創傷性腦損傷係由外力撞擊所引起的腦組織損害。因顱內血腫、彌漫性腦腫脹和腦水腫造成的繼發性傷害，是導致治療效果不彰的主要原因，使得顱內壓的上升，因而產生大量的自由基。如何有效清除自由基，避免腦組織受到活性氧的傷害，是目前治療創傷性腦損傷的課題。在許多研究中，已嘗試利用抗氧化劑去清除自由基，不幸的是，無論是口服、腹腔注射或是靜脈注射，抗氧化劑經過長距離的血液循環到腦部時活性已大幅下降。本研究希望開發出一種藥物載體直接在腦部受損區域進行抗氧化劑的釋放。此藥物載體為幾丁聚醣/明膠/甘油磷酸所組成之感溫性水膠，具有良好的生物相容性及生物可降解性，以利於包覆具有抗氧化、抗菌、抗發炎、保護神經的阿魏酸，可直接注射在受損的位置進行藥物的釋放，以達到治療創傷性腦損傷的效益。實驗結果證實，在材料分析方面，此材料能夠在37 ℃下快速成膠，並在室溫維持流體的狀態，有利於將來臨床上的應用。藥物釋放方面，在24小時內能夠大量釋放抗氧化劑以去除腦損傷初期產生的自由基，而後進行緩效釋放。材料生物相容性測試結果顯示此水膠對於細胞並不會產生細胞毒性。而自由基檢測、細胞凋亡檢測、以及基因表現分析上，證實細胞在過氧化氫誘導損傷後，加入混有阿魏酸的幾丁聚醣/明膠/甘油磷酸之感溫性水膠能夠使細胞回復到正常的型態。綜合以上結果證實此水膠具有治療創傷性腦損傷之潛力。

Traumatic brain injury (TBI) is the brain trauma caused by external force. Because the intracranial hematoma, diffuse brain swelling and brain edema increased the intracranial pressure and produced a large amount of free radicals. Therefore, the secondary injury often resulted in poor therapeutic effect in the TBI treatment. How to scavenge free radicals effectively and prevent reactive oxygen species to attack cells is an important subject to treat TBI. In previous studies, scientists had tried to use the antioxidants to scavenge free radicals. Unfortunately, the activity of the antioxidants decreased after a long circulation to the brain whenever by oral, intraperitoneal injection or intravenous injection. In this study, we want to develop a drug carrier which can release antioxidants directly into the defect. We used the thermosensitive chitosan/ gelatin/ β-glycerol phosphate (C/G/GP) hydrogels as a drug carrier. The hydrogel exhibited biocompatible and biodegradable. As a result, it was suitable to combine with ferulic acid which is antioxidant, antibacterial, anti-inflammatory and neuroprotective. The C/G/GP hydrogel could directly inject into impaired site for drug releasing to treat TBI. Experimental results indicated this hydrogel could gelated at 37 ℃ rapidly and remained fluid state at room temperature. It will be conducive for clinical applications in the future. The result of drug releasing suggested there was an initial burst to release antioxidants within 24 hours and slow-releasing at extended period. It could remove the free radicals produced by the secondary injury. Biocompatibility experiment demonstrated this hydrogel was no cytotoxicity. In the ROS assay, apoptosis assay, and gene expression analysis, cell injury induced by H2O2, and the C/G/GP hydrogel mixed with ferulic acid was used to treat the injured cells. All the results revealed the injured cells could back to normal. Summary of the above results, this hydrogel could be used to treat traumatic brain injury.

誌謝 I
中文摘要 II
ABSTRACT III
目錄 IV
圖目錄 VIII
表目錄 XI
第1章 緒論 1
1.1 前言 1
1.2 現今研究 2
1.2.1 阻斷興奮性神經傳導物質 2
1.2.2 阻斷鈣離子 2
1.2.3 神經幹細胞治療 3
1.2.4 抗氧化劑治療 3
1.3 研究目的 4
第2章 理論基礎 5
2.1 創傷性腦損傷 5
2.1.1 大腦構造 5
2.1.2 TBI的原因 6
2.1.3 TBI的影響 7
2.1.4 TBI的類型 9
2.1.5 症狀 9
2.1.6 併發症 10
2.1.7 診斷 11
2.1.8 治療 12
2.2 自由基 15
2.2.1 自由基與繼發性腦損傷 16
2.2.1.1 神經能量衰竭 16
2.2.1.2 血管反應改變 17
2.2.1.3 血腦障壁功能障礙 18
2.2.1.4 發炎反應 18
2.2.1.5 興奮性毒性 19
2.3 阿魏酸 21
2.3.1 阿魏酸的抗氧化機制 21
2.3.2 阿魏酸的功用 22
2.4 高分子於體內成膠方法 23
2.4.1 溶劑交換 23
2.4.2 光聚合反應 23
2.4.3 離子鍵交聯 24
2.4.4 pH值改變 24
2.4.5 溫度改變 24
2.5 材料選擇 25
2.6 水膠的流變特性 28
第3章 材料與方法 29
3.1 實驗儀器與藥品 29
3.2 實驗流程與方法 32
3.3 材料製備 33
3.4 材料分析 34
3.4.1 流變儀分析 34
3.4.2 材料降解 34
3.4.3 藥物釋放曲線 35
3.5 生物安全性測試 35
3.5.1 材料的細胞毒性分析 35
3.5.1.1 WST-8 assay 36
3.5.1.2 LDH assay 37
3.5.1.3 Live/Dead staining 39
3.5.2 抗氧化劑之安全劑量 41
3.5.3 材料與抗氧化劑結合之細胞毒性分析 41
3.6 受損細胞對於材料的表現分析 42
3.6.1 自由基檢測 42
3.6.2 細胞凋亡檢測 43
3.6.3 基因表現分析 44
3.6.3.1 萃取RNA 46
3.6.3.2 RT-PCR（Reverse transcription polymerase chain reaction） 46
3.6.3.3 Real-time PCR 47
第4章 結果與討論 48
4.1 材料分析 48
4.1.1 流變儀分析 48
4.1.2 材料降解 52
4.1.3 藥物釋放曲線 54
4.2 材料生物安全性測試 57
4.2.1 材料的細胞毒性分析 57
4.2.2 抗氧化劑之安全劑量 62
4.2.3 材料與抗氧化劑結合之細胞毒性分析 67
4.3 受損細胞對於材料的表現分析 71
4.3.1 自由基檢測 71
4.3.2 細胞凋亡檢測 73
4.3.3 基因表現分析 75
4.3.3.1 腦源神經滋養因子 76
4.3.3.2 自由基相關因子 78
4.3.3.3 發炎相關因子 80
4.3.3.4 細胞凋亡相關因子 83
第5章 結論 87
第6章 參考文獻 89

1. Fail, M., L. Xu, M.M. Wald, and V.G. Coronado, Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths 2002-2006. 2010.
2. Vital, M., Traumatic Brain Injury: Hope Through Research. 2002.
3. O'Connell, K.M. and M.T. Littleton-Kearney, The Role of Free Radicals in Traumatic Brain Injury. Biological Research For Nursing, 2013. 15(3): p. 253-263.
4. Lin, J.W., S.H. Tsai, W.C. Tsai, W.T. Chiu, S.F. Chu, C.M. Lin, C.M. Yang, and C.C. Hung, Survey of traumatic intracranial hemorrhage in Taiwan. Surgical Neurology, 2006. 66 Suppl 2: p. S20-25.
5. Chiu, W.T., K.H. Yeh, Y.C. Li, Y.H. Gan, H.Y. Chen, and C.C. Hung, Traumatic brain injury registry in Taiwan. Neurology Research, 1997. 19: p. 261-264.
6. Kerman, M., M. Kanter, K.K. Coskun, M. Erboga, and A. Gurel, Neuroprotective effects of caffeic acid phenethyl ester on experimental traumatic brain injury in rats. J Mol Histol, 2012. 43(1): p. 49-57.
7. Ates, O., S. Cayli, E. Altinoz, I. Gurses, N. Yucel, M. Sener, A. Kocak, and S. Yologlu, Neuroprotection by resveratrol against traumatic brain injury in rats. Mol Cell Biochem, 2007. 294(1-2): p. 137-144.
8. Itoh, T., M. Imano, S. Nishida, M. Tsubaki, N. Mizuguchi, S. Hashimoto, A. Ito, and T. Satou, (-)-Epigallocatechin-3-gallate increases the number of neural stem cells around the damaged area after rat traumatic brain injury. J Neural Transm, 2012. 119(8): p. 877-890.
9. Wilkins, L.W., Anatomy & Physiology Made Incredibly Visual! 2009.
10. Institute, P.E. TBI reference summary. 1995-2012 10/23/2012; Available from: www.X-Plain.com.
11. Liao, K.H., C.K. Chang, H.C. Chang, K.C. Chang, C.F. Chen, T.Y. Chen, C.W. Chou, W.Y. Chung, Y.H. Chiang, K.S. Hong, S.H. Hsiao, Y.H. Hsu, H.L. Huang, S.C. Huang, C.C. Hung, S.S. Kung, K.N. Kuo, K.H. Li, J.W. Lin, T.G. Lin, C.M. Lin, C.F. Su, M.T. Tsai, S.H. Tsai, Y.C. Wang, T.Y. Yang, K.F. Yu, W.T. Chiu, and F. Brain Trauma, Clinical practice guidelines in severe traumatic brain injury in Taiwan. Surgical Neurology, 2009. 72 Suppl 2: p. S66-73; discussion S73-74.
12. Gilgun-Sherki, Y., Z. Rosenbaum, E. Melamed, and D. Offen, Antioxidant therapy in acute central nervous system injury: Current state. Pharmacological Reviews, 2002. 54: p. 271-284.
13. Faraci, F., Reactive oxygen species: influence on cerebral vascular tone. Journal of Applied Physiology, 2006. 100: p. 739-743.
14. Gahm, C., S. Holmin, and T. Mathiesen, Nitric oxide synthase expression after human brain contusion. Neurosurgery, 2002. 50: p. 1319-1326.
15. Beckman, J. and W. Koppenol, Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. American Journal of Physiology, 1996. 271: p. C1424-C1437.
16. Besson, V., I. Margaill, M. Plotkine, and C. Marchand-Verrecchia, Deleterious activation of poly(ADP-ribose)polymerase-1 in brain after in vivo oxidative stress. Free Radical Research, 2003. 37: p. 1201-1208.
17. Ansari, M.A., K.N. Roberts, and S.W. Scheff, Oxidative stress and modification of synaptic proteins in hippocampus after traumatic brain injury. Free Radical Biology & Medicine, 2008. 45(4): p. 443-452.
18. Cherian, L., J. Goodman, and C. Robertson, Brain nitric oxide changes after controlled cortical impact injury in rats. Journal of Neurophysiology, 2000. 83: p. 2171-2178.
19. Park, C.O. and H.G. Yi, Apoptotic change and NOS activity in the experimental animal diffuse axonal injury model. Yonsei Medical Journal, 2001. 42: p. 518-526.
20. Xiong, Y., F.S. Shie, J. Zhang, C.P. Lee, and Y.S. Ho, Prevention of mitochondrial dysfunction in post-traumatic mouse brain by superoxide dismutase. Journal of Neurochemistry, 2005. 95(3): p. 732-744.
21. Huttemann, M., I. Lee, C.W. Kreipke, and T. Petrov, Suppression of the inducible form of nitric oxide synthase prior to traumatic brain injury improves cytochrome c oxidase activity and normalizes cellular energy levels. Neuroscience, 2008. 151(1): p. 148-154.
22. Deng, Y., B.M. Thompson, X. Gao, and E.D. Hall, Temporal relationship of peroxynitrite-induced oxidative damage, calpain-mediated cytoskeletal degradation and neurodegeneration after traumatic brain injury. Experimental Neurology, 2007. 205(1): p. 154-165.
23. Halliwell, B. and S. Chirico, Lipid peroxidation: Its mechanism, measurement and significance. American Journal of Clinical Nutrition, 1993. 57: p. 715S-725S.
24. DeWitt, D., B. Mathew, J. Chaisson, and D. Prough, Peroxynitrite reduces vasodilatory responses to reduced intravascular pressure, calcitonin gene-related peptide, and cromakalim in isolated middle cerebral arteries. Journal of Cerebral Blood Flow and Metabolism, 2001. 21: p. 253-261.
25. Brzezinska, A., D. Gebremedhin, W. Chilian, B. Kalyanaraman, and S. Elliott, Peroxynitrite reversibly inhibits Ca2+-activated K+ channels in rat cerebral artery smooth muscle cells. American Journal of Physiology Heart and Circulatory Physiology, 2000. 278: p. H1883-H1890.
26. Petrov, T. and J. Rafols, Acute alterations of endothelin-1 and iNOS expression and control of the brain microcirculation after head trauma. Neurological Research, 2001. 23: p. 139-143.
27. Erdinc¸ler, P., S. Tu¨zgen, U. Erdinc¸ler, E. Og˘uz, A. Korpinar, N. Ciplak, and C. Kuday, Influence of aging on bloodbrain-barrier permeability and free radical formation following experimental brain cold injury. Acta Neurochirurgica, 2002. 144: p. 195-200.
28. Jayakumar, A., R. Rao, K. Panickar, M. Moriyama, P. Reddy, and M. Norenberg, Trauma-induced cell swelling in cultured astrocytes. Journal of Neuropathology & Experimental Neurology, 2008. 67: p. 417-427.
29. Morita-Fujimura, Y., M. Fujimura, Y. Gasche, J. Copin, and P. Chan, Overexpression of copper and zinc superoxide dismutase in transgenic mice prevents the induction and activation of matrix metalloproteinases after cold injury-induced brain trauma. Journal of Cerebral Blood Flow and Metabolism, 2000. 20: p. 130-138.
30. Cederberg, D. and P. Siesjo, What has inflammation to do with traumatic brain injury? Child's Nervous System, 2010. 26(2): p. 221-226.
31. Dohi, K., H. Ohtaki, T. Nakamachi, S. Yofu, K. Satoh, K. Miyamoto, D. Song, S. Tsunawaki, S. Shioda, and T. Aruga, Gp91phox (NOX2) in classically activated microglia exacerbates traumatic brain injury. Journal of Neuroinflammation, 2010. 7: p. 41.
32. Yi, J.H. and A.S. Hazell, Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury. Neurochemistry International, 2006. 48(5): p. 394-403.
33. Camacho, A. and L. Massieu, Role of glutamate transporters in the clearance and release of glutamate during ischemia and its relation to neuronal death. Archives of Medical Research, 2006. 37(1): p. 11-18.
34. Srinivasan, M., A.R. Sudheer, and V.P. Menoe, Ferulic acid: therapeutic potential through its antioxidant property. Journal of Clinical Biochemistry and Nutrition, 2007. 40: p. 92-100.
35. Hosoda, A., Y. Ozaki, A. Kashiwada, M. Mutoh, K. Wakabayashi, K. Mizuno, E. Nomura, and H. Taniguchi, Syntheses of ferulic acid derivatives and their suppressive effects on cyclooxygenase-2 promoter activity. Bioorganic & Medicinal Chemistry, 2002. 10(4): p. 1189-1196.
36. Ou, L., L.Y. Kong, X.M. Zhang, and M. Niwa, Oxidation of ferulic acid by Momordica charantia peroxidase and related anti-inflammation activity changes. Biological and Pharmaceutical Bulletin 2003. 26(11): p. 1511-1516.
37. Sakai, S., H. Ochiai, K. Nakajima, and K. Terasawa, Inhibitory effect of ferulic acid on macrophage inflammatory protein-2 production in a murine macrophage cell line, RAW264.7. Cytokine, 1997. 9(4): p. 242-248.
38. Khanduja, K.L., P.K. Avti, S. Kumar, N. Mittal, K.K. Sohi, and C.M. Pathak, Anti-apoptotic activity of caffeic acid, ellagic acid and ferulic acid in normal human peripheral blood mononuclear cells: a Bcl-2 independent mechanism. Biochim Biophys Acta, 2006. 1760(2): p. 283-289.
39. Sultana, R., A. Ravagna, H. Mohmmad-Abdul, V. Calabrese, and D.A. Butterfield, Ferulic acid ethyl ester protects neurons against amyloid beta- peptide(1-42)-induced oxidative stress and neurotoxicity: relationship to antioxidant activity. Journal of Neurochemistry, 2005. 92(4): p. 749-758.
40. Sultana, R., Ferulic acid ethyl ester as a potential therapy in neurodegenerative disorders. Biochim Biophys Acta, 2012. 1822(5): p. 748-752.
41. Ruel-Gariepy, E. and J.C. Leroux, In situ-forming hydrogels--review of temperature-sensitive systems. European Journal of Pharmaceutics and Biopharmaceutics, 2004. 58(2): p. 409-426.
42. Ono, K., Y. Saito, H. Yura, K. Ishikawa, A. Kurita, T. Akaike, and M. Ishihara, Photocrosslinkable chitosan as a biological adhesive. Journal of Biomedical, 2000. 49: p. 289–295.
43. Burkoth, A.K. and K.S. Anseth, A review of photocrosslinked polyanhydrides:: in situ forming degradable networks. Biomaterials, 2000. 21: p. 2395-2404.
44. Rowley, J.A., G. Madlambayan, and D.J. Mooney, Alginate hydrogels as synthetic extracellular matrix materials. Biomaterials, 1999. 20(1): p. 45-53.
45. Kuo, K.C. and P.X. Ma, Ionically crosslinked alginate hydrogels as sca!olds for tissue engineering: Part 1. Structure, gelation rate and mechanical properties. Biomaterials, 2001. 22: p. 511-521.
46. Gutowska, A., B. Jeong, and M. Jasionowski, Injectable gels for tissue engineering. Anat Rec, 2001. 263(4): p. 342-349.
47. Chenite, A., C. Chaput, D. Wang, C. Combes, M.D. Buschmann, C.D. Hoemann, J.C. Leroux, B.L. Atkinson, F. Binette, and A. Selmani, Novel injectable neutral solutions of chitosan form biodegradable gels in situ. Biomaterials, 2000. 21: p. 2155-2161.
48. Ta, H.T., C.R. Dass, and D.E. Dunstan, Injectable chitosan hydrogels for localised cancer therapy. J Control Release, 2008. 126(3): p. 205-216.
49. Flory, P.J., Principles of polyer chemistry. 1953, Ithaca, NY: Cornell University Press.
50. Mortimer, S., A.J. Ryan, and J.L. Stanford, Rheological behavior and gel-point determination for a model Lewis acid- initiated chain growth epoxy resin. Macromolecules, 2001. 34: p. 2973-2980.
51. Takasu, N., The Changes of the Lysosomal Enzyme Activities in Injured Brain Tissue. Arch Jap Chir, 1977. 46(4): p. 396-405.
52. Sato, K., Studies on Lysosomal Enzyme in the Cerebrospinal Fluid. Arch Jap Chir, 1978. 47(1): p. 42-53.
53. Ishiyama, M., Y. Miyazono, K. Sasamoto, Y. Ohkura, and K. Ueno, A highly water-soluble disulfonated tetrazolium salt as a chromogenic indicator for NADH as well as cell viability. Talanta, 1977. 44(7): p. 1299-1305.
54. Association, of, Medical, Laboratory, and Immunologists, Journal of immunological methods, Elsevier: Amsterdam,. p. v.
55. Roy, I., T.Y. Ohulchanskyy, D.J. Bharali, H.E. Pudavar, R.A. Mistretta, N. Kaur, and P.N. Prasad, Optical tracking of organically modified silica nanoparticles as DNA carriers: a nonviral, nanomedicine approach for gene delivery. Proc Natl Acad Sci U S A, 2005. 102(2): p. 279-284.
56. Cheng, Y.H., S.H. Yang, and F.H. Lin, Thermosensitive chitosan-gelatin-glycerol phosphate hydrogel as a controlled release system of ferulic acid for nucleus pulposus regeneration. Biomaterials, 2011. 32(29): p. 6953-6961.
57. Invitrogen, Click-iT® TUNEL Alexa Fluor® Imaging Assay. 2008.
58. Cheng, Y.H., S.H. Yang, W.Y. Su, Y.C. Chen, K.C. Yang, T.K. Cheng, S.C. Wu, and F.H. Lin, Thermosensitive Chitosan–Gelatin–Glycerol Phosphate Hydrogels as a Cell Carrier for Nucleus Pulposus Regeneration An In Vitro Study. Tissue Engineering Part A, 2010. 16: p. 695-703.
59. Ruel-Garie´pya, E., A. Cheniteb, C. Chaputb, S. Guirguisa, and J.C. Leroux, Characterization of thermosensitive chitosan gels for the sustained delivery of drugs. International Journal of Pharmaceutics, 2000. 203: p. 89-98.
60. Ruel-Garie´pya, E., G. Leclairb, P. Hildgenb, A. Guptac, and J.C. Lerouxa, Thermosensitive chitosan-based hydrogel containing liposomes for the delivery of hydrophilic molecules. Journal of Controlled Release, 2002. 82: p. 373-383.
61. Ruel-Gariépy, E., M. Shive, A. Bichara, M. Berrada, D. Le Garrec, A. Chenite, and J.-C. Leroux, A thermosensitive chitosan-based hydrogel for the local delivery of paclitaxel. European Journal of Pharmaceutics and Biopharmaceutics, 2004. 57(1): p. 53-63.
62. Molinaro, G., J.C. Leroux, J. Damas, and A. Adam, Biocompatibility of thermosensitive chitosan-based hydrogels: an in vivo experimental approach to injectable biomaterials. Biomaterials, 2002. 23: p. 2717-2722.
63. Butterfield, D., A. Castegna, C. Pocernich, J. Drake, G. Scapagnini, and V. Calabrese, Nutritional approaches to combat oxidative stress in Alzheimer’s disease. Journal of Nutritional Biochemistry, 2002. 13: p. 444–461.
64. Kim, H.S., J.Y. Cho, D.H. Kim, J.J. Yam, H.K. Lee, H.W. Suh, and D.K. Sing, Inhibitory Effects of Long-Term Administration of Ferulic Acid on Microglial Activation Induced by Intracerebroventricular Injection of β-Amyloid Peptide (1—42) in Mice. Biological and Pharmaceutical Bulletin, 2004. 27(1): p. 120-121.
65. Vermeulen, K., D.R. Van Bockstaele, and Z.N. Berneman, The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell proliferation, 2003. 36(131-149).
66. Leker, R.R. and E. Shohami, Cerebral ischemia and trauma-different etiologies yet similar mechanisms: neuroprotective opportunities. Brain Research Reviews, 2002. 39(1): p. 55-73.
67. Oppenheim, R.W., D. Prevette, and Q.W. Yin, Control of embryonic motoneuron survival in vivo by ciliary neurotrophic factor. Science, 1991. 251: p. 1616-1618.
68. McAllister, A.K., L.C. Katz, and D.C. Lo, Neurotrophins and synaptic plasticity. Annual Review of Neuroscience, 1999. 22: p. 295–318.
69. Tyler, W.J., M. Alonso, C.R. Bramham, and L.D. Pozzo-Miller, From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem, 2002. 9(5): p. 224-237.
70. Riley, C.P., T.C. Cope, and C.R. Buck, CNS neurotrophins are biologically active and expressed by multiple cell types. Journal of Molecular Histology, 2004. 35: p. 771–783.
71. Meynaar, I.A., H.M. Oudemans-van Straaten, J. van der Wetering, P. Verlooy, E.H. Slaats, R.J. Bosman, J.I. van der Spoel, and D.F. Zandstra, Serum neuron-specific enolase predicts outcome in post-anoxic coma: a prospective cohort study. Intensive Care Medicine, 2003. 29(2): p. 189-195.
72. Gahm, C., S. Holmin, and T. Mathiesen, Temporal profiles and cellular sources of three nitric oxide synthase isoforms in the brain after experimental contusion. Neurosurgery, 2000. 46(1): p. 169-177.
73. Kasprzak, H.A., A. Woźniak, G. Drewa, and B. Woźniak, Enhanced lipid peroxidation processes in patients after brain contusion. Journal of Neurotrauma, 2001. 18(8): p. 793-797.
74. Arvin, B., L.F. Neville, F.C. Barone, and G.Z. Feuerstein, The role of inflammation and cytokines in brain injury. Neuroscience & Biobehavioral Reviews, 1996. 20(3): p. 445-452.
75. Brites, D., The evolving landscape of neurotoxicity by unconjugated bilirubin: role of glial cells and inflammation. Front Pharmacol, 2012. 3: p. 88.
76. Goodman, J.C., C.S. Robertson, R.G. Grossman, and R.K. Narayan, Elevation of tumor necrosis factor in head injury. Journal of Neuroimmunology, 1990. 30(2-3): p. 213-217.
77. Taupin, V., 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 peripheral-type (p site) benzodiazepine ligand. Journal of Neuroimmunology, 1993. 42(2): p. 177-185.
78. Liu, T., P.C. McDonnell, P.R. Young, R.F. White, A.L. Siren, J.M. Hallenbeck, F.C. Barone, and G.Z. Feurestein, Interleukin-1 beta mRNA expression in ischemic rat cortex. Stroke, 1993. 24(11): p. 1746-1750.
79. Wang, X., T.L. Yue, F.C. Barone, R.F. White, R.C. Gagnon, and G.Z. Feuerstein, Concomitant cortical expression of TNF-alpha and IL-1 beta mRNAs follows early response gene expression in transient focal ischemia. Molecular and Chemical Neuropathology, 1994. 23(2-3): p. 103-114.
80. Keshavarzi, Z., M. Khaksari, Z. Razmi, A. Soltani Hekmat, V. Naderi, and S. Rostami, The effects of cyclooxygenase inhibitors on the brain inflammatory response following traumatic brain injury in rats. Iranian Journal of Basic Medical Sciences, 2012. 15(5): p. 1102-1105.
81. Green, D.R., A. Oberst, C.P. Dillon, R. Weinlich, and G.S. Salvesen, RIPK-dependent necrosis and its regulation by caspases: a mystery in five acts. Mol Cell, 2011. 44(1): p. 9-16.
82. Clark, R.S., J. Chen, S.C. Watkins, P.M. Kochanek, M. Chen, R.A. Stetler, J.E. Loeffert, and S.H. Graham, Apoptosis-suppressor gene bcl-2 expression after traumatic brain injury in rats. Journal of Neuroscience, 1997. 17(23): p. 9172-9182.
83. Raghupathi, R., S.C. Fernandez, H. Murai, S.P. Trusko, R.W. Scott, W.K. Nishioka, and T.K. McIntosh, BCL-2 overexpression attenuates cortical cell loss after traumatic brain injury in transgenic mice. Journal of Cerebral Blood Flow & Metabolism, 1988. 18(11): p. 1259-1269.
84. Ucar, T., G. Tanriover, I. Gurer, M.Z. Onal, and S. Kazan, Modified experimental mild traumatic brain injury model. J Trauma, 2006. 60(3): p. 558-565.
85. Albert-Weissenberger, C. and A.L. Siren, Experimental traumatic brain injury. Exp Transl Stroke Med, 2010. 2(1): p. 16.