Effects of aerobic exercise with simultaneous cerebrolysin drug administration on spatial memory in adult male rat model of Parkinson's disease
Subject Areas : Veterinary Clinical Pathology
Seyed Zanyar Athari
1
,
Alireza Nourazar
2
,
Daryoush Mohajeri
3
1 - Ph.D. Student of Medical Physiology, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran.
2 - Assistant Professor, Department of Basic Science, Faculty of Veterinary Medicine, Tabriz Medical Sciences Branch, Islamic Azad University, Tabriz, Iran.
3 - Professor, Department of Pathobiology, Faculty of Veterinary Medicine, Tabriz Medical Sciences Branch, Islamic Azad University, Tabriz, Iran.
Keywords: Rat, s disease, Aerobic exercise, spatial memory, Cerebrolysin, Parkinson',
Abstract :
Memory impairment is a complication of Parkinson's disease (PD). Cerebrolysin has neurotrophic effects and stimulates neuronal growth. Exercise also increases brain growth factors and improves spatial memory. This study aimed to evaluate the effect of aerobic exercise and concomitant use of cerebrolysin on spatial memory in male rats model of PD. 36 male Wistar rats weighing 250±20 were randomly divided into 6 equal groups: surgical sham, PD (6-hydroxydopamine unilateral single injection), positive control (levodopa, 12 mg/kg-po, 21 days), cerebrolysin (538 mg/kg-ip, 21days), treadmill exercise (daily for 30 minutes, 60% VO2 max, 21 days) and cerebrolysin with exercise. The cerberolysin plus exercise group was treated similarly. Finally, a spatial memory test with Morris water maze was performed in the studied groups, and after euthanasia, brain tissue was sampled to study the pathological changes in hippocampus. Data were analyzed by ANOVA test and Tukey post-hoc at the level of p<0.05 by Graphpad software. PD induction reduced spatial memory indices. Cerebrolysine increased spatial memory factors (p<0.05). Aerobic exercise improved spatial memory parameters such as cerebrolysin (p<0.05). Statistically, exercise with cerebrolysine had the best effect on improving spatial memory indices. The pathological results were consistent with the results of spatial memory. This study states that aerobic exercise and cerebrolysin treatment simultaneously improved spatial memory and pathological changes in the hippocampus in PD rats.
References:
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Alzoubi, K.H., Al-ibbini, A.M. and Nuseir, K.Q. (2018). Prevention of memory impairment induced by post-traumatic stress disorder by cerebrolysin. Psychiatry Research, 270: 430-437.
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Belotto, M.F., Magdalon, J., Rodrigues, H.G., Vinolo, M.A.R., Curi, R., Pithon-Curi, T.C., et al. (2010). Moderate exercise improves leucocyte function and decreases inflammation in diabetes. Clinical and Experimental Immunology, 162(2): 237-243.
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Kempadoo, K.A., Mosharov, E.V., Choi, S.J., Sulzer, D. and Kandel, E.R. (2016). Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory. Proceedings of the National Academy of Sciences, 113(51): 14835-14840.
Kramer, A.F. and Erickson, K.I. (2007). Capitalizing on cortical plasticity: influence of physical activity on cognition and brain function. Trends in Cognitive Sciences, 11(8): 342-348.
Lemon, N. and Manahan-Vaughan, D. (2006). Dopamine D1/D5 Receptors Gate the Acquisition of Novel Information through Hippocampal Long-Term Potentiation and Long-Term Depression. Journal of Neuroscience, 26(29): 7723-7729.
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Aarsland, D., Bronnick, K., Williams-Gray, C., Weintraub, D., Marder, K., Kulisevsky, J., et al. (2010). Mild cognitive impairment in Parkinson disease: A multicenter pooled analysis. Neurology, 75(12): 1062-1069.
Alcántara‐González, F., Mendoza‐Perez, C.R., Zaragoza, N., Juarez, I., Arroyo‐García, L.E., Gamboa, C., et al. (2012). Combined administration of cerebrolysin and donepezil induces plastic changes in prefrontal cortex in aged mice. Synapse, 66(11): 938-949.
Álvarez, X.A., Lombardi, V.R.M., Fernández-Novoa, L., García, M., Sampedro, C., Cagiao, A., et al. (2000). Cerebrolysin® reduces microglial activation in vivo and in vitro: a potential mechanism of neuroprotection, in Advances in Dementia Research. Vienna: Springer Vienna, 281-292.
Alzoubi, K.H., Al-ibbini, A.M. and Nuseir, K.Q. (2018). Prevention of memory impairment induced by post-traumatic stress disorder by cerebrolysin. Psychiatry Research, 270: 430-437.
Athari, S.Z., Farajdokht, F., Sadigh-Eteghad, S., Mohajeri, D., Nourazar, M.A. and Mohaddes, G. (2022). Hydroxychloroquine attenuated motor impairment and oxidative stress in a rat 6-hydroxydopamine model of Parkinson's disease. International Journal of Neuroscience, 1-13.
Balestrino, R. and Schapira, A.H.V. (2020). Parkinson disease. European Journal of Neurology, 27(1): 27-42.
Belotto, M.F., Magdalon, J., Rodrigues, H.G., Vinolo, M.A.R., Curi, R., Pithon-Curi, T.C., et al. (2010). Moderate exercise improves leucocyte function and decreases inflammation in diabetes. Clinical and Experimental Immunology, 162(2): 237-243.
Bethus, I., Tse, D. and Morris, R.G.M. (2010). Dopamine and Memory: Modulation of the Persistence of Memory for Novel Hippocampal NMDA Receptor-Dependent Paired Associates. Journal of Neuroscience, 30(5): 1610-1618.
Blum, D., Torch, S., Lambeng, N., Nissou, M.F., Benabid, A.L., Sadoul, R., et al. (2001). Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson’s disease. Progress in Neurobiology, 65(2): 135-172.
Carvalho, M.M., Campos, F.L., Marques, M., Soares-Cunha, C., Kokras, N., Dalla, C., et al. (2017). Effect of Levodopa on Reward and Impulsivity in a Rat Model of Parkinson’s Disease. Frontiers in Behavioral Neuroscience, 11: 145.
Cassilhas, R.C., Lee, K.S., Fernandes, J., Oliveira, M.G.M.D., Tufik, S., Meeusen, R., et al. (2012). Spatial memory is improved by aerobic and resistance exercise through divergent molecular mechanisms. Neuroscience, 202: 309-317.
Crowley, E.K., Nolan, Y.M. and Sullivan, A.M. (2019). Exercise as a therapeutic intervention for motor and non-motor symptoms in Parkinson’s disease: Evidence from rodent models. Progress in Neurobiology, 172: 2-22.
Da Cunha, C., Angelucci, M.E.M., Canteras, N.S., Wonnacott, S. and Takahashi, R.N. (2002). The lesion of the rat substantia nigra pars compacta dopaminergic neurons as a model for Parkinson’s disease memory disabilities. Cellular and molecular neurobiology, 22(3): 227-37.
De Leonibus, E., Pascucci, T., Lopez, S., Oliverio, A., Amalric, M. and Mele, A. (2007). Spatial deficits in a mouse model of Parkinson disease. Psychopharmacology, 194(4): 517-525.
Deumens, R., Blokland, A. and Prickaerts, J. (2002). Modeling Parkinson’s Disease in Rats: An Evaluation of 6-OHDA Lesions of the Nigrostriatal Pathway, Experimental Neurology, 175(2): 303-317.
Devi, S.A. and Kiran, T.R. (2004). Regional responses in antioxidant system to exercise training and dietary Vitamin E in aging rat brain. Neurobiology of Aging, 25(4): 501-508.
Dias, V., Junn, E. and Mouradian, M.M. (2013). The Role of Oxidative Stress in Parkinson’s Disease. Journal of Parkinson’s Disease, 3(4): 461-491.
During, M. and Cao, L. (2006). VEGF, a Mediator of the Effect of Experience on Hippocampal Neurogenesis. Current Alzheimer Research, 3(1): 29-33.
Duty, S. and Jenner, P. (2011). Animal models of Parkinson’s disease: a source of novel treatments and clues to the cause of the disease. British Journal of Pharmacology, 164(4): 1357-1391.
Flores, G. and Atzori, M. (2014). The Potential of Cerebrolysin in the Treatment of Schizophrenia. Pharmacology & Pharmacy, 5(7): 691-704.
Georgy, G.S., Nassar, N.N., Mansour, H.A. and Abdallah, D.M. (2013). Cerebrolysin Ameloriates Cognitive Deficits in Type III Diabetic Rats. PLoS ONE. Edited by Boraud, T., 8(6): e64847.
Giralt, A., Saavedra, A., Carretón, O., Xifró, X., Alberch, J. and Pérez-Navarro, E. (2011). Increased PKA signaling disrupts recognition memory and spatial memory: role in Huntington’s disease. Human Molecular Genetics, 20(21): 4232-4247.
Hamilton, T.J., Wheatley, B.M., Sinclair, D.B., Bachmann, M., Larkum, M.E. and Colmers, W.F. (2010). Dopamine modulates synaptic plasticity in dendrites of rat and human dentate granule cells. Proceedings of the National Academy of Sciences, 107(42): 18185-18190.
Hansen, N. and Manahan-Vaughan, D. (2014) Dopamine D1/D5 Receptors Mediate Informational Saliency that Promotes Persistent Hippocampal Long-Term Plasticity. Cerebral Cortex, 24(4): 845-858.
Hartbauer, M., Hutter-Paier, B. and Windisch, M. (2001). Effects of Cerebrolysin on the outgrowth and protection of processes of cultured brain neurons. Journal of Neural Transmission, 108(5): 581-592.
Hattori, S., Naoi, M. and Nishino, H. (1994). Striatal dopamine turnover during treadmill running in the rat: relation to the speed of running. Brain Research Bulletin, 35(1): 41-49.
Hoveida, R., Alaei, H., Oryan, S., Parivar, K. and Reisi, P. (2011). Treadmill running improves spatial memory in an animal model of Alzheimer's disease. Behavioural Brain Research, 216(1): 270-274.
Hsueh, S.C., Chen, K.Y., Lai, J.H., Wu, C.C., Yu, Y.W., Luo, Y., et al. (2018). Voluntary Physical Exercise Improves Subsequent Motor and Cognitive Impairments in a Rat Model of Parkinson’s Disease. International Journal of Molecular Sciences, 19(2): 508.
Jay, T.M. (2003). Dopamine: a potential substrate for synaptic plasticity and memory mechanisms. Progress in Neurobiology, 69(6): 375-390.
Kalia, L. V. and Lang, A.E. (2015). Parkinson’s disease. The Lancet, 386(9996): 896-912.
Kempadoo, K.A., Mosharov, E.V., Choi, S.J., Sulzer, D. and Kandel, E.R. (2016). Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory. Proceedings of the National Academy of Sciences, 113(51): 14835-14840.
Kramer, A.F. and Erickson, K.I. (2007). Capitalizing on cortical plasticity: influence of physical activity on cognition and brain function. Trends in Cognitive Sciences, 11(8): 342-348.
Lemon, N. and Manahan-Vaughan, D. (2006). Dopamine D1/D5 Receptors Gate the Acquisition of Novel Information through Hippocampal Long-Term Potentiation and Long-Term Depression. Journal of Neuroscience, 26(29): 7723-7729.
Marcelino, T.B., Longoni, A., Kudo, K.Y., Stone, V., Rech, A., De Assis, A.M., et al. (2013). Evidences that maternal swimming exercise improves antioxidant defenses and induces mitochondrial biogenesis in the brain of young Wistar rats. Neuroscience, 246: 28-39.
Mattson, M.P., Gleichmann, M. and Cheng, A. (2008). Mitochondria in Neuroplasticity and Neurological Disorders. Neuron, 60(5): 748-766.
Mocchetti, I., Bachis, A., Nosheny, R.L. and Tanda, G. (2007). Brain-derived neurotrophic factor expression in the substantia nigra does not change after lesions of dopaminergic neurons. Neurotoxicity Research, 12(2): 135-143.
Noor, N.A., Mohammed, H.S., Mourad, I.M., Khadrawy, Y.A. and Ezz, H.S.A. (2016). A promising therapeutic potential of cerebrolysin in 6-OHDA rat model of Parkinson’s disease. Life Sciences, 155: 174-179.
Paxinos, G. and Watson, C. (2014). The Rat Brain in Stereotaxic Coordinates, 7th, Elsevier Academic Press, pp: 66-85.
Pereira, A.C., Huddleston, D.E., Brickman, A.M., Sosunov, A.A., Hen, R., McKhann, G.M., et al. (2007). An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proceedings of the National Academy of Sciences, 104(13): 5638-5643.
Plosker, G.L. and Gauthier, S. (2009). Cerebrolysin. Drugs & Aging, 26(11): 893-915.
Van Praag, H., Christie, B.R., Sejnowski, T.J. and Gage, F.H. (1999). Running enhances neurogenesis, learning, and long-term potentiation in mice. Proceedings of the National Academy of Sciences, 96(23): 13427-13431.
Van Praag, H. (2005). Exercise Enhances Learning and Hippocampal Neurogenesis in Aged Mice. Journal of Neuroscience, 25(38): 8680-8685.
Real, C.C., Ferreira, A.F.B., Chaves-Kirsten, G.P., Torrão, A.D.S., Pires, R.S. and Britto, L.R.G.D. (2013). BDNF receptor blockade hinders the beneficial effects of exercise in a rat model of Parkinson’s disease. Neuroscience, 237: 118-129.
Requejo, C., Ruiz-Ortega, J.A., Cepeda, H., Sharma, A., Sharma, H.S., Ozkizilcik, A., et al. (2018). Nanodelivery of Cerebrolysin and Rearing in Enriched Environment Induce Neuroprotective Effects in a Preclinical Rat Model of Parkinson’s Disease. Molecular Neurobiology, 55(1): 286-299.
Rockenstein, E., Torrance, M., Mante, M., Adame, A., Paulino, A., Rose, J.B., et al. (2006). Cerebrolysin decreases amyloid-β production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer’s disease, Journal of Neuroscience Research, 83(7): 1252-1261.
Rockenstein, E., Desplats, P., Ubhi, K., Mante, M., Florio, J., Adame, A., et al. (2015). Neuropeptide Treatment with Cerebrolysin Enhances the Survival of Grafted Neural Stem Cell in an α-Synuclein Transgenic Model of Parkinson’s Disease. Journal of Experimental Neuroscience, 9(2): JEN.S25521.
Roghani, M., Behzadi, G. and Baluchnejadmojarad, T. (2002). Efficacy of elevated body swing test in the early model of Parkinson’s disease in rat. Physiology & Behavior, 76(4–5): 507-510.
Sayal, N. (2015) Exercise training increases size of hippocampus and improves memory. Annals of Neurosciences, 22(2): 107.
Soke, F., Kocer, B., Fidan, I., Keskinoglu, P. and Guclu-Gunduz, A. (2021). Effects of task-oriented training combined with aerobic training on serum BDNF, GDNF, IGF-1, VEGF, TNF-α, and IL-1β levels in people with Parkinson's disease: A randomized controlled study. Experimental Gerontology, 150: 111384.
Solis‐Gaspar, C., Vazquez‐Roque, R.A., De Jesús Gómez‐Villalobos, M. and Flores, G. (2016). Cerebrolysin improves memory and ameliorates neuronal atrophy in spontaneously hypertensive aged rats. Synapse, 70(9): 378-389.
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