Neurochemical Research

, Volume 42, Issue 4, pp 1230–1239 | Cite as

Resistance Exercise Reduces Seizure Occurrence, Attenuates Memory Deficits and Restores BDNF Signaling in Rats with Chronic Epilepsy

  • Alexandre Aparecido de Almeida
  • Sérgio Gomes da Silva
  • Glauber Menezes Lopim
  • Diego Vannucci Campos
  • Jansen Fernandes
  • Francisco Romero Cabral
  • Ricardo Mario AridaEmail author
Original Paper


Epilepsy is a disease characterized by recurrent, unprovoked seizures. Cognitive impairment is an important comorbidity of chronic epilepsy. Human and animal model studies of epilepsy have shown that aerobic exercise induces beneficial structural and functional changes and reduces the number of seizures. However, little is yet understood about the effects of resistance exercise on epilepsy. We evaluated the effects of a resistance exercise program on the number of seizures, long-term memory and expression/activation of signaling proteins in rats with epilepsy. The number of seizures was quantified by video-monitoring and long-term memory was assessed by an inhibitory avoidance test. Using western blotting, multiplex and enzyme-linked immunosorbent assays, we determined the effects of a 4-week resistance exercise program on IGF-1 and BDNF levels and ERK, CREB, mTOR activation in the hippocampus of rats with epilepsy. Rats with epilepsy submitted to resistance exercise showed a decrease in the number of seizures compared to non-exercised epileptic rats. Memory deficits were attenuated by resistance exercise. Rats with epilepsy showed an increase in IGF-1 levels which were restored to control levels by resistance exercise. BDNF levels and ERK and mTOR activation were decreased in rats with epilepsy and resistance exercise restored these to control levels. In conclusion, resistance exercise reduced seizure occurrence and mitigated memory deficits in rats with epilepsy. These resistance exercise-induced beneficial effects can be related to changes in IGF-1 and BDNF levels and its signaling protein activation. Our findings indicate that the resistance exercise might be included as complementary therapeutic strategy for epilepsy treatment.


Epilepsy Seizures Resistance exercise Long-term memory IGF-1 BDNF 



This research study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; #300605/2013-07); Fundacão de Amparo à Pesquisa do Estado de São Paulo/ Programa Núcleos de Excelência (FAPESP/PRONEX; #14/00035-1; #2013/12692-4; #2011/50680-2).

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflicts of interest. All authors read and approved the final manuscript.


  1. 1.
    Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel J Jr, Forsgren L, French JA, Glynn M, Hesdorffer DC, Lee BI, Mathern GW, Moshe SL, Perucca E, Scheffer IE, Tomson T, Watanabe M, Wiebe S (2014) ILAE official report: a practical clinical definition of epilepsy. Epilepsia 55(4):475–482CrossRefPubMedGoogle Scholar
  2. 2.
    Bell B, Lin JJ, Seidenberg M, Hermann B (2011) The neurobiology of cognitive disorders in temporal lobe epilepsy. Nat. Rev Neurol 7(3):154–164CrossRefGoogle Scholar
  3. 3.
    Meador KJ (2002) Cognitive outcomes and predictive factors in epilepsy. Neurology 58(8 Suppl 5):S21–S26CrossRefPubMedGoogle Scholar
  4. 4.
    Helmstaedter C, Kockelmann E (2006) Cognitive outcomes in patients with chronic temporal lobe epilepsy. Epilepsia 47(Suppl 2):96–98CrossRefPubMedGoogle Scholar
  5. 5.
    Lopim GM, Vannucci Campos D, Gomes da Silva S, de Almeida AA, Lent R, Cavalheiro EA, Arida RM (2016) Relationship between seizure frequency and number of neuronal and non-neuronal cells in the hippocampus throughout the life of rats with epilepsy. Brain Res 1634:179–186CrossRefPubMedGoogle Scholar
  6. 6.
    Pitkänen A, Sutula TP (2002) Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy. Lancet Neurol 1(3):173–181CrossRefPubMedGoogle Scholar
  7. 7.
    Nakken KO (1999) Physical exercise in outpatients with epilepsy. Epilepsia 40(5):643–651CrossRefPubMedGoogle Scholar
  8. 8.
    Nakken KO, Bjorholt PG, Johannessen SI, Loyning T, Lind E (1990) Effect of physical training on aerobic capacity, seizure occurrence, and serum level of antiepileptic drugs in adults with epilepsy. Epilepsia 31(1):88–94CrossRefPubMedGoogle Scholar
  9. 9.
    Eriksen HR, Ellertsen B, Gronningsaeter H, Nakken KO, Loyning Y, Ursin H (1994) Physical exercise in women with intractable epilepsy. Epilepsia 35(6):1256–1264CrossRefPubMedGoogle Scholar
  10. 10.
    McAuley JW, Long L, Heise J, Kirby T, Buckworth J, Pitt C, Lehman KJ, Moore JL, Reeves AL (2001) A prospective evaluation of the effects of a 12-week outpatient exercise program on clinical and behavioral outcomes in patients with epilepsy. Epilepsy Behav 2(6):592–600CrossRefPubMedGoogle Scholar
  11. 11.
    Arida RM, Scorza FA, dos Santos NF, Peres CA, Cavalheiro EA (1999) Effect of physical exercise on seizure occurrence in a model of temporal lobe epilepsy in rats. Epilepsy Res 37(1):45–52CrossRefPubMedGoogle Scholar
  12. 12.
    Arida RM, Sanabria ER, da Silva AC, Faria LC, Scorza FA, Cavalheiro EA (2004) Physical training reverts hippocampal electrophysiological changes in rats submitted to the pilocarpine model of epilepsy. Physiol Behav 83(1):165–171CrossRefPubMedGoogle Scholar
  13. 13.
    Arida RM, Scorza CA, Scorza FA, Gomes da Silva S, da Graca Naffah-Mazzacoratti M, Cavalheiro EA (2007) Effects of different types of physical exercise on the staining of parvalbumin-positive neurons in the hippocampal formation of rats with epilepsy. Prog Neuropsychopharmacol Biol Psychiatry 31(4):814–822CrossRefPubMedGoogle Scholar
  14. 14.
    Lim BV, Shin MS, Lee JM, Seo JH (2015) Treadmill exercise prevents GABAergic neuronal loss with suppression of neuronal activation in the pilocarpine-induced epileptic rats. J Exerc Rehabil 11(2):80–86CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Sartori CR, Pelágio FC, Teixeira SA, Valentinuzzi VS, Nascimento AL, Rogério F, Muscará MN, Ferrari EA, Langone F (2009) Effects of voluntary running on spatial memory and mature brain-derived neurotrophic factor expression in mice hippocampus after status epilepticus. Behav Brain Res 203(2):165–172CrossRefPubMedGoogle Scholar
  16. 16.
    Gomes FG, Gomes Da Silva S, Cavalheiro EA, Arida RM (2014) Beneficial influence of physical exercise following status epilepticus in the immature brain of rats. Neuroscience 274:69–81CrossRefPubMedGoogle Scholar
  17. 17.
    Lee M, Carroll TJ (2007) Cross education: possible mechanisms for the contralateral effects of unilateral resistance training. Sports Med 37(1):1–14CrossRefPubMedGoogle Scholar
  18. 18.
    Fry AC (2004) The role of resistance exercise intensity on muscle fibre adaptations. Sports Med 34(10):663–679CrossRefPubMedGoogle Scholar
  19. 19.
    Weinberg L, Hasni A, Shinohara M, Duarte A (2014) A single bout of resistance exercise can enhance episodic memory performance. Acta Psychol (Amst) 153:13–19CrossRefGoogle Scholar
  20. 20.
    Peixinho-Pena LF, Fernandes J, de Almeida AA, Novaes Gomes FG, Cassilhas R, Venancio DP, de Mello MT, Scorza FA, Cavalheiro EA, Arida RM (2012) A strength exercise program in rats with epilepsy is protective against seizures. Epilepsy Behav 25(3):323–328CrossRefPubMedGoogle Scholar
  21. 21.
    Cassilhas RC, Viana VA, Grassmann V, Santos RT, Santos RF, Tufik S, Mello MT (2007) The impact of resistance exercise on the cognitive function of the elderly. Med Sci Sports Exerc 39(8):1401–1407CrossRefPubMedGoogle Scholar
  22. 22.
    Chang YK, Etnier JL (2009) Effects of an acute bout of localized resistance exercise on cognitive performance in middle-aged adults: A randomized controlled trial study. Psychology of Sport Exercise 10(1):19–24CrossRefGoogle Scholar
  23. 23.
    Liu-Ambrose T, Nagamatsu LS, Graf P, Beattie BL, Ashe MC, Handy TC (2010) Resistance training and executive functions: a 12-month randomized controlled trial. Arch Intern Med 170(2):170–178CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Tsai CL, Wang CH, Pan CY, Chen FC (2015) The effects of long-term resistance exercise on the relationship between neurocognitive performance and GH, IGF-1, and homocysteine levels in the elderly. Front. Behav Neurosci 9:23Google Scholar
  25. 25.
    Weier AT, Pearce AJ, Kidgell DJ (2012) Strength training reduces intracortical inhibition. Acta Physiol (Oxf) 206(2):109–119CrossRefGoogle Scholar
  26. 26.
    Cassilhas RC, Lee KS, Fernandes J, Oliveira MG, Tufik S, Meeusen R, de Mello MT (2012) Spatial memory is improved by aerobic and resistance exercise through divergent molecular mechanisms. Neuroscience 202:309–317CrossRefPubMedGoogle Scholar
  27. 27.
    Cassilhas RC, Lee KS, Venancio DP, Oliveira MG, Tufik S, de Mello MT (2012) Resistance exercise improves hippocampus-dependent memory. Braz J Med Biol Res 45(12):1215–1220CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Fernandes J, Soares JCK, do Amaral Baliego LGZ, Arida RM (2016) A single bout of resistance exercise improves memory consolidation and increases the expression of synaptic proteins in the hippocampus. Hippocampus. doi:  10.1002/hipo.22590 PubMedGoogle Scholar
  29. 29.
    Novaes Gomes FG, Fernandes J, Vannucci Campos D, Cassilhas RC, Viana GM, D’Almeida V, de Moraes Rego MK, Buainain PI, Cavalheiro EA, Arida RM (2014) The beneficial effects of strength exercise on hippocampal cell proliferation and apoptotic signaling is impaired by anabolic androgenic steroids. Psychoneuroendocrinology 50:106–117CrossRefPubMedGoogle Scholar
  30. 30.
    Carro E, Nunez A, Busiguina S, Torres-Aleman I (2000) Circulating insulin-like growth factor I mediates effects of exercise on the brain. J Neurosci 20(8):2926–2933PubMedGoogle Scholar
  31. 31.
    Carro E, Trejo JL, Busiguina S, Torres-Aleman I (2001) Circulating insulin-like growth factor I mediates the protective effects of physical exercise against brain insults of different etiology and anatomy. J Neurosci 21(15):5678–5684PubMedGoogle Scholar
  32. 32.
    Trejo JL, Llorens-Martin MV, Torres-Aleman I (2008) The effects of exercise on spatial learning and anxiety-like behavior are mediated by an IGF-I-dependent mechanism related to hippocampal neurogenesis. Mol Cell Neurosci 37(2):402–411CrossRefPubMedGoogle Scholar
  33. 33.
    Rotwein P (1991) Structure, evolution, expression and regulation of insulin-like growth factors I and II. Growth Factors 5(1):3–18CrossRefPubMedGoogle Scholar
  34. 34.
    Anlar B, Sullivan KA, Feldman EL (1999) Insulin-like growth factor-I and central nervous system development. Horm Metab Res 31(2–3):120–125CrossRefPubMedGoogle Scholar
  35. 35.
    D’Ercole AJ, Ye P, O’Kusky JR (2002) Mutant mouse models of insulin-like growth factor actions in the central nervous system. Neuropeptides 36(2–3):209–220CrossRefPubMedGoogle Scholar
  36. 36.
    Ye P, Li L, Richards RG, DiAugustine RP, D’Ercole AJ (2002) Myelination is altered in insulin-like growth factor-I null mutant mice. J Neurosci 22(14):6041–6051PubMedGoogle Scholar
  37. 37.
    Binder DK, Scharfman HE (2004) Brain-derived neurotrophic factor. Growth Factors 22(3):123–131CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, Greenberg ME (1997) Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 275(5300):661–665CrossRefPubMedGoogle Scholar
  39. 39.
    Butler AA, Yakar S, Gewolb IH, Karas M, Okubo Y, LeRoith D (1998) Insulin-like growth factor-I receptor signal transduction: at the interface between physiology and cell biology. Comp Biochem Physiol B Biochem Mol Biol 121(1):19–26CrossRefPubMedGoogle Scholar
  40. 40.
    Zheng WH, Kar S, Quirion R (2002) Insulin-like growth factor-1-induced phosphorylation of transcription factor FKHRL1 is mediated by phosphatidylinositol 3-kinase/Akt kinase and role of this pathway in insulin-like growth factor-1-induced survival of cultured hippocampal neurons. Mol Pharmacol 62(2):225–233CrossRefPubMedGoogle Scholar
  41. 41.
    Zheng WH, Quirion R (2004) Comparative signaling pathways of insulin-like growth factor-1 and brain-derived neurotrophic factor in hippocampal neurons and the role of the PI3 kinase pathway in cell survival. J Neurochem 89(4):844–852CrossRefPubMedGoogle Scholar
  42. 42.
    Cheng CM, Cohen M, Tseng V, Bondy CA (2001) Endogenous IGF1 enhances cell survival in the postnatal dentate gyrus. J Neurosci Res 64(4):341–347CrossRefPubMedGoogle Scholar
  43. 43.
    Kaplan DR, Miller FD (2000) Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol 10(3):381–391CrossRefPubMedGoogle Scholar
  44. 44.
    Parrizas M, LeRoith D (1997) Insulin-like growth factor-1 inhibition of apoptosis is associated with increased expression of the bcl-xL gene product. Endocrinology 138(3):1355–1358CrossRefPubMedGoogle Scholar
  45. 45.
    Parrizas M, Saltiel AR, LeRoith D (1997) Insulin-like growth factor 1 inhibits apoptosis using the phosphatidylinositol 3′-kinase and mitogen-activated protein kinase pathways. J Biol Chem 272(1):154–161CrossRefPubMedGoogle Scholar
  46. 46.
    Okereke O, Kang JH, Ma J, Hankinson SE, Pollak MN, Grodstein F (2007) Plasma IGF-I levels and cognitive performance in older women. Neurobiol Aging 28(1):135–142CrossRefPubMedGoogle Scholar
  47. 47.
    Jiang G, Wang W, Cao Q, Gu J, Mi X, Wang K, Chen G, Wang X (2015) Insulin growth factor-1 (IGF-1) enhances hippocampal excitatory and seizure activity through IGF-1 receptor-mediated mechanisms in the epileptic brain. Clin Sci (Lond) 129(12):1047–1060CrossRefGoogle Scholar
  48. 48.
    Liu G, Gu B, He XP, Joshi RB, Wackerle HD, Rodriguiz RM, Wetsel WC, McNamara JO (2013) Transient inhibition of TrkB kinase after status epilepticus prevents development of temporal lobe epilepsy. Neuron 79(1):31–38CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Gu B, Huang YZ, He XP, Joshi RB, Jang W, McNamara JO (2015) A peptide uncoupling BDNF receptor TrkB from phospholipase Cγ1 prevents epilepsy induced by status epilepticus. Neuron 88(3):484–491CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    LaFrance WC Jr, Leaver K, Stopa EG, Papandonatos GD, Blum AS (2010) Decreased serum BDNF levels in patients with epileptic and psychogenic nonepileptic seizures. Neurology 75(14):1285–1289CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Walsh JJ, Scribbans TD, Bentley RF, Kellawan JM, Gurd B, Tschakovsky ME (2016) Neurotrophic growth factor responses to lower body resistance training in older adults. Appl Physiol Nutr Metab 41(3):315–323CrossRefPubMedGoogle Scholar
  52. 52.
    Turski WA, Cavalheiro EA, Schwarz M, Czuczwar SJ, Kleinrok Z, Turski L (1983) Limbic seizures produced by pilocarpine in rats: behavioural, electroencephalographic and neuropathological study. Behav Brain Res 9(3):315–335CrossRefPubMedGoogle Scholar
  53. 53.
    Racine RJ (1972) Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 32(3):281–294CrossRefPubMedGoogle Scholar
  54. 54.
    Lowenstein DH, Bleck T, Macdonald RL (1999) It’s time to revise the definition of status epilepticus. Epilepsia 40(1):120–122CrossRefPubMedGoogle Scholar
  55. 55.
    Moreira KM, Hipolide DC, Nobrega JN, Bueno OF, Tufik S, Oliveira MG (2003) Deficits in avoidance responding after paradoxical sleep deprivation are not associated with altered [3H]pirenzepine binding to M1 muscarinic receptors in rat brain. Brain Res 977(1):31–37CrossRefPubMedGoogle Scholar
  56. 56.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding. Anal Biochem 72:248–254CrossRefPubMedGoogle Scholar
  57. 57.
    Field A (2009) Testes não paramétricos. In: Descobrindo a estatística usando o SPSS, 2ª edn. Artmed, Porto Alegre, pp 474–513Google Scholar
  58. 58.
    Smith DB, Craft BR, Collins J, Mattson RH, Cramer JA (1986) Behavioral characteristics of epilepsy patients compared with normal controls. Epilepsia 27(6):760–768CrossRefPubMedGoogle Scholar
  59. 59.
    Bassil F, Fernagut PO, Bezard E, Meissner WG (2014) Insulin, IGF-1 and GLP-1 signaling in neurodegenerative disorders: targets for disease modification? Prog Neurobiol 118:1–18CrossRefPubMedGoogle Scholar
  60. 60.
    Borst SE, De Hoyos DV, Garzarella L, Vincent K, Pollock BH, Lowenthal DT, Pollock ML (2001) Effects of resistance training on insulin-like growth factor-I and IGF binding proteins. Med Sci Sports Exerc 33(4):648–653CrossRefPubMedGoogle Scholar
  61. 61.
    Giovannini MG, Lana D, Pepeu G (2015) The integrated role of ACh, ERK and mTOR in the mechanisms of hippocampal inhibitory avoidance memory. Neurobiol Learn Mem 119:18–33CrossRefPubMedGoogle Scholar
  62. 62.
    Walz R, Roesler R, Quevedo J, Rockenbach IC, Amaral OB, Vianna MR, Lenz G, Medina JH, Izquierdo I (1999) Dose-dependent impairment of inhibitory avoidance retention in rats by immediate post-training infusion of a mitogen-activated protein kinase kinase inhibitor into cortical structures. Behav Brain Res 105(2):219–223CrossRefPubMedGoogle Scholar
  63. 63.
    Bekinschtein P, Katche C, Slipczuk LN, Igaz LM, Cammarota M, Izquierdo I, Medina JH (2007) mTOR signaling in the hippocampus is necessary for memory formation. Neurobiol Learn Mem 87(2):303–307CrossRefPubMedGoogle Scholar
  64. 64.
    Lana D, Cerbai F, Di Russo J, Boscaro F, Giannetti A, Petkova-Kirova P, Pugliese AM, Giovannini MG (2013) Hippocampal long term memory: effect of the cholinergic system on local protein synthesis. Neurobiol Learn Mem 106:246–257CrossRefPubMedGoogle Scholar
  65. 65.
    Atkins CM, Selcher JC, Petraitis JJ, Trzaskos JM, Sweatt JD (1998) The MAPK cascade is required for mammalian associative learning. Nat Neurosci 1(7):602–609CrossRefPubMedGoogle Scholar
  66. 66.
    Hattiangady B, Rao MS, Shetty AK (2004) Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus. Neurobiol Dis 17(3):473–490CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Alexandre Aparecido de Almeida
    • 1
  • Sérgio Gomes da Silva
    • 2
    • 3
  • Glauber Menezes Lopim
    • 1
  • Diego Vannucci Campos
    • 1
  • Jansen Fernandes
    • 1
  • Francisco Romero Cabral
    • 2
    • 4
  • Ricardo Mario Arida
    • 1
    Email author
  1. 1.Departamento de FisiologiaUniversidade Federal de São PauloSão PauloBrazil
  2. 2.Hospital Israelita Albert EinsteinSão PauloBrazil
  3. 3.Núcleo de Pesquisas Tecnológicas, Programa Integrado em Engenharia BiomédicaUniversidade de Mogi das CruzesMogi das CruzesBrazil
  4. 4.Faculdade de Ciências Médicas da Santa Casa de São PauloSão PauloBrazil

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