The effect of four weeks of aerobic exercise on cognitive function and expression levels of PGC1α and VEGF genes in the hippocampus of old rats
Subject Areas : Sports Science and HealthyEnsieh Ahmadpour 1 , Maghsoud Peeri 2 , Mohammad Ali Azarbayjani 3
1 - PhD. Student, Central Tehran Branch, Islamic Azad University, Tehran, Iran
2 - Professor, Central Tehran Branch, Islamic Azad University, Tehran, Iran
3 - Professor, Central Tehran Branch, Islamic Azad University, Tehran, Iran.
Keywords: spatial memory, Male wistar rats, Learning, Aging, Aerobic exercise, Hippocampus,
Abstract :
Aging is an important risk factor for cognitive functions. On the other hand, exercise improves brain health and improves cognitive functions. However, the mechanisms of these benefits have not yet been fully elucidated. Therefore, the present study was conducted with the aim of investigating the effect of four weeks of intermittent aerobic exercise with moderate intensity on cognitive function and the expression level of PGC1α and VEGF genes in the hippocampus of old rats. For this purpose, 20-month-old male Wistar rats were divided into 2 exercise training groups (number = 8 heads) and control (number = 8 heads). The animals of the sports group performed intermittent aerobic training with moderate intensity for 4 weeks, 5 days a week. In order to investigate learning and spatial memory, the animals were subjected to the Morris water maze test 48 hours after the last training session. Then, the animals were killed and the hippocampal tissue was extracted. Real time-PCR method was used to measure gene expression. Statistical analysis was done using independent t-test and Pearson's correlation coefficient at a significant level of P£0.05. The results showed that aerobic exercise improved learning performance (P ≥ 0.05) and spatial memory (P ≥ 0.001) and the expression level of PGC1α (P ≥ 0.01) and VEGF (P ≥ 0.001) Increasing. Also, a significant positive correlation between PGC1α gene expression and VEGF gene expression in the hippocampus was observed (p≥0.001, r=0.894). In addition, there was a significant inverse relationship between VEGF gene expression and the average time spent to find the platform (p≥0.05, r=-0.578), and there was a significant positive relationship with the time spent in the quadrant of the target circle (p≥0.01, r=0.713). In general, aerobic exercise improves learning performance and spatial memory in old animals; It seems that exercise-induced upregulation of the PGC1α/VEGF signaling pathway in the brain is at least partially involved in this adaptation.
خدادادی، داور؛ قراخانلو، رضا؛ نقدی، ناصر؛ سلیمی، مونا؛ عظیمی، سید محمد؛ شاهد، اتابک (1396). تأثیر ۴ هفته پیش آمادهسازی ورزشی بر سطح آمیلوئیدبتای محلول و اختلال حافظه در رتهای مبتلا به بیماری آلزایمر القاء شده با تزریق Aβ۱-۴۲. مجله علوم پزشکی رازی،۲۴(۱۶۵)، ص۷۶-۶۶.
رضایی، رسول؛ نورشاهی، مریم؛ بیگدلی، محمدرضا؛ خداقلی، فریبا؛ حقپرست، عباس (1394). تاثیر هشت هفته تمرین هوازی تداومی و تناوبی شدید بر مقادیر VEGF-A و VEGFR-2 بافت مغز موشهای صحرایی نر ویستار. فیزیولوژی ورزش و فعالیت بدنی، 8(2)، ص 1213-1221.
زارعزاده مهریزی، علی اصغر؛ رجبی، حمید؛ قراخانلو، رضا؛ نقدی، ناصر؛ عظیمی دخت، سید محمدعلی (1398). تأثیر هشت هفته تمرین هوازی بر بیان ژن عامل القای هایپوکسی (HIF-1α)، عامل رشد اندوتلیال عروق (VEGF) و آنژیواستاتین هیپوکامپ موشهای صحرایی نر نژاد ویستار. مجله دانشگاه علوم پزشکی شهید صدوقی یزد، ۲۷(۱۱)، ص۲۰۶۳-۲۰۷۵.
عظیمی، سید محمد؛ قراخانلو، رضا؛ نقدی، ناصر؛ خدادادی، داور؛ زارعزاده مهریزی، علی اصغر (1398). تأثیر دویدن روی نوارگردان با شدت کم بر بیان ژنهای PGC-1α، FNDC5 و BDNF در هیپوکامپ موشهای صحرایی نر. مطالعات کاربردی علوم زیستی در ورزش، 7(14)، ص 101-91.
Adams, R.H. & Alitalo, K. (2007). Molecular regulation of angiogenesis and lymphangiogenesis. Nature reviews Molecular cell biology, 8(6), p.464-478.
Arany, Z. & et al. (2008). HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α. Nature, 451(7181), p.1008-1012.
Azimi, M., Gharakhanlou, R., Naghdi, N., Khodadadi, D. & Heysieattalab, S. (2018). Moderate Treadmill Exercise Ameliorates Amyloid-β-Induced Learning and Memory Impairment, possibly via Increasing AMPK Activity and Up-regulation of the PGC-1α/FNDC5/BDNF Pathway. Peptides, Vol. 102, p. 78-88.
Baker, L.D. & et al. (2012). High-intensity physical activity modulates diet effects on cerebrospinal amyloid-β levels in normal aging and mild cognitive impairment. Journal of Alzheimer's Disease, 28(1), p.137-146.
Bates, K., Verdile, G., Li, Q., Ames, D., Hudson, P., Masters, C. & Martins, R. (2009). Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests. Mol Psychiatry,14(12), p.1144. DOI: 10.1038/mp.2008.96
Cai, J., Ahmad, S., Jiang, W.G., Huang, J., Kontos, C.D., Boulton, M. & Ahmed, A. (2003). Activation of vascular endothelial growth factor receptor-1 sustains angiogenesis and Bcl-2 expression via the phosphatidylinositol 3-kinase pathway in endothelial cells. Diabetes, 52(12), p.2959-2968.
Cao, L., Jiao, X., Zuzga, D.S., Liu, Y., Fong, D.M., Young, D. & During, M.J. (2004). VEGF links hippocampal activity with neurogenesis, learning and memory. Nature genetics, 36(8), p. 827-835.
Chang, S.-H. & et al. (2009). VEGF-A induces angiogenesis by perturbing the cathepsin-cysteine protease inhibitor balance in venules, causing basement membrane degradation and mother vessel formation. Cancer research, 69(10), p.4537-4544.
Cotman, C.W., Berchtold, N.C. & Christie, L.-A. (2007). Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends in neurosciences,30(9), p.464-472.
de la Torre, J.C. (2004). Is Alzheimer's disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. The Lancet Neurology, 3(3), p.184-190.
Ding, Y.-H., Li, J., Zhou, Y., Rafols, J.A., Clark, J.C. & Ding, Y. (2006). Cerebral angiogenesis and expression of angiogenic factors in aging rats after exercise. Current neurovascular research, 3(1), p.15-23.
Fabel, K. & et al. (2003). VEGF is necessary for exercise‐induced adult hippocampal neurogenesis. European Journal of Neuroscience, 18(10), p.2803-2812.
Farshbaf, M.J., Ghaedi, K., Megraw, T.L., Curtiss, J., Faradonbeh, M. S., Vaziri, P. & Nasr-Esfahani, M.H. (2016). Does PGC1α/FNDC5/BDNF elicit the beneficial effects of exercise on neurodegenerative disorders? Neuromolecular medicine,18(1), p.1-15.
Finck, B.N. & Kelly, D.P. (2006). PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. The Journal of clinical investigation,116(3), p.615-622.
Intlekofer, K.A. & Cotman, C.W. (2013). Exercise counteracts declining hippocampal function in aging and Alzheimer's disease. Neurobiology of disease, No.57, p.47-55.
Karakilic, A. & et al. (2021). Regular aerobic exercise increased VEGF levels in both soleus and gastrocnemius muscles correlated with hippocampal learning and VEGF levels. Acta neurobiologiae experimentalis, 81(1).
Khodadadi, D., Gharakhanlou, R., Naghdi, N., Salimi, M., Azimi, M., Shahed, A. & Heysieattalab, S. (2018). Treadmill Exercise Ameliorates Spatial Learning and Memory Deficits Through Improving the Clearance of Peripheral and Central Amyloid-Beta Levels. Neurochemical Research, 43(8), p.1561-1574. DOI: 10.1007/s11064-018-2571-2 1-14.
Kleim, J.A., Cooper, N.R. & VandenBerg, P.M. (2002). Exercise induces angiogenesis but does not alter movement representations within rat motor cortex. Brain research,934(1), p.1-6.
Lambrechts, D. & Carmeliet, P. (2006). VEGF at the neurovascular interface: therapeutic implications for motor neuron disease. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1762(11-12), p.1109-1121.
Leeuwis, A.E. & et al. (2018). Cerebral blood flow and cognitive functioning in a community-based, multi-ethnic cohort: the SABRE study. Frontiers in aging neuroscience, 18(10), p.279. DOI: 10.3389/fnagi.2018.00279 10, 279.
Liang, D., Chang, J.R., Chin, A.J., Smith, A., Kelly, C., Weinberg, E.S. & Ge, R. (2001). The role of vascular endothelial growth factor (VEGF) in vasculogenesis, angiogenesis, and hematopoiesis in zebrafish development. Mechanisms of development,108(1-2), p.29-43.
Oosthuyse, B. & et al. (2001). Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nature genetics, 28(2), p.131-138.
Pati, S., Orsi, S.A., Moore, A.N. & Dash, P.K. (2009). Intra-hippocampal administration of the VEGF receptor blocker PTK787/ZK222584 impairs long-term memory. Brain research, 1256, p.85-91.
Pfaffl, M.W. (2001). A new mathematical model for relative quantification in real-time RT–PCR. Nucleic acids research, 29(9), p. e45-e45.
Prior, B.M., Yang, H. & Terjung, R.L. (2004). What makes vessels grow with exercise training? Journal of Applied Physiology,97(3), p.1119-1128.
Radák, Z., Sasvári, M., Nyakas, C., Pucsok, J., Nakamoto, H. & Goto, S. (2000). Exercise preconditioning against hydrogen peroxide-induced oxidative damage in proteins of rat myocardium. Archives of biochemistry and biophysics, 376(2), p.248-251.
Rivard, A. & et al. (2000). Age-dependent defect in vascular endothelial growth factor expression is associated with reduced hypoxia-inducible factor 1 activity. Journal of Biological Chemistry,275(38), p.29643-29647.
Rolland, Y., van Kan, G.A. & Vellas, B. (2010). Healthy brain aging: role of exercise and physical activity. Clinics in geriatric medicine, 26(1), p.75-87.
Ruiz de Almodovar, C., Lambrechts, D., Mazzone, M. & Carmeliet, P. (2009). Role and therapeutic potential of VEGF in the nervous system. Physiological reviews, 89(2), p.607-648.
Steiner, J.L., Murphy, E.A., McClellan, J.L., Carmichael, M.D. & Davis, J.M. (2011). Exercise training increases mitochondrial biogenesis in the brain. Journal of Applied Physiology, 111(4), p.1066-1071.
Sulpice, E. & et al. (2009). Cross‐talk between the VEGF‐A and HGF signalling pathways in endothelial cells. Biology of the Cell,101(9), p.525-539.
Swain, R.A. & et al. (2003). Prolonged exercise induces angiogenesis and increases cerebral blood volume in primary motor cortex of the rat. Neuroscience,117(4), p.1037-1046.
Viboolvorakul, S. & Patumraj, S. (2014). Exercise training could improve age-related changes in cerebral blood flow and capillary vascularity through the upregulation of VEGF and eNOS. BioMed research international, DOI: 10.1155/2014/230791
Wang, Y., Galvan, V., Gorostiza, O., Ataie, M., Jin, K. & Greenberg, D.A. (2006). Vascular endothelial growth factor improves recovery of sensorimotor and cognitive deficits after focal cerebral ischemia in the rat. Brain research, 1115(1), p.186-193.
Wrann, C.D. & et al. (2013). Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell metabolism, 18(5), p.649-659.
Yu, L. & Yang, S. (2010). AMP-activated protein kinase mediates activity-dependent regulation of peroxisome proliferator-activated receptor γ coactivator-1α and nuclear respiratory factor 1 expression in rat visual cortical neurons. Neuroscience, 169(1), p.23-38.
Zagaar, M., Alhaider, I., Dao, A., Levine, A., Alkarawi, A., Alzubaidy, M. & Alkadhi, K. (2012). The beneficial effects of regular exercise on cognition in REM sleep deprivation: behavioral, electrophysiological and molecular evidence. Neurobiology of disease, 45(3), p.1153-1162.
_||_