Alterações centrais e periféricas em modelo Murino para doença de Huntington: caracterização e uma nova abordagem terapêutica

Abstract

Huntington's disease (HD) is a neurodegenerative disorder, with devastating effects that usually arise in adulthood. Clinically, it is characterized by motor, behavioral, and cognitive decline. However, patients with HD can also develop cardiovascular disorders causing sudden death (the second cause of death). Despite the clinical importance, cardiac alterations observed in HD are still poorly understood. The present thesis was divided into two subprojects. In the first subproject, using a murine model for HD (BACHD line), we investigated possible cardiac changes (along with the mechanisms of action) that have not yet been described. Our results showed significant cardiac variations both in vivo and in vitro. The observed cardiac impulse conduction disturbances were associated with a prolongation of the action potential, as well as, the presence of cellular arrhythmias. In addition, we detected impairments in the cardiomyocyte relaxation phase, which was corroborated by changes in intracellular calcium handling and in molecular structures. The heart damage was triggered by oxidative stress, which modulated the activity of important enzymes (for example CaMKII), characterized for the first time by our research group. In the second subproject, we used the Phα1β isoform of the venom of the spider Phoneutria nigriventer as a pharmacological tool against neuronal death in BACHD mice. We treated the mice with this toxin by two different injections and analyzed its possible neuroprotective action. We observed that the toxin improved motor parameters, which may be related to a local neuronal preservation besides muscles structure, which no longer presented atrophy in BACHD animals. The mechanism of action of this isoform was associated with a decrease in glutamate release and caspase-3 expression in spinal cord neurons. Thus, in this work we describe the cardiac alterations in the BACHD model; moreover, we provide new evidence of a neuroprotective potential of the Phα1β isoform. The results obtained from this thesis have already been published or submitted to publication and may contribute to the development of new therapeutic approaches, providing novel substrates for the treatment of this disabling disease.