Protective effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline against dopaminergic neurodegeneration in the extrapyramidal structures produced by intracerebral injection of rotenone.
The aim of this paper was to investigate whether rotenone, a pesticide causing experimental parkinsonism, causes direct damage to dopaminergic structure when injected intracerebrally and whether this action may be prevented by peripheral administration of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), an endogenous compound with anti-dopaminergic activity. Male Wistar rats were injected unilaterally into the median forebrain bundle with 2 microg rotenone, and received 1MeTIQ, 50 mg/kg i.p. 1 h before and then daily for 21 d. To compare the effect of intracerebral and peripheral treatment, rotenone was also given once or for 7 d in a dose of 10 mg/kg s.c. Dopamine, serotonin and their metabolites were assessed by HPLC in the substantia nigra and striatum. While a single subcutaneous rotenone dose did not produce any change in striatal dopamine metabolism, the multiple treatments resulted in changes suggesting a shift in the metabolism towards oxidative desamination and reduction of O-methylation. In contrast to systemic injections, intracerebral-administered rotenone produced a decrease in dopamine and its metabolites content in the striatum (dopamine decrease by 70%) and substantia nigra (dopamine decrease by 35%), without affecting the serotonin system. As those changes were observed 21 d after the injection of rotenone, they suggest a durable neurotoxic effect. The treatment with 1MeTIQ strongly reduced the fall of striatal dopamine concentration. The data suggest that rotenone given peripherally affects metabolic processes in dopaminergic neurons, and this seems to result from its neurotoxic action, which may be observed after an intracerebral injection. 1MeTIQ is able to counteract the damaging action of rotenone and seems to be a potential neuroprotective agent.
Antkiewicz-Michaluk
Lucyna
L
Department of Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland. antkiew@if-pan.krakow.pl
Wardas
Jadwiga
J
Michaluk
Jerzy
J
Romaska
Irena
I
Bojarski
Andrzej
A
Vetulani
Jerzy
J
D000818:Animals; D001480:Basal Ganglia Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D001923:Brain Chemistry / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D007267:Injections; D007279:Injections, Subcutaneous; D008297:Male; D008474:Medial Forebrain Bundle; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D012701:Serotonin / Q000378:metabolism; D013238:Stereotaxic Techniques; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000627:therapeutic use*; D014475:Uncoupling Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity*
D018696:Neuroprotective Agents; D044005:Tetrahydroisoquinolines; D014475:Uncoupling Agents; D012402:Rotenone; D012701:Serotonin; C050386:1-methyl-1,2,3,4-tetrahydroisoquinoline; D004298:Dopamine