NO, a molecular messenger synthesized by NOS from L-arginine and molecular oxygen, is thought to have a function in memory and in long-term potentiation. At high concentrations NO is neurotoxic and may play a role in neurodegeneration.  AD and PD are thought to be associated with increased microglial activity, suggesting that NO production may be increased.

NO, the free radical neuromodulator, has been implicated as a neurotoxin. Neurons containing NOS also contain NADPH-diaphorase and are resistant to NO toxicity. NADPH-diaphorase -containing neurons within the striatum are spared in patients with PD and AD. The possible involvement of NO in the neuropathogenesis of striatal derangement is discussed. Major focus is also placed on three structurally distinct isoforms of NOS included neuronal (nNOS), endothelial (eNOS) and inducible (iNOS). Both disorders involve increased oxidative stress, metabolic impairment and abnormal protein aggregation. An     early event in AD that is believed to trigger synaptic dysfunction and neuronal death is the increased production and aggregation of amyloid beta-peptide. The deposition of beta-amyloid peptides in the brain in form of senile plaque is the key event responsible for AD pathology. Among various mechanisms that have been proposed to explain the neurotoxicity of beta-amyloid deposits, a new one suggests recently that beta-amyloid peptides may be indirectly toxic for neurons by activating microglial cells to produce NO by type 1 NOS.  NO generation is also synergically induced by beta-amyloid peptide and cytokines in astrocytes, the effect of beta-amyloid peptide is due to the induction of the expression of the gene of inducible NOS. These astrocytes, activated by deposited beta-amyloid peptides and cytokines, may play a role in neuronal damage via the indirect NO mechanism. The high-output pathway of NO production expressed by NOS2 in vivo may also contribute to pathogenesis in AD. Several lines of evidence suggest that the endothelial constitutive NOS may have a role in AD.  NO production by microglial cells, astrocytes, and brain microvessels is enhanced in patients with AD. There is growing evidence that NO is involved in neuronal death in AD, and the oxidative stress caused by NO in the brain could be a pathogenic mechanism    in AD.

Remarkable efforts are being made to elucidate the dominant factors that result in the pathogenesis of AD&PD.  Growing data from experimental models and human brain studies suggest that oxidative/nitrative stresses are prominent features of these diseases and subsequent protein modifications resulting from oxidative/nitrative damage contribute to the formation of intracytoplasmic inclusions characteristic of each disease. Inflammatory reaction is thought to be an important contributor to neuronal damage in AD&PD. Among the toxic agents released in brain tissues by activated cells, we focus attention in this review on NO, elucidating the pathways important in the production of and defense from free radicals may lead to insight in developing new pharmacologic strategies.