Cell death of dopamine neurons in aging and Parkinson's disease

Dopamine neurons in the substantia nigra of human brain are selectively vul nerable and the number decline by aging at 5-10% per decade. Enzymatic and non-enzymatic oxidation of dopamine generates reactive oxygen species, whic h induces apoptotic cell death in dopamine neurons. Parkinson's disease (PD ) is also caused by selective cell death of dopamine neurons in this brain region. The pathogenesis of Parkinson's disease remains to be an enigma, bu t it was found that an endogenous MPTP-like neurotoxin, 1(R), 2(N)dimethyl- 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [N-methyl(R)salsolinol, NM(R)S al], may be one of the pathogenic agents of PD. NM(R)Sal increases in cereb rospinal fluid from untreated parkinsonian patients, and two enzymes, a (R) salsolinol synthase and a neutral N-methyltransferase, synthesize this neur otoxin in the nigro-striatum. The activity of a neutral N-methyltransferase is significantly higher in lymphocytes from parkinsonian patients than in control. The mechanism of cell death by this toxin was proved to be by the induction of apoptosis, by use of dopaminergic SH-SY5Y cells. The apoptosis was suppressed by anti-oxidants, suggesting that the generation of reactiv e oxygen species may initiate cellular death process. These results indicat e that in aging and PD oxidative stress induces degeneration of dopamine ne urons, and the antioxidant therapy may delay the decline of dopamine neuron s in the brain. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.