1-methyl-1,2,3,4-tetrahydroisoquinoline protects against rotenone-induced mortality and biochemical changes in rat brain.
The effect of single and multiple administration of the neurotoxic pesticide, rotenone, and the potentially neuroprotective compound, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), on the concentration of dopamine and its metabolites (homovanillic acid-HVA, 3,4-dihydroxyphenylacetic acid-DOPAC, and 3-methoxytyramine-3-MT)) in three brain areas was studied by high-performance liquid chromatography (HPLC) with electrochemical detection in Wistar rats. The rate of dopamine catabolism in the striatum along the N-oxidative and O-methylation pathways was assessed by calculation of the ratio of dopamine metabolites to dopamine. In addition, the effect of rotenone on mortality and general behavior of rats was investigated. We have found that the neurotoxic pesticide, rotenone, administered in a single dose (12 mg/kg s.c.) did not produce evident behavioral or biochemical effects. In contrast, repeated administration of rotenone in doses (12-15 mg/kg) causing abnormalities in general behavior, produced considerable mortality and dramatic increases in dopamine metabolism, which may be ascribed to an increase in the oxidative pathway. Interestingly, it depressed the concentration of the extracellular dopamine metabolite, 3-MT. These behavioral and biochemical changes were effectively counteracted by administration of 1MeTIQ before each dose of rotenone. In summary, we demonstrated that multiple systemic rotenone injections are strongly toxic, and induce alterations of cerebral dopamine metabolism, and that 1MeTIQ may be considered as a potential protective agent against environmental factors affecting the function of the dopaminergic system.
Antkiewicz-Michaluk
Lucyna
L
Department of Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland. antkiew@if-pan.krakow.pl
Karolewicz
Beata
B
Romańska
Irena
I
Michaluk
Jerzy
J
Bojarski
Andrzej J
AJ
Vetulani
Jerzy
J
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000031:analogs & derivatives* / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006719:Homovanillic Acid / Q000378:metabolism; D007306:Insecticides / Q000008:administration & dosage* / Q000633:toxicity; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000008:administration & dosage* / Q000633:toxicity; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D015996:Survival Rate; D044005:Tetrahydroisoquinolines
D018492:Dopamine Antagonists; D007306:Insecticides; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D012402:Rotenone; D015102:3,4-Dihydroxyphenylacetic Acid; C050386:1-methyl-1,2,3,4-tetrahydroisoquinoline; C001746:3-methoxytyramine; D004298:Dopamine; D006719:Homovanillic Acid