1,2,3,4-Tetrahydroisoquinoline protects terminals of dopaminergic neurons in the striatum against the malonate-induced neurotoxicity.
Malonate, a reversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, is frequently used as a model neurotoxin to produce lesion of the nigrostriatal dopaminergic system in animals due to particular sensitivity of dopamine neurons to mild energy impairment. This model of neurotoxicity was applied in our study to explore neuroprotective potential of 1,2,3,4-tetrahydroisoquinoline (TIQ), an endo- and exogenous substance whose function in the mammalian brain, despite extensive studies, has not been elucidated so far. Injection of malonate at a dose of 3 mumol unilaterally into the rat left medial forebrain bundle resulted in the 54% decrease in dopamine (DA) concentration in the ipsilateral striatum and, depending on the examined striatum regions, caused 24-44% reduction in [3H]GBR12,935 binding to the dopamine transporter (DAT). TIQ (50 mg/kg i.p.) administered 4 h before malonate infusion and next once daily for successive 7 days prevented both these effects of malonate. Such TIQ treatment restored DA content and DAT binding almost to the control level. The results of the present study indicate that TIQ may act as a neuroprotective agent in the rat brain. An inhibition of the enzymatic activities of monoamine oxidase and gamma-glutamyl transpeptidase as well as an increase in the striatal levels of glutathione and nitric oxide found after TIQ administration and reported in our earlier studies are considered to be potential factors that may be involved in the TIQ-mediated protection of dopamine terminals from malonate toxicity.
Lorenc-Koci
Elzbieta
E
Department of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12, Smetna Street, PL-31-343 Kraków, Poland.
Gołembiowska
Krystyna
K
Wardas
Jadwiga
J
D000704:Analysis of Variance; D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects; D008297:Male; D008314:Malonates; D008474:Medial Forebrain Bundle / Q000166:cytology / Q000187:drug effects; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013385:Succinate Dehydrogenase / Q000187:drug effects; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*
D008314:Malonates; D018696:Neuroprotective Agents; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline; C030290:malonic acid; D013385:Succinate Dehydrogenase; D004298:Dopamine