The effects of exercise on hippocampal inflammatory cytokine levels, brain oxidative stress markers and memory impairments induced by lipopolysaccharide in rats

  • Zahra Jahangiri
  • Zahra GholamnezhadEmail author
  • Mahmoud Hosseini
Original Article


The exercise effects on behavioral tests, hippocampal and cortical oxidative stress, and hippocampal inflammatory cytokines of lipopolysaccharide (LPS) administered rats were investigated. The rats were divided into four groups (N = 8): (1) control; (2) moderate training (MT, 15 m/min, 30 min/day, 9 weeks); (3) LPS (1 mg/kg LPS) and (4) LPS + MT (1 mg/kg LPS; 15 m/min, 30 min/day, 9 weeks). LPS was injected 2 h before the behavioral experiments during the last week of training. Finally, the rats’ brain were removed for biochemical assessments. LPS increased escape latency and traveled distance to reach the platform in Morris water maze (MWM) test (P < 0.05–P < 0.001). In the passive avoidance (PA) test, LPS decreased the latency to enter the dark compartment and the time spent in the light compartment and increased the time spent in the dark compartment (P < 0.01–P < 0.001), while MT improved the rats performances in MWM and PA tests (P < 0.01–P < 0.001). Additionally, LPS increased tumor necrosis factor α (TNF-α), interleukin 1 beta (IL-1β) and C-reactive protein levels in the hippocampal tissues, malondialdehyde (MDA) and nitric oxide metabolite in hippocampal and cortical tissues, and decreased thiol contents and catalase (CAT) and superoxide dismutase (SOD) activity in hippocampal and cortical tissues compared to the control group (P < 0.01-P < 0.001); while moderate training decreased the levels of TNF-α, IL-1β and MDA; increased thiol contents, and SOD and CAT activity in the LPS + MT compared to the LPS group (P < 0.001). These results indicated that moderate training improved LPS-induced learning and memory impairments by attenuating the hippocampal cytokine levels and brain oxidative damage.


Moderate training Lipopolysaccharide Learning Memory Cytokine Oxidative damage 



The results described in this paper are part of M.Sc. student’s thesis. The authors would like to thank the Vice Presidency of Research of Mashhad University of Medical Sciences for financial support.

Compliance with ethical standards

Conflict of interests

The authors declare no conflicts of interests in this study.


  1. Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126CrossRefGoogle Scholar
  2. Ahn JH, Choi JH, Park JH, Kim IH, Cho JH, Lee JC, Koo HM, Hwangbo G, Yoo KY, Lee CH, Hwang IK, Cho JH, Choi SY, Kwon YG, Kim YM, Kang IJ, Won MH (2016) Long-term exercise improves memory deficits via restoration of myelin and microvessel damage, and enhancement of neurogenesis in the aged gerbil Hippocampus after ischemic stroke. Neurorehabil Neural Repair 30:894–905. CrossRefGoogle Scholar
  3. Anaeigoudari A, Shafei MN, Soukhtanloo M, Sadeghnia HR, Reisi P, Beheshti F, Mohebbati R, Mousavi SM, Hosseini M (2015) Lipopolysaccharide-induced memory impairment in rats is preventable using 7-nitroindazole. Arq Neuropsiquiatr 73:784–790. CrossRefGoogle Scholar
  4. Anaeigoudari A, Soukhtanloo M, Reisi P, Beheshti F, Hosseini M (2016a) Inducible nitric oxide inhibitor aminoguanidine, ameliorates deleterious effects of lipopolysaccharide on memory and long term potentiation in rat. Life Sci 158:22–30. CrossRefGoogle Scholar
  5. Anaeigoudari A, Soukhtanloo M, Shafei MN, Sadeghnia HR, Reisi P, Beheshti F, Behradnia S, Mousavi SM, Hosseini M (2016b) Neuronal nitric oxide synthase has a role in the detrimental effects of lipopolysaccharide on spatial memory and synaptic plasticity in rats. Pharmacol Rep 68:243–249CrossRefGoogle Scholar
  6. Baradaran B, Baghaei B, Tartibian B (2013) Catalase enzyme gene expression and oxidant markers’ levels in trained women&58; effect of incremental exercise journal of Shahid Sadoughi University of medical. Sciences 20:778–788Google Scholar
  7. Bargi R, Asgharzadeh F, Beheshti F, Hosseini M, Sadeghnia HR, Khazaei M (2017) The effects of thymoquinone on hippocampal cytokine level, brain oxidative stress status and memory deficits induced by lipopolysaccharide in rats. Cytokine 96:173–184. CrossRefGoogle Scholar
  8. Beheshti F, Hosseini M, Shafei MN, Soukhtanloo M, Ghasemi S, Vafaee F, Zarepoor L (2017) The effects of Nigella sativa extract on hypothyroidism-associated learning and memory impairment during neonatal and juvenile growth in rats. Nutr Neurosci 20:49–59CrossRefGoogle Scholar
  9. Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of ageing and cognitive decline. Nature 464:529–535. CrossRefGoogle Scholar
  10. Cassilhas RC, Tufik S, de Mello MT (2016) Physical exercise, neuroplasticity, spatial learning and memory. Cell Mol Life Sci 73:975–983. CrossRefGoogle Scholar
  11. Chen YW, Li YT, Chen YC, Li ZY, Hung CH (2012) Exercise training attenuates neuropathic pain and cytokine expression after chronic constriction injury of rat sciatic nerve. Anesth Analg 114:1330–1337. CrossRefGoogle Scholar
  12. Cobley JN, Fiorello ML, Bailey DM (2018) 13 reasons why the brain is susceptible to oxidative stress. Redox Biol 15:490–503. CrossRefGoogle Scholar
  13. Czerniawski J, Miyashita T, Lewandowski G, Guzowski JF (2015) Systemic lipopolysaccharide administration impairs retrieval of context-object discrimination, but not spatial, memory: evidence for selective disruption of specific hippocampus-dependent memory functions during acute neuroinflammation. Brain Behav Immun 44:159–166. CrossRefGoogle Scholar
  14. Deng XH, Ai WM, Lei DL, Luo XG, Yan XX, Li Z (2012) Lipopolysaccharide induces paired immunoglobulin-like receptor B (PirB) expression, synaptic alteration, and learning-memory deficit in rats. Neuroscience 209:161–170. CrossRefGoogle Scholar
  15. Diniz BS, Mendes-Silva AP, Silva LB, Bertola L, Vieira MC, Ferreira JD, Nicolau M, Bristot G, da Rosa ED, Teixeira AL, Kapczinski F (2018) Oxidative stress markers imbalance in late-life depression. J Psychiatr Res 102:29–33. CrossRefGoogle Scholar
  16. Donzis EJ, Tronson NC (2014) Modulation of learning and memory by cytokines: signaling mechanisms and long term consequences. Neurobiol Learn Mem 115:68–77. CrossRefGoogle Scholar
  17. Dvorakova-Lorenzova A et al (2006) The decrease in C-reactive protein concentration after diet and physical activity induced weight reduction is associated with changes in plasma lipids, but not interleukin-6 or adiponectin. Metab Clin Exp 55:359–365. CrossRefGoogle Scholar
  18. Farzanegi P, Mousavi M, Ghanbari-Niaki A (2013) Effect of Pistacia atlantica extract on glutathione peroxidase tissue levels and total oxidative capacity of liver and plasma lipid profile of rats. ZJRMS 15:59–63Google Scholar
  19. Fruhauf PK, Ineu RP, Tomazi L, Duarte T, Mello CF, Rubin MA (2015) Spermine reverses lipopolysaccharide-induced memory deficit in mice. J Neuroinflammation 12:3. CrossRefGoogle Scholar
  20. Gholamnezhad Z, Boskabady MH, Hosseini M, Sankian M, Khajavi Rad A (2014) Evaluation of immune response after moderate and overtraining exercise in wistar rat. Iran J Basic Med Sci 17:1–8Google Scholar
  21. Habeeb AF (1972) [37] reaction of protein sulfhydryl groups with Ellman's reagent. Methods Enzymol 25:457–464. CrossRefGoogle Scholar
  22. Hennigan A, Trotter C, Kelly AM (2007) Lipopolysaccharide impairs long-term potentiation and recognition memory and increases p75NTR expression in the rat dentate gyrus. Brain Res 1130:158–166. CrossRefGoogle Scholar
  23. Hosseini M, Harandizadeh F, Niazmand S, Soukhtanloo M, Faizpour A, Ghasemabady M (2014) The role for nitric oxide on the effects of hydroalcoholic extract of Achillea wilhelmsii on seizure. Avicenna J Phytomed 4:251–259Google Scholar
  24. Jahangiri Z, Gholamnezhad Z, Hosseini M (2018) Neuroprotective effects of exercise in rodent models of memory deficit and Alzheimer's. Metab Brain Dis 34:21–37. CrossRefGoogle Scholar
  25. Janero DR (1990) Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radic Biol Med 9:515–540CrossRefGoogle Scholar
  26. Ji LL, Gomez-Cabrera MC, Vina J (2006) Exercise and hormesis: activation of cellular antioxidant signaling pathway. Ann N Y Acad Sci 1067:425–435. CrossRefGoogle Scholar
  27. Kacem M, Simon G, Leschiera R, Misery L, ElFeki A, Lebonvallet N (2015) Antioxidant and anti-inflammatory effects of Ruta chalepensis L. extracts on LPS-stimulated RAW 264.7 cells. In Vitro Cell Dev Biol Anim 51:128–141CrossRefGoogle Scholar
  28. Kanamaru T, Kamimura N, Yokota T, Iuchi K, Nishimaki K, Takami S, Akashiba H, Shitaka Y, Katsura KI, Kimura K, Ohta S (2015) Oxidative stress accelerates amyloid deposition and memory impairment in a double-transgenic mouse model of Alzheimer's disease. Neurosci Lett 587:126–131. CrossRefGoogle Scholar
  29. Kaveh M, Eidi A, Nemati A, Boskabady MH (2017) The extract of Portulaca oleracea and its constituent, alpha linolenic acid affects serum oxidant levels and inflammatory cells in sensitized rats. Iran J Allergy Asthma Immunol 16:256–270Google Scholar
  30. Kheir-Eldin AA, Motawi TK, Gad MZ, Abd-ElGawad HM (2001) Protective effect of vitamin E, β-carotene and N-acetylcysteine from the brain oxidative stress induced in rats by lipopolysaccharide. Int J Biochem Cell Biol 33:475–482CrossRefGoogle Scholar
  31. Khodabandehloo F, Hosseini M, Rajaei Z, Soukhtanloo M, Farrokhi E, Rezaeipour M (2013) Brain tissue oxidative damage as a possible mechanism for the deleterious effect of a chronic high dose of estradiol on learning and memory in ovariectomized rats. Arq Neuropsiquiatr 71:313–319CrossRefGoogle Scholar
  32. Kim H et al (2003) Modulation of immune responses by treadmill exercise in Sprague-Dawley rats. J Sports Med Phys Fitness 43:99–104Google Scholar
  33. Kim GH, Kim JE, Rhie SJ, Yoon S (2015a) The role of oxidative stress in neurodegenerative diseases. Exp Neurobiol 24:325–340CrossRefGoogle Scholar
  34. Kim K, Sung YH, Seo JH, Lee SW, Lim BV, Lee CY, Chung YR (2015b) Effects of treadmill exercise-intensity on short-term memory in the rats born of the lipopolysaccharide-exposed maternal rats. J Exerc Rehabil 11:296–302. CrossRefGoogle Scholar
  35. Kovac A, Zilka N, Kazmerova Z, Cente M, Zilkova M, Novak M (2011) Misfolded truncated protein tau induces innate immune response via MAPK pathway. J Immunol (Baltim, Md : 1950) 187:2732–2739. Google Scholar
  36. Lin HB, Yang XM, Li TJ, Cheng YF, Zhang HT, Xu JP (2009) Memory deficits and neurochemical changes induced by C-reactive protein in rats: implication in Alzheimer's disease. Psychopharmacology 204:705–714. CrossRefGoogle Scholar
  37. Madesh M, Balasubramanian KA (1997) A microtiter plate assay for superoxide using MTT reduction method. Indian J Biochem Biophys 34:535–539Google Scholar
  38. Nazem A, Sankowski R, Bacher M, Al-Abed Y (2015) Rodent models of neuroinflammation for Alzheimer's disease. J Neuroinflammation 12:74. CrossRefGoogle Scholar
  39. Peake J, Suzuki K (2004) Neutrophil activation, antioxidant supplements and exercise-induced oxidative stress. Exerc Immunol Rev 10:129–141Google Scholar
  40. Radak Z, Hart N, Sarga L, Koltai E, Atalay M, Ohno H, Boldogh I (2010) Exercise plays a preventive role against Alzheimer's disease. J Alzheimers Dis 20:777–783. CrossRefGoogle Scholar
  41. Radak Z, Ishihara K, Tekus E, Varga C, Posa A, Balogh L, Boldogh I, Koltai E (2017) Exercise, oxidants, and antioxidants change the shape of the bell-shaped hormesis curve. Redox Biol 12:285–290. CrossRefGoogle Scholar
  42. Ravaglia G, Forti P, Maioli F, Chiappelli M, Montesi F, Tumini E, Mariani E, Licastro F, Patterson C (2007) Blood inflammatory markers and risk of dementia: the Conselice study of brain aging. Neurobiol Aging 28:1810–1820. CrossRefGoogle Scholar
  43. Reisi P, Alaei H, Babri S, Sharifi MR, Mohaddes G (2009) Effects of treadmill running on spatial learning and memory in streptozotocin-induced diabetic rats. Neurosci Lett 455:79–83. CrossRefGoogle Scholar
  44. Roig M, Nordbrandt S, Geertsen SS, Nielsen JB (2013) The effects of cardiovascular exercise on human memory: a review with meta-analysis. Neurosci Biobehav Rev 37:1645–1666. CrossRefGoogle Scholar
  45. Rovio S, Kåreholt I, Helkala EL, Viitanen M, Winblad B, Tuomilehto J, Soininen H, Nissinen A, Kivipelto M (2005) Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease. Lancet Neurol 4:705–711. CrossRefGoogle Scholar
  46. Saffarzadeh F, Eslamizade M, Nemati Karimooy H, Hadjzadeh M, Khazaei M, Hosseini M (2010) The effect of L-Arginin on Morris water maze tasks of ovariectomized rats. Acta Physiol Hung 97:216–223CrossRefGoogle Scholar
  47. Sastre M, Klockgether T, Heneka MT (2006) Contribution of inflammatory processes to Alzheimer's disease: molecular mechanisms. Int J Dev Neurosci 24:167–176. CrossRefGoogle Scholar
  48. Steiner JL, Murphy EA, McClellan JL, Carmichael MD, Davis JM (2011) Exercise training increases mitochondrial biogenesis in the brain. J Appl Physiol (Bethesda, Md : 1985) 111:1066–1071. CrossRefGoogle Scholar
  49. Stigger F, Marcolino MAZ, Portela KM, Plentz RDM (2018) Effects of exercise on inflammatory, oxidative and neurotrophic biomarkers on cognitively impaired individuals diagnosed with dementia or mild cognitive impairment: a systematic review and meta-analysis. J Gerontol A Biol Sci Med Sci.
  50. Thomson LM, Sutherland RJ (2005) Systemic administration of lipopolysaccharide and interleukin-1beta have different effects on memory consolidation. Brain Res Bull 67:24–29. CrossRefGoogle Scholar
  51. Tyagi E, Agrawal R, Nath C, Shukla R (2008) Influence of LPS-induced neuroinflammation on acetylcholinesterase activity in rat brain. J Neuroimmunol 205:51–56CrossRefGoogle Scholar
  52. Valero J, Mastrella G, Neiva I, Sanchez S, Malva JO (2014) Long-term effects of an acute and systemic administration of LPS on adult neurogenesis and spatial memory. Front Neurosci 8:83. CrossRefGoogle Scholar
  53. van Praag H, Shubert T, Zhao C, Gage FH (2005) Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci 25:8680–8685. CrossRefGoogle Scholar
  54. Wes PD, Sayed FA, Bard F, Gan L (2016) Targeting microglia for the treatment of Alzheimer's. Disease. Glia 64:1710–1732. CrossRefGoogle Scholar
  55. Wilkins HM, Swerdlow RH (2016) Relationships between mitochondria and Neuroinflammation: implications for Alzheimer's disease. Curr Top Med Chem 16:849–857CrossRefGoogle Scholar
  56. Wu CW, Chen YC, Yu L, Chen HI, Jen CJ, Huang AM, Tsai HJ, Chang YT, Kuo YM (2007) Treadmill exercise counteracts the suppressive effects of peripheral lipopolysaccharide on hippocampal neurogenesis and learning and memory. J Neurochem 103:2471–2481. CrossRefGoogle Scholar
  57. Yirmiya R, Goshen I (2011) Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 25:181–213. CrossRefGoogle Scholar
  58. Yu F, Xu B, Song C, Ji L, Zhang X (2013) Treadmill exercise slows cognitive deficits in aging rats by antioxidation and inhibition of amyloid production. Neuroreport 24:342–347. CrossRefGoogle Scholar
  59. Zarifkar A, Choopani S, Ghasemi R, Naghdi N, Maghsoudi AH, Maghsoudi N, Rastegar K, Moosavi M (2010) Agmatine prevents LPS-induced spatial memory impairment and hippocampal apoptosis. Eur J Pharmacol 634:84–88. CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Zahra Jahangiri
    • 1
    • 2
  • Zahra Gholamnezhad
    • 1
    • 2
    Email author
  • Mahmoud Hosseini
    • 1
    • 3
  1. 1.Neurogenic Inflammation Research CenterMashhad University of Medical SciencesMashhadIran
  2. 2.Department of Physiology, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
  3. 3.Division of Neurocognitive Sciences, Psychiatry and Behavioral Sciences Research CenterMashhad University of Medical SciencesMashhadIran

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