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Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease

SCIENCE 2000年第5492期290卷 767-773页

作者： Kordower, JH Emborg, ME Bloch, J Ma, SY Chu, YP Leventhal, L McBride, J Chen, EY Palfi, S Roitberg, BZ Brown, WD Holden, JE Pyzalski, R Taylor, MD Carvey, P Ling, ZD Trono, D Hantraye, P Déglon, N Aebischer, P Rush Presbyterian St Lukes Med Ctr Dept Neurol Sci Chicago IL 60612 USA Rush Presbyterian St Lukes Med Ctr Dept Pharmacol Chicago IL 60612 USA Univ Lausanne Sch Med Div Surg Res Lausanne Switzerland Univ Lausanne Sch Med Gene Therapy Ctr Lausanne Switzerland Univ Wisconsin Dept Med Phys Madison WI 53706 USA Univ Wisconsin Dept Radiol Madison WI 53706 USA Univ Geneva Fac Med Dept Genet & Microbiol Geneva Switzerland Serv Hosp Frederic Joliot CEA Dept Rech Med Direct Rech MedCNRSUnite Rech Associe 2210 Orsay France Ecole Polytech Fed Lausanne Swiss Fed Inst Technol CH-1015 Lausanne Switzerland

Lentiviral delivery of glial cell Line-derived neurotrophic factor (Lenti-GDNF) was tested for its trophic effects upon degenerating nigrostriatal neurons in nonhuman primate models of Parkinson's disease (PD). We injected lenti-GDNF into the striatum and substantia nigra of nonlesioned aged rhesus monkeys or young adult rhesus monkeys treated 1 week prior with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Extensive GDNF expression with anterograde and retrograde transport was seen in all animals. In aged monkeys, Lenti-GDNF augmented dopaminergic function. In MPTP-treated monkeys, lenti-GDNF reversed functional deficits and completely prevented nigrostriatal degeneration. Additionally, Lenti-GDNF injections to intact rhesus monkeys revealed Long-term gene expression (8 months). In MPTP-treated monkeys, lenti-GDNF treatment reversed motor deficits in a hand-reach task. These data indicate that GDNF delivery using a Lentiviral vector system can prevent nigrostriatal degeneration and induce regeneration in primate models of PD and might be a viable therapeutic strategy for PD patients.

关键词： 1-甲基-4-苯基-1 2 3 6-四氢吡啶衰老抗原 CD/分析二羟苯丙氨酸/类似物和衍生物二羟苯丙氨酸/代谢疾病模型动物多巴胺/代谢基因表达遗传载体胶质细胞源性神经营养因子慢病毒属/遗传学猕猴新纹状体/代谢新纹状体/病理学神经变性/预防和控制神经生长因子类神经组织蛋白质类/遗传学神经组织蛋白质类/代谢神经组织蛋白质类/治疗应用神经元/酶学帕金森病/代谢帕金森病/病理学帕金森病/病理生理学帕金森病/治疗帕金森障碍/代谢帕金森障碍/病理学帕金森障碍/病理生理学帕金森障碍/治疗精神运动性行为黑质/代谢黑质/病理学酪氨酸单氧化酶/代谢动物女(雌)性

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Striatal fosB expression is causally linked with L-DOPA-induced abnormal involuntary movements and the associated upregulation of striatal prodynorphin mRNA in a rat model of Parkinson's disease

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NEUROBIOLOGY OF DISEASE 1999年第6期6卷 461-474页

作者： Andersson, M Hilbertson, A Cenci, MA Univ Lund Dept Physiol Sci Div Neurobiol Wallenberg Neurosci Ctr S-22362 Lund Sweden

Rats with unilateral dopamine-denervating lesions sustained a 3-week treatment with a daily L-DOPA dose that is in the therapeutic range for Parkinson's disease. In most of the treated animals, chronic L-DOPA administration gradually induced abnormal involuntary movements affecting cranial, trunk, and limb muscles on the side of the body contralateral to the lesion. This effect was paralleled by an induction of FosB-like immunoreactive proteins in striatal subregions somatotopically related to the types of movements that had been elicited by L-DOPA. The induced proteins showed both regional and cellular colocalization with prodynorphin mRNA. Intrastriatal infusion of fosB antisense inhibited the development of dyskinetic movements that were related to the striatal subregion targeted and produced a local specific downregulation of prodynorphin mRNA. These data provide compelling evidence of a causal role for striatal fosB induction in the development of L-DOPA-induced dyskinesia in the rat and of a positive regulation of prodynorphin gene expression by FosB-related transcription factors. (C) 1999 Academic Press.

关键词：反义成分(遗传学)/药理学细菌蛋白质类/遗传学细菌蛋白质类/代谢生物学标记细胞计数疾病模型动物运动失调/病理生理学脑啡肽类/遗传学左旋多巴/药理学新纹状体/药物作用新纹状体/代谢神经变性/化学诱导神经元/细胞学神经元/药物作用帕金森障碍/病理生理学蛋白质前体/遗传学原癌基因蛋白质c-fos RNA 信使/分析 RNA 信使/代谢大鼠 Sprague-Dawley 黑质/细胞学黑质/药物作用转录因子腹侧被盖区/细胞学腹侧被盖区/药物作用动物女(雌)性大鼠

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Nigrostriatal collaterals to thalamus degenerate in parkinsonian animal models

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ANNALS OF NEUROLOGY 2001年第3期50卷 321-329页

作者： Freeman, A Ciliax, B Bakay, R Daley, J Miller, RD Keating, G Levey, A Rye, D Emory Univ Dept Neurol Atlanta GA 30322 USA Rush Presbyterian St Lukes Med Ctr Chicago IL 60612 USA

Movement, cognition, emotion, and positive reinforcement are influenced by mesostriatal, mesocortical, and mesolimbic dopamine systems. We describe a fourth major pathway originating from mesencephalic dopamine neurons: a mesothalamic system. The dopamine transporter, specific to dopamine containing axons, was histochemically visualized in thalamic motor and limbic-related nuclei and regions that modulate behavioral state as opposed to sensory nuclei in rats, nonhuman primates, and humans. Anatomical tracing established this innervation's origin via axon collaterals from the mesostriatal pathway. These findings implicate the thalamus as a novel site for disease specific alterations in dopamine neurotransmission, such as exist with nigral. degeneration attending Parkinson's disease. This was confirmed in hemiparkinsonian animals where reduction of thalamic dopamine innervation occurred coincident with signs of active axonal degeneration. Individual mesencephalic dopamine neurons therefore have the potential to modulate normal and pathologic behavior not only through traditional nigrostriatal. pathways but also by way of axon collaterals that innervate the thalamus.

关键词：载体蛋白质类/代谢纹状体/病理学纹状体/病理生理学疾病模型动物多巴胺/代谢多巴胺质膜转运蛋白质类恒河猴膜糖蛋白类膜转运蛋白质类神经组织蛋白质类神经通路/病理学神经通路/病理生理学帕金森障碍/病理学帕金森障碍/病理生理学大鼠 Sprague-Dawley 黑质/病理学黑质/病理生理学丘脑/病理学丘脑/病理生理学动物人类大鼠

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Modern medical therapy for idiopathic Parkinson syndrome

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ANAESTHESIST 2000年第1期49卷 43-50页

作者： Gasser, T Univ Munich Klinikum Grosshadern Neurol Klin D-81377 Munich Germany

Die Ätiologie der Erkrankung ist unbekannt. Ähnlich wie bei der Alzheimer-Demenz stützt jedoch die Identifizierung seltener monogener, autosomal dominant oder rezessiv erblicher Formen die Hypothese, daß genetische Faktoren bei der Krankheitsentstehung eine wichtige Rolle spielen, obwohl bei der großen Mehrzahl der Patienten keine weiteren Familienangeörigen betroffen sind.

关键词：抗震颤麻痹药/治疗应用帕金森障碍/药物疗法帕金森障碍/病理生理学人类

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Motor slowing and parkinsonian signs in aging rhesus monkeys mirror human aging

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JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES 2000年第10期55卷 B473-B480页

作者： Zhang, ZM Andersen, A Smith, C Grondin, R Gerhardt, G Gash, D Univ Kentucky Coll Med Med Ctr Dept Anat & Neurobiol Lexington KY 40536 USA Univ Kentucky Coll Med Dept Neurol Lexington KY 40536 USA Univ Kentucky Coll Med Magnet Resonance Imaging & Spect Ctr Lexington KY 40536 USA Univ Colorado Hlth Sci Ctr Dept Pharmacol Neurosci Training Program Denver CO 80262 USA Univ Colorado Hlth Sci Ctr Dept Psychiat Neurosci Training Program Denver CO 80262 USA Univ Colorado Hlth Sci Ctr Rocky Mt Ctr Sensor Technol Denver CO 80262 USA

Motor slowing is a universal feature of human aging, and parkinsonian signs are commonly expressed in human senescence. In the present study, age-associated declines in motor functions in 31 female rhesus monkeys were quantified by activity monitors and an automated test panel, and the incidence of parkinsonian signs was scored using a movement dysfunction assessment scale. Activity levels in middle-aged monkeys (12-17 years old) were less than half that of young animals (5-8 years old) and were further depressed in aged monkeys (21-27 years old). Movement dysfunction scores increased significantly with increasing age. Two or more parkinsonian signs were exhibited by 20% of the middle-aged monkeys and 36% of the aged monkeys. slowing performance times on fine-motor hand tasks correlated significantly with increasing age. Motor learning was seen in all age groups, but improved faster in the young monkeys. The data suggest that aging rhesus monkeys provide an appropriate model to analyze the biological processes leading to motor slowing and the expression of parkinsonian signs in human senescence.

关键词：衰老/生理学衰老/心理学前肢/生理学学习/生理学猕猴/生理学运动活动/生理学运动(Movement)/生理学帕金森障碍/病理生理学反应时间动物人类

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Magnetic resonance imaging and proton spectroscopic alterations correlate with parkinsonian signs in patients with cirrhosis

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GASTROENTEROLOGY 2000年第3期119卷 774-781页

作者： Spahr, L Vingerhoets, F Lazeyras, F Delavelle, J DuPasquier, R Giostra, E Mentha, G Terrier, F Hadengue, A Univ Hosp Div Gastroenterol CH-1211 Geneva 14 Switzerland Univ Hosp Div Hepatol CH-1211 Geneva Switzerland Univ Hosp Dept Neurol CH-1211 Geneva 14 Switzerland Univ Hosp Dept Radiol CH-1211 Geneva 14 Switzerland Univ Hosp Transplantat Unit CH-1211 Geneva 14 Switzerland

Background & Aims: The relationship between abnormalities found by magnetic resonance imaging (MRI) and proton spectroscopy (MRS) and the clinical signs of hepatic encephalopathy is not well characterized. Motor disturbances have been described, suggesting that basal ganglia (BG) are altered. Methods: We evaluated 19 unselected consecutive patients with biopsy-proven cirrhosis evaluated for liver transplantation for the presence of parkinsonian signs using the Unified Parkinson's Disease Rating Scale (UPDRS) and Purdue Pegboard test, and correlated these neurologic abnormalities with MRI and MRS studies, Brain MRI intensities were expressed as signal-to-noise ratios. MRS findings obtained from one voxel in the BG and one in the occipital white matter (WM) were expressed as metabolite ratios. Six healthy subjects had normal values, Results: Compared with healthy subjects, patients with subclinical or grade 1 hepatic encephalopathy had hyperintensity in occipital WM and all BG tissues except thalamus and reduced Ino/Cr and Cho/Cr ratios in both voxels. In the BG, MRI intensity was correlated with the UPDRS (P < 0.05, r = 0.56), The Cho/Cr ratio also correlated with both UPDRS (P < 0.02, r = -0.59) and Pegboard scores (P < 0.02, r = 0.61). Conclusions: in cirrhosis, parkinsonian signs correlate with BG alterations detected by MRI and MRS.

关键词：脑/病理学肝性脑病/诊断肝性脑病/病理生理学肝性脑病/心理学肝硬化/诊断肝硬化/病理生理学肝硬化/心理学肝硬化/外科学肝移植磁共振成像磁共振波谱学神经病学检查帕金森障碍/病理生理学帕金森障碍/心理学前瞻性研究精神病状态评定量表成年人女(雌)性人类男(雄)性中年人

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Spinocerebellar ataxia type 2 presenting as familial levodopa-responsive parkinsonism

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ANNALS OF NEUROLOGY 2001年第6期50卷 812-815页

作者： Shan, DE Soong, BW Sun, CM Lee, SJ Liao, KK Liu, RS Taipei Vet Gen Hosp Inst Neurol Taipei 11217 Taiwan Taipei Vet Gen Hosp Natl PET Cyclotron Ctr Taipei 11217 Taiwan Natl Yang Ming Univ Dept Neurol Taipei 112 Taiwan Natl Yang Ming Univ Dept Phys Therapy Taipei 112 Taiwan

A genetic analysis identified 2 patients, approximately one-tenth of our patients with familial parkinsonism, who had expanded trinucleotide repeats in SCA2 genes. The reduction of F-18-dopa distribution in both the putamen and caudate nuclei confirmed that the nigrostriatal dopaminergic system was involved in parkinsonian patients with SCA2 mutation.

关键词：脑/代谢脑/病理生理学脑/放射性核素显像中国氟放射性同位素/代谢步态左旋多巴/类似物和衍生物左旋多巴/代谢神经组织蛋白质类帕金森障碍/诊断帕金森障碍/药物疗法帕金森障碍/遗传学帕金森障碍/病理生理学系谱蛋白质类/遗传学脊髓小脑共济失调/诊断脊髓小脑共济失调/遗传学脊髓小脑共济失调/病理生理学体层摄影术发射型计算机三核苷酸重复/遗传学成年人老年人女(雌)性人类男(雄)性中年人

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