Inhibition of mitochondrial respiration by 1,2,3,4-tetrahydroisoquinoline-like endogenous alkaloids in mouse brain.
Since the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism, it has been postulated that (a) MPTP-like toxin(s) such as 1,2,3,4-tetrahydroisoquinoline (TIQ) may induce Parkinson's disease. As the neuronal degeneration in MPTP-induced parkinsonism is thought to be caused by the inhibition of the mitochondrial respiration by 1-methyl-4-phenylpyridinium ion (MPP+), we studied the effects of TIQ-like alkaloids including dopamine-derived ones on the mitochondrial respiration using mouse brains. TIQ, tetrahydropapaveroline (THP), and tetrahydropapaverine (THPV) produced significant inhibition of the state 3 and 4 respiration and respiratory control ratio supported by glutamate + malate, the activity of Complex I and the ATP synthesis. Among those compounds, THPV was most potent. Toxic properties of these compounds on mitochondria were quite similar to that of MPP+. Our results support the hypothesis that (a) MPTP- or MPP(+)-like substance(s) may be responsible for the nigral degeneration in Parkinson's disease.
Suzuki
K
K
Department of Neurology, Jichi Medical School, Tochigi, Japan.
Mizuno
Y
Y
Yoshida
M
M
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure*; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008293:Malates / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone); D010101:Oxygen Consumption / Q000187:drug effects*; D010300:Parkinson Disease / Q000378:metabolism; D011773:Pyruvates / Q000378:metabolism; D019289:Pyruvic Acid; D011808:Quinone Reductases / Q000378:metabolism; D044005:Tetrahydroisoquinolines; D013765:Tetrahydropapaveroline / Q000494:pharmacology
D005971:Glutamates; D007546:Isoquinolines; D008293:Malates; D011773:Pyruvates; D044005:Tetrahydroisoquinolines; C063395:tetrahydropapaverine; D018698:Glutamic Acid; D013765:Tetrahydropapaveroline; C014843:1,2,3,4-tetrahydroisoquinoline; C030298:malic acid; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D016660:NAD(P)H Dehydrogenase (Quinone); D011808:Quinone Reductases