Neuroprotection by silencing iNOS expression in a 6-OHDA model of Parkinson's disease.
In this study, we investigated the protective role of silenced iNOS expression in neuron death in the nigrostriatal pathway in a 6-OHDA animal model of Parkinson's disease (PD). The animal model was established by intrastriatal infusion of a single dose of 6-OHDA. Silencing of iNOS expression was established by intrastriatal infusion of adenovirus-carried iNOS-targeted small interfering RNA (siRNA). Apomorphine-induced rotation behavior was measured. Expression of iNOS, OX-42, and TH; levels of DA, DOPAC, and HVA in the striatum; and the levels of p53 phosphorylation, Bax, and cleaved caspase-3 (CC3) in the substantia nigra were measured. We demonstrated that co-infusion of 6-OHDA with adenovirus expressing siRNA of iNOS blocked the activation of microglia, iNOS transcription, and p53-Bax-CC3 apoptotic cascade as well as significantly blocking 6-OHDA-induced decreases in DA, DOPAC, HVA, and TH levels and effectively decreased rotation number. Our study highlighted the role of iNOS in the neurodegeneration of nigrostriatal dopaminergic neurons in the 6-OHDA animal model of PD and suggested that the microglial activation-iNOS-p53-Bax-CC3 apoptotic pathway plays a key role in the neurodegeneration in the 6-OHDA model.
Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, People's Republic of China.
Min
M
Li
Fu-rong
FR
Dai
Xiao-ping
XP
Du
Qi-dong
QD
Yang
Yuxiang
Y
Chen
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001058:Apomorphine / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D003342:Corpus Striatum / Q000166:cytology; D059290:Dopaminergic Neurons / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013565:Sympatholytics / Q000633:toxicity; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000978:Antiparkinson Agents; D034741:RNA, Small Interfering; D013565:Sympatholytics; D016159:Tumor Suppressor Protein p53; D016627:Oxidopamine; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D001058:Apomorphine