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Translational analysis of the therapeutic mechanisms of deep brain stimulation in Parkinson's disease

Grant number: 19/13781-7
Support type:Regular Research Grants
Duration: March 01, 2020 - February 28, 2022
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal researcher:Rosana de Lima Pagano
Grantee:Rosana de Lima Pagano
Home Institution: Hospital Sírio-Libanês. Sociedade Beneficente de Senhoras (SBSHSL). São Paulo , SP, Brazil
Assoc. researchers: Clement Hamani ; Erich Talamoni Fonoff ; Raquel Chacon Ruiz Martinez


Parkinson's disease (PD) is a complex neurodegenerative disease that causes progressive dysfunction of dopaminergic and non-dopaminergic neurons, associated with chronic inflammatory response in the central nervous system. PD includes motor and non-motor symptoms, and its treatment is eminently symptomatic, starting with an effective pharmacological approach that loses its effect over time generating several complications. At this stage, the gold standard of treatment is the deep brain stimulation (DBS) of the subthalamic nucleus (STN). It was observed by our group that STN-DBS induces evident clinical improvement and considerably reduces the dosage of levodopa in patients with PD, as well as reverses motor alterations and hypernociception in hemiparkinsonian rats; however, the mechanisms by which important clinical findings occur are largely unknown. In this project we will investigate the effect of STN-DBS on the indirect motor pathway, evaluating nigral alpha-synuclein, striatal dopamine, expression of inflammatory markers in the nigrostriatal pathway and modulation of the striatopallidal pathway in hemiparkinsonian rats. We will also investigate the effect of STN-DBS on the nociceptive pathway of the animals, evaluating the expression of monoamines in the descending analgesic pathway, opioidergic modulation system and spinal SP expression. In parallel, the expression of dopaminergic metabolites and modulators of neurodegeneration (GFAP, alpha-synuclein, DJ-1 and TGM-2) in the cerebrospinal fluid will be evaluated in patients with PD before and 6 months after STN-DBS, such as inflammatory modulators (cytokines, chemokines and TGM-2) and nociception (beta-endorphin and SP) in plasma. We hypothesized that DBS is able to inhibit the inflammatory response in the indirect motor pathway by increasing the sensitivity of the system to levodopa, without interfering with nigral neurodegeneration. We further hypothesized that DBS is capable of activating the descending analgesic pathway and the spinal inhibitory system, as well as reducing the systemic inflammatory response. With this work we intend to elucidate part of the mechanism of action of DBS, focusing on neuroinflammation and motor and nociceptive response, in order to guide the improvement of more effective therapeutic interventions to patients with PD. (AU)

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