Peroxynitrite and mitochondrial dysfunction in the pathogenesis of Parkinson's disease.
Nitric oxide (NO), in excess, behaves as a cytotoxic substance mediating the pathological processes that cause neurodegeneration. The NO-induced dopaminergic cell loss causing Parkinson's disease (PD) has been postulated to include the following: an inhibition of cytochrome oxidase, ribonucleotide reductase, mitochondrial complexes I, II, and IV in the respiratory chain, superoxide dismutase, glyceraldehyde-3-phosphate dehydrogenase; activation or initiation of DNA strand breakage, poly(ADP-ribose) synthase, lipid peroxidation, and protein oxidation; release of iron; and increased generation of toxic radicals such as hydroxyl radicals and peroxynitrite. NO is formed by the conversion of L-arginine to L-citrulline by NO synthase (NOS). At least three NOS isoforms have been identified by molecular cloning and biochemical studies: a neuronal NOS or type 1 NOS (nNOS), an immunologic NOS or type 2 NOS (iNOS), and an endothelial NOS or type 3 NOS (eNOS). The enzymatic activities of eNOS or nNOS are induced by phosphorylation triggered by Ca(2+) entering cells and binding to calmodulin. In contrast, the regulation of iNOS seems to depend on de novo synthesis of the enzyme in response to a variety of cytokines, such as interferon-gamma and lipopolysaccharide. The evidence that NO is associated with neurotoxic processes underlying PD comes from studies using experimental models of this disease NOS inhibitors can prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Furthermore, NO fosters dopamine depletion, and the said neurotoxicity is averted by nNOS inhibitors such as 7-nitroindazole working on tyrosine hydroxylase-immunoreactive neurons in substantia nigra pars compacta. Moreover, mutant mice lacking the nNOS gene are more resistant to MPTP neurotoxicity when compared with wild-type littermates. Selegiline, an irreversible inhibitor of monoamine oxidase B, is used in PD as a dopaminergic function-enhancing substance. Selegiline and its metabolite, desmethylselegiline, reduce apoptosis by altering the expression of a number of genes, for instance, superoxide dismutase, Bcl-2, Bcl-xl, NOS, c-Jun, and nicotinamide adenine nucleotide dehydrogenase. The selegiline-induced antiapoptotic activity is associated with prevention of a progressive reduction of mitochondrial membrane potential in preapoptotic neurons. As apoptosis is critical to the progression of neurodegenerative disease, including PD, selegiline or selegiline-like compounds to be discovered in the future may be efficacious in treating PD.
Ebadi
Manuchair
M
Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND 58203, USA. mebadi@medicine.nodak.edu
Sharma
Sushil K
SK
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D053938:DNA Fragmentation; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D004298:Dopamine / Q000172:deficiency / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051843:Synucleins
D005609:Free Radicals; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D051843:Synucleins; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D000080242:8-Hydroxy-2'-Deoxyguanosine; D019001:Nitric Oxide Synthase; D003849:Deoxyguanosine; D004298:Dopamine