Increased vulnerability of parkin knock down PC12 cells to hydrogen peroxide toxicity: The role of salsolinol and NM-salsolinol

Dopamine-derived neurotoxins, 1-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (salsolinol) and 1(R),2(N)-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (NM-salsolinol) are the two most possible 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-like endogenous neurotoxin candidates that involved in the pathogenesis of Parkinson’s disease (PD). The levels of endogenously synthesized salsolinol and NM-salsolinol are increased in the cerebrospinal fluid (CSF) of PD patients. Both of them lead to neurotoxicity in dopaminergic cells by inhibiting mitochondrial electron transport chain. To study the role of salsolinol and NM-salsolinol in Parkin deficiency-induced dopaminergic cell damage, we determined the cellular level of oxidative stress, the formation of salsolinol and NM-salsolinol, the level of mitochondrial damage and cell viability with/without the presence of exogenous H2O2 using differentiated dopaminergic PC12 cells. Our data show that parkin knock down elevates cellular oxidative stress, salsolinol and NM-salsolinol levels, which are responsible for the higher cell mortality in Parkin-deficient cells upon exposure to exogenous H2O2. The level of mitochondrial membrane potential loss, cristae disruption and the release of cytochrome c increased significantly along with the increased level of salsolinol and NM-salsolinol, whereas compared to parkin knock down cells in the presence of H2O2, the mitochondrial damage and higher cell mortality were both diminished when the levels of salsolinol and NM-salsolinol was reduced. The results not only indicate the elevated level of salsolinol and NM-salsolinol, but also reveal the potential role of salsolinol and NM-salsolinol in parkin knock down-induced cell vulnerability. We assume that parkin deficiency is the trigger of excessive oxidative stress, elevated endogenous neurotoxin levels and mitochondrial damage, which eventually results in cell death of dopaminergic cells.

► Parkin-deficient PC12 showed vulnerability to H2O2.
► The vulnerability to H2O2 is related to high salsolinol and NM-sasolinol levels.
► High salsolinol and NM-salsolinol cause cell death via mitochondrial damage.