DNA strand scission and PC12 cell death induced by salsolinol and copper

The naturally occurring neurotoxin, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol; SAL), has been speculated to contribute to Parkinson's disease and neuropathology of chronic alcoholism. In the present study, we found the capability of SAL to cause DNA cleavage in the presence of Cu(ll). Incubation of SAL and CuCl2 with calf thymus DNA caused strand breaks. Likewise, SAL in combination with Cu(ll) mediated the strand scission in øX174 RFI supercoiled DNA in a time-related manner. Neither Cu(ll) nor the catechol alone induced any appreciable DNA cleavage. The reaction of SAL with Cu(ll) was accompanied by the reduction of Cu(ll) to Cu(I). Furthermore, SAL induced cell death in cultured PC12 cells, which was exacerbated by Cu(ll). From these data, it seems likely that SAL undergoes redox cycling catalyzed by Cu(ll) to generate reactive species which may be responsible for the neurotoxic action of this catechol isoquinoline.