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.
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106.
L M
LM
Sayre
F J
FJ
Wang
P K
PK
Arora
N J
NJ
Riachi
S I
SI
Harik
C L
CL
Hoppel
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