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-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP+) cause parkinsonism in humans and other primates has prompted consideration of possible endogenous MPTP/MPP(+)-like neurotoxins 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 beta-carbolinium compounds that are presumed to form following Pictet-Spengler cyclization of serotonin. We also evaluated N-methylisoquinolinium, a putative endogenous neurotoxin, in the same manner. The latter compound exhibited MPP(+)-like mitochondrial respiratory inhibition, whereas the beta-carbolinium compounds, although more potent inhibitors of electron transport, exhibited weak accumulation-dependent enhancement of inhibition in intact mitochondria. It is interesting that the beta-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 beta-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.
Sayre
L M
LM
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106.
Wang
F J
FJ
Arora
P K
PK
Riachi
N J
NJ
Harik
S I
SI
Hoppel
C L
CL
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D000838:Anions; D004298:Dopamine / Q000502:physiology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009243:NAD / Q000037:antagonists & inhibitors / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects*; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology*; D011806:Quinolinium Compounds / Q000494:pharmacology; D051381:Rats; D013386:Succinates / Q000378:metabolism; D019802:Succinic Acid; D013775:Tetraphenylborate / Q000494:pharmacology
D000838:Anions; D009498:Neurotoxins; D011726:Pyridinium Compounds; D011806:Quinolinium Compounds; D013386:Succinates; D009243:NAD; C051351:N-methylisoquinolinium; D013775:Tetraphenylborate; D019802:Succinic Acid; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine