Efeito do exercício físico nas alterações inflamatórias e comportamentais causadas por crises no modelo de epilepsia lesional induzida por pilocarpina

• Ano de defesa: 2020
• Autor(a) principal: Santos, Rodrigo Correia [UNIFESP]
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Exercise; Temporal Lobe Epilepsy; Cognition; Cytokines; Purinergic P2X7 Receptors; Inflammation; Exercício; Epilepsia Do Lobo Temporal; Cognição; Citocinas; Receptores Purinérgicos P2X7; Inflamação
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=9691059; https://hdl.handle.net/11600/64214

Introduction: Mesial Temporal Lobe Epilepsy (ELTM) is a more prevalent form among epilepsies, representing about 40% of all cases and 60% of temporal lobe epilepsies (TLE). A hippocampal sclerosis is a pathophysiological alteration most frequently observed in the ELTM. Cell death in ELTM has been associated with the cognitive impairment present in many patients who also have seizures resistant to antiepileptic drug treatment. Neuroinflammation and oxidative stress have been reported as key factors in the development and progress of ELTM. Recent studies show an association between klotho protein decline, responsible for regulating phosphate excretion and vitamin D synthesis in the kidney, with age-related changes, cognitive impairment mainly. The experimental model of pilocarpine-induced lesion epilepsy reproduces the main electrophysiological, pathophysiological and behavioral characteristics of ELTM. It has been widely used to investigate mechanisms involved with epileptogenesis, aiming at new therapeutic approaches. The effect of exercise on neuroinflammatory and behavioral changes was tested in the present study. Objectives: Evaluate the effect of aerobic exercise on behavioral (seizure frequency, locomotion, anxiety and memory) and molecular (klotho protein expression and P2X7 proinflammatory markers, cytokines and NLRP3 proteasome) changes in the brain of rats submitted to lithium-associated pilocarpine lesional epilepsy model. Methods: Adult Wistar rats were injected with lithium chloride (127 mM / kg, i.p.) and 18 h after with methylscopolamine (1 mg / kg, s.c.) followed by pilocarpine (30 mg / kg, s.c.) 20 min after for induction of status epilepticus (SE). Both animals that presented 2 h of SE and controls treated with saline, instead of pilocarpine, were submitted to voluntary aerobic exercise training for 30 days. After this period, the animals that received pilocarpine were filmed for 30 days to evaluate the frequency of seizures. After this period, all animals of the studied groups were submitted to behavioral tests: open field locomotion, discriminative avoidance and object recognition. At the end of the behavioral tests, the animals were euthanized and the hippocampus homogenized for the analysis of TNF-α, IL-1β and IL-6 by ELISA, and Western blot P2X7, NLRP3 and klotho proteins. Results: The data showed that epileptic rats that exercised presented smaller number of seizures compared to sedentary epileptic rats, however, there were no differences regarding anxiety, locomotion and memory parameters between groups. Biochemical analyzes showed that epileptic rats had high levels of TNF-α, IL-1β, IL-6, P2X7 and NLRP3 in the hippocampus and exercise significantly reduced these markers. There was no significant difference in klotho protein quantification between the epilepsy and control groups, with and without exercise, although the data show an increase in the average concentration of epileptic animals xix compared to the control group. Conclusion: Physical exercise has been shown to be beneficial because it reverses most of the molecular changes caused by seizures. Exercise reduced P2X7 receptor expression as well as cytokines and NLRP3 inflammasome in the hippocampus. Exercise caused a reduction in seizure frequency and this may be a result of the decrease in expression of the pro-inflammatory markers studied. However, no behavioral changes in locomotion, anxiety and cognitive impairment were detected, as well as no significant difference in klotho protein expression in the hippocampus of exercise and sedentary epilepsy rats compared to their respective controls. Further studies employing larger numbers of older animals may unravel the role of klotho protein in cognitive impairment associated with epilepsy in preclinical models and clinical studies.