JBiSE  Vol.4 No.2 , February 2011
High resolution nuclear magnetic resonance investigation of metabolic disturbances induced by focal traumatic brain injury in a rat model: a pilot study
Abstract: Experimental models of traumatic brain injury (TBI) provide a useful tool for understanding the cerebral metabolic changes induced by this pathological condition. Here, we report on the time course of changes in cerebral metabolites after TBI using high-resolution proton magnetic resonance spectroscopy (NMR). Extracts from adult male Sprague-Dawley rats were subjected to fluid lateral percussion and were then examined by NMR at 3, 24 and 48 h after the injury. A metabolomic approach was carried out to identify the cerebral metabolites impacted by the TBI and their quantitative temporal changes. Lactate, valine and ascorbate were the three first metabolites to be significantly modified after TBI. The quantitative elevation for these compounds last for the entire experimental time explored. Within 24 hours post-TBI, a significant elevation in choline-derivates, alanine and glucose were also measured. On the other hand, N-acetyl aspartate, a neuronal marker, and myo- inositol, an important organic osmolyte in the mammalian brain, were not significantly impacted in the chronic phase of TBI.
Cite this paper: nullLemaire, L. , Seguin, F. , Franconi, F. , Bon, D. , Pasco, A. , Boildieu, N. and Le Jeune, J. (2011) High resolution nuclear magnetic resonance investigation of metabolic disturbances induced by focal traumatic brain injury in a rat model: a pilot study. Journal of Biomedical Science and Engineering, 4, 110-118. doi: 10.4236/jbise.2011.42016.

[1]   Thurman, D., Alverson, C., Dunn, K., Guerrero, J. (1999) Traumatic brain injury in the United States: A public health perspective. Journal of Head Trauma Rehabilitation, 14, 602-615. doi:10.1097/00001199-199912000-00009

[2]   Kay, A. and Teasdale, G. (2001) Head injury in the United Kingdom. World Journal of Surgery, 25, 1210- 1220. doi:10.1007/s00268-001-0084-6

[3]   Mathe, J., Richard, I. and Rome, J. (2005) Serious brain injury and public health, epidemiologic and financial considerations, comprehensive management and care. Ann Fr Anesth Reanim, 24, 688-694.

[4]   Theodoraki, E.M., Katsaragakis, S., Koukouvinos, C. and Parpoula, C. (2010) Innovative data mining approaches for outcome prediction of trauma patients. Journal of Biomedical Science and Engineering, 3, 791-798. doi:10.4236/jbise.2010.38105

[5]   Sahuquillo, J., Poca, M.A. and Amoros, S. (2001) Current aspects of pathophysiology and cell dysfunction after severe head injury. Current Pharmaceutical Design, 7, 1475-1503. doi:10.2174/1381612013397311

[6]   Graham, D.I., Adams, J.H. and Doyle, D (1978) Ischaemic brain damage in fatal non-missile head injuries. Journal of the Neurological Sciences, 39, 213-234.

[7]   Pasco, A., Ter Minassian, A., Chapon, C., Lemaire, L., Franconi, F., Darabi, D., Caron, C., Benoit, J.P. and Le Jeune, J.J. (2006) Dynamics of cerebral edema and the apparent diffusion coefficient of water changes in patients with severe traumatic brain injury. A prospective MRI study. European Radiology, 16, 1501-1508.

[8]   Ueda, T., Iwata, A., Komatsu, H., Aihara, N., Yamada, K., Ugawa, S. and Shimada, S. (2001) Diffuse brain injury induces local expression of Na+/myo-inositol cotransporter in the rat brain. Molecular Brain Research, 86, 63-69. doi:10.1016/S0169-328X(00)00261-8

[9]   Zhong, C., Zhao, X., Van, K.C., Bzdega, T., Smyth, A., Zhou, J., Kozikowski, A.P., Jiang, O'Connor, W.T., Berman, R.F., Neale, J.H. and Lyeth, B.G. (2006) NAAG peptidase inhibitor increases dialysate NAAG and reduces glutamate, aspartate and GABA levels in the dorsal hippocampus following fluid percussion injury in the rat. Journal of Neurochemistry, 97, 1015-1025.

[10]   Zhou, Z., Daugherty, W.P., Sun, D., Levasseur, J.E., Altememi, N., Hamm, R.J., Rockswold, G.L. and Bullock, M.R. (2007) Protection of mitochondrial function and improvement in cognitive recovery in rats treated with hyperbaric oxygen following lateral fluid-percussion injury. Journal of Neurosurgery, 106, 687-694.

[11]   Martinez-Murillo, R., Fernandez, A.P., Serrano, J., Rodrigo, J., Salas, E., Mourelle, M. and Martinez, A. (2007) The nitric oxide donor LA 419 decreases brain damage in a focal ischemia model. Neuroscience Letters, 415, 149- 153. doi:10.1016/j.neulet.2007.01.011

[12]   Chapon, C., Franconi, F., Lacoeuille, F., Hindré, F., Saulnier, P., Benoit, J.-P., Le Jeune, J.-J. and Lemaire, L. (2009) Imaging E-selectin expression following traumatic brain injury in the rat using a targeted USPIO contrast agent. Magnetic Resonance Materials in Physics, Biology and Medicine, 22, 167-174.

[13]   Bellander, B.M., Lidman, O., Ohlsson, M., Meijer, B., Piehl, F. and Svensson, M. (2010) Genetic regulation of microglia activation, complement expression, and neurodegeneration in a rat model of traumatic brain injury. Experimental Brain Research, 205, 103-114.

[14]   Schuhmann, M.U., Stiller, D., Skardelly, M., Bernarding, J., Klinge, P.M., Samii, A., Samii, M. and Brinker, T. (2003) Metabolic changes in the vicinity of brain contusions: A proton magnetic resonance spectroscopy and histology study. Journal of Neurotrauma, 20, 725-743. doi:10.1089/089771503767869962

[15]   Bartnik, B.L., Sutton, R.L., Fukushima, M., Harris, N.G., Hovda, D.A. and Lee, S.M. (2005) Upregulation of pentose phosphate pathway and preservation of tricarboxylic acid cycle flux after experimental brain injury. Journal of Neurotrauma, 22, 1052-1065.

[16]   Viant, M.R., Lyeth, B.G., Miller, M.G. and Berman, R.F. (2005) An NMR metabolomic investigation of early metabolic disturbances following traumatic brain injury in a mammalian model. NMR Biomed, 18, 507-516. doi:10.1002/nbm.980

[17]   Pascual, J.M., Solivera, J., Prieto, R., Barrios, L., Lopez-Larrubia, P., Cerdan, S. and Roda, J.M. (2007) Time course of early metabolic changes following diffuse traumatic brain injury in rats as detected by H NMR spectroscopy. Journal of Neurotrauma, 24, 944-959.

[18]   Casey, P.A., McKenna, M.C., Fiskum, G., Saraswati, M. and Robertson, C.L. (2008) Early and sustained alterations in cerebral metabolism after traumatic brain injury in immature rats. Journal of Neurotrauma, 25, 603-614. doi:10.1089/neu.2007.0481

[19]   Catchpole, G.S., Beckmann, M., Enot, D.P., Mondhe, M., Zywicki, B., Taylor, J., Hardy, N., Smith, A., King, R.D., Kell, D.B., Fiehn, O. and Draper, J. (2005) Hierarchical metabolomics demonstrates substantial compositional similarity between genetically modified and conventional potato crops. Proceedings of the National Academy of Sciences, 102, 14458-14462.

[20]   Soga, T. (2007) Capillary electrophoresis-mass spectrometry for metabolomics. Methods in Molecular Biology, 358, 129-137. doi:10.1007/978-1-59745-244-1_8

[21]   Dettmer, K., Aronov, P.A. and Hammock, B.D. (2007) Mass spectrometry-based metabolomics. Mass Spectrometry Reviews, 26, 51-78.

[22]   Brindle, J.T., Antti, H., Holmes, E., Tranter, G., Nicholson, J.K., Bethell, H.W., Clarke, S., Schofield, P.M., McKilligin, E., Mosedale, D.E. and Grainger, D.J. (2002) Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics. Nature Medicine, 8, 1439-1444.

[23]   Griffiths, J.R. and Stubbs, M. (2003) Opportunities for studying cancer by metabolomics: preliminary observations on tumors deficient in hypoxia-inducible factor 1. Advances in Enzyme Regulation, 43, 67-76.

[24]   Morvan, D. and Demidem, A. (2007) Metabolomics by proton nuclear magnetic resonance spectroscopy of the response to chloroethylnitrosourea reveals drug efficacy and tumor adaptive metabolic pathways. Cancer Research, 67, 2150-2159. doi:10.1158/0008-5472.CAN-06-2346

[25]   Viant, M.R. (2007) Revealing the metabolome of animal tissues using 1H nuclear magnetic resonance spectroscopy. Methods in Molecular Biology, 358, 229-246.

[26]   Barba, I., Jaimez-Auguets, E., Rodriguez-Sinovas, A. and Garcia-Dorado, D. (2007) 1H NMR-based metabolomic identification of at-risk areas after myocardial infarction in swine. Magnetic Resonance Materials in Physics, Biology and Medicine, 20, 265-271. doi:10.1007/s10334-007-0097-8

[27]   Silvestre, V., Goupry, S., Trierweiler, M., Robins, R. and Akoka, S. (2001) Determination of substrate and product concentrations in lactic acid bacterial fermentations by proton NMR using the ERETIC method. Analytical Chemistry, 73, 1862-1868.

[28]   Morales, D.M., Marklund, N., Lebold, D., Thompson, H.J., Pitkanen, A., Maxwell, W.L., Longhi, L., Laurer, H., Maegele, M., Neugebauer, E., Graham, D.I., Stocchetti, N., McIntosh, T.K. (2005) Experimental models of traumatic brain injury: do we really need to build a better mousetrap? Neuroscience, 136, 971-989.

[29]   Bartnik, B.L., Lee, S.M., Hovda, D.A. and Sutton, R.L. (2007) The fate of glucose during the period of decreased metabolism after fluid percussion injury: A 13C NMR study. Journal of Neurotrauma, 24, 1079-1092.

[30]   Bartnik, B.L., Hovda, D.A. and Lee, P.W. (2007) Glucose metabolism after traumatic brain injury: Estimation of pyruvate carboxylase and pyruvate dehydrogenase flux by mass isotopomer analysis. Journal of Neurotrauma, 24, 181-194. doi:10.1089/neu.2006.0038

[31]   Pasco, A., Lemaire, L., Franconi, F., Lefur, Y., Noury, F., Saint-Andre, J.P., Benoit, J.P., Cozzone, P.J. and Le Jeune, J.J. (2007) Perfusional deficit and the dynamics of cerebral edemas in experimental traumatic brain injury using perfusion and diffusion-weighted magnetic resonance imaging. Journal of Neurotrauma, 24, 1321-1330.

[32]   Thompson, H.J., Lifshitz, J., Marklund, N., Grady, M.S., Graham, D.I., Hovda, D.A. and McIntosh, T.K. (2005) Lateral fluid percussion brain injury: A 15-year review and evaluation. Journal of Neurotrauma, 22, 42-75.

[33]   Wishart, D.S., Knox, C., Guo, A.C., Eisner, R., Young, N., Gautam, B., Hau, D.D., Psychogios, N., Dong, E., Bouatra, S., Mandal, R., Sinelnikov, I., Xia, J., Jia, L., Cruz, J.A., Lim, E., Sobsey, C.A., Shrivastava, S., Huang, P., Liu, P., Fang, L., Peng, J., Fradette, R., Cheng, D., Tzur, D., Clements, M., Lewis, A., De Souza, A., Zuniga, A., Dawe, M., Xiong, Y., Clive, D., Greiner, R., Nazyrova, A., Shaykhutdinov, R., Li, L., Vogel, H.J. and Forsythe, I. (2009) HMDB: A knowledgebase for the human metabolo

[34]   Lundberg, P., Vogel, T., Malusek, A., Lundquist, P.-O. and Cohen, L. (2005) MDL—The Magnetic Resonance Metabolomics Database ( 22th Annual Meeting of the European Society for Magnetic Resonance in Medicine and Biology, Magnetic Resonance Materials in Physics, Biology and Medicine, 18, Basel, S168-S169.

[35]   Simoes, R.V., Martinez-Aranda, A., Martin, B., Cerdan, S., Sierra, A. and Arus, C. (2008) Preliminary characterization of an experimental breast cancer cells brain metastasis mouse model by MRI/MRS. Magnetic Resonance Materials in Physics, Biology and Medicine, 21, 237-249.

[36]   Sakowitz, O.W., Unterberg, A.W. and Stover, J.F. (2002) Neuronal activity determined by quantitative EEG and cortical microdialysis is increased following controlled cortical impact injury in rats. Acta Neurochirurgica Supplementum, 81, 221-223.

[37]   Hlatky, R., Furuya, Y., Valadka, A.B., Goodman, J.C. and Robertson, C.S. (2002) Comparison of microdialysate arginine and glutamate levels in severely head-injured patient. Acta Neurochirurgica Supplementum, 81, 347- 349.

[38]   Schuhmann, M.U., Stiller, D., Skardelly, M., Thomas, S., Samii, M. and Brinker, T. (2002) Long-time in-vivo metabolic monitoring following experimental brain contusion using proton magnetic resonance spectroscopy. Acta Neurochirurgica Supplementum, 81, 209-212.

[39]   Takahashi, M., Billups, B., Rossi, D., Sarantis, M., Hamann, M. and Attwell, D. (1997) The role of glutamate transporters in glutamate homeostasis in the brain. Journal of Experimental Biology, 200, 401-409.

[40]   Lewen, A., Matz, P. and Chan, P.H. (2000) Free radical pathways in CNS injury. Journal of Neurotrauma, 17, 871-890. doi:10.1089/neu.2000.17.871

[41]   Tyurin, V.A., Tyurina, Y.Y., Borisenko, G.G., Sokolova, T.V., Ritov, V.B., Quinn, P.J., Rose, M., Kochanek, P., Graham, S.H. and Kagan, V.E. (2000) Oxidative stress following traumatic brain injury in rats: Quantitation of biomarkers and detection of free radical intermediates. Journal of Neurochemistry, 75, 2178-2189.

[42]   Bayir, H., Tyurin, V.A., Tyurina, Y.Y., Viner, R., Ritov, V., Amoscato, A.A., Zhao, Q., Zhang, X.J., Janesko-Feldman, K.L., Alexander, H., Basova, L.V., Clark, R.S., Kochanek, P.M. and Kagan, V.E. (2007) Selective early cardiolipin peroxidation after traumatic brain injury: an oxidative lipidomics analysis. Annals of Neurology, 62, 154-169.

[43]   Hillered, L., Nilsson, P., Ungerstedt, U. and Ponten, U. (1990) Trauma-induced increase of extracellular ascorbate in rat cerebral cortex. Neuroscience Letters, 113, 328-332. doi:10.1016/0304-3940(90)90606-A

[44]   Liebler, D.C., Kling, D.S. and Reed, D.J. (1986) Antioxidant protection of phospholipid bilayers by alpha- tocopherol. Control of alpha-tocopherol status and lipid peroxidation by ascorbic acid and glutathione. The Journal of Biological Chemistry, 261, 12114-12119.

[45]   Fillenz, M. and O'Neill, R.D. (1986) Effects of light reversal on the circadian pattern of motor activity and voltammetric signals recorded in rat forebrain. Journal of Physiology, 374, 91-101.

[46]   Ross, B.D., Ernst, T., Kreis, R., Haseler, L.J., Bayer, S., Danielsen, E., Bluml, S., Shonk, T., Mandigo, J.C., Caton, W., Clark, C., Jensen, S.W., Lehman, N.L., Arcinue, E., Pudenz, R. and Shelden, C.H. (1998) 1H MRS in acute traumatic brain injury. Journal of Magnetic Resonance Imaging, 8, 829-840. doi:10.1002/jmri.1880080412

[47]   Cecil, K.M., Lenkinski, R.E., Meaney, D.F., McIntosh, T.K. and Smith, D.H. (1998) High-field proton magnetic resonance spectroscopy of a swine model for axonal injury. Journal of Neurochemistry, 70, 2038-2044.

[48]   Fortuna, S., Pestalozza, S., Lorenzini, P., Bisso, G.M., Morelli, L. and Michalek, H. (1997) Transient global brain hypoxia-ischemia in adult rats: Neuronal damage, glial proliferation, and alterations in inositol phospholipid hydrolysis. Neurochemistry International, 31, 563- 569. doi:10.1016/S0197-0186(97)00005-3

[49]   Zhao, X., Ahram, A., Berman, R.F., Muizelaar, J.P. and Lyeth, B.G. (2003) Early loss of astrocytes after experimental traumatic brain injury. Glia, 44, 140-152.

[50]   Ross, B. and Michaelis, T. (1994) Clinical applications of magnetic resonance spectroscopy. Magn Reson Q, 10, 191-247.

[51]   Huang, W., Wang, H., Kekuda, R., Fei, Y.J., Friedrich, A., Wang, J., Conway, S.J., Cameron, R.S., Leibach, F.H. and Ganapathy, V. (2000) Transport of N-acetylaspartate by the Na(+)-dependent high-affinity dicarboxylate transporter NaDC3 and its relevance to the expression of the transporter in the brain. Journal of Pharmacol Exp Ther, 295, 392-403.

[52]   Tsai, G., van Kammen, D.P., Chen, S., Kelley, M.E., Grier, A. and Coyle, J.T. (1998) Glutamatergic neurotransmission involves structural and clinical deficits of schizophrenia. Biol Psychiatry, 44, 667-674. doi:10.1016/S0006-3223(98)00151-6

[53]   Kawamata, T., Katayama, Y., Hovda, D.A., Yoshino, A. and Becker, D.P. (1992) Administration of excitatory amino acid antagonists via microdialysis attenuates the increase in glucose utilization seen following concussive brain injury. Cerebral Blood Flow & Metabolism, 12, 12-24.

[54]   Xiong, Y., Peterson, P.L., Muizelaar, J.P. and Lee, C.P. (1997) Amelioration of mitochondrial function by a novel antioxidant U-101033E following traumatic brain injury in rats. Journal of Neurotrauma, 14, 907-917.

[55]   Imaizumi, M., Kim, H.J., Zoghbi, S.S., Briard, E., Hong, J., Musachio, J.L., Ruetzler, C., Chuang, D.M., Pike, V.W., Innis, R.B. and Fujita, M. (2007) PET imaging with [11C] PBR28 can localize and quantify upregulated peripheral benzodiazepine receptors associated with cerebral ischemia in rat. Neuroscience Letters, 411, 200-205. doi:10.1016/j.neulet.2006.09.093

[56]   Grossman, R., Shohami, E., Alexandrovich, A., Yatsiv, I., Kloog, Y. and Biegon, A. (2003) Increase in peripheral benzodiazepine receptors and loss of glutamate NMDA receptors in a mouse model of closed head injury: A quantitative autoradiographic study. Neuroimage, 20, 1971-1981. doi:10.1016/j.neuroimage.2003.06.003

[57]   Nilsson, P., Hillered, L., Ponten, U. and Ungerstedt, U. (1990) Changes in cortical extracellular levels of energy-related metabolites and amino acids following concussive brain injury in rats. Journal of Cereb Blood Flow Metab, 10, 631-637.

[58]   Assaf, Y., Holokovsky, A., Berman, E., Shapira, Y., Shohami, E. and Cohen, Y. (1999) Diffusion and perfusion magnetic resonance imaging following closed head injury in rats. Journal of Neurotrauma, 16, 1165-1176. doi:10.1089/neu.1999.16.1165

[59]   Beaumont, A., Marmarou, A., Hayasaki, K., Barzo, P., Fatouros, P., Corwin, F., Marmarou, C. and Dunbar, J. (2000) The permissive nature of blood brain barrier (BBB) opening in edema formation following traumatic brain injury. Journal of Experimental Biology, 76, 125- 129.