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Pre-Ischemic Treadmill Training for Prevention of Ischemic Brain Injury via Regulation of Glutamate and Its Transporter GLT-1

DOI: 10.3390/ijms13089447

Keywords: glutamate, glutamate transporter-1 (GLT-1), pre-ischemic treadmill training, ischemia, neuroprotection

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Abstract:

Pre-ischemic treadmill training exerts cerebral protection in the prevention of cerebral ischemia by alleviating neurotoxicity induced by excessive glutamate release following ischemic stroke. However, the underlying mechanism of this process remains unclear. Cerebral ischemia-reperfusion injury was observed in a rat model after 2 weeks of pre-ischemic treadmill training. Cerebrospinal fluid was collected using the microdialysis sampling method, and the concentration of glutamate was determined every 40 min from the beginning of ischemia to 4 h after reperfusion with high-performance liquid chromatography (HPLC)-fluorescence detection. At 3, 12, 24, and 48 h after ischemia, the expression of the glutamate transporter-1 (GLT-1) protein in brain tissues was determined by Western blot respectively. The effect of pre-ischemic treadmill training on glutamate concentration and GLT-1 expression after cerebral ischemia in rats along with changes in neurobehavioral score and cerebral infarct volume after 24 h ischemia yields critical information necessary to understand the protection mechanism exhibited by pre-ischemic treadmill training. The results demonstrated that pre-ischemic treadmill training up-regulates GLT-1 expression, decreases extracellular glutamate concentration, reduces cerebral infarct volume, and improves neurobehavioral score. Pre-ischemic treadmill training is likely to induce neuroprotection after cerebral ischemia by regulating GLT-1 expression, which results in re-uptake of excessive glutamate.

References

[1]  Goldstein, L.B.; Bushnell, C.D.; Adams, R.J.; Appel, L.J.; Braun, L.T.; Chaturvedi, S.; Creager, M.A.; Culebras, A.; Eckel, R.H.; Hart, R.G.; et al. Guidelines for the primary prevention of stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011, 42, 517–584.
[2]  Cotman, C.W.; Berchtold, N.C.; Christie, L.A. Exercise builds brain health: Key roles of growth factor cascades and inflammation. Trends Neurosci 2007, 30, 464–472.
[3]  Yang, Y.R.; Wang, R.Y.; Wang, P.S.; Yu, S.M. Treadmill training effects on neurological outcome after middle cerebral artery occlusion in rats. Can. J. Neurol. Sci 2003, 30, 252–258.
[4]  Ding, Y.H.; Ding, Y.; Li, J.; Bessert, D.A.; Rafols, J.A. Exercise pre-conditioning strengthens brain microvascular integrity in a rat stroke model. Neurol. Res 2006, 28, 184–189.
[5]  Guo, M.; Cox, B.; Mahale, S.; Davis, W.; Carranza, A.; Hayes, K.; Sprague, S.; Jimenez, D.; Ding, Y. Pre-ischemic exercise reduces matrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in stroke. Neuroscience 2008, 151, 340–351.
[6]  Curry, A.; Guo, M.; Patel, R.; Liebelt, B.; Sprague, S.; Lai, Q.; Zwagerman, N.; Cao, F.X.; Jimenez, D.; Ding, Y. Exercise pre-conditioning reduces brain inflammation in stroke via tumor necrosis factor-alpha, extracellular signal-regulated kinase 1/2 and matrix metalloproteinase-9 activity. Neurol. Res 2010, 32, 756–762.
[7]  Guyot, L.L.; Diaz, F.G.; O’Regan, M.H.; McLeod, S.; Park, H.; Phillis, J.W. Real-time measurement of glutamate release from the ischemic penumbra of the rat cerebral cortex using a focal middle cerebral artery occlusion model. Neurosci. Lett 2001, 299, 37–40.
[8]  Hinzman, J.M.; Thomas, T.C.; Quintero, J.E.; Gerhardt, G.A.; Lifshitz, J. Disruptions in the regulation of extracellular glutamate by neurons and glia in the rat striatum two days after diffuse brain injury. J. Neurotrauma 2012, 29, 1197–1208.
[9]  Beart, P.M.; O’Shea, R.D. Transporters for l-glutamate: An update on their molecular pharmacology and pathological involvement. Br. J. Pharmacol 2007, 150, 5–17.
[10]  Sims, K.D.; Robinson, M.B. Expression patterns and regulation of glutamate transporters in the developing and adult nervous system. Crit. Rev. Neurobiol 1999, 13, 169–197.
[11]  Suchak, S.K.; Baloyianni, N.V.; Perkinton, M.S.; Williams, R.J.; Meldrum, B.S.; Rattray, M. The ‘glial’ glutamate transporter, EAAT2 (Glt-1) accounts for high affinity glutamate uptake into adult rodent nerve endings. J. Neurochem 2003, 84, 522–532.
[12]  Jia, J.; Hu, Y.S.; Wu, Y.; Liu, G.; Yu, H.X.; Zheng, Q.P.; Zhu, D.N.; Xia, C.M.; Cao, Z.J. Pre-ischemic treadmill training affects glutamate and gamma aminobutyric acid levels in the striatal dialysate of a rat model of cerebral ischemia. Life Sci 2009, 84, 505–511.
[13]  Zhang, F.; Jia, J.; Wu, Y.; Hu, Y.; Wang, Y. The effect of treadmill training pre-exercise on glutamate receptor expression in rats after cerebral ischemia. Int. J. Mol. Sci 2010, 11, 2658–2669.
[14]  Liu, A.J.; Hu, Y.Y.; Li, W.B.; Xu, J.; Zhang, M. Cerebral ischemic pre-conditioning enhances the binding characteristics and glutamate uptake of glial glutamate transporter-1 in hippocampal CA1 subfield of rats. J. Neurochem 2011, 119, 202–209.
[15]  Gong, S.J.; Chen, L.Y.; Zhang, M.; Gong, J.X.; Ma, Y.X.; Zhang, J.M.; Wang, Y.J.; Hu, Y.Y.; Sun, X.C.; Li, W.B.; Zhang, Y. Intermittent hypobaric hypoxia preconditioning induced brain ischemic tolerance by up-regulating glial glutamate transporter-1 in rats. Neurochem. Res 2012, 37, 527–537.
[16]  Kanai, Y.; Hediger, M.A. The glutamate/neutral amino acid transporter family SLC1: Molecular, physiological and pharmacological aspects. Pflugers Arch 2004, 447, 469–479.
[17]  Verma, R.; Mishra, V.; Sasmal, D.; Raghubir, R. Pharmacological evaluation of glutamate transporter 1 (GLT-1) mediated neuroprotection following cerebral ischemia/reperfusion injury. Eur. J. Pharmacol 2010, 638, 65–71.
[18]  Tanaka, K.; Watase, K.; Manabe, T.; Yamada, K.; Watanabe, M.; Takahashi, K.; Iwama, H.; Nishikawa, T.; Ichihara, N.; Kikuchi, T.; et al. Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 1997, 276, 1699–1702.
[19]  Mimura, K.; Tomimatsu, T.; Minato, K.; Jugder, O.; Kinugasa-Taniguchi, Y.; Kanagawa, T.; Nozaki, M.; Yanagihara, I.; Kimura, T. Ceftriaxone preconditioning confers neuroprotection in neonatal rats through glutamate transporter 1 upregulation. Reprod. Sci 2011, 18, 1193–1201.
[20]  Kawahara, K.; Kosugi, T.; Tanaka, M.; Nakajima, T.; Yamada, T. Reversed operation of glutamate transporter GLT-1 is crucial to the development of preconditioning-induced ischemic tolerance of neurons in neuron/astrocyte co-cultures. Glia 2005, 49, 349–359.
[21]  Torp, R.; Lekieffre, D.; Levy, L.M.; Haug, F.M.; Danbolt, N.C.; Meldrum, B.S.; Ottersen, O.P. Reduced postischemic expression of a glial glutamate transporter, GLT1, in the rat hippocampus. Exp. Brain Res 1995, 103, 51–58.
[22]  Zhang, M.; Li, W.B.; Geng, J.X.; Li, Q.J.; Sun, X.C.; Xian, X.H.; Qi, J.; Li, S.Q. The upregulation of glial glutamate transporter-1 participates in the induction of brain ischemic tolerance in rats. J. Cereb Blood Flow Metab 2007, 27, 1352–1368.
[23]  Münch, C.; Zhu, B.G.; Leven, A.; Stamm, S.; Eink?rn, H.; Schwalenst?cker, B.; Ludolph, A.C.; Riepe, M.W.; Meyer, T. Differential regulation of 5′ splice variants of the glutamate transporter EAAT2 in an in vivo model of chemical hypoxia induced by 3-nitropropionic acid. J. Neurosci. Res 2003, 71, 819–825.
[24]  Pow, D.V.; Naidoo, T.; Lingwood, B.E.; Healy, G.N.; Williams, S.M.; Sullivan, R.K.P.; O’Driscoll, S.; Colditz, P.B. Loss of glial glutamate transporters and induction of neuronal expression of GLT-1B in the hypoxic neonatal pig brain. Dev. Brain Res 2004, 153, 1–11.
[25]  Rauen, T.; Wiessner, M. Fine tuning of glutamate uptake and degradation in glial cells: Common transcriptional regulation of GLAST1 and GS. Neurochem. Int 2000, 37, 179–189.
[26]  Genda, E.N.; Jackson, J.G.; Sheldon, A.L.; Locke, S.F.; Greco, T.M.; O’Donnell, J.C.; Spruce, L.A.; Xiao, R.; Guo, W.; Putt, M.; et al. Co-compartmentalization of the astroglial glutamate transporter, GLT-1, with glycolytic enzymes and mitochondria. J. Neurosci 2011, 31, 18275–18288.
[27]  Zhang, Q.; Wu, Y.; Zhang, P.; Sha, H.; Jia, J.; Hu, Y.; Zhu, J. Exercise induces mitochondrial biogenesis after brain ischemia in rats. Neuroscience 2012, 205, 10–17.
[28]  Swain, R.A.; Harris, A.B.; Wiener, E.C.; Dutka, M.V.; Morris, H.D.; Theien, B.E.; Konda, S.; Engberg, K.; Lauterbur, P.C.; Greenough, W.T. Prolonged exercise induces angiogenesis and increases cerebral blood volume in primary motor cortex of the rat. Neuroscience 2003, 117, 1037–1046.
[29]  Bullitt, E.; Rahman, F.N.; Smith, J.K.; Kim, E.; Zeng, D.; Katz, L.M.; Marks, B.L. The effect of exercise on the cerebral vasculature of healthy aged subjects as visualized by MR angiography. AJNR Am. J. Neuroradiol 2009, 30, 1857–1863.
[30]  Benedek, A.; Móricz, K.; Jurányi, Z.; Gigler, G.; Lévay, G.; Hársing, L.G., Jr; Mátyus, P.; Szénási, G.; Albert, M. Use of TTC staining for the evaluation of tissue injury in the early phases of reperfusion after focal cerebral ischemia in rats. Brain Res. 2006, 1116, 159–165.
[31]  Jia, J.; Hu, Y.S.; Wu, Y.; Yu, H.X.; Liu, G.; Zhu, D.N.; Xia, C.M.; Cao, Z.J.; Zhang, X.; Guo, Q.C. Treadmill pre-training suppresses the release of glutamate resulting from cerebral ischemia in rats. Exp. Brain Res 2010, 204, 173–179.
[32]  Longa, E.Z.; Weinstein, P.R.; Carlson, S.; Cummins, R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 1989, 20, 84–91.
[33]  Huang, Z.; Huang, P.L.; Panahian, N.; Dalkara, T.; Fishman, M.C.; Moskowitz, M.A. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 1994, 265, 1883–1885.
[34]  Zhang, Q.; Wu, Y.; Sha, H.; Zhang, P.; Jia, J.; Hu, Y.; Zhu, J. Early exercise affects mitochondrial transcription factors expression after cerebral ischemia in rats. Int. J. Mol. Sci 2012, 13, 1670–1679.

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