Neuroprotection by Silencing iNOS Expression in a 6-OHDA Model of Parkinson’s Disease

Abstract

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.