Sport Sciences for Health

, Volume 15, Issue 1, pp 65–72 | Cite as

Positive effect of moderate-intensity aerobic activity on pentylenetetrazol-induced epileptic behaviors in pregnant mice and cognitive performance in adult male offspring

  • Ayoob Sabaghi
  • Ali HeyraniEmail author
  • Amir Kiani
  • Namdar Yousofvand
Original Article



Epilepsy is one of the common neurological disorders. It has been reported that physical activity can be a complementary therapy to treat seizures. Therefore, the present study was designed to investigate the effect of aerobic training on pentylenetetrazol (PTZ)-induced seizure in pregnant mice.


The kindled female mice were divided into eight groups including (1) pregnant mice (PC) treated with PTZ without physical training (PT), (2) PC treated with PTZ with aerobic training (AT), (3) PC treated with normal saline (NS), (4) PC without any injection in pregnancy, (5) non-PC treated with PTZ without PT, (6) non-PC treated with PTZ with AT, (7) non-PC treated with NS and (8) non-PC without any injection. The seizure activity was measured for half an hour after PTZ injection and anxiety activity was assessed 2 h after PTZ injection. Also, at postnatal day 94, cognitive performance at male offspring of the groups was evaluated.


The results showed that aerobic training reduced seizure severity and restored seizure-induced anxiety in pregnant and non-pregnant mice to control levels. It was also observed that aerobic activity during pregnancy would restore the cognitive function of the offspring in pregnant mice treated with PTZ to the male offspring’s level in control group.


Generally, the results of this study showed that moderate-intensity AT is an appropriate treatment strategy for reducing the severity of seizure, seizure-induced anxiety and also prevents cognitive impairment due to seizure induction during pregnancy in the male offspring.


Seizyre Pregnancy Aerobic training Anxiety Cognitive performance Offspring 


Author contributions

AS conceived and designed the study. AS, AH and AK were responsible for acquisition, analysis and interpretation of data and drafting of the manuscript. AS was responsible for participant recruitment and contributed to analysis and interpretation of data and correction of the manuscript. AS, AK and NY were involved in critical revision of the manuscript. AS was responsible for statistical analysis and revision of the manuscript. AS and AK performed critical revision of the manuscript regarding important intellectual content. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional and national research committee (IRB number; 2212538/01) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

All participants provide written, informed consent after being informed about the protocol and purpose of the study. It was approved by the ethics Committee of the Razi university of Kermanshah, Iran.


  1. 1.
    Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE et al (2014) ILAE official report: a practical clinical definition of epilepsy. Epilepsia 55(4):475–482Google Scholar
  2. 2.
    Ablah E, Hesdorfferr DC, Liuc Y et al (2014) Prevalence of epilepsy in rural Kansas. Epilepsy Res 108(4):792–801Google Scholar
  3. 3.
    Cossa AC, Lima DC, do Vale TG, de Alencar Rocha AK, da Graça Naffah-Mazzacoratti M, da Silva Fernandes MJ et al (2016) Maternal seizures can affect the brain developing of offspring. Metab Brain Dis 31:891Google Scholar
  4. 4.
    Pourmotabbed A, Nedaei SE, Cheraghi M, Moradian S, Touhidi A, Aeinfar M, Seyfi Z, Pourmotabbed T (2011) Effect of prenatal pentylenetetrazol-induced kindling on learning and memory of male offspring. Neuroscience 172:205–211Google Scholar
  5. 5.
    Leal-Campanario R, Alarcon-Martinez L, Rieiro H, Martinez-Conde S, Alarcon-Martinez T, Zhao X et al (2017) Abnormal capillary vasodynamics contribute to ictal neurodegeneration in epilepsy. Sci Rep 7:43276Google Scholar
  6. 6.
    Li Y, Gonzalez P, Zhang L (2012) Fetal stress and programming of hypoxic/ischemic-sensitive phenotype in the neonatal brain: mechanisms and possible interventions. Prog Neurobiol 98(2):145–165Google Scholar
  7. 7.
    Beltramini GC, Cendes F, Yasuda CL (2015) The effects of antiepileptic drugs on cognitive functional magnetic resonance imaging. Quant Imaging Med Surg 5(2):238–246Google Scholar
  8. 8.
    Mattson RH, Gidal BE (2004) Fractures, epilepsy, and antiepileptic drugs. Epilepsy Behav 5(Suppl 2):S36–S40 (review) Google Scholar
  9. 9.
    Meador K, Reynolds MW, Crean S, Fahrbach K, Probst C (2008) Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy 81(1):1–13Google Scholar
  10. 10.
    Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Sabers A et al (2011) EURAP study group. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol 10:609–617Google Scholar
  11. 11.
    Bromley R, Weston J, Adab N, Greenhalgh J, Sanniti A, McKay AJ et al (2014) Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child. Cochrane Database Syst Rev 30(10):CD010236Google Scholar
  12. 12.
    Nakken KO, Loyning A, Loyning T, Gløersen G, Larsson PG (1997) Does physical exercise influence the occurrence of epileptiform EEG discharges in children? Epilepsia 38:279–284Google Scholar
  13. 13.
    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 2:592–600Google Scholar
  14. 14.
    Arida RM, de Jesus VA, Cavalheiro EA (1998) Effect of physical exercise on kindling development. Epilepsy Res 30:127–132Google Scholar
  15. 15.
    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 37:45–52Google Scholar
  16. 16.
    Arida RM, Sanabria ER, 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 83:165–171Google Scholar
  17. 17.
    Arida RM, Scorza CA, Scorza FA, Cavalheiro M EA (2007) Gomes da Silva S, da Grac¸a Naffah-azzacoratti. 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 31:814–822Google Scholar
  18. 18.
    Zhang B, Zhang JW, Wang WP, Dong RF, Tian S, Zhang C (2017) Effect of lamotrigine on epilepsy-induced cognitive impairment and hippocampal neuronal apoptosis in pentylenetetrazole-kindled animal model. Synapse 71:e21945Google Scholar
  19. 19.
    Rajabzadeh A, Bideskan AE, Fazel A, Sankian M, Rafatpanah H, Haghir H (2012) The effect of PTZ-induced epileptic seizures on hippocampal expression of PSA-NCAM in offspring born to kindled rats. J BiomedSci 31 19:56Google Scholar
  20. 20.
    Becker A, Grecksch G, Ruthrich HL, Pohle W, Marx B, Matthies H (1992) Kindling and its consequences on learning in rats. BehavNeuralBiol 57:37–43Google Scholar
  21. 21.
    Zybura-Broda K, Amborska R, AmbrozekLatecka M, Wilemska J, Bogusz A, Bucko J et al (2016) Epigenetics of epileptogenesis-evoked upregulation of matrix metalloproteinase-9 in hippocampus. PLoS ONE 11(8):e0159745Google Scholar
  22. 22.
    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 22:274:69–81Google Scholar
  23. 23.
    Salari AA, Fatehi-Gharehlar L, Motayagheni N, Homberg JR (2016) Fluoxetine normalizes the effects of prenatal maternal stress on depression- and anxiety-like behaviors in mouse dams and male offspring. Behav Brain Res 311:354–367Google Scholar
  24. 24.
    Gomes da Silva S, de Almeida AA, Fernandes J, Lopim GM, Cabral FR, Scerni DA, et al (2016) Maternal exercise during pregnancy increases BDNF levels and cell numbers in the hippocampal formation but not in the cerebral cortex of adult rat offspring. PLoSOne 15:e0147200Google Scholar
  25. 25.
    Wang N, Liu Y, Ma Y, Wen D (2017) High-intensity interval versus moderate-intensity continuous training: superior metabolic benefits in diet-induced obesity mice. Life Sci 191:122–131Google Scholar
  26. 26.
    Henriques I, Lopes-Pacheco M, Padilha GA, Marques PS, Magalhães RF, Antunes MA et al (2016) Moderate aerobic training improves cardiorespiratory parameters in elastase-induced emphysema. Front Physiol 7:329Google Scholar
  27. 27.
    Sharma RK, Singh T, Mishra A, Goel RK (2017) Relative safety of different antidepressants for treatment of depression in chronic epileptic animals associated with depression. J Epilepsy Res 7(1):25–32Google Scholar
  28. 28.
    Kameda SR, Fukushiro DF, Trombin TF, Procópio-Souza R, Patti CL, Hollais AW et al (2011) Adolescent mice are more vulnerable than adults to single injection-induced behavioral sensitization to amphetamine. Pharmacol Biochem Behav 98(2):320–324Google Scholar
  29. 29.
    Ngoupaye GT, Yassi FB, Bahane DAN, Bum EN (2017) Combined corticosterone treatment and chronic restraint stress lead to depression associated with early cognitive deficits in mice. Metab Brain Dis 33(2):421–431Google Scholar
  30. 30.
    Rabbani M, Hajhashemi V, Mesripour A (2009) Increase in brain corticosterone concentration and recognition memory impairment following morphine withdrawal in mice. Stress 12(5):451–456Google Scholar
  31. 31.
    Campos DV, Lopim GM, de Almeida VS, Amado D, Arida RM (2016) Effects of different physical exercise programs on susceptibility to pilocarpine-induced seizures in female rats. Epilepsy Behav 64:262–267Google Scholar
  32. 32.
    Chen JX, Zhao X, Yue GX, Wang ZF (2007) Influence of acute and chronic treadmill exercise on rat plasma lactate and brain NPY, L-ENK, DYN A1–13. Cell Mol Neurobiol 27:1–10Google Scholar
  33. 33.
    Gall C, Lauterborn J, Bundman M, Murray K, Isackson P (1991) Seizures and the regulation of neurotrophic factor and neuropeptide gene expression in brain. Epilepsy Res Suppl 4:225–245Google Scholar
  34. 34.
    Chaouloff F (1989) Physical exercise and brain monoamines: a review. Acta Physiol Scand 137:1–13Google Scholar
  35. 35.
    Westerberg V, Lewis J, Corcoran ME (1984) Depletion of noradrenaline fails to affect kindling seizures. Exp Neurol 84:237–240Google Scholar
  36. 36.
    Arida RM, Cavalheiro EA, Silva AC, Scorza FA (2008) Physical activity and epilepsy: proven and predicted benefits. Sports Med 38:607–615Google Scholar
  37. 37.
    Sloviter RS, Sollas AL, Barbaro NM, Laxer KD (1991) Calcium-binding protein (calbindin-D28K) and parvalbumin immunocytochemistry in the normal and epileptic human hippocampus. J Comp Neurol 308:381–396Google Scholar
  38. 38.
    Henry JF, Sherwin BB (2012) Hormones and cognitive functioning during late pregnancy and postpartum: a longitudinal study. Behav Neurosci 126(1):73–85Google Scholar
  39. 39.
    Tauboll E, Sveberg L, Svalheim S (2015) Interactions between hormones and epilepsy. Seizure 28:3–11Google Scholar
  40. 40.
    Moezi L, Hassanipour M, Zaeri M, Ghorbani H, Shafaroodi H (2015) The influence of ovariectomy on anti-convulsant effect of pioglitazone in mice. Pathophysiology 3:159–163Google Scholar
  41. 41.
    Battino D, Tomson T, Bonizzoni E, Craig J, Lindhout D, Sabers A et al (2013) Seizure control and treatment changes in pregnancy: observations from the EURAP epilepsy pregnancy registry. Epilepsia 54:1621–1627Google Scholar
  42. 42.
    Reisinger T, Newman M, Loring D, Pennell P, Meador K (2013) Antiepileptic drug clearance and seizure frequency during pregnancy in women with epilepsy. Epilepsy Behav 29:13–18Google Scholar
  43. 43.
    Kwon O-Y, Park S-P (2014) Depression and anxiety in people with epilepsy. J Clin Neurol 10(3):175–188Google Scholar
  44. 44.
    Mohler H (2006) GABAA receptors in central nervous system disease: anxiety, epilepsy, and insomnia. J Recept Signal Transduct Res 26:731–740Google Scholar
  45. 45.
    Ekonomou A, Smith AL, Angelatou F (2001) Changes in AMPA receptor binding and subunit messenger RNA expression in hippocampus and cortex in the pentylenetetrazole-induced ‘kindling’ model of epilepsy. Brain Res Mol Brain Res 95(1–2):27–35Google Scholar
  46. 46.
    Tran L, Lasher B, Young K, Keele N (2013) Depletion of serotonin in the basolateral amygdala elevates glutamate receptors and facilitates fear-potentiated startle. Transl Psychiatry 3(9):e298Google Scholar
  47. 47.
    Frantz AL, Regner GG, Pflüger P, Coelho VR, da Silva LL, Viau CM et al (2017) Manual acupuncture improves parameters associated with oxidative stress and inflammation in PTZ-induced kindling in mice. Neurosci Lett 20:661:33–40Google Scholar
  48. 48.
    Salim S (2014) Oxidative stress and psychological disorders. Curr Neuropharmacol 12(2):140–147Google Scholar
  49. 49.
    Dao AT, Zagaar MA, Salim S, Eriksen JL, Alkadhi KA (2014) Regular exercise prevents non-cognitive disturbances in a rat model of Alzheimer’s disease. Int J Neuropsychoph 17:593–602Google Scholar
  50. 50.
    Lalanza JF, Sanchez-Roige S, Gagliano H, Fuentes S, Bayod S, Camins A et al (2012) Physiological and behavioural consequences of long-term moderate treadmill exercise. Psychoneuroendocrinology 37:1745–1754Google Scholar
  51. 51.
    Anderson E, Shivakumar G (2013) Effects of exercise and physical activity on anxiety. Front Psychiatry 4:27Google Scholar
  52. 52.
    Ghodrati-Jaldbakhan S, Ahmadalipour A, Rashidy-Pour A, Vafaei AA, Miladi-Gorji H, Alizadeh M (2017) Low- and high-intensity treadmill exercise attenuates chronic morphine-induced anxiogenesis and memory impairment but not reductions in hippocampal BDNF in female rats. Brain Res 15:20–28Google Scholar
  53. 53.
    Munehiro T, Kitaoka K, Ueda Y, Maruhashi Y, Tsuchiya H (2012) Establishment of an animal model for delayed-onset muscle soreness after high-intensity eccentric exercise and its application for investigating the efficacy of low-load eccentric training. J Orthop Sci 17(3):244–252Google Scholar
  54. 54.
    Vieira JM, Carvalho FB, Gutierres JM, Soares MS, Oliveira PS, Rubin MA, Morsch et al (2017) Caffeine prevents high-intensity exercise-induced increase in enzymatic antioxidant and Na+–K+–ATPase activities and reduction of anxiolytic like-behaviour in rats. Redox Rep 22(6):493–500Google Scholar
  55. 55.
    Rosa EF, Takahashi S, Aboulafia J, Nouailhetas VL, Oliveira MG (2007) Oxidative stress induced by intense and exhaustive exercise impairs murine cognitive function. J Neurophysiol 98(3):1820–1826Google Scholar
  56. 56.
    Pal S, Chaki B, Chattopadhyay S, Bandyopadhyay A (2018) High-intensity exercise induced oxidative stress and skeletal muscle damage in postpubertal boys and girls: a comparative study. J Strength Cond Res 32(4):1045–1052Google Scholar
  57. 57.
    Ho Y-H, Lin Y-T, Wu C-WJ, Chao Y-M, Chang AYW, Chan JY H (2015) Peripheral inflammation increases seizure susceptibility via the induction of neuroinflammation and oxidative stress in the hippocampus. J Biomed Sci 22(1):46Google Scholar
  58. 58.
    Ashrafi MR, Shams S, Nouri M, Mohseni M, Shabanian R, Yekaninejad MS et al (2007) A probable causative factor for an old problem: selenium and glutathione peroxidase appear to play important roles in epilepsy pathogenesis. Epilepsia 48:1750–1755Google Scholar
  59. 59.
    Arida RM, Scorza FA, Terra VC, Scorza CA, de Almeida AC, Cavalheiro EA (2009) Physical exercise in epilepsy: what kind of stressor is it? Epilepsy Behav 16:381–387Google Scholar
  60. 60.
    Brown DA, Johnson MS, Armstrong CJ, Lynch JM, Caruso NM, Ehlers LB, et al (2007) Short-term treadmill running in the rat: what kind of stressor is it? J Appl Physiol 103(6):1979–1985Google Scholar
  61. 61.
    Tolmacheva EA, Oitzl MS, van Luijtelaar G (2012) Stress, glucocorticoids and absences in a genetic epilepsy model. Horm Behav 61:706–710Google Scholar
  62. 62.
    Sachs BD, Ni JR, Caron MG (2014) Sex differences in response to chronic mild stress and congenital serotonin deficiency. Sychoneuroendocrinology 40:123–129Google Scholar
  63. 63.
    Hodes GE, Kana V, Menard C, Merad M, Russo SJ (2015) Neuroimmune mechanisms of depression. Nat Neurosci 18:1386–1393Google Scholar
  64. 64.
    Russo SJ, Nestler EJ (2013) The brain reward circuitry in mood disorders. Nat Rev Neurosci 14:609–625Google Scholar
  65. 65.
    Brancato A, Bregman D, Ahn HF, Pfau ML, Menard C, Cannizzaro C et al (2017) Sub-chronic variable stress induces sex-specific effects on glutamatergic synapses in the nucleus accumbens. Neuroscience 14(350):180–189Google Scholar
  66. 66.
    Neumann ID, Johnstone HA, Hatzinger M, Liebsch G, Shipston M, Russell JA et al (1998) Attenuated neuroendocrine responses to emotional and physical stressors in pregnant rats involve adenohypophysial changes. J Physiol 508(Pt 1):289–300Google Scholar
  67. 67.
    Boersma GJ, Lee RS, Cordner ZA, Ewald ER, Purcell RH, Moghadam AA, Tamashiro KL (2014) Prenatal stress decreases Bdnf expression and increases methylation of Bdnf exon IV in rats. Epigenetics 9(3):437–447Google Scholar
  68. 68.
    Akhavan MM, Emami-Abarghoie M, Safari M, Sadighi-Moghaddam B, Vafaei AA, Bandegi AR, Rashidy-Pour A (2008) Serotonergic and noradrenergic lesions suppress the enhancing effect of maternal exercise during pregnancy on learning and memory in rat pups. Neuroscience 151(4):1173–1183Google Scholar
  69. 69.
    Kim H, Lee SH, Kim SS, Yoo JH, Kim CJ (2007) The influence of maternal treadmill running during pregnancy on short-term memory and hippocampal cell survival in rat pups. Int J Dev Neurosci 25(4):243–249Google Scholar
  70. 70.
    Bick-Sander A, Steiner B, Wolf SA, Babu H, Kempermann G (2006) Running in pregnancy transiently increases postnatal hippocampal neurogenesis in the offspring. Proc Natl Acad Sci USA 7(10):3852–3857 103(Google Scholar

Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Authors and Affiliations

  • Ayoob Sabaghi
    • 1
  • Ali Heyrani
    • 1
    Email author
  • Amir Kiani
    • 2
  • Namdar Yousofvand
    • 3
  1. 1.Department of Physical Education and Sport SciencesRazi UniversityKermanshahIran
  2. 2.Pharmaceutical Sciences Research Center, School of PharmacyKermanshah University of Medical SciencesKermanshahIran
  3. 3.Department of BiologyRazi UniversityKermanshahIran

Personalised recommendations