Several mediators of neurodegeneration have been found so far, one such being nitric oxide (NO). NO is a novel neuronal messenger molecule. NO was initially noted for its effects on the vascular smooth muscle after being released from the endothelium. The identification of NO as a gaseous, non-conventional neurotransmitter has lead to splurge of studies about the involvement of NO in the physiological and pathophysiologic processes in the immune and nervous system.

There are three known isoforms of nitric oxide synthase (NOS) responsible for the production of NO in vivo viz. neuronal NOS (nNOS), endothelial NOS (eNOS) - responsible for cardiovascular actions, and inducible NOS (iNOS) - originally found in macrophages and involved mainly in immunological processes. Although all forms can be found in the CNS, the neurotransmission can be attributed primarily to the NO produced by nNOS located in the neurons. NO is produced from L-Arginine and oxygen by nitric oxide synthase (NOS). The production of NO from L-Arginine by nNOS is a Ca2+ - calmodulin dependant process and is stimulated by activation of the N-Methyl D-Aspartate (NMDA) receptors, which are known for allowing influx of Ca2+ ions. iNOS action is also Ca2+ independent and releases excess amounts of NO for a long duration upon induction. Since nitric oxide being directly or indirectly implicated in several processes that lead to neurodegeneration several mechanisms are speculated.

Reactive nitrogen species are generated by the biochemical reactions of NO or by enzymatic catalysis of NO metabolism. NO reacts with the superoxide anion generated through dopamine metabolism and mitochondrial aerobic respiration to form peroxy nitrate ion (ONOO-). In the presence of cupric ions, ONOO- is heterolytically cleaved to form hydroxyl radical and nitronium cation. During mitochondrial dysfunction and glutamate excitotxicity, the excessive intracellular calcium accumulation leads to over-activation of calcium dependant enzymes, such as nNOS. Then again, the excess NO so produced reacts with superoxide to form ONOO-. NO and peroxynitrate ion mediate several free radical reactions, causing oxidative stress. NO is also generated by NMDA receptor-mediated activation of NOS through Ca2+ ions, causing degeneration of neighboring neurons. Activation of excitatory receptors results in an influx of calcium, followed by activation of nNOS which finally leads to generation of ONOO?. Inhibition of nNOS has shown neuroprotective effects in primates in the MPTP model of neurodegeneration.

Astrocytes and microglia, the surrounding glial cells in the brain show increased expression of iNOS which produces sustained high levels of NO, when activated by the cytokines. Activation of microglia contributes to release of pro inflammatory cytokines, nitric oxide and reactive oxygen intermediates through increased arachidonic acid synthesis. The pro inflammatory cytokines such as TNF-a and IL-6 have also been found to up regulate the expression of iNOS. At higher concentrations or progressive generation, NO has also been reported to be mediate apoptosis through caspase activation. A mechanism proposed suggests inhibition of caspase-3 by NO by nitrosylation of cysteine. Apoptosis can also be triggered the DNA damage caused by ONOO-.

In the recent years, nitric oxide has emerged from a neuromodulators to a mediator in neurodegeneration. It has been found to play a pivotal role not only in the exacerbation of the neuronal damage but also initiating the process. Therapies directed towards controlling the nitric oxide level may prove useful. Selective NOS inhibitors, free radical scavengers and glutamate receptor antagonists may prove useful in nueroprotective therapy.

- (The authors are with Pharmacy Group, Birla Institute of Technology and Science, India)