Antagonistic pleiotropic effects of nitric oxide in the pathophysiology of Parkinson's disease

• Published in: Free radical research 2015-09, Vol.49 (9), p.1129-1139
• Main Authors: Tripathy, D., Chakraborty, J., Mohanakumar, K. P.
• Format: Article
• Language: English
• Subjects: Animals; Basal Ganglia - metabolism; Brain - metabolism; Brain - pathology; Cell Proliferation; Disease Progression; Dopamine - metabolism; Dopaminergic Neurons - metabolism; drug target; Humans; Inflammation - metabolism; inflammatory mediators; Mice; Microglia - metabolism; Nerve Degeneration - metabolism; Neurodegenerative Diseases - metabolism; Neuroprotective Agents - pharmacology; Neurotoxins - metabolism; Nitric Oxide - metabolism; Nitric Oxide Synthase - metabolism; Oxidative Stress; Parkinson Disease - metabolism; Parkinson Disease - physiopathology; progressive neurodegeneration; reactive oxygen species; Reactive Oxygen Species - metabolism; Substantia Nigra - metabolism
• ISSN: 1071-5762; 1029-2470
• DOI: 10.3109/10715762.2015.1045505

Sporadic Parkinson's disease (PD) is a geriatric disorder with unknown etiology, specifically affecting the nigrostriatal dopaminergic (DA-ergic) pathway of the brain. Amongst several contributing factors, nitric oxide (NO*) is considered to inflict injury to DA-ergic neurons, and to influence PD progression. Supportive evidence for this comes from animal models of PD, where inhibitors of NO* synthase (NOS) are found to protect against DA-ergic neuronal death, and NOS-deficient mice are found to be resistant to PD-producing neurotoxins. Presence of nitrated proteins and upregulated levels of NOS in human postmortem PD brain samples have rendered further support to this contention. While NO* from neuronal NOS contributes to neurodegeneration in PD, NO* produced by inducible NOS from proliferating microglia as inflammatory responses to neuronal insults are suggested to mediate the disease progression. Another view that NO* in small doses serves as a neuroprotective agent in the brain is also discussed, in light of experimental evidence available in vitro and in vivo. This view is based on the argument that NO* could form harmless nitrites and nitrates on reaction with endogenously produced reactive oxygen species (ROS) within the cells. This review essentially discusses the possibilities of considering NO* as a secondary response of DA-ergic cell death, while oxidative stress is the primary cause. Once neurons undergo death processes following uncontrolled oxidative insult, the resulting gliosis-mediated NO* accelerates the events as a secondary mediator. Since the time of initiation of DA-ergic cell death cannot be predicted, NO* could be an ideal molecular target to halt the disease progression.