Mechanisms involved in medullary neurodegeneration in Parkinson's Disease

Abstract

Parkinson's disease (PD) is a neurodegenerative idiopathic, chronic and progressive disease and it is physiopathologically characterized by the loss of dopaminergic neurons in the compact portion of the substantia nigra (SN). New evidence supported the hypothesis that the SN neurodegeneration observed in PD is the result of complex interactions between genetic abnormalities, environmental toxins, mitochondrial dysfunction and other cellular processes as well as disruption of the blood brain barrier in the SN area. The DP has classic symptoms like muscular rigidity, bradykinesia, tremor at rest and postural changes, which lead to loss of life quality. In addition to these motor symptoms, patients who have the DP also feature non-motor symptoms, like respiratory deficiency. Recent study from our laboratory has suggested a correlation between the changes in respiratory activity and neurodegeneration of the brainstem regions where are neurons that control respiratory activity. Thus, the main objective of this project is to understand the mechanisms that lead to this neurodegeneration in the medullary regions that control breathing. Therefore, in this design we will evaluate, in the DP induction model by bilateral injection of 6-hydroxy-dopamine (6-OHDA) in the caudate-putamen (CPu), a selective neurotoxic agent for catecholaminergic cell, which generates large inflammatory response, oxidative stress, disruption of the blood brain barrier and / or if there is a change in the expression of microRNAs involved in DP in the brainstem regions involved in the neural control of breathing, as retrotrapezoid nucleus, nucleus of the solitary tract, Pre-Botzinger complex and rostral ventrolateral respiratory group. For this, the functional respiratory assessments by whole body plethysmography, and neuroanatomical and biochemical by immunohistochemistry, Western blot and rRT-PCR will be performed.Key Words: Parkinson's disease, breathing, 6-OHDA, neurodegeneration, blood brain barrier, oxidative stress, mitochondrial dysfunction, epigenetics (AU)