Dopaminergic Neurotoxicity In Vivo and Inhibition of Mitochondrial Respiration In Vitro by Possible Endogenous Pyridinium-Like Substances

Elucidation of the mechanism(s) by which 1-methyI-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite l-methyl-4-phenylpyridinium (MPP+) cause parkinsonism in humans and other primates has prompted consideration of possible endogenous MPTP/MPP+-like ncurotoxins in the etiology of idiopathic Parkinson's disease. Here we examined inhibition of mitochondrial respiration in vitro and neurotoxicity in rats in vivo produced by β-carbolinium compounds that are presumed to form following Pictet-Spengler cyclization of serotonin. We also evaluated N-methyiisoquinolinium, a putative endogenous neurotoxin, in the same manner. The latter compound exhibited MPP+ like mitochondrial respiratory inhibition, whereas the β-carbotinitim compounds, although more potent inhibitors of electron transport, exhibited weak accumulation- dependent enhancement of inhibition in intact mitochondria. It is interesting that the β-carbolinium compounds inhibited succinate-as well as glutamate-supported respiration, and are best described as inhibitor-uncouplers. The results of partitioning experiments suggest that both the low accumulation potential and the inhibition of succinate respiration may be a consequence of the β-carboliniums being in equilibrium with neutral “anhydro” bases. Relative to MPP+, all compounds tested had weak dopaminergic uptake activity in vitro and weak dopaminergic toxicity in vivo, consistent with other findings of relatively low neurotoxic potential for presumed endogenous pyridiniums.