Behavioral effects of manganese injected in the rat substantia nigra are potentiated by dicumarol, a DT-diaphorase inhibitor.
The purpose of this study was to evaluate the contribution of DT-diaphorase inhibition to in vivo neurodegenerative effects of dopamine (DA) oxidation to the corresponding o-quinones. The neurotoxicity to nigrostriatal DA neurons was induced by injection of manganese pyrophosphate (Mn(3+)) complex as a prooxidizing agent alone or together with the DT-diaphorase inhibitor dicumarol into the right rat substantia nigra. The behavioral effects were compared with those induced after selective lesions of dopaminergic neurons with 6-hydroxydopamine (6-OHDA). Intranigral injection of Mn(3+) and Mn(3+) plus dicumarol produced significant impairment in motor behavior compared with control animals. However, the effect seen in the Mn(3+) plus dicumarol injected group was significantly more severe than that observed in the Mn(3+) alone injected group. In motor activity and rearing behavior, the simultaneous injection of Mn(3+) plus dicumarol produced a 6-OHDA-like impairment. Similar effects were observed in the acquisition of a conditioned avoidance response (CAR). Dicumarol significantly impaired avoidance conditioning although without affecting the motor behavior. The behavioral effects were correlated to the extent of striatal tyrosine hydroxylase (TH)-positive fiber loss. Rats receiving unilateral intranigral Mn(3+) and Mn(3+) plus dicumarol injections exhibited a significant reduction in nigrostriatal TH-positive fiber density in medial forebrain bundle compared with the contralateral noninjected side. In conclusion, this study provides evidence that the neurotoxicity of Mn(3+) in vivo is potentiated by DT-diaphorase inhibition, suggesting that this enzyme could play a neuroprotective role in the nigrostriatal DA systems.
Díaz-Véliz
Gabriela
G
Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biológicas (ICBM), Facultad de Medicina, Universidad de Chile, P.O. Box 16038, 9, Santiago, Chile. gdiaz@med.uchile.cl
Mora
Sergio
S
Gómez
Patricia
P
Dossi
Ma Teresa
MT
Montiel
Juan
J
Arriagada
Christian
C
Aboitiz
Francisco
F
Segura-Aguilar
Juan
J
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001728:Dicumarol / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D008345:Manganese / Q000008:administration & dosage / Q000494:pharmacology*; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology; D016627:Oxidopamine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000502:physiology*; D013565:Sympatholytics / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D004791:Enzyme Inhibitors; D013565:Sympatholytics; D008345:Manganese; D001728:Dicumarol; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D016660:NAD(P)H Dehydrogenase (Quinone)