Hurdle Aerobic Exercise Increases Angiogenesis and Neuroplasticity in the Hippocampus and Improves the Spatial Memory Ability of Middle-aged Mice

Irfannuddin Irfannuddin; Minarma Siagian; Sri Jusman; Jan Purba; Ermita Ilyas; Nurhadi Ibrahim

doi:10.3889/oamjms.2020.3840

Authors

Irfannuddin Irfannuddin Department of Physiology, Faculty of Medicine, Universitas Sriwijaya, Palembang, Indonesia
Minarma Siagian Department of Physiology, Faculty of Medicine, Universitas Indonesia, Depok, Indonesia
Sri Jusman Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Indonesia, Depok, Indonesia
Jan Purba Department of Neurology, Faculty of Medicine, Universitas Indonesia, Depok, Indonesia
Ermita Ilyas Department of Physiology, Faculty of Medicine, Universitas Indonesia, Depok, Indonesia
Nurhadi Ibrahim Department of Physiology, Faculty of Medicine, Universitas Indonesia, Depok, Indonesia

DOI:

https://doi.org/10.3889/oamjms.2020.3840

Keywords:

Hurdle aerobic exercise, VEGF, Drebrin-A, Spatial memory, Neuroglobin

Abstract

BACKGROUND: Complex aerobic exercise is believed to induce positive effects on neuron structure and cognitive function. Long-term and continual cognitive stimulation increases neuroplasticity by stimulating the synthesis of neuronal growth proteins and the formation of new synapses. Exercise also increases the ability of neurons to survive and improves brain vascularization. Further investigations should be conducted to explore what types of aerobic exercise are beneficial for cognitive function.

AIM: This study investigated the effects of hurdle aerobic exercise on developmentally regulated brain protein-A (Drebrin-A) as a neuroplasticity indicator, and on vascular endothelial growth factor (VEGF) as an angiogenesis marker in the hippocampus.

METHODS: This study was an experimental study with post-test only control group design. Thirty-three adult mice were divided into control, hurdle aerobic runner (HAR), and plain aerobic runner (PAR) groups (n = 11 for each group). Fiberglass running wheels were originally designed and modified to assemble hurdles inside with adjustable speed. Speed adaptation was intended to achieve aerobic intensity. The experiment was performed 5 times a week for 8 weeks. The Morris water maze test (MWMT) was used to assess spatial memory ability. One day after the last running exercise and final MWMT, the mice were sacrificed and the right side of the hippocampus was obtained for Drebrin-A analysis by enzyme-linked immunosorbent assay (ELISA). The entire right side brain tissue after hippocampus was removed then used for the neuroglobin ELISA assay. To analyze VEGF expression and calculation of blood vessel, the left side of the brain was prepared for hematoxylin eosin and immunohistochemistry staining. To assess the effect of exercise on vascular widening, the analysis of the slides was performed by calculating the percentage of blood vessels with diameters more than 15 μm. One-way ANOVA and Fisher’s least significant difference test was used for statistical analysis.

RESULTS: There was a significant difference in the levels of Drebrin-A between the HAR and PAR groups. Both exercise groups had higher levels of Drebrin-A than the control group. HAR and PAR groups exhibited significantly higher percentages of blood vessels expressing VEGF in hippocampus compared to control. HAR and PAR groups had the higher percentages of larger vessels compare to control. There was no significant difference of neuroglobin levels among the three groups. Both the HAR and PAR groups exhibited better spatial memory than the control group.

CONCLUSION: Both aerobic exercises induced positive effects on brain angiogenesis, while the intensity of aerobic exercises did not result in high hypoxic stress in the brain.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Petersen RC, Stevens JC, Ganguli M, Tangalos EG, Cummings JL, Dekosky ST. Practice parameter: Early detection of dementia and mild cognitive impairment (evidence-based review): Report of the quality standards subcommittee of the American academy of neurology. Neurology. 2001;56(9):1133- 42. https://doi.org/10.1212/wnl.56.9.1133 PMid:11342677

Van-Der Borght K, Havekes R, Bos T, Eggen BJ, Van Der Zee EA. Exercise improves memory acquisition and retrieval in Y-maze task: Relationship with hippocampal neurogenesis. Behav Neurosci. 2007;121(2):234-44. https://doi. org/10.1037/0735-7044.121.2.324 PMid:17469921

Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, et al. Exercise training increases size of hippocampus and improves memory. PNAS. 2011;108(7):3017-22. PMid:21282661

Lou SJ, Liua JY, Chang H, Chen PJ. Hippocampal neurogenesis and gene expression depend on exercise intensity in juvenile rats. Brain Res. 2008;1210:48-55. https://doi.org/10.1016/j. brainres.2008.02.080 PMid:18423578

Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science. 4th ed. New York, US: McGraw-Hill; 2000.

Um HS, Kang EB, Koo JH, Kim HT. Treadmill exercise represses neuronal cell death in an aged transgenic mouse model of Alzheimer’s disease. Neurosci Res. 2011;69(2):161-73. https:// doi.org/10.1016/j.neures.2010.10.004 PMid:20969897

van Praag H. Neurogenesis and exercise: The past and future direction. Neuromolecular Med. 2008;10(2):128-40. http://doi. org/10.1007/s12017-008-8028-z PMid:18286389

Mcmorris T, Tomporowsky PD, Audiffren M. Summary and direction for future research. In: Mcmorris T, Tomporowsky PD, Audiffren M, editors. Exercise and Cognitive Function. Oxford, UK: Wiley-Blackwell; 2009. https://doi.org/10.1002/9780470740668. ch16

Diamond A. Effects of physical exercise on executive functions: Going beyond simply moving to moving with thought. Ann Sports Med Res. 2015;2(1):1-4. PMid:26000340

Pellis SM, Pellis VC. Rough-and-tumble play and the development of the social brain. Curr Dir Psychol Sci. 2007;16:95-8. https:// doi.org/10.1111/j.1467-8721.2007.00483.x

Morris RG, Garrud P, Rawlins JN, O’keefee J. Place navigation impaired in rats with hippocampal lesions. Nature. 1982;297(5868):681-3. https://doi.org/10.1038/297681a0 PMid:7088155

Billat VL, Mouisel E, Roblot N, Melki J. Inter- and intra strain variation in mouse critical running speed. J Appl Physiol. 2004;98(4):1258-63. https://doi.org/10.1152/ japplphysiol.00991.2004 PMid:15542571

Kania BF, Wronska D, Zieba D. Introduction of neural plasticity mechanism. J Behav Brain Sci. 2017;7:41-9. https://doi. org/10.4236/jbbs.2017.72005

Sekino Y, Kojima N, Shirao T. Role of actin cytoskeleton in dendritic spine morphogenesis. Neurochem Int. 2007;51(2- 4):92-104. https://doi.org/10.1016/j.neuint.2007.04.029 PMid:17590478

Koganezawa N, Hanamura K, Sekino Y, Shirao T. The role of drebrin in dendritic spines. Mol Cell Neurosci. 2017;84:85-92. https://doi.org/10.1016/j.mcn.2017.01.004 PMid:28161364

Shirao T, Hanamura K, Koganezawa N, Ishizuka Y, Yamazaki H, Sekino Y. The role of drebrin in neurons. J Neurochem. 2017;141(6):819-34. https://doi.org/10.1111/jnc.13988 PMid:28199019

Thomas AG, Andrea D, Bandettini PA, Berg HJ. The effects of aerobic activity on brain structure. Front Psychol. 2012;3(86):1-9. PMid:22470361

Macias M, Dwornik A, Skup M, Czarkowska-Bauch J. Confocal visualization on the effect of shor-term locomotor exercise on BDNF and TrkB distribution in the lumbar spinal cord of the rat: The enhancement of BDNF in dendrites? Acta Neurobiol Exp. 2005;65(2):177-82. https://doi. org/10.1111/j.1460-9568.2007.05498.x PMid:15960303

Meeusen R, Meirleir KD. Exercise and brain neurotransmission. Sports Med. 1995;20(3):160-88. PMid:8571000

Mayford M, Siegelbaum SA, Kandel ER. Synapses and memory storage. Cold Spring Harb Perspect Biol. 2012;4:1-18. https:// doi.org/10.1101/cshperspect.a005751 PMid:22496389

Touzani K, Puthanveettil SV, Kandel ER. Consolidation of learning strategies during spatial working memory task requires protein synthesis in the prefrontal cortex. PNAS. 2007;104(13):5632- 37. https://doi.org/10.1073/pnas.0611554104

Ohno H, Shirato K, Sakurai T, Ogasawara J, Sumitani Y, Sato S, et al. Effect of exercise on HIF-1 and VEGF signaling. J Phys Fitness Sports Med. 2012;1(1):5-16. https://doi.org/10.7600/ jpfsm.1.5

Radak Z, Zhao Z, Koltai E, Ohno H, Atalay M. Oxygen consumption and usage during physical exercise: The balance between oxidative stress and ROS-dependent adaptive signaling. Antioxid Redox Signal. 2013;18(10):1208-45. https:// doi.org/10.1089/ars.2011.4498 PMid:22978553

Gilany K, Vafakhah M. Hypoxia: A review. J Paramed Sci. 2010;1(2):43-60.

Ramakrishnan S, Anand V, Roy S. Vascular endothelial growth factor signaling in hypoxia and inflammation. J Neuroimmune Pharmacol. 2014;9(2):142-60. https://doi.org/10.1007/ s11481-014-9531-7 PMid:24610033

Prior BM, Yang HT, Terjung RL. What makes vessels grow with exercise training? J Appl Physiol. 2014;97(3):1119-28. https:// doi.org/10.1152/japplphysiol.00035.2004 PMid:15333630

Sanz-Cameno P, Trapero-Marugán M, Chaparro M, Jones EA, Moreno-Otero R. Angiogenesis: From chronic liver inflammation to hepatocellular carcinoma. J Oncol. 2010;2010:1-7. https:// doi.org/10.1155/2010/272170 PMid:20592752

Bao P, Kodra A, Canic MT, Golinko MS, Ehrlich HP, Brem H. The role of vascular endothelial growth factor in wound healing. J Surg Res. 2009;153(2):347-58. https://doi.org/10.1016/j. jss.2008.04.023 PMid:19027922

Van Praag H. Exercise and the brain, something to chew on. Trends Neurosci. 2009;32(5):283-90. PMid:19349082

Lopez CL, Leroith D, Aleman IT. Insulin-like growth factor 1 is required for vessel remodeling in the adult brain. PNAS. 2004;101(26):9833-8. https://doi.org/10.1073/ pnas.0400337101

Bullitt E, Rahman FN, Smith JK, Kim E, Zeng D, Katz LM, et al. The effect of exercise on the cerebral vasculature of healthy aged subjects as visualized by MR angiography. Am J Neuroradiol. 2009;30(10):1857-63. https://doi.org/10.3174/ajnr. a1695 PMid:19589885

Sun Y, Jin K, Mao Xo, Zhu Y, Greeberg DA. Neuroglobin is upregulated by and protects neurons from hypoxic ischemic injury. PNAS. 2001;98(26):15306-11. https://doi.org/10.1073/ pnas.251466698 PMid:11742077

Yoon J, Seo Y, Kim J, Lee I. Hippocampus is required for paired associate memory with neither delay nor trial uniqueness. Learn Mem. 2012;19(1):1-8. https://doi.org/10.1101/lm.024554.111 PMid:22174309

Raychaudhuri S, Skommer J, Henty K, Birch N, Brittain T. Neuroglobin protects nerve cells from apoptosis by inhibiting the intrinsic pathway of cell death. Apoptosis. 2010;15(4):401- 11. https://doi.org/10.1007/s10495-009-0436-5 PMid:20091232

Kirk-Sanchez NJ, Mcgough EL. Physical exercise and cognitive performance in the elderly: Current perspectives. Clin Interv Aging. 2014;9:51-62. https://doi.org/10.2147/cia.s39506 PMid:24379659

Fediani Y, Dewi MR, Irfannuddin I, Saleh MI, Dhaini S. The effect of regular aerobic exercise on urinary brain-derived neurotrophic factor in children. Paediatr Indones. 2014;54(6):351-7. https:// doi.org/10.14238/pi54.6.2014.351-7