GM1 Administration Prevents Alterations in BCL‐2 and Bax Expression in Substantia Nigra Neurons Following MPTP Administrationa

Previously, we and others have shown an alteration in the expression of the antiapoptotic factor and antioxidant, Bcl-2, and its homolog the proapoptotic factor, Bax, in substantia nigra tissue from C57 black mice challenged with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This has led to the suggestion that changes in expression of these genes may reflect an attempt by substantia nigra dopaminergic neurons to control oxidative stress induced by inhibition of complex 1 in the mitochondrial electron transport chain. Expression of apoptosis-related genes may help determine whether a neuron survives or dies after injury. Since previous studies in this lab have shown that the monosialoganglioside GM1 can rescue damaged dopamine neurons and promote survival, the present study was conducted to examine the extent to which GM1 can regulate altered Bcl-2 and Bax gene expression in animals challenged with MPTP. Exposure to MPTP (single s.c. injection at 30 mg/kg) caused altered expression of Bcl-2 and Bax mRNA and protein, in the ventral mesencephalic region as demonstrated by RT-PCR and immunohistochemistry. Maximal up-regulation of Bcl-2 and Bax mRNA occurred at 12 h postinjection with a return to normal levels within 24 h for Bcl-2. Bax expression remained elevated at 24 h after MPTP administration. Immunohistochemical labeling in the substantia nigra also showed elevated levels of expression for Bcl-2 and Bax protein, concomitant to the increased mRNA levels, while tyrosine hydroxylase immunohistochemical staining in MPTP-treated animals remained unchanged from that seen in normal animals. The coadministration of MPTP (single s.c. injection at 30 mg/kg) and GM1 (single i.p. injection at 30 mg/kg, 5 min post-MPTP) prevented the previously described increase in both Bcl-2 and Bax mRNA expression in the ventral mesencephalon. In GM1-treated animals both Bcl-2 and Bax mRNA showed a steady-state expression at all time points examined. Similarly, the expression levels of both Bcl-2 and Bax proteins remained unchanged in GM1-treated animals, as did staining for tyrosine hydroxylase. These results suggest that GM1 has the potential to alter the natural course of the neuronal degeneration in Parkinson's disease by influencing gene expression that might be involved in the progressive loss of dopaminergic neurons.