the effect of 4 weeks exercise on mRNA of GDNF in rat’s hippocampus with AD induced by Aβ1-42 injection

Document Type : Research Paper

Authors

1 Ph.D. Student of Exercise Physiology, Faculty of Humanities, Tarbiat Modares University, Tehran, Iran

2 Professor of Exercise Physiology, Faculty of Humanities, Tarbiat Modares University, Tehran, Iran.

3 Associate professor of Exercise Physiology, Faculty of Humanities, Tarbiat Modares University, Tehran, Iran

4 Ph.D. of Exercise Physiology, Faculty of Humanities, Tarbiat Modares University, Tehran, Iran

Abstract
Abstract: Alzheimer's disease (AD) is the most common form of dementia and amyloid
peptides playing a central role in its pathogenesis. Recently, regular exercise has been
considered as one of the most important non-pharmacological mechanisms to contrast with
AD. The aim of this study was to investigate the effect of 4 weeks exercise on mRNA of GDNF in rat’s hippocampus with AD induced by Aβ1-42 injection.
Methods: 56 male rats with mean±SD weight of 195±20 g were randomly divided
Into four groups: training group, Aβ-42 induction + training group, Aβ-42 induction group and control group. injection of Aβ1-42 into the hippocampus was performed. Seven days
after surgery, rats of each groups were either sacrificed or subjected to behavioral
testing, randomly. Real-Time PCR were used for investigation of mRNA GDNF.
Results: there is a significant difference between the groups. Gene expression level in training group was higher and in the Aβ-42 induction group was lower (p < 0.001). Moreover, spatial learning and memory were significantly better in the exercise + AD than AD group (p < 0.01).
Conclusion: It seems that 4 weeks of exercise could improve spatial memory and learning. Moreover, aerobic exercise could increase the level of neurotrophic factors gene expression specially GDNF in rat’s hippocampus.

Keywords

  1. Heneka MT, O'Banion MK. Inflammatory processes in Alzheimer's disease. Journal of Neuroimmunology. 2007;184(1-2):69-91. https://pubmed.ncbi.nlm.nih.gov/17222916/
  2. Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiological Reviews.2001;81(2):741-66. https://journals.physiology.org/doi/full/10.1152/physrev.2001.81.2.741
  3. Cunningham C. Microglia and neurodegeneration: the role of systemic inflammation. Glia. 2013;61(1):71-90. https://pubmed.ncbi.nlm.nih.gov/22674585/
  4. Marsland AL, Gianaros PJ, Abramowitch SM, Manuck SB, Hariri AR. Interleukin-6 covaries inversely with hippocampal grey matter volume in middle-aged adults. BiolPsychiatry.2008;64(6):484-90. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562462/
  5. J.A. Funk, J. Gohlke, A.D. Kraft, C.A. McPherson, J.B. Collins, G.J. Harry Voluntary exercise protects hippocampal neurons from trimethyltin injury: Possible role of interleukin-6 to modulate tumor necrosis factor receptor-mediated neurotoxicity Brain, Behavior, and Immunity. 2011;25:1063-1077. https://pubmed.ncbi.nlm.nih.gov/21435392/
  6. Kesler S, Janelsins M, Koovakkattu D, Palesh O, Mustian K, Morrow G, Dhabhar FS. Reduced hippocampal volume and verbal memory performance associated with interleukin-6 and tumor necrosis factor-alpha levels in chemotherapy-treated breast cancer survivors. Brain Behav Immun. 2013;30(Suppl):S109–16. https://pubmed.ncbi.nlm.nih.gov/22698992/
  7. De Felice FG. Alzheimer’s disease and insulin resistance: translating basic science into clinical applications. J Clin Invest. 2013;123:531–9. https://pubmed.ncbi.nlm.nih.gov/23485579/
  8. Mattson MP. Energy intake and exercise as determinants of brain health and vulnerability to injury and disease. Cell Metab. 2012;16:706–22Ohwatashi A, Ikeda S, Harada K, Kamikawa Y, Yoshida A. Exercise enhanced functional recovery and expression of GDNF after photochemically induced cerebral infarction in the rat. EXCLI Journal. 2013;12:693https://pubmed.ncbi.nlm.nih.gov/23168220/.
  9. Dobos N, Korf J, Luiten P, Eisel U. Neuroinflamma tion in Alzheimer’s disease and Major Depression .Biol Psychiatry. 2010;67:503–504.  https://pubmed.ncbi.nlm.nih.gov/20185031
  10. Diniz BS, Teixeira AL, Ojopi EB, Talib LL, Mendonça VA, Gattaz WF, Forlenza OV. Higher serum sTNFR1 level predicts conversion from mild cognitive impairment to Alzheimer’s disease. J Alzheimers Dis. 2010;22:1305-11. 93-102. https://pubmed.ncbi.nlm.nih.gov/20930310/
  11. Zagaar M, Alhaider I, Dao A, Levine A, Alkarawi A, Alzubaidy M, et al. The beneficial effects of regular exercise on cognition in REM sleep deprivation: behavioral, electrophysiological and molecular evidence. Neurobiology of Disease. 2012;45(3):1153-62. https://pubmed.ncbi.nlm.nih.gov/22227452/
  12. Lin T-W, Shih Y-H, Chen S-J, Lien C-H, Chang C-Y, Huang T-Y, et al. Running exercise delays neurodegeneration in amygdala and hippocampus of Alzheimer’s disease (APP/PS1) transgenic mice. Neurobiology of Learning and Memory. 2015;118:189-97. https://pubmed.ncbi.nlm.nih.gov/25543023/
  13. Airaksinen MS, Saarma M. The GDNF family: signalling, biological functions and therapeutic value. Nature Reviews Neuroscience. 2002;3(5):383 -94https://www.sciencedirect.com/science/article/pii/S1476558617304475.
  14. Marksteiner J, Kemmler G, Weiss EM, Knaus G, Ullrich C, Mechtcheriakov S, et al. Five out of 16 plasma signaling proteins are enhanced in plasma of patients with mild cognitive impairment and Alzheimer's disease. Neurobiology of Aging. 2011;32(3):539-40https://europepmc.org/article/med/19395124
  15. Straten G, Saur R, Laske C, Gasser T, Annas P, Basun H, et al. Influence of lithium treatment on GDNF serum and CSF concentrations in patients with early Alzheimer's disease. Current Alzheimer Research. 2011;8(8):853-9. https://pubmed.ncbi.nlm.nih.gov/21875410/
  16. Sullivan AM, O’Keeffe GW. Neurotrophic factor therapy for Parkinson's disease: past, present and future. Neural regeneration Research. 2016;11(2):25-7. https://pubmed.ncbi.nlm.nih.gov/27073356/
  17. Ohwatashi A, Ikeda S, Harada K, Kamikawa Y, Yoshida A. Exercise enhanced functional recovery and expression of GDNF after photochemically induced cerebral infarction in the rat. EXCLI Journal. 2013:12:693-700. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653718/
  18. Wick M, Teng L, Mu X, Springer JE, Davis BM. Overexpression of GDNF induces and maintains hyperinnervation of muscle fibers and multiple end-plateformations. Exp Neurol. 2001;171:342-50. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637874/
  19. Airavaara M, Pletnikova O, Doyle ME, Zhang YE, Troncoso JC, Liu Q-R. Identification of novel GDNF isoforms and cis-antisense GDNFOS gene and their regulation in human middle temporal gyrus of Alzheimer disease. Journal of BiologicalChemistry.2011;286(52):45093-102. https://europepmc.org/article/pmc/pmc3247946
  20. Palasz E, Folcik R, Gasiorowska A, Niewiadomski W, Niewiadomska G. Treadmill training lessens dopaminergic deficiency, enhances BDNF and GDNF biosynthesis, and reduces brain inflammation in the MPTP mouse model of Parkinson’s disease. Parkinsonism & Related Disorders. 2018;46:e41. https://pubmed.ncbi.nlm.nih.gov/32050617/
  21. Campos C, Rocha NB, Lattari E, Paes F, Nardi AE, Machado S. Exercise-induced neuroprotective effects on neurodegenerative diseases: the key role of trophic factors. Expert Review of Neurotherapeutics. 2016;16(6):723-34. https://pubmed.ncbi.nlm.nih.gov/27086703/
  22. Afzalpour ME, Chadorneshin HT, Foadoddini M, Eivari HA. Comparing interval and continuous exercise training regimens on neurotrophic factors in rat brain. Physiology & Behavior. 2015;147:78-83. https://pubmed.ncbi.nlm.nih.gov/25868740/
  23. Piotrowicz Z, Chalimoniuk M, Płoszczyca K, Czuba M, Langfort J. Acute normobaric hypoxia does not affect the simultaneous exercise-induced increase in circulating BDNF and GDNF in young healthy men: A feasibility study. PloS One.2019Oct23;14(10):e0224207. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6808427/
  24. Zagaar M, Alhaider I, Dao A, Levine A, Alkarawi A, Alzubaidy M, et al. The beneficial effects of regular exercise on cognition in REM sleep deprivation: behavioral, electrophysiological and molecular evidence. Neurobiology of Disease.2012;45(3):1153-62. https://pubmed.ncbi.nlm.nih.gov/22227452/
  25. Mohammadpour JD, Hosseinmardi N, Janahmadi M, Fathollahi Y, Motamedi F, Rohampour K. Non-selective NSAIDs improve the amyloid-β-mediated suppression of memory and synaptic plasticity. Pharmacology Biochemistry and Behavior.2015;132:33-41. https://europepmc.org/article/med/25697476
  26. BÜTTNER-ENNEVER, JEAN. “The Rat Brain in Stereotaxic Coordinates, 3rd edn.” Journal of Anatomy vol. 191,Pt 2 (1997): 315–317. anatomy/issue/216538F2232A9165439EA8FCC0F8A5BB
  27. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods. 2001;25(4):4028https://pubmed.ncbi.nlm.nih.gov/11846609/.
  28. Campos C, Rocha NB, Lattari E, Paes F, Nardi AE, Machado S. Exercise-induced neuroprotective effects on neurodegenerative diseases: the key role of trophic factors. Expert Review of Neurotherapeutics. 2016;16(6):723-34. https://pubmed.ncbi.nlm.nih.gov/27086703/
  29. Khorshidahmad T, Tabrizian K, Vakilzadeh G, Nikbin P, Moradi S, Hosseini-Sharifabad A, et al. Interactive effects of a protein kinase AII inhibitor and testosterone on spatial learning in the Morris water maze. Behavioural Brain Research. 2012;228(2):432-9. https://pubmed.ncbi.nlm.nih.gov/22209852/
  30. McCullough MJ, Gyorkos AM, Spitsbergen JM. Short-term exercise increases GDNF protein levels in the spinal cord of young and old rats. Neuroscience.2013;240:258-68. https://pubmed.ncbi.nlm.nih.gov/23500094/
  31. Revilla S, Ursulet S, Álvarez-López MJ, Castro-Freire M, Perpiñá U, García-Mesa Y, et al. Lenti-GDNF gene therapy protects against Alzheimer's disease-like neuropathology in 3xTg‐AD mice and MC65 cells. CNS Neuroscience & Therapeutics. 2014;20(11):961-72. https://pubmed.ncbi.nlm.nih.gov/25119316/
  32. Azimi M, Gharakhanlou R, Naghdi N, Khodadadi D, Heysieattalab S. Moderate treadmill exercise ameliorates amyloid-β-induced learning and memory impairment, possibly via increasing AMPK activity and up-regulation of the PGC-1α/FNDC5/BDNFpathway.Peptides2018;102:78-88. https://europepmc.org/article/med/29309801

 

Sport Physiology
Volume 13, Issue 49
March 2021
Pages 169-198

  • Receive Date 13 October 2019
  • Revise Date 04 February 2020
  • Accept Date 05 February 2020