PATHOGENESIS OF NEURODEGENERATIVE DISEASES AND THE EFFECT OF NATURAL PRODUCTS ON NITRIC OXIDE PRODUCTION IMPLICATING IN THESE DISEASES

Nitric oxide (NO) is a free radical synthesized from L-arginine by three isoforms of NO synthase (NOS). NO is involved in a wide range of physiological functions. It functions as neurotransmitter by modulating the release of glutamate and the neurotransmission of N-methyl-D-aspartate (NMDA) receptor, as neuro-endothelial-derived relaxing factor through the action on guanylyl cyclase (sGC), and as inflammatory molecule in response to proinflammatory cytokines or bacterial endotoxin. NO is also implicated in multiple pathological conditions such as acute and chronic neurodegenerative. In spite of the different mechanisms of pathogenesis for these neurodegenerative diseases, NO may play a pivotal role in the pathological conditions of these diseases. Under pathological conditions, NO is produced either from activated neuronal NOS (nNOS) in neuron or inducible NOS (iNOS) in glial cells by increased intracellular calcium concentration through glutamate-NMDA receptor interaction or by inflammatory cytokinemediated signaling pathway, respectively. NO and its toxic metabolite peroxynitrite (ONOO) directly injure membrane integrity or impair mitochondrial function leading to DNA break, lipid peroxidation, and protein nitrosylation. These events consequently activate caspase-cascade or poly-(ADP-ribose) polymerase 1 (PARP) resulting in apoptotic or necrotic cell death. Much effort is devoted to search the specific inhibitors of NOS from natural resource as neuroprotectants. We summarized here the reported natural products that target NO/NOS pathway by blocking iNOS expression, attenuating the activity of nNOS, disturbing upstream signaling of nNOS, scavenging ONOO(superscript -), or inhibiting tyrosine nitration. These natural products may offer possible therapeutics to prevent and/or to treat these neurodegenerative diseases.