Efeito dos moduladores alostéricos positivos do receptor metabotrópico de glutamato 5, CDPPB e VU0409551, em camundongos modelo da doença de Huntington

Abstract

Huntington's disease (DH) is a hereditary and progressive neurodegenerative disorder that inevitably leads to death. Glutamate plays an important role in a wide variety of functions in the central nervous system by activating ionotropic and metabotropic glutamate receptors (mGluRs). mGluR5 in particular has potential as a target for the development of new therapeutic agents to treat a wide range of neurological and psychiatric disorders, as well as neurodegenerative disease, such as HD. Previous studies have shown that mGluR5 positive allosteric modulators are effective in reducing neuronal cell death triggered by glutamate insult, as well as in activating neuroprotective pathways, such as ERK1/2 and AKT in vitro. The main goal of this study was to determine whether CDPPB and VU0409551 would be able to promote neuroprotection in vivo and rescue the memory deficit that takes place in HD. Our results demonstrate that CDPPB treatment improves the pathological and phenotypic signs exhibited by a mouse model of HD, the BACHD. CDPPB treatment increased the phosphorylation levels of ERK1/2 and AKT, enhanced the expression of BDNF, reduced the formation of toxic aggregates of the mutated huntingtin protein (HTT) and decreased neuronal cell loss in BACHD animals. Moreover, behavioral studies have shown that CDPPB chronic treatment improved BACHD mice motor and cognitive deficits. VU0409551 subchronic treatment was effective to reverse the memory deficit exhibited by BACHD mice and to improve parameters related to synaptic plasticity, stabilizing mGluR5 at the cell surface and stimulating cell signaling pathways important for synaptic plasticity and promoting increased density and maturation of the dendritic spines.