RESEARCH ARTICLE Physical exercise alters the activation of downstream proteins related to BDNF-TrkB signaling in male Wistar rats with epilepsy Alexandre Aparecido de Almeida 1,2 | S  ergio Gomes da Silva 3,4 | Glauber Menezes Lopim 1 | Diego Vannucci Campos 1 | Jansen Fernandes 1 | Francisco Romero Cabral 3,5 | Ricardo Mario Arida 1 1 Departamento de Fisiologia, Universidade Federal de S~ao Paulo, S~ao Paulo, Brazil 2 Instituto Federal Goiano (IF Goiano), Campus Ceres, Ceres, Brazil 3 Hospital Israelita Albert Einstein, S~ao Paulo, Brazil 4 Universidade de Mogi das Cruzes, Mogi das Cruzes, Brazil 5 Faculdade de Ci^ encias M edicas da Santa Casa de S~ao Paulo, S~ao Paulo, Brazil Correspondence Ricardo Mario Arida, Departamento de Fisiologia, Universidade Federal de S~ao Paulo, Rua Botucatu 862, Ed. Ci^ encias Biom edicas, 58 Andar, Vila Clementino, 04023-900, S~ao Paulo (SP), Brasil. Email: arida.nexp@epm.br Funding Information This research study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnol  ogico (CNPq; 300605/ 2013-07), Fundac~ao de Amparo a Pesquisa do Estado de S~ao Paulo (14/00035-1; 2013/12692-4; 2013/13725-3), and Programa N ucleos de Excel^ encia (FAPESP- MCT/CNPq-PRONEX 2011/50680-2). Abstract There are a considerable number of studies concerning the behavioral effects of physical exercise on the epileptic brain; however, the intracellular signaling mechanisms involved remain unclear. We investigated the effects of aerobic exercise on hippocampal levels of brain-derived neurotro- phic factor (BDNF), expression of its receptor tropomyosin receptor kinase B (TrkB), and activation of intracellular proteins related to BDNF-TrkB signaling in male Wistar rats with pilocarpine- induced epilepsy. Thirty days after the first spontaneous seizure, rats from the exercise group undertook a 30-day physical exercise program on the treadmill. Thereafter, BDNF levels, expres- sion of TrkB, and activation of intracellular proteins were quantified by enzyme-linked immunosorbent assay, Western blotting, and multiplex assay, respectively. Statistical analyses were conducted using nonparametric tests. Rats with epilepsy presented decreased BDNF levels compared with control rats. BDNF levels increased significantly in the exercise group compared with the epileptic and control groups. Expression of full-length and truncated TrkB was increased in rats with epilepsy, and physical exercise restored its expression to control levels. RAC-alpha ser- ine/threonine-protein kinase, mammalian target of rapamycin, and extracellular signal-regulated kinase activation were reduced in rats with epilepsy, and exercise increased activation compared with control and epilepsy groups. Increased cAMP response element binding protein activation was observed in the exercise group compared with the epilepsy group. Our findings indicate that the beneficial effects of exercise in the epileptic brain can be in part related to alterations in the activation of proteins related to the BDNF-TrkB signaling pathway. KEYWORDS BDNF, cell signaling, epilepsy, physical exercise 1 | INTRODUCTION Since the second half of the 20th century, studies have been reporting the beneficial effects of physical exercise on the epileptic brain. G€ otze and colleagues were the first to investigate the beneficial effect of physical exercise on seizure threshold (G€ otze, Kubicki, Munter, & Teichmann, 1967). Subsequent clinical and experimental studies have investigated the effects of different exercise models on the behavioral, electrophysiological, cellular, molecular, and biochemical parameters in Significance Epilepsy is a very common neurological disorder. Clinical and experimental studies have reported positive effects of physical exercise in epilepsy. The underlying biological mechanisms involved in beneficial effects remain unclear. In this study, we focused on the protein activation related to BDNF-TrkB signal- ing pathways after a physical exercise program. Our findings strengthen the potential complementary therapeutic impact of physical exercise on people with epilepsy. J Neuro Res. 2017;1–10. wileyonlinelibrary.com/journal/jnr VC 2017 Wiley Periodicals, Inc. | 1 Received: 28 June 2017 | Revised: 16 October 2017 | Accepted: 17 October 2017 DOI: 10.1002/jnr.24196