Efeito neuroprotetor dos moduladores alostéricos positivos do receptor metabotrópico de glutamato 5 na doença de Huntington

Abstract

Huntington's disease (HD) is a neurodegenerative disorder, progressive and hereditary, that evolves inevitably to death. Stimulation of metabotropic glutamate receptor 5 (mGluR5), which is coupled to Gq, promotes increased levels of IP3 and intracellular Ca2+, which can cause excitotoxicity. However, activation of this receptor is also able to promote the activation of neuroprotective pathways, including AKT and ERK, making this a good object of study. Recent data demonstrate that mGluR5 positive allosteric modulators (PAMs) may favor the activation of certain signaling pathways over others. The results obtained by our study demonstrate that the mGluR5 PAMs, DFB, CDPPB and VU1545, are able to protect primary cultured striatal neurons from cell death induced by glutamate insult. In vivo experiments using a transgenic mouse model of HD (BACHD) indicate that these animals exhibit HD-related symptoms, including impaired motor and cognitive functions. Moreover, CDPPB sub-chronic administration was effective to ameliorate this cognitive impairment.