A interação entre os sistemas glutamatérgico e endocanabinóide promove neuroproteção em cultura primária de neurônios corticoestriatais

Abstract

The metabotropic glutamate receptor 5 (mGluR5) is coupled to the Gq protein. Stimulation of mGluR5 leads to activation of cell signaling pathways important for survival, such as the activation of AKT and extracellular signal-regulated kinase (ERK) proteins. The cannabinoid receptor 1 (CB1) is coupled to the Gi/0 protein and also leads to activation of ERK and AKT. Since previously published data indicate that there is a close relationship between the glutamatergic and cannabinoid systems, we investigated a possible link between the activation of CB1 and mGluR5 to promote neuroprotection of primary cultured corticostriatal neurons. Cell death was assessed in neurons incubated with glutamate in the presence or absence of URB597 and JZL184, which are inhibitors of enzymes that hydrolyze anandamida and 2-AG endocannabinoids, respectively, and the positive allosteric modulator of mGluR5, CDPPB. URB597, JZL184 or CDPPB promoted neuroprotection against neuronal cell death induced by glutamate. Surprisingly, the CB1 antagonist, AM251 reversed neuroprotection induced not only by URB597 and JZL184, but also by CDPPB. Furthermore, MPEP, which is an mGluR5 negative allosteric modulator, was also able to inhibit neuroprotection mediated by CDPPB, URB597 and JZL184. Moreover, CDPPB, URB597 and JZL184, in the presence or absence of glutamate, promoted activation of ERK1/2 and AKT above basal levels. However, MPEP and AM251 were both capable of blocking ERK1/2 and AKT activation mediated by CDPPB, URB597 and JZL184. In addition, neuroprotection and ERK1/2 and AKT activation mediated by the tested drugs could not be observed in either mGluR5 knockout or CB1 knockdown neurons. Thus, mGluR5 and CB1 appear to activate similar cell signaling pathways to trigger neuroprotection.