ENDOGENOUSLY OCCURRING BETA-CARBOLINE INDUCES PARKINSONISM IN NONPRIMATE ANIMALS - A POSSIBLE CAUSATIVE PROTOXIN IN IDIOPATHIC PARKINSONS-DISEASE

To examine whether simple beta-carbolines induce parkinsonian-like sym ptoms in vivo via N-methylation, the simple beta-carbolines norharman (NH), 2-mono-N-methyllated norharmanium cation (2-MeNH+), and 9-mono-N '-methylnorharman (9-MeNH) were systematically administered to C57BL/6 mice for 7 days. These substances induced bradykinesia with reduction of locomotion activity. NH or 2-MeNH+ decreased dopamine (DA) content s to 50-70% of values in controls in the striatum and midbrain. 9-MeNH potently decreased not only DA but also serotonin content in various regions, Immunohistochemical examination revealed that the numbers of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta of NH- and 9-MeNH-treated mice were diminished to 76 and 66% of values in control mice, respectively. The formation of a toxic meta bolite, 2,9-di-N,N'-methylated norharmanium cation (2,9-Me2NH+), was 1 4 and eight times higher in the brain of mice receiving 9-MeNH than th at in NH-and 2-MeNH+-treated mice, respectively. In cultured mesenceph alic cells from rat embryo, 2,9-Me2NH+ selectively killed TH-positive neurons only at a lower dose but was toxic to all neurons at higher do ses. Thus, the excess formation of 2,9-Me2NH+ would induce nonspecific neurotoxicity. These results indicated that 9-indole nitrogen methyla tion should be the limiting step in the development of the toxicity. N H, a selective dopaminergic toxin precursor, is sequentially methylate d to form 2,9-Me2NH+, which could be an underlying factor in idiopathi c Parkinson's disease.