1‐Benzyl‐1,2,3,4‐tetrahydroisoquinoline, a Parkinsonism‐inducing endogenous toxin, increases α‐synuclein expression and causes nuclear damage in human dopaminergic cells

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Abstract
1‐Benzyl‐1,2,3,4‐tetrahydroisoquinoline (1BnTIQ), an endogenous neurotoxin, is known to cause parkinsonism in rodents and nonhuman primates. The levels of 1BnTIQ in cerebrospinal fluid of patients with Parkinson's disease (PD) were reported to be three times higher than those in control subjects. In the present study, we have evaluated the effects of 1BnTIQ on α‐synuclein (α‐syn) expression together with biochemical and morphological changes in human dopaminergic SH‐SY5Y cells in culture. 1BnTIQ at lower concentrations (1–50 μM) increased α‐syn protein expression in a time‐ and dose‐dependent manner in these cells. There was also up‐regulation of α‐syn mRNA by 1BnTIQ. Inhibition of complex I by rotenone and depletion of glutathione by L‐buthionine sulfoxamine also correlated with an increase in α‐syn expression, suggesting that oxidative stress may cause an increase in α‐syn levels in dopaminergic cells. Furthermore, 1BnTIQ significantly depleted glutathione levels. 1BnTIQ at higher concentrations (500 μM) increased reactive oxygen species levels, decreased ATP levels, and caused nuclear damage in the cells. The 1BnTIQ‐induced α‐syn up‐regulation was inhibited by cotreatment with the antioxidants selegiline, coenzyme Q10, and N‐acetylcystein and the caspase inhibitor DEVD‐CHO. Taken together, these results suggest that α‐syn up‐regulation and oxidative stress are contributing factors in 1BnTIQ‐induced neurotoxicity in dopaminergic neurons in PD.