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Pharmacological strategies for the prevention of the respiratory abnormalities in an animal model of Parkinson´s s disease

Grant number: 17/18074-1
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): May 01, 2018
Effective date (End): April 30, 2021
Field of knowledge:Biological Sciences - Pharmacology - Autonomic Pharmacology
Principal Investigator:Ana Carolina Thomaz Takakura
Grantee:Luara Augusta da Costa e Silva Braga Batista
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Parkinson's disease (PD) is a debilitating neurological condition that affects approximately 1% of the elderly population. It is characterized by motor symptoms, such as bradykinesia, tremors, and postural instability. In addition, non-motor autonomic symptoms can be present, such as constipation, orthostatic hypotension and respiratory abnormalities. The respiratory symptoms, such as obstructive sleep apnea, can lead do the death of patients diagnosed with PD. Therefore, the study of respiratory symptoms in PD can contribute to the development of more effective or preventive treatments. Animals with lesion of the nigrostriatal fibers present hypoventilation and a deficit in the response to hypercapnia, in addition to glial alterations. The respiratory abnormalities are related to a reduction in the number of noradrenergic neurons of the Locus Coeruleus, orexinergic signaling and an increase in oxidative stress. Therefore, the objective of this project is to perform different pharmacological treatments aimed at facilitating noradrenergic signaling (imipramine: an antidepressant that acts as a noradreanaline and serotonin reuptake inhibitor), orexinergic signaling (URB597: endocannabinoid hydrolysis inhibitor) and reducing oxidative stress (caffeine: a non-selective antagonist of adenosine receptors) and to observe the respiratory and neuroanatomical abnormalities in animals submitted to the model of PD. These alterations include an attenuation of the ventilatory responses to hypercapnia associated with an astrocytic reduction and an increase in microgliga in the retrotrapezoide nucleus, a reduction of orexinergic signaling and an increase in oxidative stress. Moreover, it is observed a neurodegeneration of the retrotrapezoid nucleus and of the substantia nigra. The results of this project can contribute to the development of new therapies for the respiratory symptoms of PD. In addition, it contributes to the understanding of the neural substrate of these symptoms. (AU)