An endogenous dopaminergic neurotoxin, N-methyl-(R)-salsolinol, induces DNA damage in human dopaminergic neuroblastoma SH-SY5Y cells

Abstract

Recently, an endogenous neurotoxin, 1(R),2(N)-dimethyl-6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline [N-methyl-(R)-salsolinol], was found to elicit parkinsonism in rats with selective depletion of dopamine neurons in the substantia nigra without necrotic tissue reaction. The mechanism of the cell death was examined by detection of DNA damage using a single-cell gel electrophoresis (comet) assay in human dopaminergic neuroblastoma SH-SY5Y cells. Only N-methylsalsolinol was found to induce DNA damage, whereas other catechol isoquinolines, such as (R)-salsolinol, (S)-salsolinol, and 1,2- dimethyl-6,7-dihydroxyisoquinolinium ion, did not. The (R)-enantiomer of N- methylsalsolinol damaged DNA much more profoundly than the (S)-enantiomer. Cycloheximide protected the cells from DNA damage, suggesting that an apoptotic process may account for the DNA damage. Morphological changes indicating apoptotic cell death were also confirmed. Antioxidants and deprenyl reduced DNA damage, indicating that the damage was initiated by oxidative stress and that neuroprotection by deprenyl may be partially ascribed to its prevention of DNA damage. Apoptosis induced by neurotoxins may be a mechanism underlying the cell death of dopamine neurons in the substantia nigra of Parkinson's disease.