RESUMEN

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic neurotoxicity and behavioral impairment in rodents similar to Parkinson's disease. The MPTP mouse model is widely used to evaluate new protective agents. EGb 761 is a well-defined mixture of active compounds extracted from Ginkgo biloba leaves according to a standardized procedure. We have shown that EGb 761 attenuates the loss of striatal dopamine levels and prevents the neurodegeneration of the nigrostriatal pathway induced by MPTP. This finding shows that neuroprotective effects of EGb 761 act, in part, on the dopamine system. Therefore, this study investigates whether EGb 761 exerts dopaminergic neuroprotection through the regulation of dopamine-related gene expression in MPTP-induced Parkinsonism. Male C57BL/6J mice were injected with MPTP (30 mg/kg, i.p.) for 5 days and later with EGb 761 (40 mg/kg, i.p.) daily for 18 days. The expression of selected genes was evaluated in the striatum and midbrain by quantitative PCR. The genes for tyrosine hydroxylase (Th), vesicular monoamine transporter 2 (Vmat2), dopamine transporter (Dat), dopamine D2 receptor (Da-d2r), and transcription factors (Pitx3 and Nurr1) related to dopamine neurotransmission were selected for the analysis. EGb 761 administration to MPTP-treated mice protected Th (41%), Vmat2 (15%), Dat (102%), Da-d2r (46%), Pitx3 (63%), and Nurr1 (148%) mRNA levels in the midbrain, all of which were up-regulated. However, EGb 761 partially reversed the MPTP effect exclusively for Th (48%) and Nurr1 (96%) mRNA in the striatum. Only Th and Nurr1 mRNA and protein levels were regulated by EGb 761 in both regions of the nigrostriatal pathway. This result could be related to the regulation of their transcription. Our results suggest that EGb 761-associated neuroprotection against MPTP neurotoxicity is related to the regulation of the dopamine genes. Moreover, this neuroprotection also involves the regulation of transcription factors such as Nurr1 that are important for the functional maintenance of dopaminergic neurons.

Asunto(s)

Antiparkinsonianos/uso terapéutico , Encéfalo/metabolismo , Dopamina/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Animales , Antiparkinsonianos/farmacología , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Dopamina/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Ginkgo biloba , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Extractos Vegetales/farmacología , ARN Mensajero/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Tirosina 3-Monooxigenasa/genética , Tirosina 3-Monooxigenasa/metabolismo , Proteínas de Transporte Vesicular de Monoaminas/genética , Proteínas de Transporte Vesicular de Monoaminas/metabolismo