Assuntos
Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Intoxicação por MPTP , Doença de Parkinson/metabolismo , Selegilina/farmacologia , Animais , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doença de Parkinson Secundária/etiologia , Fatores de TempoRESUMO
The ability of 1-deprenyl to protect against the parkinsonian effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been attributed to the inhibition of conversion of MPTP to MPP+ (1-methyl-4-phenylpyridinium) catalyzed by MAO-B. We report here that deprenyl-treatment in mice has an additional neuroprotective element associated with the rapid metabolization of 1-deprenyl to 1-methamphetamine and 1-amphetamine. 1-Methamphetamine and 1-amphetamine inhibit MPP(+)-uptake into striatal synaptosomes prepared from rats. Post-treatment by 1-deprenyl, 1-methamphetamine, 1-amphetamine (at times when MPTP is no longer present in the striatum of mice) protects against neurotoxicity in C57BL mice by blocking the uptake of MPP+ into dopaminergic neurons, and even against the neurotoxicity induced by 2'CH3-MPTP, which is partly bioactivated by MAO-A. These findings may have clinical implications since deprenyl has recently been found to delay the progression of Parkinson's disease.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/análogos & derivados , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/antagonistas & inibidores , Anfetaminas/metabolismo , Neurotoxinas/antagonistas & inibidores , Selegilina/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Animais , Corpo Estriado/metabolismo , Antagonistas de Dopamina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Pargilina/farmacologia , Ratos , Ratos EndogâmicosRESUMO
Methamphetamine (5 mg/kg) administered 30 min prior to each injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (3 x 30 mg/kg, at 24 h intervals) prevents the reduction of striatal levels of dopamine and its metabolites in C57BL mice. Methamphetamine and amphetamine inhibit the uptake of 1-methyl-4-phenylpyridinium (MPP+) by striatal synaptosomes of rats. A 30-min post-treatment with methamphetamine or amphetamine also prevents the MPTP-induced dopamine depletion, suggesting that their protective effect is related to the blockade of MPP+ uptake into dopaminergic neurons. Since amphetamine and methamphetamine are themselves neurotoxins at higher doses, this work demonstrated the protection against the actions of one neurotoxin by the administration of another.
