Physical exercise effects on brain health and cognitive performance have been described. Synaptic remodeling in hippocampus induced by physical exercise has been described in animal models, but the underlying mechanisms remain poorly understood. Changes in astrocytes, the glial cells involved in synaptic remodeling, need more characterization. We investigated the effect of moderate treadmill exercise (20？min/day) for 4 weeks on some parameters of astrocytic activity in rat hippocampal slices, namely, glial fibrillary acidic protein (GFAP), glutamate uptake and glutamine synthetase (GS) activities, glutathione content, and S100B protein content and secretion, as well as brain-derived neurotrophic factor (BDNF) levels and glucose uptake activity in this tissue. Results show that moderate treadmill exercise was able to induce a decrease in GFAP content (evaluated by ELISA and immunohistochemistry) and an increase in GS activity. These changes could be mediated by corticosterone, whose levels were elevated in serum. BDNF, another putative mediator, was not altered in hippocampal tissue. Moreover, treadmill exercise caused a decrease in NO content. Our data indicate specific changes in astrocyte markers induced by physical exercise, the importance of studying astrocytes for understanding brain plasticity, as well as reinforce the relevance of physical exercise as a neuroprotective strategy. 1. Introduction Studies have shown that physical exercise can have profound effects on cardiovascular, pulmonary, and the musculoskeletal system, as well as the central nervous system (CNS) [1, 2]. Moderate physical activity improves memory and learning [3–8] and is associated with a lower risk for Alzheimer's dementia [9], Parkinson's disease [10] and other types of neurodegenerative diseases [2]. One of the regions of CNS more affected by exercise is the hippocampus. A putative mechanism, through which the exercise exerts its effects on the hippocampus, is the induction of brain-derived neurotrophic factor (BDNF) [11]. Astrocytes, the most abundant glial cells, particularly those of the glutamatergic type, are very important elements in neurotransmission [12, 13] and antioxidant defense, and this action involves the synthesis and secretion of glutathione (GSH) [14]. These cells are responsible for glutamate removal from the synaptic cleft and its conversion, through glutamine synthetase (GS) catalysis, into glutamine for replacement in the neurons. Moreover, increments in energy demand and functional activity during exercise may require functional and structural
References
[1]
H. van Praag, “Exercise and the brain: something to chew on,” Trends in Neurosciences, vol. 32, no. 5, pp. 283–290, 2009.
[2]
Q. Ma, “Beneficial effects of moderate voluntary physical exercise and its biological mechanisms on brain health,” Neuroscience Bulletin, vol. 24, no. 4, pp. 265–270, 2008.
[3]
H. van Praag, B. R. Christie, T. J. Sejnowski, and F. H. Gage, “Running enhances neurogenesis, learning, and long-term potentiation in mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 23, pp. 13427–13431, 1999.
[4]
M. K. Jedrziewski, V. M. Y. Lee, and J. Q. Trojanowski, “Physical activity and cognitive health,” Alzheimer's and Dementia, vol. 3, no. 2, pp. 98–108, 2007.
[5]
Z. Radák, T. Kaneko, S. Tahara et al., “Regular exercise improves cognitive function and decreases oxidative damage in rat brain,” Neurochemistry International, vol. 38, no. 1, pp. 17–23, 2001.
[6]
H. Ogonovszky, I. Berkes, S. Kumagai et al., “The effects of moderate-, strenuous- and over-training on oxidative stress markers, DNA repair, and memory, in rat brain,” Neurochemistry International, vol. 46, no. 8, pp. 635–640, 2005.
[7]
E. T. Ang, G. S. Dawe, P. T. H. Wong, S. Moochhala, and Y. K. Ng, “Alterations in spatial learning and memory after forced exercise,” Brain Research, vol. 1113, no. 1, pp. 186–193, 2006.
[8]
L. Grace, S. Hescham, L. A. Kellaway, K. Bugarith, and V. A. Russell, “Effect of exercise on learning and memory in a rat model of developmental stress,” Metabolic Brain Disease, vol. 24, no. 4, pp. 643–657, 2009.
[9]
C. W. Cotman and N. C. Berchtold, “Exercise: a behavioral intervention to enhance brain health and plasticity,” Trends in Neurosciences, vol. 25, no. 6, pp. 295–301, 2002.
[10]
A. D. Smith and M. J. Zigmond, “Can the brain be protected through exercise? Lessons from an animal model of parkinsonism,” Experimental Neurology, vol. 184, no. 1, pp. 31–39, 2003.
[11]
J. A. Zoladz and A. Pilc, “The effect of physical activity on the brain derived neurotrophic factor: from animal to human studies,” Journal of Physiology and Pharmacology, vol. 61, no. 5, pp. 533–541, 2010.
[12]
V. Parpura and R. Zorec, “Gliotransmission: exocytotic release from astrocytes,” Brain Research Reviews, vol. 63, no. 1-2, pp. 83–92, 2010.
[13]
G. Perea and A. Araque, “GLIA modulates synaptic transmission,” Brain Research Reviews, vol. 63, no. 1-2, pp. 93–102, 2010.
[14]
R. Dringen, “Metabolism and functions of glutathione in brain,” Progress in Neurobiology, vol. 62, no. 6, pp. 649–671, 2000.
[15]
J. Li, Y. H. Ding, J. A. Rafols, Q. Lai, J. P. McAllister II, and Y. Ding, “Increased astrocyte proliferation in rats after running exercise,” Neuroscience Letters, vol. 386, no. 3, pp. 160–164, 2005.
[16]
M. E. Gibbs, D. Hutchinson, and L. Hertz, “Astrocytic involvement in learning and memory consolidation,” Neuroscience and Biobehavioral Reviews, vol. 32, no. 5, pp. 927–944, 2008.
[17]
J. Correale and A. Villa, “Cellular elements of the blood-brain barrier,” Neurochemical Research, vol. 34, no. 12, pp. 2067–2077, 2009.
[18]
M. Bergami, S. Santi, E. Formaggio et al., “Uptake and recycling of pro-BDNF for transmitter-induced secretion by cortical astrocytes,” Journal of Cell Biology, vol. 183, no. 2, pp. 213–221, 2008.
[19]
P. G. Haydon and G. Carmignoto, “Astrocyte control of synaptic transmission and neurovascular coupling,” Physiological Reviews, vol. 86, no. 3, pp. 1009–1031, 2006.
[20]
L. Rodrigues, M. F. Dutra, J. Ilha et al., “Treadmill training restores spatial cognitive deficits and neurochemical alterations in the hippocampus of rats submitted to an intracerebroventricular administration of streptozotocin,” Journal of Neural Transmission, vol. 117, no. 11, pp. 1295–1305, 2010.
[21]
P. N. de Senna, J. Ilha, P. P. A. Baptista et al., “Effects of physical exercise on spatial memory and astroglial alterations in the hippocampus of diabetic rats,” Metabolic Brain Disease, vol. 26, no. 4, pp. 269–279, 2011.
[22]
E. T. Ang, P. T. H. Wong, S. Moochhala, and Y. K. Ng, “Cytokine changes in the horizontal diagonal band of broca in the septum after running and stroke: a correlation to glial activation,” Neuroscience, vol. 129, no. 2, pp. 337–347, 2004.
[23]
K. Santin, R. F. da Rocha, F. Cechetti et al., “Moderate exercise training and chronic caloric restriction modulate redox status in rat hippocampus,” Brain Research, vol. 1421, pp. 1–10, 2011.
[24]
P. R. Burghardt, L. J. Fulk, G. A. Hand, and M. A. Wilson, “The effects of chronic treadmill and wheel running on behavior in rats,” Brain Research, vol. 1019, no. 1-2, pp. 84–96, 2004.
[25]
R. M. Melo, E. Martinho Jr., and L. C. Michelini, “Training-induced, pressure-lowering effect in SHR: wide effects on circulatory profile of exercised and nonexercised muscles,” Hypertension, vol. 42, no. 4, pp. 851–857, 2003.
[26]
D. Scopel, C. Fochesatto, H. Cimarosti et al., “Exercise intensity influences cell injury in rat hippocampal slices exposed to oxygen and glucose deprivation,” Brain Research Bulletin, vol. 71, no. 1–3, pp. 155–159, 2006.
[27]
C. B. O. Netto, S. Conte, M. C. Leite et al., “Serum S100B protein is increased in fasting rats,” Archives of Medical Research, vol. 37, no. 5, pp. 683–686, 2006.
[28]
M. C. Leite, F. Galland, G. Brolese et al., “A simple, sensitive and widely applicable ELISA for S100B: methodological features of the measurement of this glial protein,” Journal of Neuroscience Methods, vol. 169, no. 1, pp. 93–99, 2008.
[29]
F. Tramontina, M. C. Leite, K. Cereser et al., “Immunoassay for glial fibrillary acidic protein: antigen recognition is affected by its phosphorylation state,” Journal of Neuroscience Methods, vol. 162, no. 1-2, pp. 282–286, 2007.
[30]
A. Swarowsky, L. Rodrigues, R. Biasibetti et al., “Glial alterations in the hippocampus of rats submitted to ibotenic-induced lesion of the nucleus basalis magnocellularis,” Behavioural Brain Research, vol. 190, no. 2, pp. 206–211, 2008.
[31]
A. P. Thomazi, G. F. Godinho, J. M. Rodrigues et al., “Ontogenetic profile of glutamate uptake in brain structures slices from rats: sensitivity to guanosine,” Mechanisms of Ageing and Development, vol. 125, no. 7, pp. 475–481, 2004.
[32]
A. M. Feoli, I. Siqueira, L. M. V. Almeida et al., “Brain glutathione content and glutamate uptake are reduced in rats exposed to pre- and postnatal protein malnutrition,” Journal of Nutrition, vol. 136, no. 9, pp. 2357–2361, 2006.
[33]
R. W. Browne and D. Armstrong, “Reduced glutathione and glutathione disulfide,” Methods in Molecular Biology, vol. 108, pp. 347–352, 1998.
[34]
J. M. Hevel and M. A. Marletta, “Nitric-oxide synthase assays,” Methods in Enzymology, vol. 233, pp. 250–258, 1994.
[35]
A. Quincozes-Santos, P. Nardin, D. F. Souza et al., “The janus face of resveratrol in astroglial cells,” Neurotoxicity Research, vol. 16, no. 1, pp. 30–41, 2009.
[36]
L. P. Garetto, E. A. Richter, M. N. Goodman, and N. B. Ruderman, “Enhanced muscle glucose metabolism after exercise in the rat: the two phases,” The American Journal of Physiology, vol. 246, no. 6, pp. E471–475, 1984.
[37]
F. A. Voltarelli, C. A. Gobatto, and M. A. de Mello, “Determination of anaerobic threshold in rats using the lactate minimum test,” Brazilian Journal of Medical and Biological Research, vol. 35, no. 11, pp. 1389–1394, 2002.
[38]
E. T. Ang and F. Gomez-Pinilla, “Potential therapeutic effects of exercise to the brain,” Current Medicinal Chemistry, vol. 14, no. 24, pp. 2564–2571, 2007.
[39]
A. T. U. Schaefers, K. Grafen, G. Teuchert-Noodt, and Y. Winter, “Synaptic remodeling in the dentate gyrus, CA3, CA1, subiculum, and entorhinal cortex of mice: effects of deprived rearing and voluntary running,” Neural Plasticity, vol. 2010, Article ID 870573, 11 pages, 2010.
[40]
M. Haber, L. Zhou, and K. K. Murai, “Cooperative astrocyte and dendritic spine dynamics at hippocampal excitatory synapses,” Journal of Neuroscience, vol. 26, no. 35, pp. 8881–8891, 2006.
[41]
E. C. Beattie, D. Stellwagen, W. Morishita et al., “Control of synaptic strength by glial TNFα,” Science, vol. 295, no. 5563, pp. 2282–2285, 2002.
[42]
A. Panatier, D. T. Theodosis, J. P. Mothet et al., “Glia-derived D-serine controls NMDA receptor activity and synaptic memory,” Cell, vol. 125, no. 4, pp. 775–784, 2006.
[43]
J. Middeldorp and E. M. Hol, “GFAP in health and disease,” Progress in Neurobiology, vol. 93, no. 3, pp. 421–443, 2011.
[44]
C. W. Cotman, N. C. Berchtold, and L. A. Christie, “Exercise builds brain health: key roles of growth factor cascades and inflammation,” Trends in Neurosciences, vol. 30, no. 9, pp. 464–472, 2007.
[45]
G. van Hall, M. Str？mstad, P. Rasmussen et al., “Blood lactate is an important energy source for the human brain,” Journal of Cerebral Blood Flow and Metabolism, vol. 29, no. 6, pp. 1121–1129, 2009.
[46]
E. Lezi, J. Lu, J. M. Burns, and R. H. Swerdlow, “Effect of exercise on mouse liver and brain bioenergetic infrastructures,” Experimental Physiology, vol. 98, pp. 207–219, 2013.
[47]
L. F. Eng, R. S. Ghirnikar, and Y. L. Lee, “Glial fibrillary acidic protein: GFAP-thirty-one years (1969–2000),” Neurochemical Research, vol. 25, no. 9-10, pp. 1439–1451, 2000.
[48]
N. R. Nichols, D. Agolley, M. Zieba, and N. Bye, “Glucocorticoid regulation of glial responses during hippocampal neurodegeneration and regeneration,” Brain Research Reviews, vol. 48, no. 2, pp. 287–301, 2005.
[49]
I. Rozovsky, M. Wei, D. J. Stone et al., “Estradiol (E2) enhances neurite outgrowth by repressing glial fibrillary acidic protein expression and reorganizing laminin,” Endocrinology, vol. 143, no. 2, pp. 636–646, 2002.
[50]
V. Menet, M. Giménez Y Ribotta, N. Chauvet et al., “Inactivation of the glial fibrillary acidic protein gene, but not that of vimentin, improves neuronal survival and neurite growth by modifying adhesion molecule expression,” Journal of Neuroscience, vol. 21, no. 16, pp. 6147–6158, 2001.
[51]
H. Tanaka, A. Katoh, K. Oguro et al., “Disturbance of hippocampal long-term potentiation after transient ischemia in GFAP deficient mice,” Journal of Neuroscience Research, vol. 67, no. 1, pp. 11–20, 2002.
[52]
C. A. Gon？alves, M. C. Leite, and P. Nardin, “Biological and methodological features of the measurement of S100B, a putative marker of brain injury,” Clinical Biochemistry, vol. 41, no. 10-11, pp. 755–763, 2008.
[53]
R. Donato and C. W. Heizmann, “S100B protein in the nervous system and cardiovascular apparatus in normal and pathological conditions,” Cardiovascular Psychiatry and Neurology, vol. 2010, Article ID 929712, 2 pages, 2010.
[54]
P. Rasmussen, P. Brassard, H. Adser et al., “Evidence for a release of brain-derived neurotrophic factor from the brain during exercise,” Experimental Physiology, vol. 94, no. 10, pp. 1062–1069, 2009.
[55]
H. Chen and A. J. Weber, “Expression of glial fibrillary acidic protein and glutamine synthetase by Müller cells after optic nerve damage and intravitreal application of brain-derived neurotrophic factor,” GLIA, vol. 38, no. 2, pp. 115–125, 2002.
[56]
W. R. Sch？bitz, C. Berger, R. Kollmar et al., “Effect of brain-derived neurotrophic factor treatment and forced arm use on functional motor recovery after small cortical ischemia,” Stroke, vol. 35, no. 4, pp. 992–997, 2004.
[57]
Y. Ye, G. Wang, H. Wang, and X. Wang, “Brain-derived neurotrophic factor (BDNF) infusion restored astrocytic plasticity in the hippocampus of a rat model of depression,” Neuroscience Letters, vol. 503, no. 1, pp. 15–19, 2011.
[58]
H. Soya, T. Nakamura, C. C. Deocaris et al., “BDNF induction with mild exercise in the rat hippocampus,” Biochemical and Biophysical Research Communications, vol. 358, no. 4, pp. 961–967, 2007.
[59]
M. Goekint, B. Roelands, E. Heyman, R. Njemini, and R. Meeusen, “Influence of citalopram and environmental temperature on exercise-induced changes in BDNF,” Neuroscience Letters, vol. 494, no. 2, pp. 150–154, 2011.
[60]
F. Cechetti, C. Fochesatto, D. Scopel et al., “Effect of a neuroprotective exercise protocol on oxidative state and BDNF levels in the rat hippocampus,” Brain Research, vol. 1188, no. 1, pp. 182–188, 2008.
[61]
A. F. B. Ferreira, C. C. Real, A. C. Rodrigues, A. S. Alves, and L. R. G. Britto, “Short-term, moderate exercise is capable of inducing structural, BDNF-independent hippocampal plasticity,” Brain Research, vol. 1425, pp. 111–122, 2011.
[62]
N. J. Laping, N. R. Nichols, J. R. Day, S. A. Johnson, and C. E. Finch, “Transcriptional control of glial fibrillary acidic protein and glutamine synthetase in vivo shows opposite responses to corticosterone in the hippocampus,” Endocrinology, vol. 135, no. 5, pp. 1928–1933, 1994.
[63]
S. R. Robinson, “Changes in the cellular distribution of glutamine synthetase in Alzheimer's disease,” Journal of Neuroscience Research, vol. 66, no. 5, pp. 972–980, 2001.
[64]
R. F. Butterworth, “Altered glial-neuronal crosstalk: cornerstone in the pathogenesis of hepatic encephalopathy,” Neurochemistry International, vol. 57, no. 4, pp. 383–388, 2010.
[65]
G. C. Brown, “Mechanisms of inflammatory neurodegeneration: INOS and NADPH oxidase,” Biochemical Society Transactions, vol. 35, no. 5, pp. 1119–1121, 2007.
[66]
X. Liu, J. Yang le, S. J. Fan, H. Jiang, and F. Pan, “Swimming exercise effects on the expression of HSP70 and iNOS in hippocampus and prefrontal cortex in combined stress,” Neuroscience Letters, vol. 476, no. 2, pp. 99–103, 2010.
[67]
Y.-H. Sung, S.-C. Kim, H.-P. Hong et al., “Treadmill exercise ameliorates dopaminergic neuronal loss through suppressing microglial activation in Parkinson's disease mice,” Life Sciences, vol. 91, no. 25-26, pp. 1309–1316, 2012.
[68]
Y. H. Leem, Y. I. Lee, H. J. Son, and S. H. Lee, “Chronic exercise ameliorates the neuroinflammation in mice carrying NSE/htau23,” Biochemical and Biophysical Research Communications, vol. 406, no. 3, pp. 359–365, 2011.
[69]
S. Salim, N. Sarraj, M. Taneja, K. Saha, M. V. Tejada-Simon, and G. Chugh, “Moderate treadmill exercise prevents oxidative stress-induced anxiety-like behavior in rats,” Behavioural Brain Research, vol. 208, no. 2, pp. 545–552, 2010.
[70]
J. S. Querido and A. W. Sheel, “Regulation of cerebral blood flow during exercise,” Sports Medicine, vol. 37, no. 9, pp. 765–782, 2007.
[71]
M. L. Goodwin, “Blood glucose regulation during prolonged, submaximal, continuous exercise: a guide for clinicians,” Journal of Diabetes Science and Technology, vol. 4, no. 3, pp. 694–705, 2010.
[72]
S. Cunnane, S. Nugent, M. Roy et al., “Brain fuel metabolism, aging, and Alzheimer's disease,” Nutrition, vol. 27, no. 1, pp. 3–20, 2011.
