrophy (RVH) and IL-1 levels in lung fragments. The number of cases of RVH was significantly higher in the monocrotaline group than in the lodenafil and control groups, as were mPAP and IL-1 levels. We conclude that lodenafil can prevent monocrotaline-induced PH, RVH, and inflammation.

Lodenafil treatment in the monocrotaline model of pulmonary hypertension in rats*

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Polonio, Igor Bastos; Acencio, Milena Marques Pagliareli; Pazetti, Rogério; de Almeida, Francine Maria; da Silva, Bárbara Soares; Pereira, Karina Aparecida Bonifácio; Souza, Rogério

2014-01-01

We assessed the effects of lodenafil on hemodynamics and inflammation in the rat model of monocrotaline-induced pulmonary hypertension (PH). Thirty male Sprague-Dawley rats were randomly divided into three groups: control; monocrotaline (experimental model); and lodenafil (experimental model followed by lodenafil treatment, p.o., 5 mg/kg daily for 28 days) Mean pulmonary artery pressure (mPAP) was obtained by right heart catheterization. We investigated right ventricular hypertrophy (RVH) and IL-1 levels in lung fragments. The number of cases of RVH was significantly higher in the monocrotaline group than in the lodenafil and control groups, as were mPAP and IL-1 levels. We conclude that lodenafil can prevent monocrotaline-induced PH, RVH, and inflammation. PMID:25210965

Neuroprotective effect of curcumin in an experimental rat model of subarachnoid hemorrhage.

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Kuo, Chang-Po; Lu, Chueng-He; Wen, Li-Li; Cherng, Chen-Hwan; Wong, Chih-Shung; Borel, Cecil O; Ju, Da-Tong; Chen, Chun-Mei; Wu, Ching-Tang

2011-12-01

Subarachnoid hemorrhage (SAH) causes a high mortality rate and morbidity. It was suggested that oxidant stress plays an important role in neuronal injury after SAH. Therefore, we assessed the effect of curcumin on reducing cerebral vasospasm and neurologic injury in a SAH model in rat. A double-hemorrhage model was used to induce SAH in rats. Groups of animals were treated with intraperitoneal injection of 20 mg/kg curcumin (curcumin group, n = 24) or dimethyl sulfoxide (vehicle group, n = 33), normal saline (SAH group, n = 34) or normal saline (sham group, n = 22), 3 h after SAH induction and daily for 6 days. Glutamate was measured before SAH induction and once daily for 7 days. Glutamate transporter-1, wall thickness and the perimeter of the basilar artery, neurologic scores, neuronal degeneration, malondialdehyde, superoxide dismutase, and catalase activities were assessed. Changes of glutamate levels were lower in the curcumin group versus the SAH and vehicle groups, especially on day 1 (56 folds attenuation vs. vehicle). Correspondingly, glutamate transporter-1 was preserved after SAH in curcumin-treated rats. In the hippocampus and the cortex, malondialdehyde was attenuated (30% and 50%, respectively). Superoxide dismutase (35% and 64%) and catalase (34% and 38%) activities were increased in the curcumin rats compared with the SAH rats. Mortality rate (relative risk: 0.59), wall thickness (30%) and perimeter (31%) of the basilar artery, neuron degeneration scores (39%), and neurologic scores (31%) were improved in curcumin-treated rats. Curcumin in multiple doses is effective against glutamate neurotoxicity and oxidative stress and improves the mortality rate in rats with SAH.

Metabolic Disorders and Diabetic Complications in Spontaneously Diabetic Torii Leprfa Rat: A New Obese Type 2 Diabetic Model

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Yusuke Kemmochi

2013-01-01

Full Text Available Spontaneously Diabetic Torii Leprfa (SDT fatty rat, established by introducing the fa allele of the Zucker fatty rat into SDT rat genome, is a new model of obese type 2 diabetes. Both male and female SDT fatty rats show overt obesity, and hyperglycemia and hyperlipidemia are observed at a young age as compared with SDT rats. With early incidence of diabetes mellitus, diabetic complications, such as nephropathy, retinopathy, and neuropathy, in SDT fatty rats were seen at younger ages compared to those in the SDT rats. In this paper, we overview pathophysiological features in SDT fatty rats and also describe new insights regarding the hematology, blood pressure, renal complications, and sexual dysfunction. The SDT fatty rats showed an increase of leukocytes, especially the monocyte count, prominent hypertension associated with salt drinking, end-stage renal disease with aging, and hypogonadism. Unlike other diabetic models, the characteristic of SDT fatty rat is to present an incidence of diabetes in females, hypertension, and retinopathy. SDT fatty rat is a useful model for analysis of various metabolic disorders and the evaluation of drugs related to metabolic disease.

Edaravone injection ameliorates cognitive deficits in rat model of Alzheimer's disease.

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Yang, Rui; Wang, Qingjun; Li, Fang; Li, Jian; Liu, Xuewen

2015-11-01

Oxidative stress plays important role in the pathogenesis of Alzheimer's disease (AD). Edaravone is a potent free radical scavenger that exerts antioxidant effects. Therefore, in this study we aimed to investigate neuroprotective effects of edaravone for AD. Wistar rats were randomly divided into three groups (n = 15): control group, model group, and treatment group, which were injected with phosphate buffered saline, Aβ1-40, and Aβ1-40 together with 5 mg/kg edaravone, respectively, into the right hippocampal dentate gyrus. Spatial learning and memory of the rats were examined by Morris water maze test. 4-Hydroxynonenal (4-HNE) level in rat hippocampus was analyzed by immunohistochemistry. Acetylcholinesterase (AChE) and choline acetylase (ChAT) activities were assayed by commercial kits. We found that edaravone ameliorated spatial learning and memory deficits in the rats. 4-HNE level in the hippocampus as well as AChE and ChAT activities in the hippocampus was significantly lower in treatment group than in model group. In conclusion, edaravone may be developed as a novel agent for the treatment of AD for improving cholinergic system and protecting neurons from oxidative toxicity.

Analgesic synergism of gabapentin and carbamazepine in rat model ...

African Journals Online (AJOL)

Analgesic synergism of gabapentin and carbamazepine in rat model of diabetic neuropathic pain. Sinan Mohammed Abdullah AL-Mahmood, Shahrin Tarmizi Bin Che Abdullah, Nik Nur Fatnoon Nik Ahmad, Abdul Hadi Bin Mohamed, Tariq Abdul Razak ...

Neuronal firing in the globus pallidus internus and the ventrolateral thalamus related to parkinsonian motor symptoms

Institute of Scientific and Technical Information of China (English)

CHEN Hai; ZHUANG Ping; ZHANG Yu-qing; LI Jian-yu; LI Yong-jie

2009-01-01

Background It has been proposed that parkinsonian motor signs result from hyperactivity in the output nucleus of the basal ganglia, which suppress the motor thalamus and cortical areas. This study aimed to explore the neuronal activity in the globus pallidus internus (GPi) and the ventrolateral thalamic nuclear group (ventral oral posterior/ventral intermediate, Vop/Vim) in patients with Parkinson's disease (PD).Methods Twenty patients with PD who underwent neurosurgery were studied. Microelectrode recording was performed in the GPi (n=10) and the Vop/Vim (n=10) intraoperatively. Electromyography (EMG) contralateral to the surgery was simultaneously performed. Single unit analysis was carried out. The interspike intervals (ISI) and coefficient of variation (CV) of ISI were calculated. Histograms of ISI were constructed. A unified Parkinson's disease rating scale (UPDRS) was used to assess the clinical outcome of surgery.Results Three hundred and sixty-three neurons were obtained from 20 trajectories. Of 175 GPi neurons, there were 15.4% with tremor frequency, 69.2% with tonic firing, and 15.4% with irregular discharge. Of 188 thalamic neurons, there were 46.8% with tremor frequency, 22.9% with tonic firing, and 30.3% with irregular discharge. The numbers of three patterns of neuron in GPi and Vop/Vim were significantly different (P <0.001). ISI analysis revealed that mean firing rate of the three patterns of GPi neurons was (80.9±63.9) Hz (n=78), which was higher than similar neurons with 62.9 Hz in a normal primate. For the Vop/Vim group, ISI revealed that mean firing rate of the three patterns of neurons (n=95) was (23.2±17.1) Hz which was lower than similar neurons with 30 Hz in the motor thalamus of normal primates. UPDRS indicated that the clinical outcome of pallidotomy was (64.3±9.5)%, (83.4±19.1)% and (63.4±36.3)%, and clinical outcome of thalamotomy was (92.2±12.9)%, (68.0±25.2)% and (44.3±27.2)% for tremor, rigidity and bradykinesia, respectively

Validation of infrared thermography in serotonin-induced itch model in rats

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Dagnæs-Hansen, Frederik; Jasemian, Yousef; Gazerani, Parisa

The number of scratching bouts is generally used as a standard method in animal models of itch. The aim of the present study was to validate the application of infrared thermography (IR-Th) in a serotonin-induced itch model in rats. Adult Sprague-Dawley male rats (n = 24) were used in 3 consecutive...... experiments. The first experiment evaluated vasomotor response (IR-Th) and scratching behavior (number of bouts) induced by intradermal serotonin (10 μl, 2%). Isotonic saline (control: 10 μl, 0.9%) and Methysergide (antagonist: 10 μl, 0.047 mg/ml) were used. The second experiment evaluated the dose......-response effect of intradermal serotonin (1%, 2% and 4%) on local temperature. The third experiment evaluated the anesthetized rats to test the local vasomotor responses in absent of scratching. Serotonin elicited significant scratching and lowered the local temperature at the site of injection. A dose...

An automatic rat brain extraction method based on a deformable surface model.

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Li, Jiehua; Liu, Xiaofeng; Zhuo, Jiachen; Gullapalli, Rao P; Zara, Jason M

2013-08-15

The extraction of the brain from the skull in medical images is a necessary first step before image registration or segmentation. While pre-clinical MR imaging studies on small animals, such as rats, are increasing, fully automatic imaging processing techniques specific to small animal studies remain lacking. In this paper, we present an automatic rat brain extraction method, the Rat Brain Deformable model method (RBD), which adapts the popular human brain extraction tool (BET) through the incorporation of information on the brain geometry and MR image characteristics of the rat brain. The robustness of the method was demonstrated on T2-weighted MR images of 64 rats and compared with other brain extraction methods (BET, PCNN, PCNN-3D). The results demonstrate that RBD reliably extracts the rat brain with high accuracy (>92% volume overlap) and is robust against signal inhomogeneity in the images. Copyright © 2013 Elsevier B.V. All rights reserved.

Schedule-induced polydipsia: a rat model of obsessive-compulsive disorder.

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Platt, Brian; Beyer, Chad E; Schechter, Lee E; Rosenzweig-Lipson, Sharon

2008-04-01

Obsessive-compulsive disorder (OCD) is difficult to model in animals due to the involvement of both mental (obsessions) and physical (compulsions) symptoms. Due to limitations of using animals to evaluate obsessions, OCD models are limited to evaluation of the compulsive and repetitive behaviors of animals. Of these, models of adjunctive behaviors offer the most value in regard to predicting efficacy of anti-OCD drugs in the clinic. Adjunctive behaviors are those that are maintained indirectly by the variables that control another behavior, rather than directly by their own typical controlling variables. Schedule-induced polydipsia (SIP) is an adjunctive model in which rats exhibit exaggerated drinking behavior (polydipsia) when presented with food pellets under a fixed-time schedule. The polydipsic response is an excessive manifestation of a normal behavior (drinking), providing face validity to the model. Furthermore, clinically effective drugs for the treatment of OCD decrease SIP. This protocol describes a rat SIP model of OCD and provides preclinical data for drugs that decrease polydipsia and are clinically effective in the treatment of OCD.

Shaofu Zhuyu Decoction Regresses Endometriotic Lesions in a Rat Model

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Guanghui Zhu

2018-01-01

Full Text Available The current therapies for endometriosis are restricted by various side effects and treatment outcome has been less than satisfactory. Shaofu Zhuyu Decoction (SZD, a classic traditional Chinese medicinal (TCM prescription for dysmenorrhea, has been widely used in clinical practice by TCM doctors to relieve symptoms of endometriosis. The present study aimed to investigate the effects of SZD on a rat model of endometriosis. Forty-eight female Sprague-Dawley rats with regular estrous cycles went through autotransplantation operation to establish endometriosis model. Then 38 rats with successful ectopic implants were randomized into two groups: vehicle- and SZD-treated groups. The latter were administered SZD through oral gavage for 4 weeks. By the end of the treatment period, the volume of the endometriotic lesions was measured, the histopathological properties of the ectopic endometrium were evaluated, and levels of proliferating cell nuclear antigen (PCNA, CD34, and hypoxia inducible factor- (HIF- 1α in the ectopic endometrium were detected with immunohistochemistry. Furthermore, apoptosis was assessed using the terminal deoxynucleotidyl transferase (TdT deoxyuridine 5′-triphosphate (dUTP nick-end labeling (TUNEL assay. In this study, SZD significantly reduced the size of ectopic lesions in rats with endometriosis, inhibited cell proliferation, increased cell apoptosis, and reduced microvessel density and HIF-1α expression. It suggested that SZD could be an effective therapy for the treatment and prevention of endometriosis recurrence.

Experimental rat lung tumor model with intrabronchial tumor cell implantation.

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Gomes Neto, Antero; Simão, Antônio Felipe Leite; Miranda, Samuel de Paula; Mourão, Lívia Talita Cajaseiras; Bezerra, Nilfácio Prado; Almeida, Paulo Roberto Carvalho de; Ribeiro, Ronaldo de Albuquerque

2008-01-01

The objective of this study was to develop a rat lung tumor model for anticancer drug testing. Sixty-two female Wistar rats weighing 208 +/- 20 g were anesthetized intraperitoneally with 2.5% tribromoethanol (1 ml/100 g live weight), tracheotomized and intubated with an ultrafine catheter for inoculation with Walker's tumor cells. In the first step of the experiment, a technique was established for intrabronchial implantation of 10(5) to 5 x 10(5) tumor cells, and the tumor take rate was determined. The second stage consisted of determining tumor volume, correlating findings from high-resolution computed tomography (HRCT) with findings from necropsia and determining time of survival. The tumor take rate was 94.7% for implants with 4 x 10(5) tumor cells, HRCT and necropsia findings matched closely (r=0.953; p<0.0001), the median time of survival was 11 days, and surgical mortality was 4.8%. The present rat lung tumor model was shown to be feasible: the take rate was high, surgical mortality was negligible and the procedure was simple to perform and easily reproduced. HRCT was found to be a highly accurate tool for tumor diagnosis, localization and measurement and may be recommended for monitoring tumor growth in this model.

Ocular changes in TgF344-AD rat model of Alzheimer's disease.

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Tsai, Yuchun; Lu, Bin; Ljubimov, Alexander V; Girman, Sergey; Ross-Cisneros, Fred N; Sadun, Alfredo A; Svendsen, Clive N; Cohen, Robert M; Wang, Shaomei

2014-01-29

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by progressive decline in learning, memory, and executive functions. In addition to cognitive and behavioral deficits, vision disturbances have been reported in early stage of AD, well before the diagnosis is clearly established. To further investigate ocular abnormalities, a novel AD transgenic rat model was analyzed. Transgenic (Tg) rats (TgF344-AD) heterozygous for human mutant APPswe/PS1ΔE9 and age-matched wild type (WT) rats, as well as 20 human postmortem retinal samples from both AD and healthy donors were used. Visual function in the rodent was analyzed using the optokinetic response and luminance threshold recording from the superior colliculus. Immunohistochemistry on retinal and brain sections was used to detect various markers including amyloid-β (Aβ) plaques. As expected, Aβ plaques were detected in the hippocampus, cortex, and retina of Tg rats. Plaque-like structures were also found in two AD human whole-mount retinas. The choroidal thickness was significantly reduced in both Tg rat and in AD human eyes when compared with age-matched controls. Tg rat eyes also showed hypertrophic retinal pigment epithelial cells, inflammatory cells, and upregulation of complement factor C3. Although visual acuity was lower in Tg than in WT rats, there was no significant difference in the retinal ganglion cell number and retinal vasculature. In this study, we observed pathological changes in the choroid and in RPE cells in the TgF344-AD rat model; choroidal thinning was observed further in human AD retina. Along with Ab deposition, the inflammatory response was manifested by microglial recruitment and complement activation. Further studies are needed to elucidate the significance and mechanisms of these pathological changes [corrected].

Alterations of the tunica vasculosa lentis in the rat model of retinopathy of prematurity.

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Favazza, Tara L; Tanimoto, Naoyuki; Munro, Robert J; Beck, Susanne C; Garcia Garrido, Marina; Seide, Christina; Sothilingam, Vithiyanjali; Hansen, Ronald M; Fulton, Anne B; Seeliger, Mathias W; Akula, James D

2013-08-01

To study the relationship between retinal and tunica vasculosa lentis (TVL) disease in retinopathy of prematurity (ROP). Although the clinical hallmark of ROP is abnormal retinal blood vessels, the vessels of the anterior segment, including the TVL, are also altered. ROP was induced in Long-Evans pigmented and Sprague Dawley albino rats; room-air-reared (RAR) rats served as controls. Then, fluorescein angiographic images of the TVL and retinal vessels were serially obtained with a scanning laser ophthalmoscope near the height of retinal vascular disease, ~20 days of age, and again at 30 and 64 days of age. Additionally, electroretinograms (ERGs) were obtained prior to the first imaging session. The TVL images were analyzed for percent coverage of the posterior lens. The tortuosity of the retinal arterioles was determined using Retinal Image multiScale Analysis (Gelman et al. in Invest Ophthalmol Vis Sci 46:4734-4738, 2005). In the youngest ROP rats, the TVL was dense, while in RAR rats, it was relatively sparse. By 30 days, the TVL in RAR rats had almost fully regressed, while in ROP rats, it was still pronounced. By the final test age, the TVL had completely regressed in both ROP and RAR rats. In parallel, the tortuous retinal arterioles in ROP rats resolved with increasing age. ERG components indicating postreceptoral dysfunction, the b-wave, and oscillatory potentials were attenuated in ROP rats. These findings underscore the retinal vascular abnormalities and, for the first time, show abnormal anterior segment vasculature in the rat model of ROP. There is delayed regression of the TVL in the rat model of ROP. This demonstrates that ROP is a disease of the whole eye.

The concentration of kynurenine in rat model of asthma.

Directory of Open Access Journals (Sweden)

Barbara Mroczko

2008-06-01

Full Text Available Asthma is a chronic inflammatory disease that involves the immune system activation. Evidence is accumulating about the role of kynurenine pathway in the immune system regulation. The kynurenine pathway includes several metabolites of tryptophan, among others kynurenine (KYN. To study the immunological system regulation in asthma a simple and sensitive models of asthma are required. In the present study we induced rat model of asthma using ovalbumin (OVA sensitization followed by challenge with OVA. The development of asthma has been confirmed by plasma total IgE measurement and the histological examination. The concentration of KYN has been determined in plasma, lungs and liver by high-performance liquid chromatography (HPLC. In OVA sensitized rats the concentration of total IgE was statistically significantly increased as compared to VEH sensitized control groups (437.6 +/- 97.7 kU/l vs 159.2 +/- 22.7 kU/l, respectively; p< 0.01. In asthmatic animals, the number of eosinophils, neutrophils and mast cells increased considerably, and epithelial lesion and the increase in airway epithelium goblet cells and edema of bronchial mucosa were present. We did not observe any significant changes in the concentration of KYN in plasma, lungs or liver between studied groups. In conclusion, the concentration of KYN remains unchanged in asthmatic animals as compared to control groups. Further studies using rat model of asthma are warranted to establish the role of kynurenine pathway regulation in asthma.

The Fischer 344 rat as a model of presbycusis.

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Syka, Josef

2010-06-01

Due to the rising number of the aged human population all over the world, presbycusis is a phenomenon that deserves the increasing attention of the medical community as regards to prevention and treatment. This requires finding appropriate animal models for human presbycusis that will be useful in future experiments. Among the available rat strains, the Fischer 344 (F344) strain promises to serve as a model producing prompt and profound presbycusis. Hearing thresholds begin to increase in this strain during the first year of life; toward the end of the second year, the thresholds are very high. The threshold shifts progress independently in both ears. The rapid deterioration of distortion product otoacoustic emissions, with the majority of outer hair cells (OHC) being present and morphologically intact, is apparently produced by the disruption of prestin. The age-related changes within inner ear function are accompanied by deterioration of acoustical signal processing within central auditory system, mainly due to impaired GABA inhibition. The loss of GABA inhibition in old animals is expressed primarily in the inferior colliculus but is also present in the cochlear nuclei and the auditory cortex. Sound-evoked behavioral reactions are also impaired in old F344 rats. Taken together, the described characteristics of the aging F344 rat auditory system supports the idea that this strain may serve as a suitable model for studying the mechanisms of presbycusis, its prevention and treatment. Copyright 2009 Elsevier B.V. All rights reserved.

Additive effect of mesenchymal stem cells and defibrotide in an arterial rat thrombosis model.

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Dilli, Dilek; Kılıç, Emine; Yumuşak, Nihat; Beken, Serdar; Uçkan Çetinkaya, Duygu; Karabulut, Ramazan; Zenciroğlu, Ayşegu L

2017-06-01

In this study, we aimed to investigate the additive effect of mesenchymal stem cells (MSC) and defibrotide (DFT) in a rat model of femoral arterial thrombosis. Thirty Sprague Dawley rats were included. An arterial thrombosis model by ferric chloride (FeCl3) was developed in the left femoral artery. The rats were equally assigned to 5 groups: Group 1-Sham-operated (without arterial injury); Group 2-Phosphate buffered saline (PBS) injected; Group 3-MSC; Group 4-DFT; Group 5-MSC + DFT. All had two intraperitoneal injections of 0.5 ml: the 1st injection was 4 h after the procedure and the 2nd one 48 h after the 1st injection. The rats were sacrificed 7 days after the 2nd injection. Although the use of human bone marrow-derived (hBM) hBM-MSC or DFT alone enabled partial resolution of the thrombus, combining them resulted in near-complete resolution. Neovascularization was two-fold better in hBM-MSC + DFT treated rats (11.6 ± 2.4 channels) compared with the hBM-MSC (3.8 ± 2.7 channels) and DFT groups (5.5 ± 1.8 channels) (P < 0.0001 and P= 0.002, respectively). The combined use of hBM-MSC and DFT in a rat model of arterial thrombosis showed additive effect resulting in near-complete resolution of the thrombus.

Protective effect of lactobacillus acidophilus and isomaltooligosaccharide on intestinal mucosal barriers in rat models of antibiotic-associated diarrhea

International Nuclear Information System (INIS)

Du Dan; Fang Lichao; Chen Bingbo; Wei Hong

2008-01-01

Objective: To investigate the protective effect of synbiotics combined lactobacillus acidophilus and iso-malto-oligosaccharide (IMO) on intestinal mucosal barriers in rat models of antibiotic-associated diarrhea(AAD). Methods: Rat models of AAD were prepared with lincomycin gavage for 5 days. The synbiotics was orally administered to the AAD rats daily at three different strengths for 7 days. The intestinal flora and intestinal mucus SIgA levels were determined on d6, d9 and d13. The histopathological changes of ileal mucosa were studied on d13. Results: In the prepared AAD model rats (on d6) there were lower intestinal mucus SIgA levels and intestinal flora disorders were demonstrated. The intestinal floras of the rats administering synbiotics were readjusted to the similar pattern of healthy rats with bacterial translocation corrected on d13 and the levels of SIgA were not significantly different from of the control (P>0.05). The histopathological picture was basically normal in the treated models on d13. Conclusion: The synbiotics combined lactobacillus acidophilus and isomaltooligosaccharide possessed good protective effect on the intestinal mucosal barrier in lincomycin induced rat models of AAD. (authors)

Physiologically-Based Pharmacokinetic (PBPK) Model for the Thyroid Hormones in the Pregnant Rat and Fetus.

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A developmental PBPK model is constructed to quantitatively describe the tissue economy of the thyroid hormones (THs), thyroxine (T4) and triiodothyronine (T3), in the rat. The model is also used to link maternal (THs) to rat fetal tissues via placental transfer. THs are importan...

Translational mixed-effects PKPD modelling of recombinant human growth hormone - from hypophysectomized rat to patients

DEFF Research Database (Denmark)

Thorsted, A; Thygesen, P; Agersø, H

2016-01-01

BACKGROUND AND PURPOSE: We aimed to develop a mechanistic mixed-effects pharmacokinetic (PK)-pharmacodynamic (PD) (PKPD) model for recombinant human growth hormone (rhGH) in hypophysectomized rats and to predict the human PKPD relationship. EXPERIMENTAL APPROACH: A non-linear mixed-effects model...... was developed from experimental PKPD studies of rhGH and effects of long-term treatment as measured by insulin-like growth factor 1 (IGF-1) and bodyweight gain in rats. Modelled parameter values were scaled to human values using the allometric approach with fixed exponents for PKs and unscaled for PDs...... s.c. administration was over predicted. After correction of the human s.c. absorption model, the induction model for IGF-1 well described the human PKPD data. CONCLUSIONS: A translational mechanistic PKPD model for rhGH was successfully developed from experimental rat data. The model links...

Skeletal growth and long-term bone turnover after enterocystoplasty in a chronic rat model

DEFF Research Database (Denmark)

Gerharz, E.W.; Gasser, J.A.; Mosekilde, Li.

2003-01-01

OBJECTIVE: To investigate skeletal growth and bone metabolism in a chronic animal model of urinary diversion.MATERIALS AND METHODS: Young male Wistar rats (120) were allocated randomly to four groups undergoing: ileocystoplasty, ileocystoplasty and resection of the ileocaecal segment, colocystopl......OBJECTIVE: To investigate skeletal growth and bone metabolism in a chronic animal model of urinary diversion.MATERIALS AND METHODS: Young male Wistar rats (120) were allocated randomly to four groups undergoing: ileocystoplasty, ileocystoplasty and resection of the ileocaecal segment...... mass ex vivo.RESULTS: Most (90%) of the rats survived the study period (8 months); six rats died from bowel obstruction at the level of the entero-anastomosis and four had to be killed because of persistent severe diarrhoea. Vital intestinal mucosa was found in all augmented bladders. There were...... no differences in bone length and volume. Loss of bone mass was almost exclusively in rats with ileocystoplasty and resection of the ileocaecal segment (-37.5%, pQCT, P

In vivo micro-CT analysis of bone remodeling in a rat calvarial defect model

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Umoh, Joseph U.; Sampaio, Arthur V.; Welch, Ian; Pitelka, Vasek; Goldberg, Harvey A.; Underhill, T. Michael; Holdsworth, David W.

2009-04-01

The rodent calvarial defect model is commonly used to investigate bone regeneration and wound healing. This study presents a micro-computed tomography (micro-CT) methodology for measuring the bone mineral content (BMC) in a rat calvarial defect and validates it by estimating its precision error. Two defect models were implemented. A single 6 mm diameter defect was created in 20 rats, which were imaged in vivo for longitudinal experiments. Three 5 mm diameter defects were created in three additional rats, which were repeatedly imaged ex vivo to determine precision. Four control rats and four rats treated with bone morphogenetic protein were imaged at 3, 6, 9 and 12 weeks post-surgery. Scan parameters were 80 kVp, 0.45 mA and 180 mAs. Images were reconstructed with an isotropic resolution of 45 µm. At 6 weeks, the BMC in control animals (4.37 ± 0.66 mg) was significantly lower (p small BMC changes in animals.

Spatial modeling of rat bites and prediction of rat infestation in Peshawar valley using binomial kriging with logistic regression.

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Ali, Asad; Zaidi, Farrah; Fatima, Syeda Hira; Adnan, Muhammad; Ullah, Saleem

2018-03-24

In this study, we propose to develop a geostatistical computational framework to model the distribution of rat bite infestation of epidemic proportion in Peshawar valley, Pakistan. Two species Rattus norvegicus and Rattus rattus are suspected to spread the infestation. The framework combines strengths of maximum entropy algorithm and binomial kriging with logistic regression to spatially model the distribution of infestation and to determine the individual role of environmental predictors in modeling the distribution trends. Our results demonstrate the significance of a number of social and environmental factors in rat infestations such as (I) high human population density; (II) greater dispersal ability of rodents due to the availability of better connectivity routes such as roads, and (III) temperature and precipitation influencing rodent fecundity and life cycle.

A novel experimental model of erectile dysfunction in rats with heart failure using volume overload.

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Silva, Fábio Henrique; Veiga, Frederico José Reis; Mora, Aline Gonçalves; Heck, Rodrigo Sader; De Oliveira, Caroline Candida; Gambero, Alessandra; Franco-Penteado, Carla Fernanda; Antunes, Edson; Gardner, Jason D; Priviero, Fernanda Bruschi Marinho; Claudino, Mário Angelo

2017-01-01

Patients with heart failure (HF) display erectile dysfunction (ED). However, the pathophysiology of ED during HF remains poorly investigated. This study aimed to characterize the aortocaval fistula (ACF) rat model associated with HF as a novel experimental model of ED. We have undertaken molecular and functional studies to evaluate the alterations of the nitric oxide (NO) pathway, autonomic nervous system and oxidative stress in the penis. Male rats were submitted to ACF for HF induction. Intracavernosal pressure in anesthetized rats was evaluated. Concentration-response curves to contractile (phenylephrine) and relaxant agents (sodium nitroprusside; SNP), as well as to electrical field stimulation (EFS), were obtained in the cavernosal smooth muscle (CSM) strips from sham and HF rats. Protein expression of endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS) and phosphodiestarese-5 in CSM were evaluated, as well as NOX2 (gp91phox) and superoxide dismutase (SOD) mRNA expression. SOD activity and thiobarbituric acid reactive substances (TBARs) were also performed in plasma. HF rats display erectile dysfunction represented by decreased ICP responses compared to sham rats. The neurogenic contractile responses elicited by EFS were greater in CSM from the HF group. Likewise, phenylephrine-induced contractions were greater in CSM from HF rats. Nitrergic response induced by EFS were decreased in the cavernosal tissue, along with lower eNOS, nNOS and phosphodiestarese-5 protein expressions. An increase of NOX2 and SOD mRNA expression in CSM and plasma TBARs of HF group were detected. Plasma SOD activity was decreased in HF rats. ED in HF rats is associated with decreased NO bioavailability in erectile tissue due to eNOS/nNOS dowregulation and NOX2 upregulation, as well as hypercontractility of the penis. This rat model of ACF could be a useful tool to evaluate the molecular alterations of ED associated with HF.

Lodenafil treatment in the monocrotaline model of pulmonary hypertension in rats

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Igor Bastos Polonio

2014-08-01

Full Text Available We assessed the effects of lodenafil on hemodynamics and inflammation in the rat model of monocrotaline-induced pulmonary hypertension (PH. Thirty male Sprague-Dawley rats were randomly divided into three groups: control; monocrotaline (experimental model; and lodenafil (experimental model followed by lodenafil treatment, p.o., 5 mg/kg daily for 28 days Mean pulmonary artery pressure (mPAP was obtained by right heart catheterization. We investigated right ventricular hypertrophy (RVH and IL-1 levels in lung fragments. The number of cases of RVH was significantly higher in the monocrotaline group than in the lodenafil and control groups, as were mPAP and IL-1 levels. We conclude that lodenafil can prevent monocrotaline-induced PH, RVH, and inflammation.

Avastin exhibits therapeutic effects on collagen-induced arthritis in rat model.

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Wang, Yong; Da, Gula; Li, Hongbin; Zheng, Yi

2013-12-01

Avastin is the monoclonal antibody for vascular endothelial growth factor (VEGF). This study aimed to investigate therapeutic effect of Avastin on type II collagen-induced arthritis. Type II chicken collagen was injected into the tails of Wistar rats, and 60 modeled female rats were randomly divided into three groups (n = 20): Avastin group, Etanercept group, and control group. Arthritis index and joint pad thickness were scored, and the pathology of back metapedes was analyzed. The results showed that compared to control group, the arthritis index, target-to-non-target ratio, synovial pathological injury index, serum levels of VEGF and tumor necrosis factor alpha, and VEGF staining were decreased significantly 14 days after Avastin or Etanercept treatment, but there were no significant differences between Avastin group and Etanercept group. These data provide evidence that Avastin exhibits similar effects to Etanercept to relieve rheumatoid arthritis in rat model and suggest that Avastin is a promising therapeutic agent for rheumatoid arthritis.

Protocol of a prospective study on the diagnostic value of transcranial duplex scanning of the substantia nigra in patients with parkinsonian symptoms

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Wuisman Piet GWM

2007-09-01

Full Text Available Abstract Background Parkinson's disease (PD is the second most common neurodegenerative disorder. As there is no definitive diagnostic test, its diagnosis is based on clinical criteria. Recently transcranial duplex scanning (TCD of the substantia nigra in the brainstem has been proposed as an instrument to diagnose PD. We and others have found that TCD scanning of substantia nigra duplex is a relatively accurate diagnostic instrument in patients with parkinsonian symptoms. However, all studies on TCD so far have involved well-defined, later-stage PD patients, which will obviously lead to an overestimate of the diagnostic accuracy of TCD. We have therefore set out to conduct a prospective study testing the diagnostic accuracy of TCD in patients with a parkinsonism of unclear origin. Methods/Design We will enrol 250 consecutive patients, who are referred to neurology outpatient clinics of two teaching hospitals, for analysis of clinically unclear parkinsonism. Patients, whose parkinsonism is clearly diagnosable at the first visit, will be excluded from the study. All patients will undergo a TCD of the substantia nigra. As a surrogate gold standard we will use the consensus clinical diagnosis reached by two independent, blinded, movement disorder specialist neurologists after 2 years follow-up. At the time of TCD, patients will also undergo a SPECT scan of the brain. Discussion As this prospective trial enrols only patients with an early-stage parkinsonism, it will yield data on the diagnostic accuracy of TCD that is relevant to daily clinical practice: The neurologist needs a diagnostic tool that provides additional information in patients with a clinically indefinable parkinsonian syndrome. The above described observational longitudinal study was designed to explicitly study this aspect in the diagnostic process. Trial registration (ITRSCC NCT00368199

Establishment of a reversible model of prehepatic portal hypertension in rats.

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Zhao, Xin; Dou, Jian; Gao, Qing-Jun

2016-08-01

The aim of the present study was to improve upon the traditional model of pre-hepatic portal hypertension in rats, and simulate the anhepatic phase of orthotopic liver transplantation without veno-venous bypass. A reversible model of portal hypertension was induced by portal vein ligation, with a label ring ligated along the portal vein. A total of 135 male Wistar rats were divided into three groups: i) Normal control (NC) group; ii) portal hypertensive control (PHTC) group; and iii) reperfusion (R) group. In the R group, rats with portal hypertension underwent simultaneous clamping of the portal triad and retrohepatic vena cava for 1 h, followed by removal of the clamps to enable blood reperfusion. Portal venography and portal vein pressure were recorded during the surgery. Arterial oxygen pressure (PaO 2 ), and alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBil) levels were determined, and pathological changes of the liver were investigated by immunohistochemical staining. The results demonstrated that, 3 weeks after portal vein ligation, the vein area and the free portal pressures in the PHTC group were significantly increased compared with those in the NC group. The serum ALT and AST levels in the R group at different time points were significantly elevated compared with those in the PHTC group, and reached their maximal levels at 24 h after reperfusion. Furthermore, the PaO 2 at 24 h after reperfusion was significantly decreased. In conclusion, the reversible model of pre-hepatic portal hypertension in rats was successfully established using the introduction of a label ring. This model may be useful for basic research focusing on the anhepatic phase of orthotopic liver transplantation without veno-venous bypass.

Simulating certain aspects of hypogravity: Effects on the mandibular incisors of suspended rats (PULEH model)

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Simmons, D. J.; Winter, F.; Morey-Holton, E. R.

1984-01-01

The effect of a hypogravity simulating model on the rate of mandibular incisor formation, dentinogenesis and, amelogenesis in laboratory rats was studied. The model is the partial unloading by elevating the hindquarters. In this system, rat hindquarters are elevated 30 to 40 deg from the cage floors to completely unload the hindlimbs, but the animals are free to move about using their forelimbs. This model replicates the fluid sift changes which occur during the weightlessness of spaceflight and produces an osteopenia in the weight bearing skeletons. The histogenesis and/or mineralization rates of the mandibular incisor during the first 19d of PULEH in young growing rats are recorded.

Curative effect of sesame oil in a rat model of chronic kidney disease.

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Liu, Chuan-Teng; Chien, Se-Ping; Hsu, Dur-Zong; Periasamy, Srinivasan; Liu, Ming-Yie

2015-12-01

Chronic kidney disease causes a progressive and irreversible loss of renal function. We investigated the curative effect of sesame oil, a natural, nutrient-rich, potent antioxidant, in a rat model of chronic kidney disease. Chronic kidney disease was induced by subcutaneously injecting uni-nephrectomized rats with deoxycorticosterone acetate (DOCA) and 1% NaCl [DOCA/salt] in drinking water. Four weeks later, the rats were gavaged with sesame oil (0.5 or 1 mL/kg per day) for 7 days. Renal injury, histopathological changes, hydroxyl radical, peroxynitrite, lipid peroxidation, Nrf2, osteopontin expression, and collagen were assessed 24 h after the last dose of sesame oil. Blood urea nitrogen, creatinine, urine volume, and albuminuria were significantly higher in the DOCA/salt treated rats than in control rats. Sesame oil significantly decreased these four tested parameters in DOCA/salt treated rats. In addition, creatinine clearance rate and nuclear Nrf2 expression were significantly decreased in the DOCA/salt treated rats compared to control rats. Sesame oil significantly decreased hydroxyl radical, peroxynitrite level, lipid peroxidation, osteopontin, and renal collagen deposition, but increased creatinine clearance rate and nuclear Nrf2 expression in DOCA/salt treated rats. We conclude that supplementation of sesame oil mitigates DOCA/salt induced chronic kidney disease in rats by activating Nrf2 and attenuating osteopontin expression and inhibiting renal fibrosis in rats. © 2015 Asian Pacific Society of Nephrology.

A novel model for NSAID induced gastroenteropathy in rats.

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Singh, Devendra Pratap; Borse, Swapnil P; Nivsarkar, Manish

2016-01-01

Progress in management of Nonsteroidal anti-inflammatory drug (NSAID) induced gastrointestinal toxicity requires the availability of appropriate experimental animal models that are as close to humans as feasible. Our objective was to develop a rat model for NSAID-induced gastroenteropathy and also to simulate the common clinical scenario of co-administration of NSAID and proton pump inhibitor (PPI) to explore if PPI contribute to exacerbation of NSAID-enteropathy. Rats were treated twice daily with pantoprazole sodium (PTZ; 10mg/kg peroral) or vehicle for a total of 10days. In some experiments, Diclofenac sodium (DCF; 9mg/kg) or vehicle was administered orally twice daily for the final 5days of PTZ/vehicle administration. After the last dose on 9th day, rats in all the groups were fasted but water was provided ad libitum. 12h after the last dose on 10th day, rats in all the groups were euthanized and their gastrointestinal tracts were assessed for haemorrhagic lesions, lipid peroxidation, intestinal permeability and gastrointestinal luminal pH alterations. Changes in haemoglobin, haematocrit and serum levels of albumin, total protein, ALT and bilirubin were calculated. The macroscopic and histological evidence suggested that administration of DCF resulted in significant gastroenteropathic damage and co-administration of PTZ resulted in significant exacerbation of NSAID enteropathy, while attenuation of NSAID induced gastropathy was observed. Our results were further supported by the significant decrease in haemoglobin and haematocrit levels and serum levels of albumin and total proteins, an increase in oxidative stress and intestinal permeability with the use of DCF either alone or in combination with PTZ. This model was developed to simulate the human clinical situation during NSAID therapy and indeed the present DCF regimen caused both gastric and small bowel alterations, such as multiple erosive lesions, together with a decrease in haemoglobin, haematocrit

Changes of cerebral contents of neuropeptides in rat models of multiple ischemic dementia (MID)

International Nuclear Information System (INIS)

Zheng Xianghong; Guo Jingcai; Song Changyi; Wang Shejiao; Chen Wei

2005-01-01

Objective: To investigate the significance of changes of cerebral contents of the neuropeptides somatostatin (SS), arginine vasopressin (AVP) and substance P in rat models of MID. Methods: The rat models consisted of 15 rats undergoing intracarotid injection of autogenous thrombus powder. Another group of 15 rats undergoing sham operation served as controls. Learning and memory ability in these rats was assessed with daily passive avoidance task testing for 10 consecutive days. The animals were sacrificed on 30d and contents of the neuropeptides in tissue homogenate from different areas of brain (frontal cortex, temporal cortex, hippocampus, thalamus and corpus striatum) were measured with (RIA). Results: On the first day of passive avoidance task testing, the frequency of errors in the MID group and the control group was about the same. From the third day on, the frequency of errors in the MID group was significantly higher than that in the control group (P<0.05). The neuropeptides contents of all these cerebral areas in the MID group were significantly higher than those in the control group (P<0.05 or P<0.01) with the only exception of the contents of substance P in thalamus (no significant difference between the contents in the two groups). Conclusion: The impairment of learning and memory in rat models with MID was possibly related to the lowered contents of SS, AVP and substance P in the brain tissue. (authors)

Evaluation of Lercanidipine in Paclitaxel-Induced Neuropathic Pain Model in Rat: A Preliminary Study

OpenAIRE

Saha, Lekha; Hota, Debasish; Chakrabarti, Amitava

2012-01-01

Objective. To demonstrate the antinociceptive effect of lercanidipine in paclitaxel-induced neuropathy model in rat. Materials and Methods. A total of 30 rats were divided into five groups of six rats in each group as follows: Gr I: 0.9% NaCl, Gr II: paclitaxel + 0.9% NaCl, Gr III: paclitaxel + lercanidipine 0.5 μg/kg, Gr IV: paclitaxel + lercanidipine 1 μg/kg, and Gr V: paclitaxel + lercanidipine 2.5 μg/kg. Paclitaxel-induced neuropathic pain in rat was produced by single intraperitoneal (i....

Adeno-associated viral vector serotype 5 poorly transduces liver in rat models.

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Paula S Montenegro-Miranda

Full Text Available Preclinical studies in mice and non-human primates showed that AAV serotype 5 provides efficient liver transduction and as such seems a promising vector for liver directed gene therapy. An advantage of AAV5 compared to serotype 8 already shown to provide efficient correction in a phase 1 trial in patients suffering from hemophilia B, is its lower seroprevalence in the general population. Our goal is liver directed gene therapy for Crigler-Najjar syndrome type I, inherited severe unconjugated hyperbilirubinemia caused by UGT1A1 deficiency. In a relevant animal model, the Gunn rat, we compared the efficacy of AAV 5 and 8 to that of AAV1 previously shown to be effective. Ferrying a construct driving hepatocyte specific expression of UGT1A1, both AAV8 and AAV1 provided an efficient correction of hyperbilirubinemia. In contrast to these two and to other animal models AAV5 failed to provide any correction. To clarify whether this unexpected finding was due to the rat model used or due to a problem with AAV5, the efficacy of this serotype was compared in a mouse and two additional rat strains. Administration of an AAV5 vector expressing luciferase under the control of a liver specific promoter confirmed that this serotype poorly performed in rat liver, rendering it not suitable for proof of concept studies in this species.

An animal model to study lower urinary tract symptoms and erectile dysfunction: the hyperlipidaemic rat.

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Rahman, Nadeem U; Phonsombat, Surat; Bochinski, Derek; Carrion, Rafael E; Nunes, Lora; Lue, Tom F

2007-09-01

To present evidence that rats fed a high-fat diet could serve as a useful animal model to study both lower urinary tract symptoms (LUTS) and erectile dysfunction (ED), as recent epidemiological studies have shown a strong association between LUTS and ED but the physiological basis behind this relationship is unknown. In all, 24 male Sprague-Dawley rats were divided into two groups: nine controls were fed a 'normal' diet and 15 were fed a high-fat diet (hyperlipidaemic rats). After 6 months all the rats had bladder and erectile functions evaluated using awake cystometry and cavernosal nerve electrostimulation, respectively. After the functional studies were completed, the penis, prostate and bladder were collected for immunohistochemical analysis. The hyperlipidaemic rats had significantly higher serum cholesterol and low-density lipoprotein than the controls (P enlargement, bladder overactivity, and ED. This rat model could be a useful research tool for understanding the common causes of LUTS and ED, as well as facilitating the development of preventive measures and better therapies to treat both conditions.

In vivo micro-CT analysis of bone remodeling in a rat calvarial defect model

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Umoh, Joseph U; Holdsworth, David W [Pre-Clinical Imaging Research Centre, Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, PO Box 5015, 100 Perth Drive, London, ON N6A 5K8 (Canada); Sampaio, Arthur V; Underhill, T Michael [Laboratory of Molecular Skeletogenesis, Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC (Canada); Welch, Ian [Animal Care and Veterinary Services, University of Western Ontario, London, ON (Canada); Pitelka, Vasek; Goldberg, Harvey A [CIHR Group in Skeletal Development and Remodelling, University of Western Ontario, London, ON (Canada)], E-mail: jumoh@imaging.robarts.ca, E-mail: asampaio@interchange.ubc.ca, E-mail: tunderhi@interchange.ubc.ca, E-mail: iwelch@uwo.ca, E-mail: vasek.pitelka@schulich.uwo.ca, E-mail: hagoldbe@uwo.ca, E-mail: david.holdsworth@imaging.robarts.ca

2009-04-07

The rodent calvarial defect model is commonly used to investigate bone regeneration and wound healing. This study presents a micro-computed tomography (micro-CT) methodology for measuring the bone mineral content (BMC) in a rat calvarial defect and validates it by estimating its precision error. Two defect models were implemented. A single 6 mm diameter defect was created in 20 rats, which were imaged in vivo for longitudinal experiments. Three 5 mm diameter defects were created in three additional rats, which were repeatedly imaged ex vivo to determine precision. Four control rats and four rats treated with bone morphogenetic protein were imaged at 3, 6, 9 and 12 weeks post-surgery. Scan parameters were 80 kVp, 0.45 mA and 180 mAs. Images were reconstructed with an isotropic resolution of 45 {mu}m. At 6 weeks, the BMC in control animals (4.37 {+-} 0.66 mg) was significantly lower (p < 0.05) than that in treated rats (11.29 {+-} 1.01 mg). Linear regression between the BMC and bone fractional area, from 20 rats, showed a strong correlation (r{sup 2} = 0.70, p < 0.0001), indicating that the BMC can be used, in place of previous destructive analysis techniques, to characterize bone growth. The high precision (2.5%) of the micro-CT methodology indicates its utility in detecting small BMC changes in animals.

Aging aggravates long-term renal ischemia-reperfusion injury in a rat model.

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Xu, Xianlin; Fan, Min; He, Xiaozhou; Liu, Jipu; Qin, Jiandi; Ye, Jianan

2014-03-01

Ischemia-reperfusion injury (IRI) has been considered as the major cause of acute kidney injury and can result in poor long-term graft function. Functional recovery after IRI is impaired in the elderly. In the present study, we aimed to compare kidney morphology, function, oxidative stress, inflammation, and development of renal fibrosis in young and aged rats after renal IRI. Rat models of warm renal IRI were established by clamping left pedicles for 45 min after right nephrectomy, then the clamp was removed, and kidneys were reperfused for up to 12 wk. Biochemical and histologic renal damage were assessed at 12 wk after reperfusion. The immunohistochemical staining of monocyte macrophage antigen-1 (ED-1) and transforming growth factor beta 1 (TGF-β1) and messenger RNA level of TGF-β1 in the kidney were analyzed. Renal IRI caused significant increases of malondialdehyde and 8-hydroxydeoxyguanosine levels and a decrease of superoxide dismutase activity in young and aged IRI rats; however, these changes were more obvious in the aged rats. IRI resulted in severe inflammation and tubulointerstitial fibrosis with decreased creatinine (Cr) clearance and increased histologic damage in aged rats compared with young rats. Moreover, we measured the ratio of Cr clearance between young and aged IRI rats. It demonstrated that aged IRI rats did have poor Cr clearance compared with the young IRI rats. ED-1 and TGF-β1 expression levels in the kidney were significantly higher in aged rats than in young rats after IRI. Aged rats are more susceptible to IRI-induced renal failure, which may associate with the increased oxidative stress, increased histologic damage, and increased inflammation and tubulointerstitial fibrosis. Targeting oxidative stress and inflammatory response should improve the kidney recovery after IRI. Copyright © 2014 Elsevier Inc. All rights reserved.

Cyclosporin A significantly improves preeclampsia signs and suppresses inflammation in a rat model.

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Hu, Bihui; Yang, Jinying; Huang, Qian; Bao, Junjie; Brennecke, Shaun Patrick; Liu, Huishu

2016-05-01

Preeclampsia is associated with an increased inflammatory response. Immune suppression might be an effective treatment. The aim of this study was to examine whether Cyclosporin A (CsA), an immunosuppressant, improves clinical characteristics of preeclampsia and suppresses inflammation in a lipopolysaccharide (LPS) induced preeclampsia rat model. Pregnant rats were randomly divided into 4 groups: group 1 (PE) rats each received LPS via tail vein on gestational day (GD) 14; group 2 (PE+CsA5) rats were pretreated with LPS (1.0 μg/kg) on GD 14 and were then treated with CsA (5mg/kg, ip) on GDs 16, 17 and 18; group 3 (PE+CsA10) rats were pretreated with LPS (1.0 μg/kg) on GD 14 and were then treated with CsA (10mg/kg, ip) on GDs 16, 17 and 18; group 4 (pregnant control, PC) rats were treated with the vehicle (saline) used for groups 1, 2 and 3. Systolic blood pressure, urinary albumin, biometric parameters and the levels of serum cytokines were measured on day 20. CsA treatment significantly reduced LPS-induced systolic blood pressure and the mean 24-h urinary albumin excretion. Pro-inflammatory cytokines IL-6, IL-17, IFN-γ and TNF-α were increased in the LPS treatment group but were reduced in (LPS+CsA) group (Ppreeclampsia signs and attenuated inflammatory responses in the LPS induced preeclampsia rat model which suggests that immunosuppressant might be an alternative management option for preeclampsia. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mathematical model of glucose-insulin homeostasis in healthy rats.

Science.gov (United States)

Lombarte, Mercedes; Lupo, Maela; Campetelli, German; Basualdo, Marta; Rigalli, Alfredo

2013-10-01

According to the World Health Organization there are over 220 million people in the world with diabetes and 3.4 million people died in 2004 as a consequence of this pathology. Development of an artificial pancreas would allow to restore control of blood glucose by coupling an infusion pump to a continuous glucose sensor in the blood. The design of such a device requires the development and application of mathematical models which represent the gluco-regulatory system. Models developed by other research groups describe very well the gluco-regulatory system but have a large number of mathematical equations and require complex methodologies for the estimation of its parameters. In this work we propose a mathematical model to study the homeostasis of glucose and insulin in healthy rats. The proposed model consists of three differential equations and 8 parameters that describe the variation of: blood glucose concentration, blood insulin concentration and amount of glucose in the intestine. All parameters were obtained by setting functions to the values of glucose and insulin in blood obtained after oral glucose administration. In vivo and in silico validations were performed. Additionally, a qualitative analysis has been done to verify the aforementioned model. We have shown that this model has a single, biologically consistent equilibrium point. This model is a first step in the development of a mathematical model for the type I diabetic rat. Copyright © 2013 Elsevier Inc. All rights reserved.

[Study on the oxidative stress in the ovaries of a rat model of polycystic ovary].

Science.gov (United States)

Gong, Jin; Wu, Dong-bo; Zhang, Lan-lan; Li, Jia; Zhao, Xing; Zhang, Dan

2015-03-01

To establish a pathological animal model of polycystic ovary (PCO) by letrozole in rats. Investigate whether PCO were mediated by the effect of oxidative stress by measuring oxidative stress levels in this cohort of rats with PCO, and proceed a new way of treatment for polycystic ovary syndrom (PCOS). 90 SD female rats aged 6 weeks were randomly divided into two groups, including a control group of 45 rats that received vehicle only [19% aqueous solution of carboxmethlycellulose (CMC), 1 mL/d] once daily orally (p.o.), and an experimental group of 45 rats, which were administered letrozole at concentrations of 1 mg/kg p.o. dissolved in 1% CMC (1 mL/d) once daily. The treatment period was 28 d. During this period, vaginal smears were collected daily for estrus cycle determination and body masses were measured every 7 d. On the day subsequent to the last letrozole dose administration, rats were killed; Uteri and ovaries were then excised and weighed for the calculation of organ indexes. Serum hormone levels, SHBG and histologic changes in the ovaries were examined. Then testosterone free index (FAD) was calculated. Oxidant status was evaluated by determination of ovarian total oxidant status (TOS), malondialdehyde (MDA) concentration and intracellular reactive oxygen species (ROS) level, while antioxidant status was evaluated by determination of total antioxidant status (TAS) and superoxide dismutase (SOD) concentration. Vaginal smear test showed the estrus cycle began to disappear from day 12 to day 15. A statistically significant difference in growth curves, ovarian weights, uterine weights and organ indexes between the groups were also observed. In rats with PCO serum testosterone (T), follicle-stimulating hormone (FSH) concentrations and free androgen index (FADI) were significantly increased compared with the control group (rats without PCO). However, rats with PCO had decreased levels of estrogen (E2), luteinizing hormone (LH), and progesterone (P) compared

Evaluation of deltamethrin kinetics and dosimetry in the maturing rat using a PBPK model

International Nuclear Information System (INIS)

Tornero-Velez, Rogelio; Mirfazaelian, Ahmad; Kim, Kyu-Bong; Anand, Sathanandam S.; Kim, Hyo J.; Haines, Wendy T.; Bruckner, James V.; Fisher, Jeffrey W.

2010-01-01

Immature rats are more susceptible than adults to the acute neurotoxicity of pyrethroid insecticides like deltamethrin (DLM). A companion kinetics study (Kim et al., in press) revealed that blood and brain levels of the neuroactive parent compound were inversely related to age in rats 10, 21, 40 and 90 days old. The objective of the current study was to modify a physiologically based pharmacokinetic (PBPK) model of DLM disposition in the adult male Sprague-Dawley rat (Mirfazaelian et al., 2006), so blood and target organ dosimetry could be accurately predicted during maturation. Age-specific organ weights and age-dependent changes in the oxidative and hydrolytic clearance of DLM were modeled with a generalized Michaelis-Menten model for growth and the summary equations incorporated into the PBPK model. The model's simulations compared favorably with empirical DLM time-courses in plasma, blood, brain and fat for the four age-groups evaluated (10, 21, 40 and 90 days old). PND 10 pups' area under the 24-h brain concentration time curve (AUC 0-24h ) was 3.8-fold higher than that of the PND 90 adults. Our maturing rat PBPK model allows for updating with age- and chemical-dependent parameters, so pyrethroid dosimetry can be forecast in young and aged individuals. Hence, this model provides a methodology for risk assessors to consider age-specific adjustments to oral Reference Doses on the basis of PK differences.

A RAT MODEL OF HEART FAILURE INDUCED BY ISOPROTERENOL AND A HIGH SALT DIET

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Rat models of heart failure (HF) show varied pathology and time to disease outcome, dependent on induction method. We found that subchronic (4wk) isoproterenol (ISO) infusion in Spontaneously Hypertensive Heart Failure (SHHF) rats caused cardiac injury with minimal hypertrophy. O...

Quercetin Decreases Insulin Resistance in a Polycystic Ovary Syndrome Rat Model by Improving Inflammatory Microenvironment.

Science.gov (United States)

Wang, Zhenzhi; Zhai, Dongxia; Zhang, Danying; Bai, Lingling; Yao, Ruipin; Yu, Jin; Cheng, Wen; Yu, Chaoqin

2017-05-01

Insulin resistance (IR) is a clinical feature of polycystic ovary syndrome (PCOS). Quercetin, derived from Chinese medicinal herbs such as hawthorn, has been proven practical in the management of IR in diabetes. However, whether quercetin could decrease IR in PCOS is unknown. This study aims to observe the therapeutic effect of quercetin on IR in a PCOS rat model and explore the underlying mechanism. An IR PCOS rat model was established by subcutaneous injection with dehydroepiandrosterone. The body weight, estrous cycle, and ovary morphology of the quercetin-treated rats were observed. Serum inflammatory cytokines were analyzed using enzyme-linked immunosorbent assay. In ovarian tissues, the expression of key genes involved in the inflammatory signaling pathway was detected through Western blot, real-time polymerase chain reaction, or immunohistochemistry. The nuclear translocation of nuclear factor κB (NF-κB) was also observed by immunofluorescence. The estrous cycle recovery rate of the insulin-resistant PCOS model after quercetin treatment was 58.33%. Quercetin significantly reduced the levels of blood insulin, interleukin 1β, IL-6, and tumor necrosis factor α. Quercetin also significantly decreased the granulosa cell nuclear translocation of NF-κB in the insulin-resistant PCOS rat model. The treatment inhibited the expression of inflammation-related genes, including the nicotinamide adenine dinucleotide phosphate oxidase subunit p22phox, oxidized low-density lipoprotein, and Toll-like receptor 4, in ovarian tissue. Quercetin improved IR and demonstrated a favorable therapeutic effect on the PCOS rats. The underlying mechanism of quercetin potentially involves the inhibition of the Toll-like receptor/NF-κB signaling pathway and the improvement in the inflammatory microenvironment of the ovarian tissue of the PCOS rat model.

Tamoxifen induces regression of estradiol-induced mammary cancer in ACI.COP-Ept2 rat model

OpenAIRE

Ruhlen, Rachel L.; Willbrand, Dana M.; Besch-Williford, Cynthia L.; Ma, Lixin; Shull, James D.; Sauter, Edward R.

2008-01-01

The ACI rat is a unique model of human breast cancer in that mammary cancers are induced by estrogen without carcinogens, irradiation, xenografts or transgenic manipulations. We sought to characterize mammary cancers in a congenic variant of the ACI rat, the ACI.COP-Ept2. All rats with estradiol implants developed mammary cancers in 5–7 months. Rats bearing estradiol-induced mammary cancers were treated with tamoxifen for three weeks. Tamoxifen reduced tumor mass, measured by magnetic resonan...

Motor Function and Dopamine Release Measurements in Transgenic Huntington’s Disease Model Rats

Science.gov (United States)

Ortiz, Andrea N.; Osterhaus, Gregory L.; Lauderdale, Kelli; Mahoney, Luke; Fowler, Stephen C.; von Hörsten, Stephan; Riess, Olaf; Johnson, Michael A.

2013-01-01

Huntington’s disease (HD) is a fatal, genetic, neurodegenerative disorder characterized by deficits in motor and cognitive function. Here, we have quantitatively characterized motor deficiencies and dopamine release dynamics in transgenic HD model rats. Behavioral analyses were conducted using a newly-developed force-sensing runway and a previously-developed force-plate actometer. Gait disturbances were readily observed in transgenic HD rats at 12 to 15 months of age. Additionally, dopamine system challenge by ip injection of amphetamine also revealed that these rats were resistant to the expression of focused stereotypy compared to wild-type controls. Moreover, dopamine release, evoked by the application of single and multiple electrical stimulus pulses applied at different frequencies, and measured using fast-scan cyclic voltammetry at carbon-fiber microelectrodes, was diminished in transgenic HD rats compared to age-matched wild-type control rats. Collectively, these results underscore the potential contribution of dopamine release alterations to the expression of motor impairments in transgenic HD rats. PMID:22418060

Novel Rat Model of Repetitive Portal Venous Embolization Mimicking Human Non-Cirrhotic Idiopathic Portal Hypertension.

Science.gov (United States)

Klein, Sabine; Hinüber, Christian; Hittatiya, Kanishka; Schierwagen, Robert; Uschner, Frank Erhard; Strassburg, Christian P; Fischer, Hans-Peter; Spengler, Ulrich; Trebicka, Jonel

2016-01-01

Non-cirrhotic idiopathic portal hypertension (NCIPH) is characterized by splenomegaly, anemia and portal hypertension, while liver function is preserved. However, no animal models have been established yet. This study assessed a rat model of NCIPH and characterized the hemodynamics, and compared it to human NCIPH. Portal pressure (PP) was measured invasively and coloured microspheres were injected in the ileocecal vein in rats. This procedure was performed weekly for 3 weeks (weekly embolization). Rats without and with single embolization served as controls. After four weeks (one week after last embolization), hemodynamics were investigated, hepatic fibrosis and accumulation of myofibroblasts were analysed. General characteristics, laboratory analyses and liver histology were collected in patients with NCIPH. Weekly embolization induced a hyperdynamic circulation, with increased PP. The mesenteric flow and hepatic hydroxyproline content was significantly higher in weekly embolized compared to single embolized rats (mesenteric flow +54.1%, hydroxyproline +41.7%). Mesenteric blood flow and shunt volumes increased, whereas splanchnic vascular resistance was decreased in the weekly embolization group. Fibrotic markers αSMA and Desmin were upregulated in weekly embolized rats. This study establishes a model using repetitive embolization via portal veins, comparable with human NCIPH and may serve to test new therapies.

Local field potential recordings in a non-human primate model of Parkinsons disease using the Activa PC + S neurostimulator

Science.gov (United States)

Connolly, Allison T.; Muralidharan, Abirami; Hendrix, Claudia; Johnson, Luke; Gupta, Rahul; Stanslaski, Scott; Denison, Tim; Baker, Kenneth B.; Vitek, Jerrold L.; Johnson, Matthew D.

2015-12-01

Objective. Using the Medtronic Activa® PC + S system, this study investigated how passive joint manipulation, reaching behavior, and deep brain stimulation (DBS) modulate local field potential (LFP) activity in the subthalamic nucleus (STN) and globus pallidus (GP). Approach. Five non-human primates were implanted unilaterally with one or more DBS leads. LFPs were collected in montage recordings during resting state conditions and during motor tasks that facilitate the expression of parkinsonian motor signs. These recordings were made in the naïve state in one subject, in the parkinsonian state in two subjects, and in both naïve and parkinsonian states in two subjects. Main results. LFPs measured at rest were consistent over time for a given recording location and parkinsonian state in a given subject; however, LFPs were highly variable between subjects, between and within recording locations, and across parkinsonian states. LFPs in both naïve and parkinsonian states across all recorded nuclei contained a spectral peak in the beta band (10-30 Hz). Moreover, the spectral content of recorded LFPs was modulated by passive and active movement of the subjects’ limbs. LFPs recorded during a cued-reaching task displayed task-related beta desynchronization in STN and GP. The bidirectional capabilities of the Activa® PC + S also allowed for recording LFPs while delivering DBS. The therapeutic effect of STN DBS on parkinsonian rigidity outlasted stimulation for 30-60 s, but there was no correlation with beta band power. Significance. This study emphasizes (1) the variability in spontaneous LFPs amongst subjects and (2) the value of using the Activa® PC + S system to record neural data in the context of behavioral tasks that allow one to evaluate a subject’s symptomatology.

Local field potential recordings in a non-human primate model of Parkinsons disease using the Activa PC + S neurostimulator

Science.gov (United States)

Connolly, Allison T; Muralidharan, Abirami; Hendrix, Claudia; Johnson, Luke; Gupta, Rahul; Stanslaski, Scott; Denison, Tim; Baker, Kenneth B; Vitek, Jerrold L; Johnson, Matthew D

2016-01-01

Objective Using the Medtronic Activa® PC + S system, this study investigated how passive joint manipulation, reaching behavior, and deep brain stimulation (DBS) modulate local field potential (LFP) activity in the subthalamic nucleus (STN) and globus pallidus (GP). Approach Five non-human primates were implanted unilaterally with one or more DBS leads. LFPs were collected in montage recordings during resting state conditions and during motor tasks that facilitate the expression of parkinsonian motor signs. These recordings were made in the naïve state in one subject, in the parkinsonian state in two subjects, and in both naïve and parkinsonian states in two subjects. Main results LFPs measured at rest were consistent over time for a given recording location and parkinsonian state in a given subject; however, LFPs were highly variable between subjects, between and within recording locations, and across parkinsonian states. LFPs in both naïve and parkinsonian states across all recorded nuclei contained a spectral peak in the beta band (10–30 Hz). Moreover, the spectral content of recorded LFPs was modulated by passive and active movement of the subjects’ limbs. LFPs recorded during a cued-reaching task displayed task-related beta desynchronization in STN and GP. The bidirectional capabilities of the Activa® PC + S also allowed for recording LFPs while delivering DBS. The therapeutic effect of STN DBS on parkinsonian rigidity outlasted stimulation for 30–60 s, but there was no correlation with beta band power. Significance This study emphasizes (1) the variability in spontaneous LFPs amongst subjects and (2) the value of using the Activa® PC + S system to record neural data in the context of behavioral tasks that allow one to evaluate a subject’s symptomatology. PMID:26469737

Neuromyelitis optica study model based on chronic infusion of autoantibodies in rat cerebrospinal fluid.

Science.gov (United States)

Marignier, R; Ruiz, A; Cavagna, S; Nicole, A; Watrin, C; Touret, M; Parrot, S; Malleret, G; Peyron, C; Benetollo, C; Auvergnon, N; Vukusic, S; Giraudon, P

2016-05-18

Devic's neuromyelitis optica (NMO) is an autoimmune astrocytopathy, associated with central nervous system inflammation, demyelination, and neuronal injury. Several studies confirmed that autoantibodies directed against aquaporin-4 (AQP4-IgG) are relevant in the pathogenesis of NMO, mainly through complement-dependent toxicity leading to astrocyte death. However, the effect of the autoantibody per se and the exact role of intrathecal AQP4-IgG are still controversial. To explore the intrinsic effect of intrathecal AQP4-IgG, independent from additional inflammatory effector mechanisms, and to evaluate its clinical impact, we developed a new animal model, based on a prolonged infusion of purified immunoglobulins from NMO patient (IgG(AQP4+), NMO-rat) and healthy individual as control (Control-rat) in the cerebrospinal fluid (CSF) of live rats. We showed that CSF infusion of purified immunoglobulins led to diffusion in the brain, spinal cord, and optic nerves, the targeted structures in NMO. This was associated with astrocyte alteration in NMO-rats characterized by loss of aquaporin-4 expression in the spinal cord and the optic nerves compared to the Control-rats (p = 0.001 and p = 0.02, respectively). In addition, glutamate uptake tested on vigil rats was dramatically reduced in NMO-rats (p = 0.001) suggesting that astrocytopathy occurred in response to AQP4-IgG diffusion. In parallel, myelin was altered, as shown by the decrease of myelin basic protein staining by up to 46 and 22 % in the gray and white matter of the NMO-rats spinal cord, respectively (p = 0.03). Loss of neurofilament positive axons in NMO-rats (p = 0.003) revealed alteration of axonal integrity. Then, we investigated the clinical consequences of such alterations on the motor behavior of the NMO-rats. In a rotarod test, NMO-rats performance was lower compared to the controls (p = 0.0182). AQP4 expression, and myelin and axonal integrity were preserved in AQP4-Ig

Behavioural inflexibility in a comorbid rat model of striatal ischemic injury and mutant hAPP overexpression.

Science.gov (United States)

Levit, Alexander; Regis, Aaron M; Garabon, Jessica R; Oh, Seung-Hun; Desai, Sagar J; Rajakumar, Nagalingam; Hachinski, Vladimir; Agca, Yuksel; Agca, Cansu; Whitehead, Shawn N; Allman, Brian L

2017-08-30

Alzheimer disease (AD) and stroke coexist and interact; yet how they interact is not sufficiently understood. Both AD and basal ganglia stroke can impair behavioural flexibility, which can be reliably modeled in rats using an established operant based set-shifting test. Transgenic Fischer 344-APP21 rats (TgF344) overexpress pathogenic human amyloid precursor protein (hAPP) but do not spontaneously develop overt pathology, hence TgF344 rats can be used to model the effect of vascular injury in the prodromal stages of Alzheimer disease. We demonstrate that the injection of endothelin-1 (ET1) into the dorsal striatum of TgF344 rats (Tg-ET1) produced an exacerbation of behavioural inflexibility with a behavioural phenotype that was distinct from saline-injected wildtype & TgF344 rats as well as ET1-injected wildtype rats (Wt-ET1). In addition to profiling the types of errors made, interpolative modeling using logistic exposure-response regression provided an informative analysis of the timing and efficiency of behavioural flexibility. During set-shifting, Tg-ET1 committed fewer perseverative errors than Wt-ET1. However, Tg-ET1 committed significantly more regressive errors and had a less efficient strategy change than all other groups. Thus, behavioural flexibility was more vulnerable to striatal ischemic injury in TgF344 rats. Copyright © 2017 Elsevier B.V. All rights reserved.

Population Structure of Rat-Derived Pneumocystis carinii in Danish Wild Rats

DEFF Research Database (Denmark)

Palmer, Robert J.; Settnes, Osvald P.; Lodal, Jens

2000-01-01

The rat model of Pneumocystis carinii pneumonia is frequently used to study human P. carinii infection, but there are many differences between the rat and human infections. We studied naturally acquired P. carinii in wild rats to examine the relevance of the rat model for human infection. P. cari...

Serrapeptase and nattokinase intervention for relieving Alzheimer's disease pathophysiology in rat model.

Science.gov (United States)

Fadl, N N; Ahmed, H H; Booles, H F; Sayed, A H

2013-07-01

Serrapeptase (SP) and nattokinase (NK) are proteolytic enzymes belonging to serine proteases. In this study, we hypothesized that SP and NK could modulate certain factors that are associated with Alzheimer's disease (AD) pathophysiology in the experimental model. Oral administration of aluminium chloride (AlCl3) in a dose of 17 mg/kg body weight (bw) daily for 45 days induced AD-like pathology in male rats with a significant increase in brain acetylcholinesterase (AchE) activity, transforming growth factor β (TGF-β), Fas and interleukin-6 (IL-6) levels. Meanwhile, AlCl3 supplementation produced significant decrease in brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) when compared with control values. Also, AlCl3 administration caused significant decline in the expression levels of disintegrin and metalloproteinase domain 9 (ADAM9) and a disintegrin and metalloproteinase domain 10 (ADAM10) genes in the brain. Histological investigation of brain tissue of rat model of AD showed neuronal degeneration in the hippocampus and focal hyalinosis with cellular as well as a cellular amyloid plaques formation. Oral administration of SP or NK in a rat model of AD daily for 45 days resulted in a significant decrease in brain AchE activity, TGF-β, Fas and IL-6 levels. Also, the treatment with these enzymes produced significant increase in BDNF and IGF-1 levels when compared with the untreated AD-induced rats. Moreover, both SP and NK could markedly increase the expression levels of ADAM9 and ADAM10 genes in the brain tissue of the treated rats. These findings were well confirmed by the histological examination of the brain tissue of the treated rats. The present results support our hypothesis that the oral administration of proteolytitc enzymes, SP and/or NK, would have an effective role in modulating certain factors characterizing AD. Thus, these enzymes may have a therapeutic application in the treatment of AD.

Bilateral Cavernous Nerve Crush Injury in the Rat Model: A Comparative Review of Pharmacologic Interventions.

Science.gov (United States)

Haney, Nora M; Nguyen, Hoang M T; Honda, Matthew; Abdel-Mageed, Asim B; Hellstrom, Wayne J G

2018-04-01

It is common for men to develop erectile dysfunction after radical prostatectomy. The anatomy of the rat allows the cavernous nerve (CN) to be identified, dissected, and injured in a controlled fashion. Therefore, bilateral CN injury (BCNI) in the rat model is routinely used to study post-prostatectomy erectile dysfunction. To compare and contrast the available literature on pharmacologic intervention after BCNI in the rat. A literature search was performed on PubMed for cavernous nerve and injury and erectile dysfunction and rat. Only articles with BCNI and pharmacologic intervention that could be grouped into categories of immune modulation, growth factor therapy, receptor kinase inhibition, phosphodiesterase type 5 inhibition, and anti-inflammatory and antifibrotic interventions were included. To assess outcomes of pharmaceutical intervention on erectile function recovery after BCNI in the rat model. The ratio of maximum intracavernous pressure to mean arterial pressure was the main outcome measure chosen for this analysis. All interventions improved erectile function recovery after BCNI based on the ratio of maximum intracavernous pressure to mean arterial pressure results. Additional end-point analysis examined the corpus cavernosa and/or the major pelvic ganglion and CN. There was extreme heterogeneity within the literature, making accurate comparisons between crush injury and therapeutic interventions difficult. BCNI in the rat is the accepted animal model used to study nerve-sparing post-prostatectomy erectile dysfunction. However, an important limitation is extreme variability. Efforts should be made to decrease this variability and increase the translational utility toward clinical trials in humans. Haney NM, Nguyen HMT, Honda M, et al. Bilateral Cavernous Nerve Crush Injury in the Rat Model: A Comparative Review of Pharmacologic Interventions. Sex Med Rev 2018;6:234-241. Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier

Postdependent state in rats as a model for medication development in alcoholism.

Science.gov (United States)

Meinhardt, Marcus W; Sommer, Wolfgang H

2015-01-01

Rational development of novel therapeutic strategies for alcoholism requires understanding of its underlying neurobiology and pathophysiology. Obtaining this knowledge largely relies on animal studies. Thus, choosing the appropriate animal model is one of the most critical steps in pre-clinical medication development. Among the range of animal models that have been used to investigate excessive alcohol consumption in rodents, the postdependent model stands out. It was specifically developed to test the role of negative affect as a key driving force in a perpetuating addiction cycle for alcoholism. Here, we will describe our approach to make rats dependent via chronic intermittent exposure to alcohol, discuss the validity of this model, and compare it with other commonly used animal models of alcoholism. We will summarize evidence that postdependent rats fulfill several criteria of a 'Diagnostic and Statistical Manual of Mental Disorders IV/V-like' diagnostic system. Importantly, these animals show long-lasting excessive consumption of and increased motivation for alcohol, and evidence for loss of control over alcohol intake. Our conclusion that postdependent rats are an excellent model for medication development for alcoholism is underscored by a summary of more than two dozen pharmacological tests aimed at reversing these abnormal alcohol responses. We will end with open questions on the use of this model. In the tradition of the Sanchis-Segura and Spanagel review, we provide comic strips that illustrate the postdependent procedure and relevant phenotypes in this review. © 2014 Society for the Study of Addiction.

Neuroprotective effects of curcumin on 6-hydroxydopamine-induced Parkinsonism in rats: behavioral, neurochemical and immunohistochemical studies.

Science.gov (United States)

Khuwaja, Gulrana; Khan, Mohd Moshahid; Ishrat, Tauheed; Ahmad, Ajmal; Raza, Syed Shadab; Ashafaq, Mohammad; Javed, Hayate; Khan, M Badruzzaman; Khan, Andleeb; Vaibhav, Kumar; Safhi, Mohammed M; Islam, Fakhrul

2011-01-12

Curcumin, the active principle of turmeric used in Indian curry is known for its antitumor, antioxidant, antiarthritic, anti-ischemic and anti-inflammatory properties and might inhibit the accumulation of destructive beta-amyloid in the brains of Alzheimer's disease patients. A Parkinsonian model in rats was developed by giving 6-hydroxydopamine (10 μg/2 μl in 0.1% ascorbic acid-saline) in the right striatum. After 3 weeks of lesioning, the behavior activities (rotarod, narrow beam test, grip test and contra-lateral rotations) were increased in a lesioned group as compared to a sham group and these activities were protected significantly with the pretreatment of curcumin. A significant protection on lipid peroxidation, glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase, tyrosine hydroxylase and D(2) receptor binding was observed in the striatum of lesioned group animals pretreated with 80 mg/kg body weight of curcumin for 21 days as compared to lesion group animals. No significant alterations on behavior and biochemical parameters were observed in sham group animals and the animals of sham group pretreated with curcumin. This study indicates that curcumin, which is an important ingredient of diet in India and also used in various systems of indigenous medicine, is helpful in preventing Parkinsonism and has therapeutic potential in combating this devastating neurologic disorder. Copyright © 2010 Elsevier B.V. All rights reserved.

Studies on the pathogenicity of anaerobes, especially Prevotella bivia, in a rat pyometra model.

Science.gov (United States)

Mikamo, H; Kawazoe, K; Izumi, K; Watanabe, K; Ueno, K; Tamaya, T

1998-01-01

OBJECTIVE: Prevotella bivia is one of the anaerobic bacteria that resides in the flora of the female genital tract. We studied the pathogenicity of P. bivia in a rat pyometra model. METHODS: The experimental animal (rat) model of pyometra was developed to investigate the pathogenicity of P. bivia in a rat pyometra model. RESULTS: In the groups inoculated with aerobes alone, the infection rate was 10% (1/10) in the Staphylococcus aureus- or Staphylococcus agalactiae-inoculated group and 20% (2/10) in the Escherichia coli-inoculated group. Infection was not established in the groups inoculated with anaerobes alone. High infection rates were observed in all the mixed-infection groups. In the S. agalactiae- and Bacteroides fragilis-, S. agalactiae- and P. bivia-, F. coli- and B. fragilis-, and E. coli- and P. bivia-inoculated groups, an infection rate of 100% (10/10) was demonstrated. The efficacy of antibiotics such as flomoxef (FMOX) could be determined using a rat pyometra model. In relation to the alteration of vaginal microbial flora during the menstrual cycle, estrogen increased the growth of P. bivia. CONCLUSION: Mixture of aerobic bacteria and P. bivia increased the pathogenicity of P. bivia. Estrogen would be useful for raising up the inflammatory change of the uterus in experimental models of genital tract infection due to P. bivia. PMID:9702587

Dynamic computed tomography (CT) in the rat kidney and application to acute renal failure models

International Nuclear Information System (INIS)

Ishikawa, Isao; Saito, Tadashi; Ishii, Hirofumi; Bansho, Junichi; Koyama, Yukinori; Tobita, Akira

1995-01-01

Renal dynamic CT scanning is suitable for determining the excretion of contrast medium in the cortex and medulla of the kidney, which is valuable for understanding the pathogenesis of disease processes in various conditions. This form of scanning would be convenient for use, if a method of application to the rat kidney were available. Therefore, we developed a method of applying renal dynamic CT to rats and evaluated the cortical and medullary curves, e.g., the corticomedullary junction time which is correlated to creatinine clearance, in various rat models of acute renal failure. The rat was placed in a 10deg oblique position and a bilateral hilar slice was obtained before and 5, 10, 15, 20, 25, 30, 40, 50, 60, 80, 100, 120, 140, 160 and 180 sec after administering 0.5 ml of contrast medium using Somatom DR. The width of the slice was 4 mm and the scan time was 3 sec. The corticomedullary junction time in normal rats was 23.0±10.5 sec, the peak value of the cortical curve was 286.3±76.7 Hounsfield Unit (HU) and the peak value of the medullary curve was 390.1±66.2 HU. Corticomedullary junction time after exposure of the kidney was prolonged compared to that of the unexposed kidney. In rats with acute renal failure, the excretion pattern of contrast medium was similar in both the glycerol- and HgCl2-induced acute renal failure models. The peak values of the cortical curve were maintained three hours after a clamp was placed at the hilar region of the kidney for one hour, and the peak values of the medullary curve were maintained during the administration of 10μg/kg/min of angiotensin II. Dynamic CT curves in the acute renal failure models examined were slightly different from those in human acute renal failure. These results suggest that rats do not provide an ideal model for human acute renal failure. However, the application of dynamic CT to the rat kidney models was valuable for estimating the pathogenesis of various human kidney diseases. (author)

Cardiovascular disease-related parameters and oxidative stress in SHROB rats, a model for metabolic syndrome.

Directory of Open Access Journals (Sweden)

Eunice Molinar-Toribio

Full Text Available SHROB rats have been suggested as a model for metabolic syndrome (MetS as a situation prior to the onset of CVD or type-2 diabetes, but information on descriptive biochemical parameters for this model is limited. Here, we extensively evaluate parameters related to CVD and oxidative stress (OS in SHROB rats. SHROB rats were monitored for 15 weeks and compared to a control group of Wistar rats. Body weight was recorded weekly. At the end of the study, parameters related to CVD and OS were evaluated in plasma, urine and different organs. SHROB rats presented statistically significant differences from Wistar rats in CVD risk factors: total cholesterol, LDL-cholesterol, triglycerides, apoA1, apoB100, abdominal fat, insulin, blood pressure, C-reactive protein, ICAM-1 and PAI-1. In adipose tissue, liver and brain, the endogenous antioxidant systems were activated, yet there was no significant oxidative damage to lipids (MDA or proteins (carbonylation. We conclude that SHROB rats present significant alterations in parameters related to inflammation, endothelial dysfunction, thrombotic activity, insulin resistance and OS measured in plasma as well as enhanced redox defence systems in vital organs that will be useful as markers of MetS and CVD for nutrition interventions.

A novel knee prosthesis model of implant-related osteo- myelitis in rats

DEFF Research Database (Denmark)

Søe, Niels H.; Jensen, Nina Vendel; Nürnberg, Birgit Meinecke

2012-01-01

There have been numerous reports of animal models of osteomyelitis. Very few of these have been prosthesis models that imitate human conditions. We have developed a new rat model of implant-related osteomyelitis that mimics human osteomyelitis, to investigate the pathology of infection after...

Simvastatin Exposure and Rotator Cuff Repair in a Rat Model.

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Deren, Matthew E; Ehteshami, John R; Dines, Joshua S; Drakos, Mark C; Behrens, Steve B; Doty, Stephen; Coleman, Struan H

2017-03-01

Simvastatin is a common medication prescribed for hypercholesterolemia that accelerates local bone formation. It is unclear whether simvastatin can accelerate healing at the tendon-bone interface after rotator cuff repair. This study was conducted to investigate whether local and systemic administration of simvastatin increased tendon-bone healing of the rotator cuff as detected by maximum load to failure in a controlled animal-based model. Supraspinatus tendon repair was performed on 120 Sprague-Dawley rats. Sixty rats had a polylactic acid membrane overlying the repair site. Of these, 30 contained simvastatin and 30 did not contain medication. Sixty rats underwent repair without a polylactic acid membrane. Of these, 30 received oral simvastatin (25 mg/kg/d) and 30 received a regular diet. At 4 weeks, 5 rats from each group were killed for histologic analysis. At 8 weeks, 5 rats from each group were killed for histologic analysis and the remaining 20 rats were killed for biomechanical analysis. One rat that received oral simvastatin died of muscle necrosis. Average maximum load to failure was 35.2±6.2 N for those receiving oral simvastatin, 36.8±9.0 N for oral control subjects, 39.5±12.8 N for those receiving local simvastatin, and 39.1±9.3 N for control subjects with a polylactic acid membrane. No statistically significant differences were found between any of the 4 groups (P>.05). Qualitative histologic findings showed that all groups showed increased collagen formation and organization at 8 weeks compared with 4 weeks, with no differences between the 4 groups at each time point. The use of systemic and local simvastatin offered no benefit over control groups. [Orthopedics. 2017; 40(2):e288-e292.]. Copyright 2016, SLACK Incorporated.

Preliminary Study of Quercetin Affecting the Hypothalamic-Pituitary-Gonadal Axis on Rat Endometriosis Model

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Yang Cao

2014-01-01

Full Text Available In this study, the endometriosis rats model was randomly divided into 6 groups: model control group, ovariectomized group, Gestrinone group, and quercetin high/medium/low dose group. Rats were killed after 3 weeks of administration. The expression levels of serum FSH and LH were detected by ELISA. The localizations and quantities of ERα, ERβ, and PR were detected by immunohistochemistry and western blot. The results showed that the mechanism of quercetin inhibiting the growth of ectopic endometrium on rat endometriosis model may be through the decreasing of serum FSH and LH levels and then reducing local estrogen content to make the ectopic endometrium atrophy. Quercetin can decrease the expression of ERα, ERβ, and PR in hypothalamus, pituitary, and endometrium, thereby inhibiting estrogen and progesterone binding to their receptors to play the role of antiestrogen and progesterone.

Tamoxifen induces regression of estradiol-induced mammary cancer in the ACI.COP-Ept2 rat model.

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Ruhlen, Rachel L; Willbrand, Dana M; Besch-Williford, Cynthia L; Ma, Lixin; Shull, James D; Sauter, Edward R

2009-10-01

The ACI rat is a unique model of human breast cancer in that mammary cancers are induced by estrogen without carcinogens, irradiation, xenografts or transgenic manipulations. We sought to characterize mammary cancers in a congenic variant of the ACI rat, the ACI.COP-Ept2. All rats with estradiol implants developed mammary cancers in 5-7 months. Rats bearing estradiol-induced mammary cancers were treated with tamoxifen for three weeks. Tamoxifen reduced tumor mass, measured by magnetic resonance imaging, by 89%. Tumors expressed estrogen receptors (ER), progesterone receptor (PR), and Erbb2. ERalpha and PR were overexpressed in tumor compared to adjacent non-tumor mammary gland. Thus, this model is highly relevant to hormone responsive human breast cancers.

Efficacy of integrative medicine in deficiency of both qi and yin in the rat model of type 2 diabetes

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Jing Zhao

2015-10-01

Conclusions: A rat model of T2DM with both qi and yin deficiency was successfully replicated. CHF appeared to be more efficacious than IM and PIO in the rat model of qi and yin deficiency pattern of T2DM, though IM and PIO were each found to have their merits and drawbacks in attenuating T2DM indicators in the rat model.

Use of Terbinafine in Mouse and Rat Models of Pneumocystis carinii Pneumonia

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Walzer, Peter D.; Ashbaugh, Alan

2002-01-01

Terbinafine, an allylamine used to treat onychomycosis, has been reported to be active against rat Pneumocystis carinii in vitro and in vivo. By contrast, our in vitro data showed that the 50% inhibitory concentration of terbinafine against rat P. carinii is 3.7 μg/ml, a level that cannot be clinically achieved in serum. In the present study, terbinafine administered orally at doses of 20 to 400 mg/kg/day and 50 to 250 mg/kg/day was ineffective therapy for mouse and rat models of pneumocystosis, respectively. These results emphasize the complexities of P. carinii drug testing and the need for caution before considering studies in humans. PMID:11796365

Automated, high accuracy classification of Parkinsonian disorders: a pattern recognition approach.

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Andre F Marquand

Full Text Available Progressive supranuclear palsy (PSP, multiple system atrophy (MSA and idiopathic Parkinson's disease (IPD can be clinically indistinguishable, especially in the early stages, despite distinct patterns of molecular pathology. Structural neuroimaging holds promise for providing objective biomarkers for discriminating these diseases at the single subject level but all studies to date have reported incomplete separation of disease groups. In this study, we employed multi-class pattern recognition to assess the value of anatomical patterns derived from a widely available structural neuroimaging sequence for automated classification of these disorders. To achieve this, 17 patients with PSP, 14 with IPD and 19 with MSA were scanned using structural MRI along with 19 healthy controls (HCs. An advanced probabilistic pattern recognition approach was employed to evaluate the diagnostic value of several pre-defined anatomical patterns for discriminating the disorders, including: (i a subcortical motor network; (ii each of its component regions and (iii the whole brain. All disease groups could be discriminated simultaneously with high accuracy using the subcortical motor network. The region providing the most accurate predictions overall was the midbrain/brainstem, which discriminated all disease groups from one another and from HCs. The subcortical network also produced more accurate predictions than the whole brain and all of its constituent regions. PSP was accurately predicted from the midbrain/brainstem, cerebellum and all basal ganglia compartments; MSA from the midbrain/brainstem and cerebellum and IPD from the midbrain/brainstem only. This study demonstrates that automated analysis of structural MRI can accurately predict diagnosis in individual patients with Parkinsonian disorders, and identifies distinct patterns of regional atrophy particularly useful for this process.

Modeling postpartum depression in rats: theoretic and methodological issues

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Ming, LI; Shinn-Yi, CHOU

2016-01-01

The postpartum period is when a host of changes occur at molecular, cellular, physiological and behavioral levels to prepare female humans for the challenge of maternity. Alteration or prevention of these normal adaptions is thought to contribute to disruptions of emotion regulation, motivation and cognitive abilities that underlie postpartum mental disorders, such as postpartum depression. Despite the high incidence of this disorder, and the detrimental consequences for both mother and child, its etiology and related neurobiological mechanisms remain poorly understood, partially due to the lack of appropriate animal models. In recent decades, there have been a number of attempts to model postpartum depression disorder in rats. In the present review, we first describe clinical symptoms of postpartum depression and discuss known risk factors, including both genetic and environmental factors. Thereafter, we discuss various rat models that have been developed to capture various aspects of this disorder and knowledge gained from such attempts. In doing so, we focus on the theories behind each attempt and the methods used to achieve their goals. Finally, we point out several understudied areas in this field and make suggestions for future directions. PMID:27469254

Modeling postpartum depression in rats: theoretic and methodological issues

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Ming LI

2018-06-01

Full Text Available The postpartum period is when a host of changes occur at molecular, cellular, physiological and behavioral levels to prepare female humans for the challenge of maternity. Alteration or prevention of these normal adaptions is thought to contribute to disruptions of emotion regulation, motivation and cognitive abilities that underlie postpartum mental disorders, such as postpartum depression. Despite the high incidence of this disorder, and the detrimental consequences for both mother and child, its etiology and related neurobiological mechanisms remain poorly understood, partially due to the lack of appropriate animal models. In recent decades, there have been a number of attempts to model postpartum depression disorder in rats. In the present review, we first describe clinical symptoms of postpartum depression and discuss known risk factors, including both genetic and environmental factors. Thereafter, we discuss various rat models that have been developed to capture various aspects of this disorder and knowledge gained from such attempts. In doing so, we focus on the theories behind each attempt and the methods used to achieve their goals. Finally, we point out several understudied areas in this field and make suggestions for future directions.

Immune-mediated effects upon oral challenge of ovalbumin-sensitized Brown Norway rats: Further characterization of a rat food allergy model

NARCIS (Netherlands)

Knippels, L.M.J.; Penninks, A.H.; Smit, J.J.; Houben, G.F.

1999-01-01

Although several in vivo antigenicity assays using parenteral immunization are operational, no full validated enteral models are available to study food allergy and allergenicity of food proteins. To further validate a developed enteral Brown Norway (BN) rat food allergy model, systemic and local

Intervention of Peiyuan Huayu Decoction on the neuron damage in model rats with acute subdural hematoma

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Xiao-Xuan Fan

2017-07-01

Full Text Available Objective: To study the intervention effect of Peiyuan Huayu Decoction on the neuron damage in model rats with acute subdural hematoma (ASDH. Methods: 160 SD rats were randomly divided into four groups, and the ASDH model rats were made by stereotactic autoblood injection, and sham operation group received craniotomy without blood injection. Sham operation group and model group were normally bred after model establishment, and 6 h after model establishment, the treatment group received intragastric administration of Peiyuan Huayu Decoction, and control group received intragastric administration of Piracetam Tablets, 1 time a day. On the 1d, 3d, 5d and 7d after model establishment, the general conditions of rats (activity, food intake and mental state were observed, blood was collected via auricula dextra, ELISA method was used to determine peripheral plasma NSE and S100毬 protein contents, routine HE staining was conducted after perfusion fixation, the neurons in blood injection side of brain tissue were counted, and the neuron damage was observed. Results: 26 rats were dead in the experiment. The general conditions of sham operation group were significantly better than those of other groups, treatment group was significantly better than model group and control group on the 5d group (P0.05; neuron count of sham operation group was basically stable, treatment group was not different from model group and control group on the 1d (P>0.05, treatment group was better than model group (P0.05 on the 3d, and treatment group was better than model group and control group on the 5d and 7d (P0.05, S100毬 protein and NSE contents decreased significantly on the 3d, and treatment group was significantly different from model group and control group (P<0.05, S100毬 protein and NSE contents increased on the 5d and 7d, the increase in treatment group was slower than that in model group and control group, and there was significant difference (P<0.05. Conclusion

Untangling cortico-striatal connectivity and cross-frequency coupling in L-DOPA-induced dyskinesia

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Jovana eBelic

2016-03-01

Full Text Available We simultaneously recorded local field potentials in the primary motor cortex and sensorimotor striatum in awake, freely behaving, 6-OHDA lesioned hemi-parkinsonian rats in order to study the features directly related to pathological states such as parkinsonian state and levodopa-induced dyskinesia. We analysed the spectral characteristics of the obtained signals and observed that during dyskinesia the most prominent feature was a relative power increase in the high gamma frequency range at around 80 Hz, while for the parkinsonian state it was in the beta frequency range. Here we show that during both pathological states effective connectivity in terms of Granger causality is bidirectional with an accent on the striatal influence on the cortex. In the case of dyskinesia, we also found a high increase in effective connectivity at 80 Hz. In order to further understand the 80- Hz phenomenon, we performed cross-frequency analysis and observed characteristic patterns in the case of dyskinesia but not in the case of the parkinsonian state or the healthy state. We noted a large decrease in the modulation of the amplitude at 80 Hz by the phase of low frequency oscillations (up to ~10 Hz across both structures in the case of dyskinesia. This may suggest a lack of coupling between the low frequency activity of the recorded network and the group of neurons active at ~80 Hz.

Effect of TheraCyte-encapsulated parathyroid cells on lumbar fusion in a rat model

OpenAIRE

Chen, Sung-Hsiung; Huang, Shun-Chen; Lui, Chun-Chung; Lin, Tzu-Ping; Chou, Fong-Fu; Ko, Jih-Yang

2012-01-01

Introduction Implantation of TheraCyte 4 × 106 live parathyroid cells can increase the bone marrow density of the spine of ovariectomized rats. There has been no published study examining the effect of such implantation on spinal fusion outcomes. The purpose of this study was to examine the effect of TheraCyte-encapsulated parathyroid cells on posterolateral lumbar fusions in a rat model. Materials and methods Forty Sprague-Dawley rats underwent single-level, intertransverse process spinal fu...

Influence of bushenhuoxue on primary visual cortex' BDNF damage in rat model of chronic elevated intraocular pressure

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Xiang Li

2013-04-01

Full Text Available AIM: To observe the effect of traditional Chinese medicine(TCMof bushenhuoxue on primary visual cortex(PVCbrain-derived neurotrophic factor(BDNFin rat model of chronic elevated intraocular pressure(EIOP, and explore the mechanism of it initially. METHODS: The rat model of chronic EIOP was established by unilaterally cauterizing 3 episcleral veins, then 30 rats were divided into 3 groups randomly: control group, model group, and treatment group. After given drugs or normal saline for 8 weeks, the rats were put to death. The effect of intraocular pressure(IOP, expression of BDNF and ultrastructure of neuron cell in the PVC was observed. RESULTS: Unilaterally cauterizing episcleral veins increased IOP of the rat model obviously, there was significant difference compared with pre-operation(P<0.01. Semi-quantitative pathological analysis on PVC showed that BDNF of total area in the model group was(82438±2597.39S/μm2,mean optical density was(1155.9±123.14, integrated optical density was(12915±673.28, compared with the control group {total area was(132370±7588.47S/μm2, mean optical density was(5365±379.65, integrated optical density was(35102±2648.5}, there were statistical differences(all P<0.05,there was statistical difference in BDNF of total area between model group and treatment group{(108980±9126.77S/μm2, P<0.05}, significant difference in mean optical density between the model group and treatment group(3220.4±413.67, P<0.05, statistical difference in integrated optical density between the model group and treatment group(23821±3431.68, P<0.05. CONCLUSION: TCM of bushenhuoxue can repair the PVC damage in the rat model of chronic EIOP by enhancing expression of BDNF, improving ultrastructure of neuron cell.

Bifidobacterium breve prevents necrotising enterocolitis by suppressing inflammatory responses in a preterm rat model.

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Satoh, T; Izumi, H; Iwabuchi, N; Odamaki, T; Namba, K; Abe, F; Xiao, J Z

2016-02-01

Necrotising enterocolitis (NEC) is associated with inflammatory responses and barrier dysfunction in the gut. In this study, we investigated the effect of Bifidobacterium breve M-16V on factors related to NEC development using an experimental rat model. Caesarean-sectioned rats were given formula milk with or without B. breve M-16V by oral gavage thrice daily, and experimental NEC was induced by exposing the rats to hypoxic conditions. Naturally delivered rats that were reared by their mother were used as healthy controls. The pathological score of NEC and the expression of molecules related to inflammatory responses and the barrier function were assessed in the ileum. B. breve M-16V reduced the pathological scores of NEC and resulted in some improvement in survivability. B. breve M-16V suppressed the increased expression of molecules related to inflammation and barrier function that resulted from NEC induction. B. breve M-16V normalised Toll-like receptor (TRL)4 expression and enhanced TLR2 expression. Our data suggest that B. breve M-16V prevents NEC development by modulating TLR expressions and suppressing inflammatory responses in a rat model.

Establishment of 9L/F344 rat intracerebral glioma model of brain tumor stem cells

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Zong-yu XIAO

2015-04-01

Full Text Available Objective To establish the 9L/F344 rat intracerebral glioma model of brain tumor stem cells.  Methods Rat 9L gliosarcoma stem-like cells were cultured in serum-free suspension. The expression of CD133 and nestin were tested by immunohistochemistry. A total of 48 inbredline male F344 rats were randomly divided into 2 groups, and 9L tumor sphere cells and 9L monolayer cells were respectively implanted into the right caudate nucleus of F344 rats in 2 groups. Survival time was observed and determined using the method of Kaplan-Meier survival analysis. Fourteen days after implantation or when the rats were dying, their brains were perfused and sectioned for HE staining, and CD133 and nestin were detected by immunohistochemistry.  Results Rat 9L tumor spheres were formed with suspension culture in serum-free medium. The gliomas formed in both groups were invasive without obvious capsule. More new vessels, bleeding and necrosis could be detected in 9L tumor spheres group. The tumor cells in both groups were positive for CD133 and nestin. There was no significant difference in the expression of CD133 and nestin between 2 groups (P > 0.05, for all. According to the expression of nestin, the tumors formed by 9L tumor sphere cells were more invasive. The median survival time of the rats bearing 9L tumor sphere cells was 15 d (95%CI: 15.219-15.781, and the median survival time of the rats bearing 9L monolayer cells was 21 d (95%CI: 20.395-21.605. There was significant difference between 2 groups (χ2 = 12.800, P = 0.000.  Conclusions 9L/F344 rat intracerebral glioma model of brain tumor stem cells is successfully established, which provides a glioma model for the future research. DOI: 10.3969/j.issn.1672-6731.2015.04.012

Diffraction enhanced imaging of a rat model of gastric acid aspiration pneumonitis.

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Connor, Dean M; Zhong, Zhong; Foda, Hussein D; Wiebe, Sheldon; Parham, Christopher A; Dilmanian, F Avraham; Cole, Elodia B; Pisano, Etta D

2011-12-01

Diffraction-enhanced imaging (DEI) is a type of phase contrast x-ray imaging that has improved image contrast at a lower dose than conventional radiography for many imaging applications, but no studies have been done to determine if DEI might be useful for diagnosing lung injury. The goals of this study were to determine if DEI could differentiate between healthy and injured lungs for a rat model of gastric aspiration and to compare diffraction-enhanced images with chest radiographs. Radiographs and diffraction-enhanced chest images of adult Sprague Dawley rats were obtained before and 4 hours after the aspiration of 0.4 mL/kg of 0.1 mol/L hydrochloric acid. Lung damage was confirmed with histopathology. The radiographs and diffraction-enhanced peak images revealed regions of atelectasis in the injured rat lung. The diffraction-enhanced peak images revealed the full extent of the lung with improved clarity relative to the chest radiographs, especially in the portion of the lower lobe that extended behind the diaphragm on the anteroposterior projection. For a rat model of gastric acid aspiration, DEI is capable of distinguishing between a healthy and an injured lung and more clearly than radiography reveals the full extent of the lung and the lung damage. Copyright © 2011 AUR. All rights reserved.

Transplantation of ES cells to Parkinson model rat irradiated with carbon ion beam

International Nuclear Information System (INIS)

Inaji, Motoki; Okauchi, Takashi; Nagai, Yuji; Nojima, Kumie; Suhara, Tetsuya

2004-01-01

The present study was designed to make a new Parkinson disease model using carbon ion beam. In this year, we irradiated right middle forebrain bundle of adult rats with charged carbon particles (290 MeV/nucleon, Mono peak, 150 Gy) and damaged right dopaminergic neurons pathway. To irradiate precisely, rats were set in the stereotactic frame with ear bars which was developed in this year. In 4 weeks after the irradiation, we performed methamphetamine induced rotation test and the autoradiography measurement on dopamine transporter using [ 11 C]PE2I to assess degeneration of dopaminergic neurons in caudate putamen (Cpu). As a result, ipsilateral rotation was observed and the distributions of dopamine transporter in the striatum decreased significantly. These results are similar to those of 6-OHDA lesioned rats, and indicate validity of this model. (author)

Animal model of rapid crystalloid infusion in rats

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Flavio Stillitano Orgaes

2013-04-01

Full Text Available PURPOSE: To describe an animal model of rapid intravenous infusion with different volumes of crystalloid and discuss the clinical findings. METHODS: Fifty six male Wistar rats were used, divided randomly in seven groups (n = 8. The rats of groups 1 to 6 received lactated Ringer´s solution intravenously, in the rate of 25 ml/min, with different volumes proportional to blood volume (BV. The rats of group 0 were submitted to the same procedure, but did not receive the fluid (control group. The data included respiratory rate, heart rate, saturation of peripheral oxygen (SpO2 in two times (before and after the infusion, and upshots (respiratory arrest and death. Dunnett´s test and ANOVA were used. RESULTS: The clinical signs significantly changed in the 2, 2.5 and 3 fold BV groups. The respiratory arrest was observed in the 1.5, 2, 2.5 and 3 fold BV groups, but death was present only in 2.5 and 3 fold BV groups. CONCLUSIONS: The infusion of crystalloid in the same volume of blood volume did not cause significant variation in respiratory and heart rate, saturation of peripheral oxygen and did not induce respiratory arrest. The infusion of a volume of 3 fold blood volume was lethal to all animals.

A New Experimental Polytrauma Model in Rats: Molecular Characterization of the Early Inflammatory Response

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Sebastian Weckbach

2012-01-01

Full Text Available Background. The molecular mechanisms of the immune response after polytrauma are highly complex and far from fully understood. In this paper, we characterize a new standardized polytrauma model in rats based on the early molecular inflammatory and apoptotic response. Methods. Male Wistar rats (250 g, 6–10/group were anesthetized and exposed to chest trauma (ChT, closed head injury (CHI, or Tib/Fib fracture including a soft tissue trauma (Fx + STT or to the following combination of injuries: (1 ChT; (2 ChT + Fx + STT; (3 ChT + CHI; (4 CHI; (5 polytrauma (PT = ChT + CHI + Fx + STT. Sham-operated rats served as negative controls. The inflammatory response was quantified at 2 hours and 4 hours after trauma by analysis of “key” inflammatory mediators, including selected cytokines and complement components, in serum and bronchoalveolar (BAL fluid samples. Results. Polytraumatized (PT rats showed a significant systemic and intrapulmonary release of cytokines, chemokines, and complement anaphylatoxins, compared to rats with isolated injuries or selected combinations of injuries. Conclusion. This new rat model appears to closely mimic the early immunological response of polytrauma observed in humans and may provide a valid basis for evaluation of the complex pathophysiology and future therapeutic immune modulatory approaches in experimental polytrauma.

A New Experimental Polytrauma Model in Rats: Molecular Characterization of the Early Inflammatory Response

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Weckbach, Sebastian; Perl, Mario; Heiland, Tim; Braumüller, Sonja; Stahel, Philip F.; Flierl, Michael A.; Ignatius, Anita; Gebhard, Florian; Huber-Lang, Markus

2012-01-01

Background. The molecular mechanisms of the immune response after polytrauma are highly complex and far from fully understood. In this paper, we characterize a new standardized polytrauma model in rats based on the early molecular inflammatory and apoptotic response. Methods. Male Wistar rats (250 g, 6–10/group) were anesthetized and exposed to chest trauma (ChT), closed head injury (CHI), or Tib/Fib fracture including a soft tissue trauma (Fx + STT) or to the following combination of injuries: (1) ChT; (2) ChT + Fx + STT; (3) ChT + CHI; (4) CHI; (5) polytrauma (PT = ChT + CHI + Fx + STT). Sham-operated rats served as negative controls. The inflammatory response was quantified at 2 hours and 4 hours after trauma by analysis of “key” inflammatory mediators, including selected cytokines and complement components, in serum and bronchoalveolar (BAL) fluid samples. Results. Polytraumatized (PT) rats showed a significant systemic and intrapulmonary release of cytokines, chemokines, and complement anaphylatoxins, compared to rats with isolated injuries or selected combinations of injuries. Conclusion. This new rat model appears to closely mimic the early immunological response of polytrauma observed in humans and may provide a valid basis for evaluation of the complex pathophysiology and future therapeutic immune modulatory approaches in experimental polytrauma. PMID:22481866

Independent mediation of unconditioned motor behavior by striatal D1 and D2 receptors in rats depleted of dopamine as neonates.

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Bruno, J P; Byrnes, E M; Johnson, B J

1995-11-01

The effects of systemic administration of DA receptor antagonists suggest that unconditioned motor behavior in rats depleted of DA as neonates continues to be dependent upon dopaminergic transmission, yet the specific contribution of D1 and D2 receptors to these behaviors has been altered. The purpose of the present study was to determine whether these depletion-induced receptor changes are occurring at the level of striatal DA terminals and their targets. The ability of bilateral intrastriatal injections (0.5 microliter) of DA receptor antagonists to induce motoric deficits was determined in adult rats treated with vehicle or 6-OHDA (100 micrograms, intraventricular) on postnatal day 3. Administration of the D1-like antagonist SCH 23390 (0.5-2.0 micrograms) or the D2-like antagonist clebopride (1.0-4.0 micrograms) induced dose-dependent akinesia, catalepsy, and somatosensory neglect in vehicle-treated controls. In contrast, neither antagonist produced deficits in rats depleted of forebrain DA as neonates. However, combined administration of SCH 23390 + clebopride induced similar akinesia, catalepsy, and somatosensory neglect in both controls and DA depleted animals. Animals depleted of DA were more sensitive than controls to the low doses of this combined D1 + D2 antagonism. These results demonstrate that activation of striatal DA receptors remains necessary for unconditioned motor behavior in rats depleted of DA as neonates. However, the specific contributions of D1- and D2-like receptors to these behaviors differ between intact animals and those depleted of DA as neonates. The ability of endogenous DA acting at either D1 or D2 receptors to support spontaneous motor behavior in rats depleted of DA as neonates may contribute to their relative sparing from parkinsonian deficits.

The rat as a model for orthodontic tooth movement--a critical review and a proposed solution

NARCIS (Netherlands)

Ren, Yijin; Maltha, Jaap C; Kuijpers-Jagtman, Anne Marie

2004-01-01

The aims of this study were to perform a systematic review of the use of rats as a model for experimental tooth movement, to give a critical evaluation of the use of elastics as a force delivery system, and to describe a newly designed well-defined model for tooth movement in rats. The literature

Recipient bone marrow-derived stromal cells prolong graft survival in a rat hind limb allotransplantation model.

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Ikeguchi, Ryosuke; Kakinoki, Ryosuke; Ohta, Souichi; Oda, Hiroki; Yurie, Hirofumi; Kaizawa, Yukitoshi; Mitsui, Hiroto; Aoyama, Tomoki; Toguchida, Junya; Matsuda, Shuichi

2017-09-01

Recent studies have indicated that bone marrow-derived stromal cells (BMSCs) have immunomodulatory properties that suppress the T cell responses that cause graft rejection. The purpose of this study is to evaluate the effect of recipient BMSCs intravenous infusion for immunomodulation in a rat vascularized composite allotransplantation model. A total of nine Wistar (WIS) rats and thirty Lewis (LEW) rats were used. BMSCs were harvested from three LEW rats. Twenty-four LEW rats were used as recipients and divided randomly into four groups: BMSC group, FK group, UT group, and Iso group. In the BMSC group, orthotopic rat hind limb transplantation was performed between WIS donor and LEW recipient rats. Recipient rats were injected intravenously with 2 × 10 6 recipient BMSCs on day 6, and with 0.2 mg/kg/day tacrolimus administered over 7 days (n = 6). In the FK group, recipient rats were treated with tacrolimus alone (n = 6). Rats in the UT group received no immunosuppressive treatment (n = 6). In the Iso group, transplantation was performed from three LEW donor rats to six LEW recipient rats without any immunosuppressive treatment (n = 6). Graft survival was assessed by daily inspection and histology. The immunological reactions of recipients were also evaluated. The graft survival of recipient rats in the BMSC group (24.5 days) was significantly prolonged in comparison with that of the FK group (18 days) (P Recipient rats in the BMSC group had significantly reduced serum IFN-γ cytokine levels (1.571 ± 0.779 pg/ml) in comparison with that of the FK group (7.059 ± 1.522 pg/ml) (P = .001). In in vitro study, BMSCs induce T cell hyporesponsiveness in a mixed lymphocyte reaction. BMSCs induce T cell hyporesponsiveness and prolong graft survival in the rat vascularized composite allotransplantation model. BMSCs exhibit immunomodulatory properties against acute rejection that can be realized without the need for significant recipient

Abnormal air righting behaviour in the spontaneously hypertensive rat model of ADHD

OpenAIRE

Dommett, Eleanor J; Rostron, Claire L

2011-01-01

The spontaneously hypertensive rat (SHR) is the most commonly used model of attention-deficit hyperactivity disorder (ADHD), displaying the main symptoms of the disorder which are responsive to psychostimulant treatments. Research to date has focused on behavioural tests investigating functioning of the striatum or prefrontal cortex in these rats. However, there is now evidence that the superior colliculus, a structure associated with head and eye movements, may also be dysfunctional in ADHD....

Effect of Qingnao tablet on blood viscosity of rat model of blood stasis induced by epinephrine

Science.gov (United States)

Xie, Guoqi; Hao, Shaojun; Ma, Zhenzhen; Liu, Xiaobin; Li, Jun; Li, Wenjun; Zhang, Zhengchen

2018-04-01

To establish a rat model of blood stasis with adrenaline (Adr) subcutaneous injection and ice bath stimulation. The effects of different doses on the blood viscosity of blood stasis model rats were observed. The rats were randomly divided into 6 groups: blank control group (no model), model group, positive control group, high, middle and low dose group. The whole blood viscosity and plasma viscosity were detected by blood viscosity instrument. Compared with the blank group, model group, high shear, low shear whole blood viscosity and plasma viscosity were significantly increased, TT PT significantly shortened, APTT was significantly prolonged, FIB increased significantly, indicating that the model was successful. Compared with the model group, can significantly reduce the Naoluotong group (cut, low cut). Qingnaopian high dose group (low cut), middle dose group (cut, low shear blood viscosity) (Pgroup, high dose group (Pgroup (Pblood rheology of blood stasis mice abnormal index, decrease the blood viscosity, blood stasis has certain hemostatic effect.

The rat as animal model in breast cancer research: a histopathological study of radiation- and hormone-induced rat mammary tumors

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Zwieten, M.J. van.

1984-01-01

One of the goals of this monograph is to present data on the frequency of mammary neoplasms following irradiation and/or hormone administration in intact and castrated female rats of three strains allowed to live their natural life spans. These data are intended to give an overview of the effects of radiation and hormonal manipulation on the mammary gland based on histological examination of necropsied rats and using standard morphological criteria for mammary tumors. The second goal of this monograph is to provide detailed histological descriptions of the mammary tumors found in the various experimental groups as well as in several groups of untreated control rats. The aims are to examine whether possible strain-related and treatment-related differences in morphology or growth patterns exist, as well as to define the pathogensis of radiation-induced rat mammary tumors through the study of early lesions. An attempt will be made to describe tumor characteristics which may be of comparative value in identifying tumor types (and their induction methods) useful as models for specific human breast neoplasms. A rat mammary tumor classification system reflecting the morphological features useful for comparative purposes is also presented. (Auth.)

Porphyromonas gingivalis and Treponema denticola Mixed Microbial Infection in a Rat Model of Periodontal Disease

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Raj K. Verma

2010-01-01

Full Text Available Porphyromonas gingivalis and Treponema denticola are periodontal pathogens that express virulence factors associated with the pathogenesis of periodontitis. In this paper we tested the hypothesis that P. gingivalis and T. denticola are synergistic in terms of virulence; using a model of mixed microbial infection in rats. Groups of rats were orally infected with either P. gingivalis or T. denticola or mixed microbial infections for 7 and 12 weeks. P. gingivalis genomic DNA was detected more frequently by PCR than T. denticola. Both bacteria induced significantly high IgG, IgG2b, IgG1, IgG2a antibody levels indicating a stimulation of Th1 and Th2 immune response. Radiographic and morphometric measurements demonstrated that rats infected with the mixed infection exhibited significantly more alveolar bone loss than shaminfected control rats. Histology revealed apical migration of junctional epithelium, rete ridge elongation, and crestal alveolar bone resorption; resembling periodontal disease lesion. These results showed that P. gingivalis and T. denticola exhibit no synergistic virulence in a rat model of periodontal disease.

A Rat Model for Muscle Regeneration in the Soft Palate

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Carvajal Monroy, Paola L.; Grefte, Sander; Kuijpers-Jagtman, Anne M.; Helmich, Maria P. A. C.; Ulrich, Dietmar J. O.; Von den Hoff, Johannes W.; Wagener, Frank A. D. T. G.

2013-01-01

Background Children with a cleft in the soft palate have difficulties with speech, swallowing, and sucking. Despite successful surgical repositioning of the muscles, optimal function is often not achieved. Scar formation and defective regeneration may hamper the functional recovery of the muscles after cleft palate repair. Therefore, the aim of this study is to investigate the anatomy and histology of the soft palate in rats, and to establish an in vivo model for muscle regeneration after surgical injury. Methods Fourteen adult male Sprague Dawley rats were divided into four groups. Groups 1 (n = 4) and 2 (n = 2) were used to investigate the anatomy and histology of the soft palate, respectively. Group 3 (n = 6) was used for surgical wounding of the soft palate, and group 4 (n = 2) was used as unwounded control group. The wounds (1 mm) were evaluated by (immuno)histochemistry (AZAN staining, Pax7, MyoD, MyoG, MyHC, and ASMA) after 7 days. Results The present study shows that the anatomy and histology of the soft palate muscles of the rat is largely comparable with that in humans. All wounds showed clinical evidence of healing after 7 days. AZAN staining demonstrated extensive collagen deposition in the wound area, and initial regeneration of muscle fibers and salivary glands. Proliferating and differentiating satellite cells were identified in the wound area by antibody staining. Conclusions This model is the first, suitable for studying muscle regeneration in the rat soft palate, and allows the development of novel adjuvant strategies to promote muscle regeneration after cleft palate surgery. PMID:23554995

Neuroprotective Effects of Herbal Extract (Rosa canina, Tanacetum vulgare and Urtica dioica) on Rat Model of Sporadic Alzheimer's Disease.

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Daneshmand, Parvaneh; Saliminejad, Kioomars; Dehghan Shasaltaneh, Marzieh; Kamali, Koorosh; Riazi, Gholam Hossein; Nazari, Reza; Azimzadeh, Pedram; Khorram Khorshid, Hamid Reza

2016-01-01

Sporadic Alzheimer's Disease (SAD) is caused by genetic risk factors, aging and oxidative stresses. The herbal extract of Rosa canina (R. canina), Tanacetum vulgare (T. vulgare) and Urtica dioica (U. dioica) has a beneficial role in aging, as an anti-inflammatory and anti-oxidative agent. In this study, the neuroprotective effects of this herbal extract in the rat model of SAD was investigated. The rats were divided into control, sham, model, herbal extract -treated and ethanol-treated groups. Drug interventions were started on the 21(st) day after modeling and each treatment group was given the drugs by intraperitoneal (I.P.) route for 21 days. The expression levels of the five important genes for pathogenesis of SAD including Syp, Psen1, Mapk3, Map2 and Tnf-α were measured by qPCR between the hippocampi of SAD model which were treated by this herbal extract and control groups. The Morris Water Maze was adapted to test spatial learning and memory ability of the rats. Treatment of the rat model of SAD with herbal extract induced a significant change in expression of Syp (p=0.001) and Psen1 (p=0.029). In Morris Water Maze, significant changes in spatial learning seen in the rat model group were improved in herbal-treated group. This herbal extract could have anti-dementia properties and improve spatial learning and memory in SAD rat model.

Transplantation of ES cells to Parkinson model rat irradiated with carbon ion beam

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Inaji, Motoki; Okauchi, Takashi; Nagai, Yuji; Nojima, Kumie

2003-01-01

The present study was designed to make better Parkinson model animal and evaluate the transplantation treatment with ES cell. In the first year, we irradiated left striatum of adult rats with charged carbon particles (290 MeV/nucleon, 5 mm spread-out Bragg peak, 100 Gy) for purpose of making Parkinson model rats. At 4, 8, 12 weeks after the irradiation, we performed the rotation test to methamphetamine and the autoradiography on dopamine D2 receptor and transporter using 11 C-raclopride and 11 C-PE2I to measure the effects of the irradiation. As a result, the number of rotation increased and the distributions of dopamine D2 receptor and transporter in the striatum decreased during the time after the irradiation. These results suggested that the secondary neural damage due to the vascular degeneration caused the progressive destruction of dopamine system. To make more stable Parkinson model rats, we need to use smaller collimator and develop the accurate stereotactic irradiation system in the further research. (author)

The effect of intrathecal delivery of bone marrow stromal cells on hippocampal neurons in rat model of Alzheimer’s disease

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Mina Eftekharzadeh

2015-05-01

Full Text Available Objective(s: Intracerebral injection of bone marrow stromal cells (BMSCs is being investigated as a therapeutic tool to prevent Alzheimer's disease (AD. Our aim was to investigate the effects of BMSCs by intrathecal injection in AD rat model. Materials and Methods: BMSCs were obtained from the bone marrow of Wistar rat and transplanted into AD rat model via intrathecal injection. The rat model had received an injection of β amyloid into the hippocampus for histological and immunohistochemical studies. Results: Histological examination of the brains in transplanted rats compared to controls demonstrated the migration of BrdU-labeled BMSCs from the site of delivery, confirmed the differentiation of BMSCs transplanted cells into the cholinergic neurons, and increased number of healthy and decreased number of dark neurons. Conclusion: Our results showed that BMSCs intratechal administration could be a promising method for treatment ofAlzheimer’s disease in rat model.

Toxicity of taurolithocholate as a model for cholestasis in the rat liver

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Spitzer, V.M.; Loo, C.Y.

1985-01-01

A model was investigated to facilitate the detection of mild diffuse liver disease. The introduction of sodium taurolithocholate(TLC) into the bloodstream of rats has been shown to produce cholestasis. This study was undertaken to assess the available control over the cholestatic effect with regulated TLC. The rat model then utilized to evaluate the ability of Tc-99m Hepatolite (IDA) to predict the extent of cholestasis in mildly diseased liver. 27 Charles River rats (300-350 grams) were studied. Pentabarbital was used for anesthesia and body temperature was maintained between 37.5 and 38.5 0 C. A standard tracheostomy and jugular vein and carotid artery cannulation was performed for the administration of the TLC and IDA and for blood sampling. The common bile duct was cannulated for bile collection. Bile was collected for 10 minutes post surgery and then the TLC, or just vehicle for controls, was administered. 5 minute bile collections continued for 60 minutes and blood samples were collected 9 times during the same hour period. The cumulative percent dose of IDA in the bile was found to be controllable while the blood clearance was not appreciably different for the doses investigated. Doses of 5.0, 3.75, 2.75 and 0 micromoles of TLC per 100 grams of rat weight were found to yield a 85%, 68% 45% and 15% cholestatic effect. The 45% cholestasis is reproducible and most clinically interesting the authors' studies. The 15% cholestasis for the control rats demonstrates a baseline cholestasis from the surgical intervention

Beneficial effect of daidzin in dry eye rat model through the suppression of inflammation and oxidative stress in the cornea.

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Xiao, Fan; Cui, Hua; Zhong, Xiao

2018-05-01

Present investigation evaluates the effect of daidzin in dry eye rat model through the suppression of inflammation and oxidative stress in the cornea. Briefly, electron spine resonance was used for the estimation of radical scavenging activity of daidzin and COX Fluorescent Activity Assay Kit was used for the estimation of PGS activity. Dry eye rat model was developed by removing the lacrimal gland and effect of daidzin was evaluated in dry eye rat model by estimating the fluorescein score, tear volume and expressions of heme oxigenase (HO-1), TNF α, Interlukin 6 (IL-6), matrix metallopeptidase 9 (MMP-9) and PGS-2. Result of the present study suggested that daidzin possess tyrosyl radical scavenging activity and thereby decreases the oxidative stress. Activity of PGS significantly increases in dry eye which was inhibited by daidzin treatment due to competitive inhibition of PGS. It also recovers the tear volume in dry eye rat model in which lacrimal gland was removed. Thus corneal erosion was improved by daidzin in dry eye rat model. Thus present study concludes that treatment with daidzin protects the cornea in dry eye rat model by suppression inflammation and oxidative stress.

Angelica Sinensis attenuates inflammatory reaction in experimental rat models having spinal cord injury.

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Xu, Jun; E, Xiao-Qiang; Liu, Hui-Yong; Tian, Jun; Yan, Jing-Long

2015-01-01

This study was aimed to evaluate the effect of Angelica Sinensis on experimental rat models in which spinal cord injury was induced by studying different factors. Different factors causing inflammation play a key role in pathophysiology of SCI. Here three groups of rats (n=15, each was used). These included a sham control group where only laminectomy was performed, SCI group where SCI was induced and AS/SCI group where although SCI was induced but Angelica Sinensis was also administered to study its effect and draw a comparison with control. The expression of I-kBα and NF-kB p65 was also studied using western blotting and after recording optical density (OD) values of western blots. MPO activity was used to measure the effect of 20 mg/kg Angelica Sinensis. The levels of proinflammatory cytokines TNF-α, IL-1β and IL-6 were also studied. As compared with SCI group and sham control it was observed that Angelica Sinensis significantly reduced the expression of I-kBα and NF-kB p65, (PSinensis in rat models can attenuate the secondary damage caused by SCI and thus help in controlling the pathology of SCI in rats.

Human activated protein C variants in a rat model of arterial thrombosis

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Dahlbäck Björn

2008-10-01

Full Text Available Abstract Background Activated protein C (APC inhibits coagulation by degrading activated factor V (FVa and factor VIII (FVIIIa, protein S (PS functioning as a cofactor to APC. Methods By mutagenesis of the vitamin K-dependent Gla domain of APC, we have recently created an APC variant having enhanced anticoagulant activity due to increased affinity for negatively charged phospholipid membranes. In the present study, the potential antithrombotic effects of this APC variant, and of a variant APC that is additionally mutated in the serine protease domain, have been evaluated in a blind randomized study in a rat model of arterial thrombosis. In this model, we have previously found the combination of bovine APC and PS to be highly antithrombotic. Four treatment groups each containing 10 rats were, in a blind random fashion, given intravenous bolus injections of wild-type or mutant variants of APC (0.8 mg/kg together with human PS (0.6 mg/kg or human PS (0.6 mg/kg alone. A control group with 20 animals where given vehicle only. Results A trend to increased patency rates was noted in a group receiving one of the APC variants, but it did not reach statistical significance. Conclusion In conclusion, administration of human APC variants having enhanced anticoagulant efficacy together with human PS in a rat model of arterial thrombosis did not give an efficient antithrombotic effect. The lack of effect may be due to species-specific differences between the human protein C system and the rat hemostatic system.

Low-level laser treatment accelerated hair regrowth in a rat model of chemotherapy-induced alopecia (CIA).

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Wikramanayake, Tongyu Cao; Villasante, Alexandra C; Mauro, Lucia M; Nouri, Keyvan; Schachner, Lawrence A; Perez, Carmen I; Jimenez, Joaquin J

2013-05-01

Chemotherapy-induced alopecia (CIA) is one of the most distressing side effects of antineoplastic chemotherapy for which there is no effective interventional approach. A low-level laser (LLL) device, the HairMax LaserComb®, has been cleared by the FDA to treat androgenetic alopecia. Its effects may be extended to other settings; we have demonstrated that LaserComb treatment induced hair regrowth in a mouse model for alopecia areata. In the current study, we tested whether LLL treatment could promote hair regrowth in a rat model for CIA. Chemotherapy agents cyclophosphamide, etoposide, or a combination of cyclophosphamide and doxorubicin were administered in young rats to induce alopecia, with or without LLL treatment. As expected, 7-10 days later, all the rats developed full body alopecia. However, rats receiving laser treatment regrew hair 5 days earlier than rats receiving chemotherapy alone or sham laser treatment (with the laser turned off). The accelerated hair regrowth in laser-treated rats was confirmed by histology. In addition, LLL treatment did not provide local protection to subcutaneously injected Shay chloroleukemic cells. Taken together, our results demonstrated that LLL treatment significantly accelerated hair regrowth after CIA without compromising the efficacy of chemotherapy in our rat model. Our results suggest that LLL should be explored for the treatment of CIA in clinical trials because LLL devices for home use (such as the HairMax LaserComb®) provide a user-friendly and noninvasive approach that could be translated to increased patient compliance and improved efficacy.

Effect of Qiangji Jianli Yin on sex hormones in male rat models of splenoasthenic syndrome

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Chen Zhixi; Xu Zhiwei; Liu Xiaobin; Zhao Hui; Chen Jinyan; Li Zhiqiang; He Zanhou

2008-01-01

Objective: To investigate the therapeutic efficacy of Qiangji Jianli Yin on male rat models of splenoasthenic syndrome through changes of serum sex hormones (T, E 2 ), amylase and histologic changes of spleen, thymus, adrenals as well as to study the material foundation of spleno-renal mutual correlationship in traditional Chinese medicine. Methods: Rat models male of splenoasthenic syndrome were established with daily gavage of rhubarb decoction (2ml 2 and amylase levels were determined with RIA on d10 and d20 and the animals were sacrificed on d20 to procure spleen, thymus and adrenals for histologic study. Control rats (n=10) were given daily gavage of distilled water only. Results: Serum E 2 and T levels in the splenoasthenic syndrome models without treatment were significantly higher than those in controls rats on dl0 (P 2 levels increased further but T levels dropped markedly and were significantly lower than those in untreated group (P 2 , T on d10 were much less in the models treated with Qiangji Jianli Yin with maintenance of E 2 /T ratio. On d20 the serum E 2 levels, though increased, were much lower than those in untreated group, hence the E 2 /T ratio was also much lower than that in untreated group and differed less from that in controls. Serum amylase levels on d10 and d20 in the splenoastheic models without treatment were significantly lower than those in controls rats (P 2 might be the material foundation responsible for the spleno-renal interrelationship. Histologic changes of spleen, thymus and adrenals might be the evidence of the traditional Chinese medicine theory of 'splenoasthenic would induce renal deficiency'. (authors)

Hsp70 Expression Profile in Preeclampsia Model of Pregnant Rat (Rattus norvegicus) after Giving the EVOO

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Irianti, E.; ilyas, S.; Rosidah; Hutahaean, S.

2017-03-01

Heat shock protein (Hsp) has long been known to protect cells from oxidative stress. In this case an increased expression is found on several cases of preeclampsia. One of the efforts to prevent preeclampsia is by giving antioxidants such as Extra Virgin Olive Oil (EVOO) or it’s better known as olive oil (Oleoa europaea), in the form of extra virgin known for its rich antioxidant content of tocopherols (vitamin E). The purpose of this study is to determine the expression levels of Hsp70 serum on pregnant white rat model of preeclampsia after being given EVOO. This type of research is true experiment; the subjects were female white rats and male virgin with Sprague Dawley, ± 8-11 weeks old, 180g BB s / d 200g, healthy and didn’t show any physical defects. Samples were 25 animals, divided into 5 groups, which consisted of different control and treatment given to T2 (rat model of preeclampsia), T3 (rat model of preeclampsia + EVOO 0.45g/bw/day), T4 (rat model of preeclampsia + EVOO 0.9g/bw/day) and T5 (rat model of preeclampsia + EVOO 1.8g/bw/day). The determination of each group was done by simple random sampling. Result on serum levels of Hsp70 that were tested by Elisa test in rats showed the average control was 14.64 mg / ml, group T2: 22:51 mg/ml, T3: 13.62 mg/ml, T4: 15.92 mg/ml, T5: 16:09 mg/ml. ANOVA test showed the P value was 0.001 <0.005, which meant there were significant differences on serum Hsp70 levels in the control and treatment pregnant rats group. It was known that there was a significant difference level of Hsp70 serum in group of control rats with T2 (P value <0.001) after LSD test was conducted, but not so with the group T3, T4, and T5, where the difference was not significant. There was a significant difference in the levels of Hsp70 serum on group T2 and T3 (P value 0.000), T4 (0004), T5 (0000). The gift of EVOO in the treatment group which was given EVOO with even low doses was able to control the induction of Hsp70 serum levels, which

Xenograft transplantation of human malignant astrocytoma cells into immunodeficient rats: an experimental model of glioblastoma.

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Miura, Flávio Key; Alves, Maria Jose Ferreira; Rocha, Mussya Cisotto; da Silva, Roseli; Oba-Shinjo, Sueli Mieko; Marie, Suely Kazue Nagahashi

2010-03-01

Astrocytic gliomas are the most common intracranial central nervous system neoplasias, accounting for about 60% of all primary central nervous system tumors. Despite advances in the treatment of gliomas, no effective therapeutic approach is yet available; hence, the search for a more realistic model to generate more effective therapies is essential. To develop an experimental malignant astrocytoma model with the characteristics of the human tumor. Primary cells from subcutaneous xenograft tumors produced with malignant astrocytoma U87MG cells were inoculated intracerebrally by stereotaxis into immunosuppressed (athymic) Rowett rats. All four injected animals developed non-infiltrative tumors, although other glioblastoma characteristics, such as necrosis, pseudopalisading cells and intense mitotic activity, were observed. A malignant astrocytoma intracerebral xenograft model with poorly invasive behavior was achieved in athymic Rowett rats. Tumor invasiveness in an experimental animal model may depend on a combination of several factors, including the cell line used to induce tumor formation, the rat strains and the status of the animal's immune system.

Plasma hormones facilitated the hypermotility of the colon in a chronic stress rat model.

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Chengbai Liang

Full Text Available OBJECTIVE: To study the relationship between brain-gut peptides, gastrointestinal hormones and altered motility in a rat model of repetitive water avoidance stress (WAS, which mimics the irritable bowel syndrome (IBS. METHODS: Male Wistar rats were submitted daily to 1-h of water avoidance stress (WAS or sham WAS (SWAS for 10 consecutive days. Plasma hormones were determined using Enzyme Immunoassay Kits. Proximal colonic smooth muscle (PCSM contractions were studied in an organ bath system. PCSM cells were isolated by enzymatic digestion and IKv and IBKca were recorded by the patch-clamp technique. RESULTS: The number of fecal pellets during 1 h of acute restraint stress and the plasma hormones levels of substance P (SP, thyrotropin-releasing hormone (TRH, motilin (MTL, and cholecystokinin (CCK in WAS rats were significantly increased compared with SWAS rats, whereas vasoactive intestinal peptide (VIP, calcitonin gene-related peptide (CGRP and corticotropin releasing hormone (CRH in WAS rats were not significantly changed and peptide YY (PYY in WAS rats was significantly decreased. Likewise, the amplitudes of spontaneous contractions of PCSM in WAS rats were significantly increased comparing with SWAS rats. The plasma of WAS rats (100 µl decreased the amplitude of spontaneous contractions of controls. The IKv and IBKCa of PCSMs were significantly decreased in WAS rats compared with SWAS rats and the plasma of WAS rats (100 µl increased the amplitude of IKv and IBKCa in normal rats. CONCLUSION: These results suggest that WAS leads to changes of plasma hormones levels and to disordered myogenic colonic motility in the short term, but that the colon rapidly establishes a new equilibrium to maintain the normal baseline functioning.

Righting elicited by novel or familiar auditory or vestibular stimulation in the haloperidol-treated rat: rat posturography as a model to study anticipatory motor control.

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Clark, Callie A M; Sacrey, Lori-Ann R; Whishaw, Ian Q

2009-09-15

External cues, including familiar music, can release Parkinson's disease patients from catalepsy but the neural basis of the effect is not well understood. In the present study, posturography, the study of posture and its allied reflexes, was used to develop an animal model that could be used to investigate the underlying neural mechanisms of this sound-induced behavioral activation. In the rat, akinetic catalepsy induced by a dopamine D2 receptor antagonist (haloperidol 5mg/kg) can model human catalepsy. Using this model, two experiments examined whether novel versus familiar sound stimuli could interrupt haloperidol-induced catalepsy in the rat. Rats were placed on a variably inclined grid and novel or familiar auditory cues (single key jingle or multiple key jingles) were presented. The dependent variable was movement by the rats to regain equilibrium as assessed with a movement notation score. The sound cues enhanced movements used to regain postural stability and familiar sound stimuli were more effective than unfamiliar sound stimuli. The results are discussed in relation to the idea that nonlemniscal and lemniscal auditory pathways differentially contribute to behavioral activation versus tonotopic processing of sound.

Improvement of Radiation-Mediated Immunosuppression of Human NSCLC Tumour Xenografts in a Nude Rat Model

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Sergey V. Tokalov

2010-01-01

Full Text Available Human tumour xenografts in a nude rat model have consistently been used as an essential part of preclinical studies for anticancer drugs activity in human. Commonly, these animals receive whole body irradiation to assure immunosuppression. But whole body dose delivery might be inhomogeneous and the resulting incomplete bone marrow depletion may modify tumour behaviour. To improve irradiation-mediated immunosuppression of human non-small cell lung cancer (NSCLC xenografts in a nude rat model irradiation (2 + 2 Gy from opposite sides of animals has been performed using a conventional X-ray tube. The described modification of whole body irradiation improves growth properties of human NSCLC xenografts in a nude rat model. The design of the whole body irradiation mediated immunosuppression described here for NSCLC xenografts may be useful for research applications involving other types of human tumours.

Characterization of Diabetic Neuropathy in the Zucker Diabetic Sprague-Dawley Rat: A New Animal Model for Type 2 Diabetes

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Eric P. Davidson

2014-01-01

Full Text Available Recently a new rat model for type 2 diabetes the Zucker diabetic Sprague-Dawley (ZDSD/Pco was created. In this study we sought to characterize the development of diabetic neuropathy in ZDSD rats using age-matched Sprague-Dawley rats as a control. Rats were examined at 34 weeks of age 12 weeks after the onset of hyperglycemia in ZDSD rats. At this time ZDSD rats were severely insulin resistant with slowing of both motor and sensory nerve conduction velocities. ZDSD rats also had fatty livers, elevated serum free fatty acids, triglycerides, and cholesterol, and elevated sciatic nerve nitrotyrosine levels. The corneas of ZDSD rats exhibited a decrease in subbasal epithelial corneal nerves and sensitivity. ZDSD rats were hypoalgesic but intraepidermal nerve fibers in the skin of the hindpaw were normal compared to Sprague-Dawley rats. However, the number of Langerhans cells was decreased. Vascular reactivity of epineurial arterioles, blood vessels that provide circulation to the sciatic nerve, to acetylcholine and calcitonin gene-related peptide was impaired in ZDSD rats. These data indicate that ZDSD rats develop many of the neural complications associated with type 2 diabetes and are a good animal model for preclinical investigations of drug development for diabetic neuropathy.

Establishment of animal model of dual liver transplantation in rat.

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Ying Zhang

Full Text Available The animal model of the whole-size and reduced-size liver transplantation in both rat and mouse has been successfully established. Because of the difficulties and complexities in microsurgical technology, the animal model of dual liver transplantation was still not established for twelve years since the first human dual liver transplantation has been made a success. There is an essential need to establish this animal model to lay a basic foundation for clinical practice. To study the physiological and histopathological changes of dual liver transplantation, "Y" type vein from the cross part between vena cava and two iliac of donor and "Y' type prosthesis were employed to recanalize portal vein and the bile duct between dual liver grafts and recipient. The dual right upper lobes about 45-50% of the recipient liver volume were taken as donor, one was orthotopically implanted at its original position, the other was rotated 180° sagitally and heterotopically positioned in the left upper quadrant. Microcirculation parameters, liver function, immunohistochemistry and survival were analyzed to evaluate the function of dual liver grafts. No significant difference in the hepatic microcirculatory flow was found between two grafts in the first 90 minutes after reperfusion. Light and electronic microscope showed the liver architecture was maintained without obvious features of cellular destruction and the continuity of the endothelium was preserved. Only 3 heterotopically positioned graft appeared patchy desquamation of endothelial cell, mitochondrial swelling and hepatocytes cytoplasmic vacuolization. Immunohistochemistry revealed there is no difference in hepatocyte activity and the ability of endothelia to contract and relax after reperfusion between dual grafts. Dual grafts made a rapid amelioration of liver function after reperfusion. 7 rats survived more than 7 days with survival rate of 58.3.%. Using "Y" type vein and bile duct prosthesis, we

Evaluation of the Zucker diabetic fatty (ZDF rat as a model for human disease based on urinary peptidomic profiles.

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Justyna Siwy

Full Text Available Representative animal models for diabetes-associated vascular complications are extremely relevant in assessing potential therapeutic drugs. While several rodent models for type 2 diabetes (T2D are available, their relevance in recapitulating renal and cardiovascular features of diabetes in man is not entirely clear. Here we evaluate at the molecular level the similarity between Zucker diabetic fatty (ZDF rats, as a model of T2D-associated vascular complications, and human disease by urinary proteome analysis. Urine analysis of ZDF rats at early and late stages of disease compared to age- matched LEAN rats identified 180 peptides as potentially associated with diabetes complications. Overlaps with human chronic kidney disease (CKD and cardiovascular disease (CVD biomarkers were observed, corresponding to proteins marking kidney damage (eg albumin, alpha-1 antitrypsin or related to disease development (collagen. Concordance in regulation of these peptides in rats versus humans was more pronounced in the CVD compared to the CKD panels. In addition, disease-associated predicted protease activities in ZDF rats showed higher similarities to the predicted activities in human CVD. Based on urinary peptidomic analysis, the ZDF rat model displays similarity to human CVD but might not be the most appropriate model to display human CKD on a molecular level.

Ranitidine reduced levodopa-induced dyskinesia in a rat model of Parkinson’s disease

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Cui G

2013-12-01

Full Text Available Guiyun Cui,1,* Xinxin Yang,1,* Xiaoying Wang,2,* Zunsheng Zhang,1 Xuanye Yue,1 Hongjuan Shi,1 Xia Shen11Department of Neurology, 2Department of Ultrasound, the Affiliated Hospital of Xuzhou Medical College, Jiangsu, People’s Republic of China *These authors contributed equally to this workBackground: Chronic administration of levodopa in Parkinson’s disease leads to debilitating involuntary movements, termed levodopa-induced dyskinesia (LID. The pathogenesis of LID is poorly understood. Previous research has shown that histamine H2 receptors are highly expressed in the input (striatum and output (globus pallidus, substantia nigra regions of the basal ganglia, particularly in the GABAergic striatopallidal and striatonigral pathways. Therefore, a histamine H2 receptor antagonist could be used to reduce LID. In the present work, we investigated whether ranitidine has the potential to diminish LID in rats with dyskinesia and explored the underlying mechanisms involved.Methods: A rat model of PD was induced by 6-hydroxydopamine. Valid PD rats were then treated with levodopa (25 mg/kg, intraperitoneally and benserazide (12.5 mg/kg, intraperitoneally for 21 days to induce a rat model of LID. The acute and chronic effects of administration of ranitidine at different doses (5 mg/kg, 10 mg/kg, and 20 mg/kg on abnormal involuntary movements, levodopa-induced rotations, and the forelimb adjusting steps test were investigated in LID rats. The chronic effect of ranitidine (10 mg/kg on the expression of Arc and proenkephalin was also evaluated.Results: Levodopa elicited increased dyskinesia in PD rats. Acute ranitidine treatment had no effect on LID, but chronic ranitidine administration (10 mg/kg, 20 mg/kg reduced LID in rats with dyskinesia. Importantly, levodopa-induced rotations were not affected by chronic treatment with ranitidine. In addition, chronic ranitidine (10 mg/kg, 20 mg/kg significantly improved stepping of the lesioned forepaw. Real

Effects of Paricalcitol and Aliskiren Combination Therapy on Experimental Diabetic Nephropathy Model in Rats

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Zehra Eren

2014-12-01

Full Text Available Background/Aims: The aim of the present study was to investigate the effect of combination of aliskiren with paricalcitol on experimental diabetic nephropathy (DN model in rats. Methods: Forty male Sprague Dawley rats were divided into 5 groups of 8 rats each, namely the control (Group C, diabetes (Group D, aliskiren (Group A, paricalcitol (Group P, and aliskiren plus paricalcitol (Group A+P groups. Aliskiren was given by oral-gavage at a dose of 50 mg/kg/day once daily for 12 weeks. Paricalcitol was given by intraperitoneally at a dose of 0,4 µg/kg/three day of week for 12 weeks. Renal function parameters, oxidative stress biomarkers, mRNA expression of renin-angiotensin system parameters and kidney histology were determined. Results: Group A+P had lower mean albümin-to-creatinine ratio (ACR (p=0.004 as well as higher creatinine clearance (CCr (pConclusion: Our data seem to suggest a potential role of aliskiren plus paricalcitol acting synergystically for reducing the progression of diabetic nephropathy in an experimental rat model.

A preclinical model for identifying rats at risk of alcohol use disorder

KAUST Repository

Jadhav, Kshitij S.; Magistretti, Pierre J.; Halfon, Olivier; Augsburger, Marc; Boutrel, Benjamin

2017-01-01

Alcohol use is one of the world's leading causes of death and disease, although only a small proportion of individuals develop persistent alcohol use disorder (AUD). The identification of vulnerable individuals prior to their chronic intoxication remains of highest importance. We propose here to adapt current methodologies for identifying rats at risk of losing control over alcohol intake by modeling diagnostic criteria for AUD: Inability to abstain during a signaled period of reward unavailability, increased motivation assessed in a progressive effortful task and persistent alcohol intake despite aversive foot shocks. Factor analysis showed that these three addiction criteria loaded on one underlying construct indicating that they represent a latent construct of addiction trait. Further, not only vulnerable rats displayed higher ethanol consumption, and higher preference for ethanol over sweetened solutions, but they also exhibited pre-existing higher anxiety as compared to resilient rats. In conclusion, the present preclinical model confirms that development of an addiction trait not only requires prolonged exposure to alcohol, but also depends on endophenotype like anxiety that predispose a minority of individuals to lose control over alcohol consumption.

A preclinical model for identifying rats at risk of alcohol use disorder

KAUST Repository

Jadhav, Kshitij S.

2017-08-21

Alcohol use is one of the world\\'s leading causes of death and disease, although only a small proportion of individuals develop persistent alcohol use disorder (AUD). The identification of vulnerable individuals prior to their chronic intoxication remains of highest importance. We propose here to adapt current methodologies for identifying rats at risk of losing control over alcohol intake by modeling diagnostic criteria for AUD: Inability to abstain during a signaled period of reward unavailability, increased motivation assessed in a progressive effortful task and persistent alcohol intake despite aversive foot shocks. Factor analysis showed that these three addiction criteria loaded on one underlying construct indicating that they represent a latent construct of addiction trait. Further, not only vulnerable rats displayed higher ethanol consumption, and higher preference for ethanol over sweetened solutions, but they also exhibited pre-existing higher anxiety as compared to resilient rats. In conclusion, the present preclinical model confirms that development of an addiction trait not only requires prolonged exposure to alcohol, but also depends on endophenotype like anxiety that predispose a minority of individuals to lose control over alcohol consumption.

External pallidal stimulation improves parkinsonian motor signs and modulates neuronal activity throughout the basal ganglia thalamic network.

Science.gov (United States)

Vitek, Jerrold L; Zhang, Jianyu; Hashimoto, Takao; Russo, Gary S; Baker, Kenneth B

2012-01-01

Deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) and the subthalamic nucleus (STN) are effective for the treatment of advanced Parkinson's disease (PD). We have shown previously that DBS of the external segment of the globus pallidus (GPe) is associated with improvements in parkinsonian motor signs; however, the mechanism of this effect is not known. In this study, we extend our findings on the effect of STN and GPi DBS on neuronal activity in the basal ganglia thalamic network to include GPe DBS using the 1-methyl-4-phenyl-1.2.3.6-tetrahydropyridine (MPTP) monkey model. Stimulation parameters that improved bradykinesia were associated with changes in the pattern and mean discharge rate of neuronal activity in the GPi, STN, and the pallidal [ventralis lateralis pars oralis (VLo) and ventralis anterior (VA)] and cerebellar [ventralis lateralis posterior pars oralis (VPLo)] receiving areas of the motor thalamus. Population post-stimulation time histograms revealed a complex pattern of stimulation-related inhibition and excitation for the GPi and VA/VLo, with a more consistent pattern of inhibition in STN and excitation in VPLo. Mean discharge rate was reduced in the GPi and STN and increased in the VPLo. Effective GPe DBS also reduced bursting in the STN and GPi. These data support the hypothesis that therapeutic DBS activates output from the stimulated structure and changes the temporal pattern of neuronal activity throughout the basal ganglia thalamic network and provide further support for GPe as a potential therapeutic target for DBS in the treatment of PD. Copyright © 2011 Elsevier Inc. All rights reserved.

Hepatocyte growth factor treatment ameliorates diarrhea and bowel inflammation in a rat model of inflammatory bowel disease.

Science.gov (United States)

Arthur, L Grier; Schwartz, Marshall Z; Kuenzler, Keith A; Birbe, Ruth

2004-02-01

Transfection of the HLA-B27 gene into normal Fischer rats induces phenotypic changes similar to inflammatory bowel disease (IBD). This study investigated the benefits of 2 doses of hepatocyte growth factor (HGF) on the manifestations of IBD in this rat model. Fischer rats and HLA-B27 rats were divided into 4 groups: Fischer rats treated with saline, HLA-B27 rats treated with saline, HGF at 150 microg/kg/d, and HGF at 300 microg/kg/d. HGF or saline was infused for 14 days via an osmotic pump attached to a catheter in the internal jugular vein. After treatment, rats were evaluated for diarrhea and reduction in gross and microscopic bowel inflammation. Statistics were determined using analysis of variance (ANOVA). A P value diarrhea by 40%, gross inflammation by 41%, and microscopic inflammation by 72% (P diarrhea by 46%, gross inflammation by 45%, and microscopic inflammation by 54% (P < or =.05). HGF administration reduces the clinical manifestations of IBD in this rat model. Similar effects were seen at both doses of HGF administration, implying that there is a plateau above which further increases in HGF levels provides no added benefit. HGF administration may be clinically useful in the management of IBD.

Intermittent Fasting Pretreatment Prevents Cognitive Impairment in a Rat Model of Chronic Cerebral Hypoperfusion.

Science.gov (United States)

Hu, Yuan; Yang, Ying; Zhang, Miao; Deng, Min; Zhang, Jun-Jian

2017-07-01

Background: Whether intermittent fasting (IF) pretreatment can prevent vascular cognitive dysfunction remains unknown to our knowledge. Objective: We investigated the effects and underlying mechanisms of IF pretreatment on cognitive dysfunction in a permanent 2-vessel occlusion (2VO) vascular dementia rat model. Methods: Male Wistar rats weighing 200 g were subjected to either IF or ad libitum feeding for 12 wk before 2VO surgery. Rats in the IF protocol underwent alternative-day feed deprivation (FD). Memory of the animals was assessed by using the Morris water maze (MWM) and the novel object recognition (NOR) test 6 wk after the surgery. After behavioral testing, malondialdehyde and glutathione concentrations, superoxide dismutase (SOD) activity, gene expression of antioxidative enzymes, inflammatory protein concentrations, and microglia density were determined in the hippocampus of rats. Results: 2-vessel occlusion operation ad libitum (2VO-AL) rats had significantly longer escape latencies on day 4 of the training phase and spent a lower percentage of time in the target quadrant (25% compared with 38% and 41%) in the MWM, and had lower discrimination ratios (47% compared with 65% and 67%) in the NOR test than 2-vessel operation and alternate-day feed deprivation (2VO-FD) and sham operation ad libitum (Sham-AL) rats, respectively ( P < 0.05). This indicates that IF helps to prevent vascular cognitive deficits. 2VO-AL rats also had higher malondialdehyde (3.54 compared with 2.15 and 1.66 nmol/mg protein) and lower glutathione concentrations (53.25 compared with 66.41 and 91.71 nmol/mg protein), lower SOD activity (100.1 compared with 133.3 and 138.5 U/mg protein), lower gene expression of antioxidative enzymes, higher expression of inflammatory proteins, and higher microglia density in the hippocampus than 2VO-FD and Sham-AL rats, respectively ( P < 0.05). This suggests that IF has antioxidative and anti-inflammatory effects. Conclusions: IF pretreatment provided

An experimental study on choroidal neovascularization induced by Krypton laser in rat model.

Science.gov (United States)

Cui, Jing; Liu, Yuanyuan; Zhang, Jingkai; Yan, Hua

2014-01-01

The purpose of this work was to study the efficacy and safety of choroidal neovascularization (CNV) formation induced by Krypton laser in Brown Norway (BN) rats, and observe the trend of the change of CNV after laser photocoagulation. Twenty-five male BN rats were involved in this study. Two eyes of one rat without any laser photocoagulation were randomly selected as the control group, and the other 48 eyes of 24 rats were selected as the experimental group. Eight eyes of four rats were randomly selected to receive the examinations of fundus fluorescein angiography (FFA), histopathology, and transmission electron microscopy 3, 7, 14, 21, 28, and 56 days after laser photocoagulation. After laser photocoagulation, the leakage appeared in burns on day 7 (59%), reached the peak on day 21 (84%), (p0.05). The thickness of CNV increased from day 7 to day 21 (p0.05). The experimental model of CNV can be successfully induced by Krypton laser in rats with a stable, long-lasting, and high success rate. After laser photocoagulation, the leakages appear on day 7, reach the peak on day 21, and remain stable after day 21.

Reduced motivation in the BACHD rat model of Huntington disease is dependent on the choice of food deprivation strategy.

Science.gov (United States)

Jansson, Erik Karl Håkan; Clemens, Laura Emily; Riess, Olaf; Nguyen, Huu Phuc

2014-01-01

Huntington disease (HD) is an inherited neurodegenerative disease characterized by motor, cognitive, psychiatric and metabolic symptoms. Animal models of HD show phenotypes that can be divided into similar categories, with the metabolic phenotype of certain models being characterized by obesity. Although interesting in terms of modeling metabolic symptoms of HD, the obesity phenotype can be problematic as it might confound the results of certain behavioral tests. This concerns the assessment of cognitive function in particular, as tests for such phenotypes are often based on food depriving the animals and having them perform tasks for food rewards. The BACHD rat is a recently established animal model of HD, and in order to ensure that behavioral characterization of these rats is done in a reliable way, a basic understanding of their physiology is needed. Here, we show that BACHD rats are obese and suffer from discrete developmental deficits. When assessing the motivation to lever push for a food reward, BACHD rats were found to be less motivated than wild type rats, although this phenotype was dependent on the food deprivation strategy. Specifically, the phenotype was present when rats of both genotypes were deprived to 85% of their respective free-feeding body weight, but not when deprivation levels were adjusted in order to match the rats' apparent hunger levels. The study emphasizes the importance of considering metabolic abnormalities as a confounding factor when performing behavioral characterization of HD animal models.

Reduced motivation in the BACHD rat model of Huntington disease is dependent on the choice of food deprivation strategy.

Directory of Open Access Journals (Sweden)

Erik Karl Håkan Jansson

Full Text Available Huntington disease (HD is an inherited neurodegenerative disease characterized by motor, cognitive, psychiatric and metabolic symptoms. Animal models of HD show phenotypes that can be divided into similar categories, with the metabolic phenotype of certain models being characterized by obesity. Although interesting in terms of modeling metabolic symptoms of HD, the obesity phenotype can be problematic as it might confound the results of certain behavioral tests. This concerns the assessment of cognitive function in particular, as tests for such phenotypes are often based on food depriving the animals and having them perform tasks for food rewards. The BACHD rat is a recently established animal model of HD, and in order to ensure that behavioral characterization of these rats is done in a reliable way, a basic understanding of their physiology is needed. Here, we show that BACHD rats are obese and suffer from discrete developmental deficits. When assessing the motivation to lever push for a food reward, BACHD rats were found to be less motivated than wild type rats, although this phenotype was dependent on the food deprivation strategy. Specifically, the phenotype was present when rats of both genotypes were deprived to 85% of their respective free-feeding body weight, but not when deprivation levels were adjusted in order to match the rats' apparent hunger levels. The study emphasizes the importance of considering metabolic abnormalities as a confounding factor when performing behavioral characterization of HD animal models.

EFFECT OF ETHANOL ON HEPATOBILIARY TRANSPORT OF CATIONIC DRUGS - A STUDY IN THE ISOLATED-PERFUSED RAT-LIVER, RAT HEPATOCYTES AND RAT MITOCHONDRIA

NARCIS (Netherlands)

STEEN, H; MEIJER, DKF; Merema, M.T.

The effect of ethanol on the hepatic uptake of various cationic drugs was studied in isolated perfused rat livers, isolated rat hepatocytes and isolated rat liver mitochondria. In isolated rat hepatocytes and in isolated perfused rat livers, the uptake of the model organic cation

An Age-Dependent Physiologically-Based Pharmacokinetic/Pharmacodynamic Model for the Organophosphorus Insecticide Chlorpyrifos in the Preweanling Rat

Energy Technology Data Exchange (ETDEWEB)

Timchalk, Chuck; Kousba, Ahmed A.; Poet, Torka S.

2007-08-01

Juvenile rats are more susceptible than adults to the acute toxicity of organophosphorus insecticides like chlorpyrifos (CPF). Age- and dose-dependent differences in metabolism may be responsible. Of importance is CYP450 activation and detoxification of CPF to chlorpyrifos-oxon (CPF-oxon) and trichloropyridinol (TCP), as well as B-esterase (cholinesterase; ChE) and A-esterase (PON-1) detoxification of CPF-oxon to TCP. In the current study, a modified physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model incorporating age-dependent changes in CYP450, PON-1, and tissue ChE levels for rats was developed. In this model, age was used as a dependent function to estimate body weight which was then used to allometrically scale both metabolism and tissue ChE levels. Model simulations suggest that preweanling rats are particularly sensitive to CPF toxicity, with levels of CPF-oxon in blood and brain disproportionately increasing, relative to the response in adult rats. This age-dependent non-linear increase in CPF-oxon concentration may potentially result from the depletion of non-target B-esterases, and a lower PON-1 metabolic capacity in younger animals. These results indicate that the PBPK/PD model behaves consistently with the general understanding of CPF toxicity, pharmacokinetics and tissue ChE inhibition in neonatal and adult rats. Hence, this model represents an important starting point for developing a computational model to assess the neurotoxic potential of environmentally relevant organophosphate exposures in infants and children.

Analgesic effect of Minocycline in rat model of inflammation-induced visceral pain

Science.gov (United States)

Kannampalli, Pradeep; Pochiraju, Soumya; Bruckert, Mitchell; Shaker, Reza; Banerjee, Banani; Sengupta, Jyoti N.

2014-01-01

The present study investigates the analgesic effect of minocycline, a semi-synthetic tetracycline antibiotic, in a rat model of inflammation-induced visceral pain. Inflammation was induced in male rats by intracolonic administration of tri-nitrobenzenesulphonic acid (TNBS). Visceral hyperalgesia was assessed by comparing the viscero-motor response (VMR) to graded colorectal distension (CRD) prior and post 7 days after TNBS treatment. Electrophysiology recordings from CRD-sensitive pelvic nerve afferents (PNA) and lumbo-sacral (LS) spinal neurons were performed in naïve and inflamed rats. Colonic inflammation produced visceral hyperalgesia characterized by increase in the VMRs to CRD accompanied with simultaneous activation of microglia in the spinal cord and satellite glial cells (SGCs) in the dorsal root ganglions (DRGs). Selectively inhibiting the glial activation following inflammation by araC (Arabinofuranosyl Cytidine) prevented the development of visceral hyperalgesia. Intrathecal minocycline significantly attenuated the VMR to CRD in inflamed rats, whereas systemic minocycline produced a delayed effect. In electrophysiology experiments, minocycline significantly attenuated the mechanotransduction of CRD-sensitive PNAs and the responses of CRD-sensitive LS spinal neurons in TNBS-treated rats. While the spinal effect of minocycline was observed within 5 min of administration, systemic injection of the drug produced a delayed effect (60 min) in inflamed rats. Interestingly, minocycline did not exhibit analgesic effect in naïve, non-inflamed rats. The results demonstrate that intrathecal injection of minocycline can effectively attenuate inflammation-induced visceral hyperalgesia. Minocycline might as well act on neuronal targets in the spinal cord of inflamed rats, in addition to the widely reported glial inhibitory action to produce analgesia. PMID:24485889

Naked DNA Immunization for Prevention of Prostate Cancer in a Dunning Rat Prostate Tumor Model

National Research Council Canada - National Science Library

Mincheff, Milcho

2003-01-01

...: H-PSMA-T, R-"PSMA"-T, H-PSA, H-PSA-T, H-PAP-T and R"PSMA"-S. Preliminary studies using the Copenhagen rat tumor prostate model showed uniform tumor development in rats that were injected subcutaneously with 100 000 AT3B-lPSMA,PSA cells...

Effect of eplerenone on serum TNF-α levels in adriamycin induced heart failure male rat models

International Nuclear Information System (INIS)

Xuan Nan; Song Liping; Xing Haiyan

2009-01-01

Objective: To investigate the effect of eplerenone on serum TNF-α levels in adriamycin induced heart failure male rat models. Methods: Forty male rat models of adriamycin-induced heart failure were prepared with weekly intraperitoneal injection of adriamycin (4/mg/kg) for six weeks. Twenty surviving models were randomly divided into two groups: (1)eplerenone-treated group, n=10, treated with garage of eplerenone 200mg/kg/d for 12 weeks (2) non-treated group n=10. All the surviving models (group (1) n=8, group (2) n=6) were sacrificed after 12 weeks with left ventricular hemodynamic function parameters tested and serum TNF-α levels measured. Ten male rats without adriamycin administration served as controls. Results: Left ventricular hemodynamic parameters in the non-treated group were significantly worse than those in controls (P<0.05). The parameters in the eplerenone treated group were significantly better than those in the non-treated group (P<0.05). The serum TNF-α levels in the non-treated group were significantly higher than those in controls (P<0.05). TNF-α levels in the eplerenone group were significantly lower than those in the non-treated group (P<0.05). Conclusion: Eplerenone could reduce the serum TNF-α levels in the rat models of heart failure. (authors)

Antibody Contributes to Heterosubtypic Immunity In the Cotton Rat Model of Influenza

Science.gov (United States)

2010-09-29

H1N2 swine influenza virus in pigs previously infected with H1N1 and/or H3N2 subtypes. Vaccine 21: 1375–1381. Wei, C.J., J.C. Boyington, P.M...contributes to heterosubtypic protection against influenza A-induced tachypnea in cotton rats" Name of Candidate: r. Timothy M. Straight Doctor of...Heterosubtypic Immunity In the Cotton Rat Model of Influenza " is appropriately acknowledged and, beyond brief excerpts, is with the permission of the

Hepatoprotective Effects of Swimming Exercise against D-Galactose-Induced Senescence Rat Model

Directory of Open Access Journals (Sweden)

Chi-Chang Huang

2013-01-01

Full Text Available This study investigates whether a 12-week swimming exercise training can prevent liver damage or senescence associated biomarkers in an experimental aging model in rats. Twenty-three male Sprague-Dawley rats were divided into four groups: vehicle treatment with sedentary control (C, , aging induction with sedentary (A, , vehicle treatment with swimming exercise (SW, , and aging induction with swimming exercise (A + SW, . Rats in groups A and AS received intraperitoneal D-galactose injections (150 mg/kg/day for 12 weeks to induce aging. Rats in groups SW and A + SW were subjected to swimming exercise training for 12 weeks. Body weight, liver weight, epididymal fat mass, blood biochemistry, and liver pathology were performed at the end of the experiment. Hepatic senescence protein markers such as β-galactosidase, p53, and p21, as well as the inflammatory mediator, IL-6, were examined. The D-galactose-treated rats exhibited increases in AST and γ-GT plasma levels and β-galactosidase protein expression compared to the control group. Swimming exercise significantly reduced BW, epididymal fat mass, γ-GT activity, and p53, p21, and IL-6 protein levels compared to the aging group. These results suggest that a 12-week swimming exercise program suppresses senescence markers and downregulates inflammatory mediator in the liver tissues of D-galactose-induced aging rats.

Cyclophosphamide Enhances Human Tumor Growth in Nude Rat Xenografted Tumor Models

Directory of Open Access Journals (Sweden)

Yingjen Jeffrey Wu

2009-02-01

Full Text Available The effect of the immunomodulatory chemotherapeutic agent cyclophosphamide (CTX on tumor growth was investigated in primary and metastatic intracerebral and subcutaneous rat xenograft models. Nude rats were treated with CTX (100 mg/kg, intraperitoneally 24 hours before human ovarian carcinoma (SKOV3, small cell lung carcinoma (LX-1 SCLC, and glioma (UW28, U87MG, and U251 tumor cells were inoculated subcutaneously, intraperitoneally, or in the right cerebral hemisphere or were infused into the right internal carotid artery. Tumor development was monitored and recorded. Potential mechanisms were further investigated. Only animals that received both CTX and Matrigel showed consistent growth of subcutaneous tumors. Cyclophosphamide pretreatment increased the percentage (83.3% vs 0% of animals showing intraperitoneal tumors. In intracerebral implantation tumor models, CTX pretreatment increased the tumor volume and the percentage of animals showing tumors. Cyclophosphamide increased lung carcinoma bone and facial metastases after intra-arterial injection, and 20% of animals showed brain metastases. Cyclophosphamide transiently decreased nude rat white blood cell counts and glutathione concentration, whereas serum vascular endothelial growth factor was significantly elevated. Cyclophosphamide also increased CD31 reactivity, a marker of vascular endothelium, and macrophage (CD68-positive infiltration into glioma cell-inoculated rat brains. Cyclophosphamide may enhance primary and metastatic tumor growth through multiple mechanisms, including immune modulation, decreased response to oxidative stress, increased tumor vascularization, and increased macrophage infiltration. These findings may be clinically relevant because chemotherapy may predispose human cancer subjects to tumor growth in the brain or other tissues.

Gender differences in organ density in a rat simulated microgravity model

Science.gov (United States)

Pettis, Christopher Ryan; Witten, Mark Lee

2004-01-01

Research investigating the physiological effects of microgravity on the human body has demonstrated a shift of body fluids in actual spaceflight and in simulated Earth-based microgravity models in both males and females, possibly causing many deleterious physiological effects. Twenty-five anatomically normal female (NF) and 20 ovariectomized (OE) Fischer 344 rats were randomly selected to be in an experimental ( 1 h of 45° head-down tilt, 45HDT) or control ( 1 h of prone position) group. At the end of the hour experimental period, the density of the brain, lungs, heart, liver, and left and right kidneys were measured using spiral computed tomography (SCT) while the rats remained in their experimental positions. A sub-group of OE rats ( N=6) was administered estrogen replacement therapy on a daily basis ( 5 μg/kg body weight, s.c.) for 4 days and then underwent 1 h of 45HDT and SCT analysis at one day, 2 days, and 5 days to determine if estrogen replacement therapy would alter organ densities. Our data demonstrate that 1 h of 45HDT produced significant increases ( pbrain, liver, left kidney, and lung of the OE female group compared to their prone controls. However, only the brain density was significantly increased in the NF group. Estrogen replacement therapy caused a significant decrease in brain organ density at the 5 day time point compared to the 24 h time point. We conclude that estrogen plays a role in fluid distribution in a rat 45HDT model.

Electropuncture influences on learning, memory, and neuropeptide expression in a rat model of vascular dementia

Institute of Scientific and Technical Information of China (English)

Ying Shao; Yanqian Fu; Lihua Qiu; Bing Yan; Xinsheng Lai; Chunzhi Tang

2008-01-01

BACKGROUND: Studies in recent years have indicated that several neuropeptide-like substances, such as arginine vasopressin (AVP), somatostatin (SS), and β-endorphine (β-EP), are involved in the process of cerebral ischemic damage to cranial nerves.OBJECTIVE: To observe the effects of electropuncture on back-shu points, as well as the influence on learning and memory, AVP, SS, and β-EP levels in plasma and brain were measured in a rat model of vascular dementia (VD). DESIGN: Randomized controlled trial.SETTING: College of Acupuncture and Massage of Guangzhou University of Chinese Medicine.MATERIALS: This experiment was performed at the Animal Experiment Center of Guangzhou University of TCM from December 2005 to December 2006. A total of 48 healthy adult male Sprague Dawley rats of SPF-grade, 180-220 g, were provided by The Animal Experiment Center of Guangzhou University of Traditional Chinese Medicine. The following instruments were used: SDQ-30 Dipolar Radio-frequency Electrocoagulator (Shanghai Operation Instrument Factory), Morris Water Maze (The Animal Experiment Center of Guangzhou University of Traditional Chinese Medicine), Type G6805-1 Treating Equipment (Huasheng Equipment Factory, Qingdao, China).METHODS: ① Eight rats were randomly selected for the control group; the remaining 40 rats underwent 4-vascular occlusion to establish a cerebral ischemia model. Due to the death of 13 rats and 2 hemiplegies during model establishment, there was a total of 25 model rats available for testing. The model rats were divided randomly into 3 groups according to their body weight: electropuncture group (n = 9), medication group (n = 8), and VD group (n = 8). ② Electropuncture group: 25 mm needles (28 gauge) were used to electropuncture (150 Hz, continuous waves, 1.0-2.0 mA, duration of 20 minutes) the following acupoints: Baihui (GV20), Geshu (BL17), Pishu (BL20), and Shenshu (BL23). The acupoints were located according to Experimental acupuncturology and were

Beneficial effect of daidzin in dry eye rat model through the suppression of inflammation and oxidative stress in the cornea

Directory of Open Access Journals (Sweden)

Fan Xiao

2018-05-01

Full Text Available Present investigation evaluates the effect of daidzin in dry eye rat model through the suppression of inflammation and oxidative stress in the cornea. Briefly, electron spine resonance was used for the estimation of radical scavenging activity of daidzin and COX Fluorescent Activity Assay Kit was used for the estimation of PGS activity. Dry eye rat model was developed by removing the lacrimal gland and effect of daidzin was evaluated in dry eye rat model by estimating the fluorescein score, tear volume and expressions of heme oxigenase (HO-1, TNF α, Interlukin 6 (IL-6, matrix metallopeptidase 9 (MMP-9 and PGS-2. Result of the present study suggested that daidzin possess tyrosyl radical scavenging activity and thereby decreases the oxidative stress. Activity of PGS significantly increases in dry eye which was inhibited by daidzin treatment due to competitive inhibition of PGS. It also recovers the tear volume in dry eye rat model in which lacrimal gland was removed. Thus corneal erosion was improved by daidzin in dry eye rat model. Thus present study concludes that treatment with daidzin protects the cornea in dry eye rat model by suppression inflammation and oxidative stress. Keywords: Daidzin, Dry eye, Radical scavenging activity, Inflammation

Long-term characterization of the diet-induced obese and diet-resistant rat model

DEFF Research Database (Denmark)

Madsen, Andreas Nygaard; Hansen, Gitte; Paulsen, Sarah Juel

2010-01-01

, namely the selectively bred diet-induced obese (DIO) and diet-resistant (DR) rat strains. We show that they constitute useful models of the human obesity syndrome. DIO and DR rats were fed either a high-energy (HE) or a standard chow (Chow) diet from weaning to 9 months of age. Metabolic characterization......, the results underscore the effectiveness of GLP-1 mimetics both as anti-diabetes and anti-obesity agents....

Cardiovascular-renal and metabolic characterization of a rat model of polycystic ovary syndrome.

Science.gov (United States)

Yanes, Licy L; Romero, Damian G; Moulana, Mohaddetheh; Lima, Roberta; Davis, Deborah D; Zhang, Huimin; Lockhart, Rachel; Racusen, Lorraine C; Reckelhoff, Jane F

2011-04-01

Polycystic ovary syndrome (PCOS) is the most common reproductive dysfunction in premenopausal women. PCOS is also associated with increased risk of cardiovascular disease when PCOS first occurs and later in life. Hypertension, a common finding in women with PCOS, is a leading risk factor for cardiovascular disease. The mechanisms responsible for hypertension in women with PCOS have not been elucidated. This study characterized the cardiovascular-renal consequences of hyperandrogenemia in a female rat model. Female Sprague-Dawley rats (aged 4-6 weeks) were implanted with dihydrotestosterone or placebo pellets lasting 90 days. After 10 to 12 weeks, blood pressure (by radiotelemetry), renal function (glomerular filtration rate, morphology, protein, and albumin excretion), metabolic parameters (plasma insulin, glucose, leptin, cholesterol, and oral glucose tolerance test), inflammation (plasma tumor necrosis factor-α), oxidative stress (mRNA expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, p22(phox), p47(phox), gp91(phox), and NOX4), nitrate/nitrite excretion and mRNA expression of components of the renin-angiotensin system (angiotensinogen, angiotensin-I-converting enzyme [ACE], and AT1 receptor) were determined. Plasma dihydrotestosterone increased 3-fold in hyperandrogenemic female (HAF) rats, whereas plasma estradiol levels did not differ compared with control females. HAF rats exhibited estrus cycle dysfunction. They also had increased food intake and body weight, increased visceral fat, glomerular filtration rate, renal injury, insulin resistance and metabolic dysfunction, oxidative stress, and increased expression of angiotensinogen and ACE and reduced AT1 receptor expression. The HAF rat is a unique model that exhibits many of the characteristics of PCOS in women and is a useful model to study the mechanisms responsible for PCOS-mediated hypertension. Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.

Changes of blood and myocardial tissue contents of IGF-I after development of acute myocardial infarction in rat models

International Nuclear Information System (INIS)

Cao Heng; Wei Youquan

2006-01-01

Objective: To study the changes of IGF-I contents in blood and myocardium after experimental acute myocardial infarction in rat models. Methods: Rat models of acute myocardial infarction were prepared with intraperitoneal injection of isoproterenol. Eight models were sacrificed 48h later and another 8 models were sacrificed 14 days after preparation. Serum and myocardium homogenate contents of IGF-I were measured with RIA in these models as well as 8 control rats. Results: The serum and myocardial contents of IGF-I increased in the models sacrificed at 48h, but were not significantly higher than those in the controls (P>0.05). At 14 th day, the levels were significantly higher than those in controls and at 48h (both P<0.05). The serum and myocardial contents of IGF-I were mutually correlated in the controls and 14 day models (r=0.9987, r=0.9992; P<0.01). Conclusion After myocardial infarction, the serum and myocardial IGF-I contents increased along with the course of disease in the rat models. (authors)

High Salt Intake Promotes Urinary Loss of Vitamin D Metabolites by Dahl Salt-Sensitive Rats in a Space Flight Model

Science.gov (United States)

Thierry-Palmer, M.; Cephas, S.; Sayavongsa, P.; Clark, T.; Arnaud, S. B.

2004-01-01

Vitamin D metabolism in the Dahl salt-sensitive (S) rat, a model of salt-induced hypertension, differs from that in the Dahl salt-resistant (R) rat. We have demonstrated that female S rats are more vulnerable than female R rats to decreases in plasma 25-hydroxyvitamin D (25-OHD) and 1,25-dihydroxyvitamin D (1,25-(OH)2D) concentrations during hind limb unloading (a space flight model). We report here on the response of the vitamin D endocrine system of S and R rats to hind limb unloading during high salt intake. Dahl female rats (9.7-week-old) were tail-suspended (hind limb unloaded) for 28 days, while fed a diet containing twice the salt in standard rat chow (2 % sodium chloride). Control rats were fed the same diet, but were not hind limb unloaded. Vitamin D metabolites were analyzed by HPLC and radioimmunoassay kits from Diasorin.

A NEW ANIMAL-MODEL FOR HUMAN PREECLAMPSIA - ULTRA-LOW-DOSE ENDOTOXIN INFUSION IN PREGNANT RATS

NARCIS (Netherlands)

FAAS, MM; SCHUILING, GA; BALLER, JFW; VISSCHER, CA; BAKKER, WW

OBJECTIVE: An animal model for preeclampsia was developed by means of an ultra-low-dose endotoxin infusion protocol in conscious pregnant rats. STUDY DESIGN: Rats received a permanent jugular vein cannula on day 0 of pregnancy, through which endotoxin (1.0 mu/kg body weight) (n = 10) or saline

The Influence of a High Salt Diet on a Rat Model of Isoproterenol-Induced Heart Failure

Science.gov (United States)

Rat models of heart failure (HF) show varied pathology and time to disease outcome, dependent on induction method. We found that subchronic (4 weeks) isoproterenol (ISO) infusion exacerbated cardiomyopathy in Spontaneously Hypertensive Heart Failure (SHHF) rats. Others have shown...

A new minimal-stress freely-moving rat model for preclinical studies on intranasal administration of CNS drugs.

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Stevens, Jasper; Suidgeest, Ernst; van der Graaf, Piet Hein; Danhof, Meindert; de Lange, Elizabeth C M

2009-08-01

To develop a new minimal-stress model for intranasal administration in freely moving rats and to evaluate in this model the brain distribution of acetaminophen following intranasal versus intravenous administration. Male Wistar rats received one intranasal cannula, an intra-cerebral microdialysis probe, and two blood cannulas for drug administration and serial blood sampling respectively. To evaluate this novel model, the following experiments were conducted. 1) Evans Blue was administered to verify the selectivity of intranasal exposure. 2) During a 1 min infusion 10, 20, or 40 microl saline was administered intranasally or 250 microl intravenously. Corticosterone plasma concentrations over time were compared as biomarkers for stress. 3) 200 microg of the model drug acetaminophen was given in identical setup and plasma, and brain pharmacokinetics were determined. In 96% of the rats, only the targeted nasal cavity was deeply colored. Corticosterone plasma concentrations were not influenced, neither by route nor volume of administration. Pharmacokinetics of acetaminophen were identical after intravenous and intranasal administration, although the Cmax in microdialysates was reached a little earlier following intravenous administration. A new minimal-stress model for intranasal administration in freely moving rats has been successfully developed and allows direct comparison with intravenous administration.

Model of excitation-contraction coupling of rat neonatal ventricular myocytes.

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Korhonen, Topi; Hänninen, Sandra L; Tavi, Pasi

2009-02-01

The neonatal rat ventricular myocyte culture is one of the most popular experimental cardiac cell models. To our knowledge, the excitation-contraction coupling (ECC) of these cells, i.e., the process linking the electrical activity to the cytosolic Ca2+ transient and contraction, has not been previously analyzed, nor has it been presented as a complete system in detail. Neonatal cardiomyocytes are in the postnatal developmental stage, and therefore, the features of their ECC differ vastly from those of adult ventricular myocytes. We present the first complete analysis of ECC in these cells by characterizing experimentally the action potential and calcium signaling and developing the first mathematical model of ECC in neonatal cardiomyocytes that we know of. We show that in comparison to adult cardiomyocytes, neonatal cardiomyocytes have long action potentials, heterogeneous cytosolic Ca2+ signals, weaker sarcoplasmic reticulum Ca2+ handling, and stronger sarcolemmal Ca2+ handling, with a significant contribution by the Na+/Ca2+ exchanger. The developed model reproduces faithfully the ECC of rat neonatal cardiomyocytes with a novel description of spatial cytosolic [Ca2+] signals. Simulations also demonstrate how an increase in the cell size (hypertrophy) affects the ECC in neonatal cardiomyocytes. This model of ECC in developing cardiomyocytes provides a platform for developing future models of cardiomyocytes at different developmental stages.

A rat model of post-traumatic stress disorder reproduces the hippocampal deficits seen in the human syndrome

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Sonal eGoswami

2012-06-01

Full Text Available Despite recent progress, the causes and pathophysiology of post-traumatic stress disorder (PTSD remain poorly understood, partly because of ethical limitations inherent to human studies. One approach to circumvent this obstacle is to study PTSD in a valid animal model of the human syndrome. In one such model, extreme and long-lasting behavioral manifestations of anxiety develop in a subset of Lewis rats after exposure to an intense predatory threat that mimics the type of life-and-death situation known to precipitate PTSD in humans. This study aimed to assess whether the hippocampus-associated deficits observed in the human syndrome are reproduced in this rodent model. Prior to predatory threat, different groups of rats were each tested on one of three object recognition memory tasks that varied in the types of contextual clues (i.e. that require the hippocampus or not the rats could use to identify novel items. After task completion, the rats were subjected to predatory threat and, one week later, tested on the elevated plus maze. Based on their exploratory behavior in the plus maze, rats were then classified as resilient or PTSD-like and their performance on the pre-threat object recognition tasks compared. The performance of PTSD-like rats was inferior to that of resilient rats but only when subjects relied on an allocentric frame of reference to identify novel items, a process thought to be critically dependent on the hippocampus. Therefore, these results suggest that even prior to trauma, PTSD-like rats show a deficit in hippocampal-dependent functions, as reported in twin studies of human PTSD.

A rat model of post-traumatic stress disorder reproduces the hippocampal deficits seen in the human syndrome.

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Goswami, Sonal; Samuel, Sherin; Sierra, Olga R; Cascardi, Michele; Paré, Denis

2012-01-01

Despite recent progress, the causes and pathophysiology of post-traumatic stress disorder (PTSD) remain poorly understood, partly because of ethical limitations inherent to human studies. One approach to circumvent this obstacle is to study PTSD in a valid animal model of the human syndrome. In one such model, extreme and long-lasting behavioral manifestations of anxiety develop in a subset of Lewis rats after exposure to an intense predatory threat that mimics the type of life-and-death situation known to precipitate PTSD in humans. This study aimed to assess whether the hippocampus-associated deficits observed in the human syndrome are reproduced in this rodent model. Prior to predatory threat, different groups of rats were each tested on one of three object recognition memory tasks that varied in the types of contextual clues (i.e., that require the hippocampus or not) the rats could use to identify novel items. After task completion, the rats were subjected to predatory threat and, one week later, tested on the elevated plus maze (EPM). Based on their exploratory behavior in the plus maze, rats were then classified as resilient or PTSD-like and their performance on the pre-threat object recognition tasks compared. The performance of PTSD-like rats was inferior to that of resilient rats but only when subjects relied on an allocentric frame of reference to identify novel items, a process thought to be critically dependent on the hippocampus. Therefore, these results suggest that even prior to trauma PTSD-like rats show a deficit in hippocampal-dependent functions, as reported in twin studies of human PTSD.

Prediction and evaluation of route dependent dosimetry of BPA in rats at different life stages using a physiologically based pharmacokinetic model

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Yang, Xiaoxia, E-mail: Xiaoxia.Yang@fda.hhs.gov; Doerge, Daniel R.; Fisher, Jeffrey W.

2013-07-01

Bisphenol A (BPA) has received considerable attention throughout the last decade due to its widespread use in consumer products. For the first time a physiologically based pharmacokinetic (PBPK) model was developed in neonatal and adult rats to quantitatively evaluate age-dependent pharmacokinetics of BPA and its phase II metabolites. The PBPK model was calibrated in adult rats using studies on BPA metabolism and excretion in the liver and gastrointestinal tract, and pharmacokinetic data with BPA in adult rats. For immature rats the hepatic and gastrointestinal metabolism of BPA was inferred from studies on the maturation of phase II enzymes coupled with serum time course data in pups. The calibrated model predicted the measured serum concentrations of BPA and BPA conjugates after administration of 100 μg/kg of d6-BPA in adult rats (oral gavage and intravenous administration) and postnatal days 3, 10, and 21 pups (oral gavage). The observed age-dependent BPA serum concentrations were partially attributed to the immature metabolic capacity of pups. A comparison of the dosimetry of BPA across immature rats and monkeys suggests that dose adjustments would be necessary to extrapolate toxicity studies from neonatal rats to infant humans. - Highlights: • A PBPK model predicts the kinetics of bisphenol A (BPA) in young and adult rats. • BPA metabolism within enterocytes is required for fitting of oral BPA kinetic data. • BPA dosimetry in young rats is different than adult rats and young monkeys.

Prediction and evaluation of route dependent dosimetry of BPA in rats at different life stages using a physiologically based pharmacokinetic model

International Nuclear Information System (INIS)

Yang, Xiaoxia; Doerge, Daniel R.; Fisher, Jeffrey W.

2013-01-01

Bisphenol A (BPA) has received considerable attention throughout the last decade due to its widespread use in consumer products. For the first time a physiologically based pharmacokinetic (PBPK) model was developed in neonatal and adult rats to quantitatively evaluate age-dependent pharmacokinetics of BPA and its phase II metabolites. The PBPK model was calibrated in adult rats using studies on BPA metabolism and excretion in the liver and gastrointestinal tract, and pharmacokinetic data with BPA in adult rats. For immature rats the hepatic and gastrointestinal metabolism of BPA was inferred from studies on the maturation of phase II enzymes coupled with serum time course data in pups. The calibrated model predicted the measured serum concentrations of BPA and BPA conjugates after administration of 100 μg/kg of d6-BPA in adult rats (oral gavage and intravenous administration) and postnatal days 3, 10, and 21 pups (oral gavage). The observed age-dependent BPA serum concentrations were partially attributed to the immature metabolic capacity of pups. A comparison of the dosimetry of BPA across immature rats and monkeys suggests that dose adjustments would be necessary to extrapolate toxicity studies from neonatal rats to infant humans. - Highlights: • A PBPK model predicts the kinetics of bisphenol A (BPA) in young and adult rats. • BPA metabolism within enterocytes is required for fitting of oral BPA kinetic data. • BPA dosimetry in young rats is different than adult rats and young monkeys

A rat model of hypohidrotic ectodermal dysplasia carries a missense mutation in the Edaradd gene

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2011-01-01

Background Hypohidrotic ectodermal dysplasia (HED) is a congenital disorder characterized by sparse hair, oligodontia, and inability to sweat. It is caused by mutations in any of three Eda pathway genes: ectodysplasin (Eda), Eda receptor (Edar), and Edar-associated death domain (Edaradd), which encode ligand, receptor, and intracellular adaptor molecule, respectively. The Eda signaling pathway activates NF-κB, which is central to ectodermal differentiation. Although the causative genes and the molecular pathway affecting HED have been identified, no curative treatment for HED has been established. Previously, we found a rat spontaneous mutation that caused defects in hair follicles and named it sparse-and-wavy (swh). Here, we have established the swh rat as the first rat model of HED and successfully identified the swh mutation. Results The swh/swh rat showed sparse hair, abnormal morphology of teeth, and absence of sweat glands. The ectoderm-derived glands, meibomian, preputial, and tongue glands, were absent. We mapped the swh mutation to the most telomeric part of rat Chr 7 and found a Pro153Ser missense mutation in the Edaradd gene. This mutation was located in the death domain of EDARADD, which is crucial for signal transduction and resulted in failure to activate NF-κB. Conclusions These findings suggest that swh is a loss-of-function mutation in the rat Edaradd and indicate that the swh/swh rat would be an excellent animal model of HED that could be used to investigate the pathological basis of the disease and the development of new therapies. PMID:22013926

A New Rat Model of Epileptic Spasms Based on Methylazoxymethanol-Induced Malformations of Cortical Development

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Eun-Hee Kim

2017-06-01

Full Text Available Malformations of cortical development (MCDs can cause medically intractable epilepsies and cognitive disabilities in children. We developed a new model of MCD-associated epileptic spasms by treating rats prenatally with methylazoxymethanol acetate (MAM to induce cortical malformations and postnatally with N-methyl-d-aspartate (NMDA to induce spasms. To produce cortical malformations to infant rats, two dosages of MAM (15 mg/kg, intraperitoneally were injected to pregnant rats at gestational day 15. In prenatally MAM-exposed rats and the controls, spasms were triggered by single (6 mg/kg on postnatal day 12 (P12 or 10 mg/kg on P13 or 15 mg/kg on P15 or multiple doses (P12, P13, and P15 of NMDA. In prenatally MAM-exposed rats with single NMDA-provoked spasms at P15, we obtain the intracranial electroencephalography and examine the pretreatment response to adrenocorticotropic hormone (ACTH or vigabatrin. Rat pups prenatally exposed to MAM exhibited a significantly greater number of spasms in response to single and multiple postnatal NMDA doses than vehicle-exposed controls. Vigabatrin treatment prior to a single NMDA dose on P15 significantly suppressed spasms in MAM group rats (p < 0.05, while ACTH did not. The MAM group also showed significantly higher fast oscillation (25–100 Hz power during NMDA-induced spasms than controls (p = 0.047. This new model of MCD-based epileptic spasms with corresponding features of human spasms will be valuable for future research of the developmental epilepsy.

Electrophysiological characterization of spinal neurons in different models of diabetes type 1- and type 2-induced neuropathy in rats.

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Schuelert, N; Gorodetskaya, N; Just, S; Doods, H; Corradini, L

2015-04-16

Diabetic polyneuropathy (DPN) is a devastating complication of diabetes. The underlying pathogenesis of DPN is still elusive and an effective treatment devoid of side effects presents a challenge. There is evidence that in type-1 and -2 diabetes, metabolic and morphological changes lead to peripheral nerve damage and altered central nociceptive transmission, which may contribute to neuropathic pain symptoms. We characterized the electrophysiological response properties of spinal wide dynamic range (WDR) neurons in three diabetic models. The streptozotocin (STZ) model was used as a drug-induced model of type-1 diabetes, and the BioBreeding/Worcester (BB/Wor) and Zucker diabetic fatty (ZDF) rat models were used for genetic DPN models. Data were compared to the respective control group (BB/Wor diabetic-resistant, Zucker lean (ZL) and saline-injected Wistar rat). Response properties of WDR neurons to mechanical stimulation and spontaneous activity were assessed. We found abnormal response properties of spinal WDR neurons in all diabetic rats but not controls. Profound differences between models were observed. In BB/Wor diabetic rats evoked responses were increased, while in ZDF rats spontaneous activity was increased and in STZ rats mainly after discharges were increased. The abnormal response properties of neurons might indicate differential pathological, diabetes-induced, changes in spinal neuronal transmission. This study shows for the first time that specific electrophysiological response properties are characteristic for certain models of DPN and that these might reflect the diverse and complex symptomatology of DPN in the clinic. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Differential Expression of microRNAs in the Ovaries from Letrozole-Induced Rat Model of Polycystic Ovary Syndrome.

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Li, Dandan; Li, Chunjin; Xu, Ying; Xu, Duo; Li, Hongjiao; Gao, Liwei; Chen, Shuxiong; Fu, Lulu; Xu, Xin; Liu, Yongzheng; Zhang, Xueying; Zhang, Jingshun; Ming, Hao; Zheng, Lianwen

2016-04-01

Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine disorder. To understand the pathogenesis of PCOS, we established rat models of PCOS induced by letrozole and employed deep sequencing to screen the differential expression of microRNAs (miRNAs) in PCOS rats and control rats. We observed vaginal smear and detected ovarian pathological alteration and hormone level changes in PCOS rats. Deep sequencing showed that a total of 129 miRNAs were differentially expressed in the ovaries from letrozole-induced rat model compared with the control, including 49 miRNAs upregulated and 80 miRNAs downregulated. Furthermore, the differential expression of miR-201-5p, miR-34b-5p, miR-141-3p, and miR-200a-3p were confirmed by real-time polymerase chain reaction. Bioinformatic analysis revealed that these four miRNAs were predicted to target a large set of genes with different functions. Pathway analysis supported that the miRNAs regulate oocyte meiosis, mitogen-activated protein kinase (MAPK) signaling, phosphoinositide 3-kinase/Akt (PI3K-Akt) signaling, Rap1 signaling, and Notch signaling. These data indicate that miRNAs are differentially expressed in rat PCOS model and the differentially expressed miRNA are involved in the etiology and pathophysiology of PCOS. Our findings will help identify miRNAs as novel diagnostic markers and therapeutic targets for PCOS.

Aberrant Pregnancy Adaptations in the Peripheral Immune Response in Type 1 Diabetes: A Rat Model.

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Bart Groen

Full Text Available Despite tight glycemic control, pregnancy complication rate in type 1 diabetes patients is higher than in normal pregnancy. Other etiological factors may be responsible for the development of adverse pregnancy outcome. Acceptance of the semi-allogeneic fetus is accompanied by adaptations in the maternal immune-response. Maladaptations of the immune-response has been shown to contribute to pregnancy complications. We hypothesized that type 1 diabetes, as an autoimmune disease, may be associated with maladaptations of the immune-response to pregnancy, possibly resulting in pregnancy complications.We studied pregnancy outcome and pregnancy-induced immunological adaptations in a normoglycemic rat-model of type 1 diabetes, i.e. biobreeding diabetes-prone rats (BBDP; 5 non-pregnant rats, 7 pregnant day 10 rats and 6 pregnant day 18 rats , versus non-diabetic control rats (i.e. congenic non-diabetic biobreeding diabetes-resistant (BBDR; 6 non-pregnant rats, 6 pregnant day 10 rats and 6 pregnant day 18 rats and Wistar-rats (6 non-pregnant, 6 pregnant day 10 rats and 5 pregnant day 18 rats.We observed reduced litter size, lower fetal weight of viable fetuses and increased numbers of resorptions versus control rats. These complications are accompanied by various differences in the immune-response between BBDP and control rats in both pregnant and non-pregnant animals. The immune-response in non-pregnant BBDP-rats was characterized by decreased percentages of lymphocytes, increased percentages of effector T-cells, regulatory T-cells and natural killer cells, an increased Th1/Th2-ratio and activated monocytes versus Wistar and BBDR-rats. Furthermore, pregnancy-induced adaptations in BBDP-rats coincided with an increased Th1/Th2-ratio, a decreased mean fluorescence intensity CD161a/NKR-P1b ratio and no further activation of monocytes versus non-diabetic control rats.This study suggests that even in the face of strict normoglycemia, pregnancy complications

Brain scan in cerebral ischemia. An experimental model in the rat

International Nuclear Information System (INIS)

Turner, J.H.

1975-01-01

A rapid embolic method for consistent induction of stroke in the rat is described. Brain scans were performed using a micro-pinhole collimator system, and the value of the model for studies in localization of radiopharmaceuticals in cerebral ischemia is demonstrated

Green tea supplementation produces better neuroprotective effects than red and black tea in Alzheimer-like rat model.

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Schimidt, Helen L; Garcia, Alexandre; Martins, Alexandre; Mello-Carpes, Pamela B; Carpes, Felipe P

2017-10-01

Green tea from Camellia sinensis plays a neuroprotective role in different neurodegenerative conditions, such as memory deficits in Alzheimer disease (AD). However, whether other teas from Camellia sinensis present similar neuroprotective effect still is not clear. Here we investigate effects of green, red and black tea supplementation on memory and hippocampus oxidative status in a rat model of Alzheimer-like disease (AD-like). Wistar male rats were supplemented with green, red or black tea during 8weeks before Aβ intra-hippocampal injection (2μL of Aβ-25-35, CA1 region). AD and sham rats were submitted to memory tests. After euthanasia, oxidative status in the bilateral hippocampus was quantified. Green and red teas avoid memory deficits in AD rats, but only green tea also avoids oxidative stress and damage in the hippocampus. Green tea was more effective for neuroprotection than red and black teas from the Camellia sinensis in the AD rat model. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pre-existing liver cirrhosis reduced the toxic effect of diethylene glycol in a rat model due to the impaired hepatic alcohol dehydrogenase.

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Ming Xing Huang; Xiao Mou Peng; Lin Gu; Gui Hua Chen

2011-09-01

Hepatic metabolizing enzymes of diethylene glycol (DEG) are impaired in liver diseases. Thus, the purpose of this study was to increase our understandings in metabolism and toxicology of DEG by clarifying the influences of pre-existing liver disease. Forty Sprague-Dawley rats with carbon tetrachloride-induced liver cirrhosis and 20 control rats were intraperitoneally administered a single dose of DEG, and randomly killed 1, 2, 5 or 8 days following exposure. Compared with control rats, the model rats had significantly higher blood CO(2)-combining power, lower blood urine nitrogen, serum creatinine and alanine aminotransferase levels on the second day and a lower mortality rate on the eighth day following DEG exposure. Enlargements of liver and kidneys and degeneration and necrosis of hepatocytes and renal tubules in the model rats was also less serious than in the control rats. Urine DEG levels were significantly higher on the first day in the model rats than the control rats (46.65 ± 8.79 mg vs 18.88 ± 6.18 mg, p activity in the model rats was significantly lower than that in the control rats, which was positively related to renal damage. The toxic effects of DEG in rats with pre-existing liver cirrhosis are significantly reduced, which may be due to the decreased hepatic ADH activity. It suggests that the metabolite of ADH is responsible for DEG poisoning, and this toxic metabolite may mainly originate in the liver.

Modeling the mechanical properties of liver fibrosis in rats.

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Zhu, Ying; Chen, Xin; Zhang, Xinyu; Chen, Siping; Shen, Yuanyuan; Song, Liang

2016-06-14

The progression of liver fibrosis changes the biomechanical properties of liver tissue. This study characterized and compared different liver fibrosis stages in rats in terms of viscoelasticity. Three viscoelastic models, the Voigt, Maxwell, and Zener models, were applied to experimental data from rheometer tests and then the elasticity and viscosity were estimated for each fibrosis stage. The study found that both elasticity and viscosity are correlated with the various stages of liver fibrosis. The study revealed that the Zener model is the optimal model for describing the mechanical properties of each fibrosis stage, but there is no significant difference between the Zener and Voigt models in their performance on liver fibrosis staging. Therefore the Voigt model can still be effectively used for liver fibrosis grading. Copyright © 2016 Elsevier Ltd. All rights reserved.

Establishment and application of rat model of acute β-irradiated skin injury

International Nuclear Information System (INIS)

Shen Guoliang; Lu Xing'an; Tang Jun; Wang Xiuzhen; Wu Shiliang; Tian Ye

2006-01-01

Objective: To establish an experimental rat model of acute β-irradiated skin injury and to study the effects of superoxide dismutase (SOD) on wound healing. Methods: Areas of buttock skin (20 mm x 40 mm) of 40 male SD rats were irradiated with 45 Gy/β-rays generated by linear accelerator, and then the forty rats were divided into two groups randomly: treatment group administrated with SOD (n=20) and control group administrated with normal saline (NS) (n=20). The wound healing time and rate were observed. The pathological changes were observed by light microscopy. The expressions of VEGF (vascular endothelial growth factor) and bFGF (basic fibroblast growth factor) were determined by SP immunohistochemical method. Results: The deep second-degree burns was observed following 45 Gy irradiation. The wound healing time in treatment group was shorter than that of the control group (P<0.05). Strongly positive (+ + +) expression of VEGF, bFGF in treatment group and positive (+ +) expression of VEGF, bFGF in the control group were observed 6 weeks, 7 weeks and 8 weeks after the irradiation, while only weakly positive (+) expressions of VEGF and bFGF in both groups 4 weeks, 5 weeks and 9 weeks after the irradiation. Conclusions: The wound model of acute β-irradiated skin injury in rat was established and used in study of the effect of medicine on wound healing. SOD can promote the wound healing of acute β-irradiated skin injury. (authors)

Characterization of liver changes in ZSF1 rats, an animal model of metabolic syndrome

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Marta Borges-Canha

Full Text Available Background: The non-alcoholic fatty liver disease is the hepatic counterpart of the metabolic syndrome. ZSF1 rats are a metabolic syndrome animal model in which liver changes have not been described yet. Aim: The characterization of liver histological and innate immunity changes in ZSF1 rats. Methods: Five groups of rats were included (n = 7 each group: healthy Wistar-Kyoto control rats (Ctrl, hypertensive ZSF1 lean (Ln, ZSF1 obese rats with a normal diet (Ob, ZSF1 obese rates with a high-fat diet (Ob-HFD, and ZSF1 obese rats with low-intensity exercise training (Ob-Ex. The animals were sacrificed at 20 weeks of age, their livers were collected for: a measurements of the area of steatosis, fibrosis and inflammation (histomorphological analysis; and b innate immunity (toll-like receptor [TLR] 2, TLR4, peroxisome proliferator-activated receptor γ [PPARγ], toll interacting protein [TOLLIP] and inflammatory marker (tumor necrosis factor-alpha [TNFvs], interleukin 1 [IL-1] expression analysis by real-time PCR. Results: Ob, Ob-HFD and Ob-Ex were significantly heavier than Ln and Ctrl animals. Ob, Ob-HFD and Ob-Ex animals had impaired glucose tolerance and insulin resistance. ZSF1 Ob, Ob-HFD and Ob-Ex presented a higher degree of steatosis (3,5x; p < 0.05 than Ctrl or ZSF1 Ln rats. Steatohepatitis and fibrosis were not observed in any of the groups. No differences in expression were observed between Ctrl, Ln and Ob animals (except for the significantly higher expression of TOLLIP observed in the Ob vs Ln comparison. Ob-HFD and Ob-Ex rats showed increased expression of PPARγ and TOLLIP as compared to other groups. However, both groups also showed increased expression of TLR2 and TLR4. Nevertheless, this did not translate into a differential expression of TNFα or IL-1 in any of the groups. Conclusion: The ZSF1 model is associated with liver steatosis but not with steatohepatitis or a significantly increased expression of innate immunity or

Study of genes associated with the 'anger-in' and 'anger-out' emotions of humans using a rat model.

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Guo, Yinghui; Zhang, Huiyun; Gao, Jie; Wei, Sheng; Song, Chunhong; Sun, Peng; Qiao, Mingqi

2015-04-01

The aim of the present study was to investigate the genes associated with 'anger-in' (tendency to suppress anger) and 'anger-out' (tendency to express anger through verbal or physical means) emotions in humans. Wistar rats were divided into five groups (n=10/group), based on the type of model and the Chinese medicinal formulation administered, and the rat models were established. The five groups were as follows: Normal control (control), anger-in model (AIM), anger-in Jingqianshu-administered (AIA), anger-out model (AOM) and anger-out Jingqianping-administered (AOA). Open-field, resident-intruder and aggressive behavior tests were carried out, as well as gene expression analysis, reverse transcription-quantitative polymerase chain reaction and western blot analyses. The body weights of the rats in the AIM and AOM groups were significantly lower than those of the control group rats. The open-field test indicated that the scores in the AOM group were significantly higher (Pemotions. Jingqianping and Jingqianshu granules attenuated the changes in the mRNA expression of 5-Htr2C , GABA B R2 and 5-Htr3B , as indicated by RT-qPCR, and showed similar effects on protein expression, as demonstrated by western blot analysis. The present study demonstrated that the anger-in and anger-out emotions of rats are closely associated with 5-Htr2C, GABA B R2 and 5-Htr3B genes, and that Jingqianshu and Jingqianping granules attenuate the abnormal behaviors of model rats. These findings may be useful for the treatment of emotional disorders associated with anger.

Microsurgical Bypass Training Rat Model: Part 2-Anastomosis Configurations.

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Tayebi Meybodi, Ali; Lawton, Michael T; Yousef, Sonia; Mokhtari, Pooneh; Gandhi, Sirin; Benet, Arnau

2017-11-01

Mastery of microsurgical anastomosis is key to achieving good outcomes in cerebrovascular bypass procedures. Animal models (especially rodents) provide an optimal preclinical bypass training platform. However, the existing models for practicing different anastomosis configurations have several limitations. We sought to optimize the use of the rat's abdominal aorta and common iliac arteries (CIA) for practicing the 3 main anastomosis configurations commonly used in cerebrovascular surgery. Thirteen male Sprague-Dawley rats underwent inhalant anesthesia. The abdominal aorta and the CIAs were exposed. The distances between the major branches of the aorta were measured to find the optimal location for an end-to-end anastomosis. Also, the feasibility of performing side-to-side and end-to-side anastomoses between the CIAs was assessed. All bypass configurations could be performed between the left renal artery and the CIA bifurcation. The longest segments of the aorta without major branches were 1) between the left renal and left iliolumbar arteries (16.9 mm ± 4.6), and 2) between the right iliolumbar artery and the aortic bifurcation (9.7 mm ± 4.7). The CIAs could be juxtaposed for an average length of 7.6 mm ± 1.3, for a side-to-side anastomosis. The left CIA could be successfully reimplanted on to the right CIA at an average distance of 9.1 mm ± 1.6 from the aortic bifurcation. Our results show that rat's abdominal aorta and CIAs may be effectively used for all the anastomosis configurations used in cerebral revascularization procedures. We also provide technical nuances and anatomic descriptions to plan for practicing each bypass configuration. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of unilateral 6-OHDA lesions on [3H]-N-propylnorapomorphine binding in striatum ex vivo and vulnerability to amphetamine-evoked dopamine release in rat

DEFF Research Database (Denmark)

Palner, Mikael; Kjaerby, Celia; Knudsen, Gitte M

2011-01-01

It has been argued that agonist ligands for dopamine D(2/3) receptors recognize a privileged subset of the receptors in living striatum, those which are functionally coupled to intracellular G-proteins. In support of this claim, the D(2/3) agonist [(3)H]-N-propylnorapomorphine ([(3)H]NPA) proved...... to be more vulnerable to competition from endogenous dopamine than was the antagonist ligand [(11)C]raclopride, measured ex vivo in mouse striatum, and subsequently in multi-tracer PET studies of analogous design. Based on these results, we predicted that prolonged dopamine depletion would result...... in a preferential increase in agonist binding, and a lesser competition from residual dopamine to the agonist binding. To test this hypothesis we used autoradiography to measure [(3)H]NPA and [(3)H]raclopride binding sites in hemi-parkinsonian rats with unilateral 6-OHDA lesions, with and without amphetamine...

A comparative behavioural study of mechanical hypersensitivity in 2 pain models in rats and humans.

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Reitz, Marie-Céline; Hrncic, Dragan; Treede, Rolf-Detlef; Caspani, Ombretta

2016-06-01

The assessment of pain sensitivity in humans has been standardized using quantitative sensory testing, whereas in animals mostly paw withdrawal thresholds to diverse stimuli are measured. This study directly compares tests used in quantitative sensory testing (pinpricks, pressure algometer) with tests used in animal studies (electronic von Frey test: evF), which we applied to the dorsal hind limbs of humans after high frequency stimulation and rats after tibial nerve transection. Both experimental models induce profound mechanical hypersensitivity. At baseline, humans and rats showed a similar sensitivity to evF with 0.2 mm diameter tips, but significant differences for other test stimuli (all P pain models (P pain sensitivity, but probe size and shape should be standardized. Hypersensitivity to blunt pressure-the leading positive sensory sign after peripheral nerve injury in humans-is a novel finding in the tibial nerve transection model. By testing outside the primary zone of nerve damage (rat) or activation (humans), our methods likely involve effects of central sensitization in both species.

A new model for the immobilization of the rat hind limb

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Coutinho E.L.

2002-01-01

Full Text Available An alternative device for the immobilization of the hind limb of the rat was developed to study the effects of chronic disuse on the soleus and tibialis anterior muscles, maintained for 3 weeks in the shortening and the stretching positions, respectively. The proposed device is made of steel mesh and cotton materials, and has some advantages when compared to cast or plaster cast: it is cheaper, lighter (12 g or 4% of the body weight of the rat and the same unit can be easily adjusted and used several times in the same animal or in animals of similar size. Immobilization is also useful to restrain the movements of the hip, knee, and ankle joints. Male rats (291 ± 35 g and aged 14 ± 2 weeks were used to develop and test the model. The soleus muscle of 18 rats was maintained in a shortened position for 21 consecutive days and lost 19 ± 7% of its length (P = 0.008 and 44 ± 6% of its weight (P = 0.002 compared to the contralateral intact muscle. No difference (P = 0.67 was found in the stretched tibialis anterior of the same hind limb when compared to the contralateral muscle. No ulcer, sore or foot swelling was observed in the animals. Immobilization was effective in producing chronic muscle disuse in the hind limbs of rats and is an acceptable alternative to the traditional methods of immobilization such as cast or plaster cast.

Disruption of model-based behavior and learning by cocaine self-administration in rats.

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Wied, Heather M; Jones, Joshua L; Cooch, Nisha K; Berg, Benjamin A; Schoenbaum, Geoffrey

2013-10-01

Addiction is characterized by maladaptive decision-making, in which individuals seem unable to use adverse outcomes to modify their behavior. Adverse outcomes are often infrequent, delayed, and even rare events, especially when compared to the reliable rewarding drug-associated outcomes. As a result, recognizing and using information about their occurrence put a premium on the operation of so-called model-based systems of behavioral control, which allow one to mentally simulate outcomes of different courses of action based on knowledge of the underlying associative structure of the environment. This suggests that addiction may reflect, in part, drug-induced dysfunction in these systems. Here, we tested this hypothesis. This study aimed to test whether cocaine causes deficits in model-based behavior and learning independent of requirements for response inhibition or perception of costs or punishment. We trained rats to self-administer sucrose or cocaine for 2 weeks. Four weeks later, the rats began training on a sensory preconditioning and inferred value blocking task. Like devaluation, normal performance on this task requires representations of the underlying task structure; however, unlike devaluation, it does not require either response inhibition or adapting behavior to reflect aversive outcomes. Rats trained to self-administer cocaine failed to show conditioned responding or blocking to the preconditioned cue. These deficits were not observed in sucrose-trained rats nor did they reflect any changes in responding to cues paired directly with reward. These results imply that cocaine disrupts the operation of neural circuits that mediate model-based behavioral control.

[Effects of telmisartan on resistin expression in a rat model of nonalcoholic steatohepatitis and insulin resistance].

Science.gov (United States)

Zhang, Qiuzan; Wang, Yanrong; Liu, Yingli; Yang, Qian; Wang, Xiuru; Wang, Qiang; Zhang, Chenming; Wang, Bangmao

2015-04-01

To investigate the effects of telmisartan on expression of resistin in serum and liver under conditions of nonalcoholic steatohepatitis (NASH) and insulin resistance using a rat model system. Forty-five male Sprague-Dawley rats were randomly divided into a normal control group (NC, n=10), a model control group (MC, n=15), a polyene phosphatidylcholine prevention group (PP, n=10), and a telmisartan prevention group (TP, n=10). The NC group was given a standard diet and the other groups were given a high-fat diet for 16 weeks in order to induce NASH. At the end of week 12, 5 rats in the MC group were sacrificed for pathology confirmation of the NASH model. At the end of week 12, the TP group was given telmisartan (8.0 mg/kg/d) and the PP group was given polyene phosphatidylcholine (8.4 mg/kg/d) for an additional 4 weeks by intragastric administration. At the end of week 16, all rats were sacrificed and body weights recorded. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglycerides (TG), resistin, insulin and fasting blood glucose were measured. The insulin resistance value, HOMA-IR, was assessed by homeostasis mode assessment. Liver expression of the resistin protein was detected by western blotting and of the resistin mRNA was detected by RT-PCR. The F test and LSD test were used for statistical analyses. Compared to the NC group, the body weight and HOMA-IR of rats in the MC group were significantly increased (Pinsulin resistance were significantly lower in the TP group than in the MC group of rats (all Pinsulin resistance in NASH rats by decreasing the expression of serum resistin, and liver resistin protein and mRNA.