Diferentes estratégias terapêuticas para danos motores e cognitivos na Doença de Parkinson em modelo pré-clínico

Abstract

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease worldwide and is characterized by motor dysfunction, although, patients can also present non-motor symptoms (NMS) such as cognitive deficits. The available treatments for PD do not prevent the progression neither has effects on cognitive impairments. This work was divided into two chapters to evaluate a pharmacological and non-pharmacological strategy over PD treatment. In the first chapter, we evaluated whether exposure to environmental enrichment (EE), a non-pharmacological instrument, could prevent the cognitive impairment and whether this damage could be related to the cholinergic system gene expression changes in PD animal model. MPTP-treatment (25 mg/kg) caused reference memory impairment in Morris Water Maze (MWM), EE exposition was able to prevent these damages, and, also, EE exposition promoted an improvement in cognition compared to control group. We also observed that gene expression of alpha 7 receptor was increased in prefrontal cortex, suggesting a possible role of this receptor in the observed effects. Thus, we can suggest that EE prevents memory deficit exhibited by PD mice model, and facilitate this process per se, however, further studies are necessary to confirm and better understand the biochemical changes involved in this process. In the second chapter, we evaluated whether the mGluR5-negative allosteric modulator (CTEP), would be effective in improving motor and cognitive deficits and reduce dopaminergic damage in a mouse model of PD and whether CTEP could decrease MPP+ induced apoptosis in Primary Cortical Neuron Cultures. MPTP-treatment (30 mg/kg) caused motor hyperactivity in open field, rotarod and grip test, also, induced an operational memory impairment in Y-maze. CTEP- treatment did not revert these behavior modifications. Our data suggests that CTEP- treatment decrease dopaminergic neuronal death in substantia nigra pars compacta in a mouse model and attenuated neuronal death in Primary Cortical Neuron Culture. Although we did not find any motor or cognitive benefit with CTEP-treatment in this Parkinson animal model, we suggested neuroprotective effect over dopaminergic neurons and Primary Cortical Neuron Culture. Therefore, more studies are required to understand CTEP-treatment potential in PD.