Studies on the interaction of roxindole with brain monoamine oxidases and dopaminergic neurones in vitro and in vivo.

Roxindole, a structurally novel psychotropic indolylbutyl-4-phenyltetrahydropyridine, was studied with respect to the formation of potentially neurotoxic pyridinium metabolites in comparison to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). In contrast to MPTP, roxindole failed to serve as a substrate for monoamine oxidases (MAO) from mouse, monkey and human brain in vitro. Accordingly, neither the putative MAO-oxidation product of roxindole (ROX+) nor MPP+ (1-methyl-4-phenylpyridinium ion) was detected in mouse striatum after high subcutaneous doses of roxindole in spite of the presence of approximately 6 micrograms of roxindole per g of striatum in these animals. After multiple subcutaneous treatments with 95.2 mg/kg roxindole, no long-term striatal dopamine depletions were observed in contrast to MPTP. Furthermore, unlike MPP+, ROX+ did not induce release of previously accumulated 3H-dopamine in mouse striatal slices indicating that ROX+ cannot utilize the dopamine uptake carrier to enter neurones. ROX+ at doses up to 100 mg/kg subcutaneously failed to alter striatal biogenic amine levels and gross behaviour of mice. Thus, no MPTP-like neurotoxic metabolites are formed from roxindole in vivo and neurotoxic effects of ROX+, even if formed in minute amounts by some MAO-independent pathway, are highly unlikely.