Ativação da proteína Akt1 por moduladores alostéricos positivos do receptor metabotrópico de glutamato 5 em cultura primária de neurônios estriatais

Abstract

Considering the high incidence of neurodegenerative disorders in several countries, including Brazil, research aiming to develop therapeutic approaches that effectively alter the course of such diseases are highly relevant. Akt1 is a protein kinase involved in neuronal survival processes, having an important role in neurodegenerative diseases. It has been demonstrated that Akt1 can be activated by the metabotropic glutamate receptor 5 (mGluR5). However, mGluR5 activation can also promote the release of intracellular Ca2+, exacerbating the process of excitotoxicity, which occurs in various neurodegenerative disorders. Based on these data, we have selected four positive allosteric modulators (PAMs) for mGluR5: CPPHA, DFB, CDPPB, VU1545, and tested whether these PAMs were able to activate Akt1, but without increasing the release of cytosolic Ca2+. Our results demonstrate that stimulation of striatal neurons with DFB, CDPPB, and VU1545 led to increased phosphorylation of Akt1, as compared to control group. Furthermore, these drugs did not cause an increase in intracellular Ca2+ release. Importantly, the phosphorylation of Akt1 by MAPs was as robust as that promoted by the mGluR5 agonist, DHPG. On the other hand, CPPHA failed to activate Akt1, but increased Ca2+ release. These results demonstrate that DFB, CDPPB, and VU1545 have the potential to protect against neuronal death, as they are able to activate protective pathways (Akt1) without activating processes that could lead to increased neuronal cell death (Ca2+).