[Intrathecal infusion of brain-derived neurotrophic factor protects nigral dopaminergic neurons from degenerative changes in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced monkey parkinsonian model].
Protective effect of BDNF on nigrostriatal dopaminergic neurons was evaluated with MPTP-induced parkinsonian model in monkey. Twelve adult female Japanese monkeys weighing about 7kg were lesioned with systemic infusion of MPTP according to the following dosing schedules. Group I: normal control (n = 2), group II: continuous infusion of 15mg of MPTP with osmotic minipump (Alzet: 2ML2, mean pumping rate 5 microliters/hour) for 14 days (n = 2), group III: bolus injections of 5mg of MPTP on day 0, 4 and 7 (n = 2), group IV: bolus injections of 5mg of MPTP on day 0 and 4 (n = 6). Half of the animals in each groups except groupI were treated with BDNF, and the other half served as control. In BDNF-treated animals, total 6.5 ml of conditioned culture medium of Chinese hamster ovary containing 1 micrograms protein/ml of BDNF was administered into cisterna magna by osmotic minipump (Alzet: 2ML2) implanted on day 0. Culture medium without BDNF activity was also administered to control animals in the same manner. Neurological findings were evaluated with the Monkey Parkinsonism Rating Scale (MPRS) by Kurlan et al. The animals were sacrificed on day 14 and histological findings of the pars compacta was investigated. All the animals in group I and II showed no symptoms during the experimental periods. Severe parkinsonism was observed in animals regardless of BDNF treatment in group III. In group IV, non-treated animals suffered parkinsonism at the end of the 1st week and deteriorated in the 2nd week. In contrast, BDNF-treated animals stayed asymptomatic during the 1st week and developed parkinsonism in the 2nd week. There were significant differences for MPRS between BDNF-treated and non-treated animals after day 6. Severe neuronal loss was observed in the parkinsonian animals in accordance with clinical symptoms. Neuronal loss was significantly milder in the BDNF-treated animals. These results revealed a protective effect of BDNF on dopaminergic neurons in MPTP-lesioned primates.
Takeda
M
M
Department of Neurosurgery, Hokkaido University School of Medicine, Sapporo, Japan.
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor; D006224:Cricetinae; D004195:Disease Models, Animal; D005260:Female; D007278:Injections, Spinal; D008251:Macaca; D009419:Nerve Tissue Proteins / Q000008:administration & dosage*; D009474:Neurons / Q000473:pathology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology
D019208:Brain-Derived Neurotrophic Factor; D009419:Nerve Tissue Proteins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine