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

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

Abstract

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)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PINHEIRO CAMPOS, ANA CAROLINA; RUIZ MARTINEZ, RAQUEL CHACON; VATTI AUADA, ALINE VIVIAN; LEBRUN, IVO; FONOFF, ERICH TALAMONI; HAMANI, CLEMENT; PAGANO, ROSANA LIMA. Effect of Subthalamic Stimulation and Electrode Implantation in the Striatal Microenvironment in a Parkinson's Disease Rat Model. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 23, n. 20, p. 17-pg., 2022-10-01. (16/07168-2, 18/18695-9, 19/13781-7)

RAVACHE, THAIS T.; BATISTUZZO, ALICE; NUNES, GABRIELA G.; GOMEZ, THIAGO G. B.; LORENA, FERNANDA B.; DO NASCIMENTO, BRUNA P. P.; BERNARDI, MARIA MARTHA; LIMA, EDUARDA R. R.; MARTINS, DANIEL O.; CAMPOS, ANA CAROLINA P.; et al. Multisensory Stimulation Reverses Memory Impairment in Adr & beta;3KO Male Mice. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 24, n. 13, p. 17-pg., 2023-07-01. (19/13781-7, 17/18277-0, 17/04491-0)