The mechanisms underlying the secondary or delayed cell death in the hippocampus and cerebral hemisphere after traumatic brain injury (TBI) have been poorly understood. Recent data suggesting that TBI may have relationship with both an inflammatory and a neurodegenerative factors are also presented. Mitogen-activated protein kinases (MAPK), which play a crucial role in signal transduction, are activated by phosphorylation in response to a variety of mitogenic signals. In this article, we review the clinical and experimental evidence for brain damage after TBI. In addition, the MAPK pathways, closely involved in signal transduction after TBI, which could therefore be a new and potentially effective therapeutic target in TBI. Further investigations are therefore necessary to better understand cerebral traumatic damage and delineate the best practice strategies needed to improve the patient outcomes after TBI.
KeywordsTraumatic Brain InjuryMitogen-Activated Protein KinaseCell Signaling
S. W. Scheff, S. A. Baldwin and R. W. Brown, “Morris Water Maze Deficits in Rats Following Traumatic Brain Injury: Lateral Controlled Cortical Impact,” Journal of Neurotrauma, Vol 14, No. 9, 1997, pp. 615-627. doi:10.1089/neu.1997.14.615
R. W. Rimel, B. Giordani, J. T. Barth and J. A. Jane, “Moderate Head Injury: Completing the Clinical Spec- trum of Brain Trauma,” Neurosurgery, Vol. 11, No. 3, 1982, pp. 344-351.
E. M. Umile, M. E. Sandel, A. Alavi, C. M. Terry and R. C. Plotkin, “Dynamic Imaging in Mild Traumatic Brain Injury: Support for the Theory of Medial Temporal Vul- nerability,” Archives of Physical Medicine and Rehabili- tation, Vol. 83, No. 11, 2002, pp. 1506-1513. doi:10.1053/apmr.2002.35092
D. D. Blatter, E. D. Bigler, S. D. Gale, S. C. Johnson, C. V. Anderson, B. M. Burnett and D. Ryser, “MR-Based Brain and Cerebrospinal Fluid Measurement After Trau- matic Brain Injury: Correlation with Neuropsychological Outcome,” American Journal of Neuroradiology, Vol. 18, No. 1, 1997, pp. 1-10.
E. D. Bigler, D. D. Blatter, C. V. Anderson, S. C. Johnson, S. D. Gale, R. O. Hopkins and B. Burnett, “Hippocampal Volume in Normal Aging and Traumatic Brain Injury,” American Journal of Neuroradiology, Vol. 18, No. 1, 1997, pp. 11-23.
E. D. Bigler, C. V. Anderson and D. D. Blatter, “Tempo- ral Lobe Morphology in Normal Aging and Traumatic Brain Injury,” American Journal of Neuroradiology Vol. 23, No. 2, 2002, pp. 255-266.
F. Tomaiuolo, G. A. Carlesimo, M. Di Paola, M. Petrides, F. Fera, R. Bonanni, R. Formisano and P. Pasqualetti, “Gross Morphology and Morphometric Sequelae in the Hippocampus, Fornix, and Corpus Callosum of Patients with Severe Non-Missile Traumatic Brain Injury without Macroscopically Detectable Lesions: a T1 Weighted MRI Study,” Journal of Neurology, Neurosurgery & Psy- chiatry, Vol. 75, No. 9, 2004, pp. 1314-1322. doi:10.1136/jnnp.2003.017046
J. W. Lighthall, C. E. Dixon and T. E. Anderson, “Ex- perimental Models of Brain Injury,” Journal of Neuro- trauma, Vol. 6, No. 2, 1989, pp. 83-97. doi:10.1089/neu.1989.6.83
Y. Chen, S. Constantini, V. Trembovler, M. Weinstock and E. Shohami, “An Experimental Model of Closed Head Injury in Mice: Pathophysiology, Histopathology, and Cognitive Deficits,” Journal of Neurotrauma, Vol. 13, No. 10, 1996, pp. 557-568.
C. E. Dixon, J. W. Lighthall and T. E. Anderson, “Physi- ologic, Histopathologic, and Cineradiographic Charac- terization of a New Fluid-Percussion Model of Experi- mental Brain Injury in the Rat,” Journal of Neurotrauma, Vol. 5, No. 2, 1988, pp. 91-104. doi:10.1089/neu.1988.5.91
R. Hicks, H. Soares, D. Smith and T. McIntosh, “Tempo- ral and Spatial Characterization of Neuronal Injury Fo- llowing Lateral Fluid-Percussion Brain Injury in the Rat,” Acta Neuropathologica (Berl), Vol. 91, No. 3, 1996, pp. 236-246. doi:10.1007/s004010050421
S. C. Cortez, T. K. Mcintosh and L. J. Noble, “Exerimen- tal Fluid Percussion Brain Injury: Vascular Disruption and Neuronal and Glial Alterations,” Brain Research, Vol. 482, No. 2, 1989, pp. 271-282. doi:10.1016/0006-8993(89)91190-6
H. Nawashiro, K. Shima and H. Chigasaki, “Selective Vulnerability of Hippocampal CA3 Neurons to Hypoxia after Mild Concussion in the Rat,” Neurological Research, Vol. 17, No. 6, 1995, pp. 455-460.
R. J. Immonen, I. Kharatishvili, H. Gr?hn, A. Pitk?nen and O. H. Gr?hn, “Quantitative MRI Predicts Long-Term Structural and Functional Outcome after Experimental Traumatic Brain Injury,” Neuroimage, Vol. 45, No. 1, 2009, pp. 1-9.
H. Ooigawa, H. Nawashiro, S. Fukui, N. Otani, A. Osumi, T. Toyooka and K. Shima, “The Fate of Nissl-Stained Dark Neurons Following Traumatic Brain Injury in Rats: Difference between Neocortex and Hippocampus Re- garding Survival Rate,” Acta Neuropathologica, Vol. 112, No. 4, 2006, pp. 471-481. doi:10.1007/s00401-006-0108-2
D. H. Lowenstein, M. J. Thomas, D. H. Smith and T. K. McIntosh, “Selective Vulnerability of Dentate Hilar Neu- Rons Following Traumatic Brain Injury: A Potential Mechanistic Link between Head Trauma and Disorders of the Hippocampus,” The Journal of Neuroscience, Vol. 12, No. 12, 1992, pp. 4846-4853.
W. D. Dietrich, O. F. Alonso and M. Halley, “Early Mi- Crovascular and Neuronal Consequences of Traumatic Brain Injury: A Light Microscopic Study in Rats,” Journal of Neurotrauma, Vol. 13, 1994, pp. 289-301. doi:10.1089/neu.1994.11.289
D. H. Smith, X. H. Chen and J. E. Pierce, “Progressive Atrophy and Neuron Death for One Year Following Brain Trauma in the Rat,” Journal of Neurotrauma, Vol. 14, No. 7, 1997, pp. 715-727. doi:10.1089/neu.1997.14.715
A. C. Conti, R. Raghupathi, J. Q. Trojanowski and T. K. Mcintosh, “Experimental Brain Injury Induces Regionally Distinct Apoptosis during the Acute and Delayed Post- Traumatic Period,” Journal of Neuroscience, Vol. 18, No. 15, 1998, pp. 5663-5672.
X. Di, J. Gordon and R. Bullock, “Fluid Percussion Brain Injury Exacerbates Glutamate-Induced Focal Damage in the Rat,” Journal of Neurotrauma, Vol. 16, No. 3, 1999, pp. 195-201. http://dx.doi.org/10.1089/neu.1999.16.195
Y. Matsushita, K. Shima, H. Nawashiro and K. Wada, “Real-Time Monitoring Of Glutamate Following Fluid Percussion Brain Injury with Hypoxia in the Rat,” Jour- nal of Neurotrauma, Vol. 17, No. 2, 2000, pp. 143-153. doi:10.1089/neu.2000.17.143
C. L. Osteen, A. H. Moore, M. L. Prins and D. A. Hovda, “Age-Dependency of 45calcium Accumulation Following Lateral Fluid Percussion: Acute and Delayed Patterns,” Journal of Neurotrauma, Vol. 18, No. 2, 2001, pp. 141- 162. doi:10.1089/08977150150502587
Y. Katayama, D. P. Becker, T. Tamura and D. A. Hovda, “Massive Increases in Extracellular Potassium and the In- Discriminate Release of Glutamate Following Concussive Brain Injury,” Journal of Neurosurgery, Vol. 73, 1990, pp. 889-900. doi:10.3171/jns.1990.73.6.0889
S. Jander, M. Schroeter, O. Peters, O. W. Witte and G. Stoll, “Cortical Spreading Depression Induces Proinflam- Matory Cytokine Gene Expression in the Rat Brain,” Journal of Cerebral Blood Flow & Metabolism, Vol. 21, 2001, pp. 218-225. doi:10.1097/00004647-200103000-00005
J. Truettner, R. Schmidt-Kastner and R. Busto, “Expres- sion of Brain-Derived Neurotrophic Factor, Nerve Growth Factor, and Heat Shock Protein HSP70 Following Fluid Percussion Brain Injury in Rats,” Journal of Neuro- trauma, Vol. 16, No. 6, 1999, pp. 471-486. doi:10.1089/neu.1999.16.471
N. M. Oyesiku, C. O. Evans and S. Houston, “Regional Changes in the Expression of Neurotrophic Factors and Their Receptors Following Acute Traumatic Brain Injury in the Adult Rat Brain,” Brain Research, Vol. 833, No. 2, 1999, pp. 161-172. doi:10.1016/S0006-8993(99)01501-2
C. C. Giza, N. S. Maria and D. A. Hovda, “N-methyl-D- Aspartate Receptor Subunit Changes after Traumatic Injury to the Developing Brain,” Journal of Neurotrauma, Vol. 23, No. 6, 2006, pp. 950-961. doi:10.1089/neu.2006.23.950
A. Kumar, L. Zou, X. Yuan, Y. Long and K. Yang, “N- methyl-D-Aspartate Receptors: Transient Loss of NR1/ NR2A/NR2B Subunits after Traumatic Brain Injury in a Rodent Model,” Journal of Neuroscience Research, Vol. 67, No. 6, 2002, pp. 781-786. doi:10.1002/jnr.10181
R. Raghupathi, D. I. Graham and T. K. McIntosh, “Apoptosis after Traumatic Brain Injury,” Journal of Neurotrauma, Vol. 17, No. 10, 2000, pp. 927-938. doi:10.1089/neu.2000.17.927
H. Katoh, K. Shima, H. Nawashiro, K. Wada and H. Chi- gasaki, “The Effect of MK-801 on Extracellular Neuroac- Tive Amino Acids in Hippocampus after Closed Head Injury Followed by Hypoxia in Rats,” Brain Research, Vol. 758, No. 1-2, 1997, pp. 153-162. doi:10.1016/S0006-8993(97)00213-8
S. Jander, M. Schroeter, O. Peters, O. W. Witte and G. Stoll, “Cortical Spreading Depression Induces Proinflam- Matory Cytokine Gene Expression in the Rat Brain,” Journal of Cerebral Blood Flow & Metabolism, Vol. 21, 2001, pp. 218-225. doi:10.1097/00004647-200103000-00005
I. Mocchetti and J. R. Wrathall, “Neurotrophic Factors in Central Nervous System Trauma,” Journal of Neuro- trauma, Vol. 12, No. 5, 1995, pp. 853-870. doi:10.1089/neu.1995.12.853
L. F. Kromer, “Nerve Growth Factor Treatment after Brain Injury Prevents Neuronal Death,” Science, Vol. 235, No. 4785, 1987, pp. 214-216.
R. R. Hicks, V. B. Martin, L. Zhang and K. B. Seroogy, “Mild Experimental Brain Injury Differentially Alters the Expression of Neurotrophin and Neurotrophin Receptor mRNAs in the Hippocampus,” Experimental Neurology, Vol. 160, No. 2, 1999, pp. 469-478. doi:10.1006/exnr.1999.7216
R. J. Mckeon, J. Silver and T. H. Large, “Expression of Full-Length trkB Receptors by Reactive Astrocytes after Chronic CNS Injury,” Experimental Neurology, Vol. 148, No. 2, 1997, pp. 558-567. doi:10.1006/exnr.1997.6698
A. Bonni, A. Brunet, A. E. West, S. R. Datta, M. A. Ta- kasu and M. E. Greenberg, “Cell Survival Promoted by the Ras-MAPK Signaling Pathway by Transcription-De- Pendent and Independent Mechanisms,” Science, Vol. 286, No. 5543, 1999, pp. 1358-1362.
S. D. Skaper and F. S. Walsh, “Neurotrophic Molecules: Strategies for Designing Effective Therapeutic Molecules in neurodegeneration,” Molecular and Cellular Neuro- science, Vol. 12, No. 4-5, 1999, pp. 179-193.
T. G. Boulton, S. H. Nye and D. J. Robbins, “ERKs: A Family of Protein-Serine/Threonine Kinases that Are Ac- tivated and Tyrosine Phosphorylated in Response to Insu- lin and NGF,” Cell, Vol. 65, No. 4, 1991, pp. 663-675.
R. Aikawa, I. Komuro, T. Yamazaki, Y. Zou, S. Kudoh, M. Tanaka and I. Shiojima, “Oxidative Stress Activates Extracellular Signal-Regulated Kinases through Src and Ras in Cultured Cardiac Myocytes of Neonatal Rats,” The Journal of Clinical Investigation, Vol. 100, No. 7, 1997, pp. 1813-1821. doi:10.1172/JCI119709
M. Kurino, K. Fukunaga, Y. Ushio and E. Miyamoto, “Activation of Mitogen-Activated Protein Kinase in Cul- Tured Rat Hippocampal Neurons by Stimulation of Glu- tamate Receptors,” Journal of Neurochemistry, Vol. 65, 1995, pp. 1282-1289. doi:10.1046/j.1471-4159.1995.65031282.x
M. Stanciu and D. B. DeFranco, “Prolonged Nuclear Re- Tention of Activated Extracellular Signal-Regulated Pro- tein Kinase Promotes Cell Death Generated by Oxidative Toxicity or Proteasome Inhibition in a Neuronal Cell Line,” Journal of Biological Chemistry, Vol. 277, No. 6, 2002, pp. 4010-4017. doi:10.1074/jbc.M104479200
S. Subramaniam, U. Zirrgiebel, O. von Bohlen Und Hal- bach, J. Strelau, C. Laliberte, D. R. Kaplan and K. Un- sicker, “ERK1/2 Activation Promotes Neuronal Degen- eration Predominantly through Plasma Membrane Da- mage and Independently of Caspase-3,” Journal of Cell Biology, Vol. 165, 2004, pp. 357-369. doi:10.1083/jcb.200403028
S. Subramaniam and K. Unsicker, “Extracellular Sig- Nal-Regulated Kinase as an Inducer of Non-Apoptotic Neuronal Death,” Neuroscience, Vol. 138, No. 4, 2006, pp. 1055-1065.
R. Seger and E. G. Krebs, “The MAPK Signaling Cas- cade,” FASEB Journal, Vol. 9, No. 9, 1995, pp. 726-735.
J. E. Cavanaugh, “Role of Extracellular Signal Regulated Kinase 5 in Neuronal Survival,” European Journal of Biochemistry, Vol. 271, No. 11, 2004, pp. 2056-2059. doi:10.1111/j.1432-1033.2004.04131.x
R. M. Wang, Q. G. Zhang, C. H. Li and G. Y. Zhang, “Activation of Extracellular Signal-Regulated Kinase 5 May Play a Neuroprotective Role in Hippocampal CA3/ DG Region after Cerebral Ischemia,” Journal of Neuro- science Research, Vol. 80, No. 3, 2005, pp. 391- 399. doi:10.1002/jnr.20433
J. M. Kyriakis and J. Avruch, “Protein Kinase Cascades Activated by Stress and Inflammatory Cytokines,” Bio- Essays, Vol. 18, No. 7, 1996, pp. 567-577.
H. Kawasaki, T. Morooka, S. Shimohara, J. Kimura, T. Hirano, Y. Gotoh and E. Nishida, “Activation and In- Volvement of p38 Mitogen-Activated Protein Kinase in Glutamate-Induced Apoptosis in Rat Cerebellar Granule Cells,” Journal of Biological Chemistry, Vol. 272, No. 30, 1997, pp. 18518-18521. doi:10.1074/jbc.272.30.18518
Z. Xia, M. Dickens, J. Raingeaud, R. J. Davis and M. E. Greenberg, “Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis,” Science, Vol. 270, No. 5240, 1995, pp. 1326-1331.
D. C. Wu, W. Ye, X. M. Che and G. Y. Yang, “Activa- tion of Mitogen-Activated Protein Kinases after Perma- nent Cerebral Artery Occlusion in Mouse Brain,” Journal of Cerebral Blood Flow & Metabolism, Vol. 20, No. 9, 2000, pp. 1320-1330. doi:10.1097/00004647-200009000-00007
T. Hayashi, K. Sakai, C. Sasaki, W. R. Zhang, H. Warita and K. Abe, “c-Jun N-terminal Kinase (JNK) and JNK In- Teracting Protein Response in Rat Brain after Transient Middle Cerebral Artery Occlusion,” Neuroscience Letters, Vol. 284, No. 3, 2000, pp. 195-199. doi:10.1016/S0304-3940(00)01024-7
S. Nakahara, K. Yone, T. Sakou, S. Wada, T. Nagamine, T. Niiyama and H. Ichijo, “Induction of Apoptosis Signal Regulating Kinase 1 (ASK1) after Spinal Cord Injury In Rats: Possible Involvement of ASK1-JNK and -p38 Pathways in Neuronal Apoptosis,” Journal of Neuropa- thology & Experimental Neurology, Vol. 58, No. 5, 1990, pp. 442-450. doi:10.1097/00005072-199905000-00003
J. W. Mandell, N. C. Gocan and S. R. Vandenberg, “Me- chanical Trauma Induces Rapid Astroglial Activation of ERK/MAP Kinase: Evidence for a Paracrine Signal,” Glia, Vol. 34, 2001, pp. 283-295.
N. Otani, H. Nawashiro, S. Fukui, N. Nomura, A. Yano, T. Miyazawa and K. Shima, “Differential Activation of the Mitogen-Activated Protein Kinase Pathways Follow- ing Traumatic Brain Injury in the Rat Hippocampus,” Journal of Cerebral Blood Flow & Metabolism, Vol. 22, 2002, pp. 327-334. doi:10.1097/00004647-200203000-00010
T. Sugino, K. Nozaki, Y. Takagi, I. Hattori, N. Hashi- moto, T. Moriguchi and E. Nishida, “Activation of Mito- Gen-Activated Protein Kinases after Transient Forebrain Ischemia in Gerbil Hippocampus,” Journal of Neurosci- ence, Vol. 20, No. 12, 2000, pp. 4506-4515.
B. R. Hu, C. L. Liu and D. J. Park, “Alteration of MAP Kinase Pathways after Transient Forebrain Ischemia,” Journal of Cerebral Blood Flow & Metabolism, Vol. 20, No. 7, 2000, pp. 1089-1095. doi:10.1097/00004647-200007000-00008
R. Raghupathi, J. K. Muir, C. T. Fulp, R. N. Pittman and T. K. McIntosh, “Acute Activation of Mitogen-Activated Protein Kinases Following Traumatic Brain Injury in the Rat: Implications for Posttraumatic Cell Death,” Experi- mental Neurology, Vol. 183, No. 2, 2003, pp. 438-448.
S. S. Grewal, R. D. York and P. J. Stork, “Extracellular- Signal-Regulated Kinase Signaling in Neurons,” Current Opinion in Neurobiology, Vol. 9, 1999, pp. 544-553. doi:10.1016/S0959-4388(99)00010-0
J. D. Sweatt, “Mitogen-Activated Protein Kinases in Syn- Aptic Plasticity and Memory,” Current Opinion in Neu- robiology, Vol. 14, No. 3, 2004, pp. 311-317. doi:10.1016/j.conb.2004.04.001
T. Mori, X. Wang, J. C. Jung, S. Tumii, A. B. Singhal, M. E. Fini and C. E. Dixon, “Mitogen-Activated Protein Kinase Inhibition in Traumatic Brain Injury: In Vitro and in Vivo Effects,” Journal of Cerebral Blood Flow & Me- tabolism, Vol. 22, No. 4, 2002, pp. 444-452. doi:10.1097/00004647-200204000-00008
N. Otani, H. Nawashiro, S. Fukui, H. Ooigawa, A. Oh- sumi, T. Toyooka and K. Shima, “Role of the Activated Extracellular Signal-Regulated Kinase Pathway on His- tological and Behavioral Outcome after Traumatic Brain Injury In Rats,” Journal of Clinical Neuroscience, Vol. 14, No. 1, 2007, pp. 42-48. doi:10.1016/j.jocn.2005.11.044
A. Y. Zobkov, K. S. Rollins, A. D. Parent, J. Zhang and R. M. Bryan, “Mechanism of Endothelin-1 Induced Contrac- Tion in Rabbit Basilar Artery,” Stroke, Vol. 31, No. 2, 2000, pp. 526-533.
B. K. Lal, S. Varma, P. J. Pappas, R. W. Hobson and W. N. Duran, “VEGF Increases Permeability of the Endothe- Lial Cell Monolayer by Action of PKB/Akt, Endothelial Nitric-Oxide Synthase, and MAP Kinase Pathways,” Mi- crovascular Research, Vol. 62, 2001, pp. 252-262.
X. Wang, T. Mori, J. C. Jung, M. E. Fini and E. H. Lo, “Secretion of Matrix Metalloproteinase-2 and -9 after Mechanical Trauma Injury in Rat Cortical Cultures And Involvement of MAP kinase,” Journal of Neurotrauma, Vol. 19, No. 5, 2002, pp. 615-625. doi:10.1089/089771502753754082
E. H. Lo, X. Wang and M. L. Cuzner, “Extracellular Pro- Teolysis in Brain Injury and Inflammation: Role for Plas- minogen Activators and Matrix Metalloproteinases,” Journal of Neuroscience Research, Vol. 69, No. 1, 2002, pp. 1-9. doi:10.1002/jnr.10270
M. Asahi, X. Wang, T. Mori, T. Sumii, J. C. Jung, M. A. Moskowitz and M. E. Fini, “Effects of Matrix Metallo- Proteinase-9 Gene Knock-Out on the Proteolysis of Blood-Brain Barrier and White Matter Components after Cerebral Ischemia,” Journal of Neuroscience, Vol. 21, No. 19, 2001, pp. 7724-7732.
T. Mori, X. Wang, T. Aoki and E. H. Lo, “Downregula- tion of Matrix Metalloproteinase-9 and Attenuation of Edema via Inhibition of ERK Mitogen Activated Protein Kinase in Traumatic Brain Injury,” Journal of Neuro- trauma, Vol. 19, No. 11, 2002, pp. 1411-1419. doi:10.1089/089771502320914642
M. C. Morganti-Kossmann, M. Rancan, P. F. Stahel and T. Kossmann, “Inflammatory Response in Acute Trau- matic Brain Injury: A Double-Edged Sword,” Current Opinion in Critical Care, Vol. 8, No. 2, 2002, pp. 101- 105. doi:10.1097/00075198-200204000-00002
V. Taupin, S. Toulmond, A. Serrano, J. Benavides and F. Zavala, “Increase in IL-6, IL-1 and TNF Levels in Rat Brain Following Traumatic Lesion. Influence of Pre- and Post-Traumatic Treatment with Ro5 4864, a Periph- eral-Type (p site) Benzodiazepine Ligand,” Journal of Neuroimmunology, Vol. 42, 1993, pp. 177-185. doi:10.1016/0165-5728(93)90008-M
L. Fan, P. R. Young, F. C. Barone, G. Z. Feuerstein, D. H. Smith and T. K. McIntosh, “Experimental Brain Injury Induces Differential Expression of Tumor Necrosis Fac- Tor-Alpha mRNA in the CNS,” Brain Research. Mo- lecular Brain Research, Vol. 36, No. 2, 1996, pp. 287- 291. doi:10.1016/0169-328X(95)00274-V
V. Balasingam, T. Tejada-Berges, E. Wright, R. Bouck- ova and V. W. Yong, “Reactive Astrogliosis in the Neo- natal Mouse Brain and Its Modulation by Cytokines,” Journal of Neuroscience Vol. 14, No. 2, 1994, pp. 846- 856.
E. Shohami, M. Novikov, R. Bass, A. Yamin and R. Gal- lily, “Closed Head Injury Triggers Early Production of TNF α and IL-6 by Brain Tissue,” Journal of Cerebral Blood Flow & Metabolism, Vol. 14, 1994, pp. 615-619. doi:10.1038/jcbfm.1994.76
K. Kinoshita, K. Chatzipanteli, E, Vitarbo, J. S. Truettner, O. F. Alonso and W. D. Dietrich, “Interleukin-1βMessen- Ger Ribonucleic Acid and Protein Levels after Fluid- Percussion Brain Injury in Rats: Importance of Injury Severity and Brain Temperature,” Neurosurgery, Vol. 51, 2002, pp. 195-203.
E. A. Vitarbo, K. Chatzipanteli, K. Kinoshita, J. S. Truett- ner, O. F. Alonso and W. D. Dietrich, “Tumor Necrosis Factorα Expression and Protein Levels after Fluid Percus- Sion Injury in Rats: The Effect of Injury Severity and Brain Temperature,” Neurosurgery, Vol. 55, No. 2, 2004, pp. 416-424.
H. D. Soares, R. R. Hicks, D. Smith and T. K. McIntosh, “Inflammatory Leukocytic Recruitment and Diffuse Neu- Ronal Degeneration Are Separate Pathological Processes Resulting from Traumatic Brain Injury,” Journal of Neu- roscience, Vol. 15, No. 12, 1995, pp. 8223-8233.
L. Meda, M. A. Cassatella, G. I. Szendrei, L. Otvos, P. Baron, M. Villalba and D. Ferrari, “Activation of Micro- Glial Cells by β-Amyloid Protein and Interferon-γ,” Na- ture, Vol. 374, No. 6523, 1995, pp. 647–650.
L. Zhang, W. Zhao and B. Li, “TNF-Alpha Induced Over- Expression of GFAP is Associated with MAPKs,” Neu- roReport, Vol. 11, No. 2, 2000, pp. 409-412.
T. G. Bush, N. Puvanachandra and C. H. Horner, “Leu- kocyte Infiltration, Neuronal Degeneration, and Neurite Outgrowth after Ablation of Scar-Forming, Reactive As- trocytes in Adult Transgenic Mice,” Neuron, Vol. 23, No. 2, 1999, pp. 297-308.
N. Sang, J. Zhang and C. Chen, “PGE2-G, a COX-2 Oxi- Dative Metabolite of 2-Arachidonylglycerol, Modulates Inhibitory Synaptic Transmission in Mouse Hippocampal Neurons,” Journal of Physiology (London), Vol. 572, 2006, pp. 735-745.
N. Sang, J. Zhang and C. Chen, “COX-2 Oxidative Me- Tabolite of Endocannabinoid 2-AG Enhances Excitatory Glutamatergic Synaptic Transmission and Induces Neuro- Toxicity,” Journal of Neurochemistry, Vol. 102, 2007, pp. 1966-1977. doi:10.1111/j.1471-4159.2007.04668.x
H. Yang, J. Zhang, K. Andreasson and C. Chen, “COX-2 Oxidative Metabolism of Endocannabinoids Augments Hippocampal Synaptic Plasticity,” Molecular and Cellu- lar Neuroscience, Vol. 37, No. 4, 2008, pp. 682-695. doi:10.1016/j.mcn.2007.12.019
R. S. Fiore, V. E. Bayer, S. L. Pelech, J. Posada, J. A. Cooper and J. M. Baraban, “p42 Mitogen-Activated Pro- Tein Kinase in Brain: Prominent Localization in Neuronal Cell Bodies and Dendrites,” Neuroscience, Vol. 55, No. 2, 1993, pp. 463-472. doi:10.1016/0006-8993(95)00587-G
S. O. Johanson, M. F. Crouch and I. A. Hendry, “Retro- grade Axonal Transport of Signal Transduction Proteins in Rat Sciatic Nerve,” Brain Research, Vol. 690, No. 1, 1995, pp. 55-63.
B. Morrison, J. H. Eberwine, D. F. Meaney and T. K. McIntosh, “Traumatic Injury Induces Differential Expres- Sion of Cell Death Genes in Organotypic Brain Slice Cultures Determined by Complementary DNA Array Hybridization,” Neuroscience, Vol. 96, No. 1, 2000, pp. 131-139.
N. Otani, H. Nawashiro, S. Fukui, N. Nomura and K. Shima, “Temporal and Spatial Profile of Phosphorylated Mitogen-Activated Protein Kinase Pathways after Lateral Fluid Percussion Injury in the Cortex of the Rat Brain,” Journal of Neurotrauma Vol. 19, No. 12, 2002, pp. 1587- 1596. doi:10.1089/089771502762300247
J. W. Mandell, N. C. Gocan and S. R. Vandenberg, “Me- chanical Trauma Induces Rapid Astroglial Activation of ERK/MAP Kinase: Evidence for a Paracrine Signal,” Glia, Vol. 34, 2001, pp. 283-295.
T. G. Bush, N. Puvanachandra, C. H. Horner, A. Polito, T. Ostenfeld, C. N. Svendsen, L. Mucke, M. H. Johnson and M. V. Sofroniew, “Leukocyte Infiltration, Neuronal De- Generation, and Neurite Outgrowth after Ablation of Scar-Forming, Reactive Astrocytes in Adult Transgenic Mice,” Neuron, Vol. 23, No. 2, 1999, pp. 297-308.
W. D. Dietrich, J. Truettner, W. Zhan, O. F. Alonso, R. Busto and M. D. Ginsberg, “Sequential Changes in Glial Fibrillary Acidic Protein and Gene Expression Following Parasagittal Fluid-Percussion Brain Injury in Rats,” Journal of Neurotrauma, Vol. 16, No. 7, 1999, pp. 567- 581. doi:10.1089/neu.1999.16.567
A. P. Lieberman, P. M. Pitha and M. L. Shin, “Poly(A) Removal Is the Kinase-Regulated Step in Tumor Necrosis Factor mRNA Decay,” Journal of Biological Chemistry, Vol. 267, No. 4, 1992, pp. 2123-2126.
R. J. Mckeon, J. Silver and T. H. Large, “Expression of Full-Length trkB Receptors by Reactive Astrocytes after Chronic CNS Injury,” Experimental Neurology, Vol. 148, No. 2, 1997, pp. 558-567. doi:10.1006/exnr.1997.6698