Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/92149
標題: 探討第一型血紅素氧化酶的神經保護作用
Targeting heme oxygenase-1 for neuroprotection
作者: Hsiao-Yun Lin
林曉筠
關鍵字: 微膠細胞;第一型血紅素氧化酶;神經退化;神經保護;microglia;HO-1;neurodegeneration;neuroprotection
引用: References 1. Montgomery, D. L. 1994. Astrocytes: form, functions, and roles in disease. Veterinary pathology 31: 145-167. 2. Wee Yong, V. 2010. Inflammation in neurological disorders: a help or a hindrance? The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 16: 408-420. 3. Lin, H. Y., B. R. Huang, W. L. Yeh, C. H. Lee, S. S. Huang, C. H. Lai, H. Lin, and D. Y. Lu. 2014. Antineuroinflammatory effects of lycopene via activation of adenosine monophosphate-activated protein kinase-alpha1/heme oxygenase-1 pathways. Neurobiology of aging 35: 191-202. 4. Ziv, Y., N. Ron, O. Butovsky, G. Landa, E. Sudai, N. Greenberg, H. Cohen, J. Kipnis, and M. Schwartz. 2006. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 9: 268-275. 5. Czeh, M., P. Gressens, and A. M. Kaindl. 2011. The yin and yang of microglia. Developmental neuroscience 33: 199-209. 6. Polazzi, E., and B. Monti. 2010. Microglia and neuroprotection: from in vitro studies to therapeutic applications. Progress in neurobiology 92: 293-315. 7. McGeer, P. L., S. Itagaki, B. E. Boyes, and E. G. McGeer. 1988. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 38: 1285-1291. 8. Ros-Bernal, F., S. Hunot, M. T. Herrero, S. Parnadeau, J. C. Corvol, L. Lu, D. Alvarez-Fischer, M. A. Carrillo-de Sauvage, F. Saurini, C. Coussieu, K. Kinugawa, A. Prigent, G. Hoglinger, M. Hamon, F. Tronche, E. C. Hirsch, and S. Vyas. 2011. Microglial glucocorticoid receptors play a pivotal role in regulating dopaminergic neurodegeneration in parkinsonism. Proc Natl Acad Sci U S A 108: 6632-6637. 9. Imamura, K., N. Hishikawa, M. Sawada, T. Nagatsu, M. Yoshida, and Y. Hashizume. 2003. Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson's disease brains. Acta Neuropathol 106: 518-526. 10. Knott, C., G. Stern, and G. P. Wilkin. 2000. Inflammatory regulators in Parkinson's disease: iNOS, lipocortin-1, and cyclooxygenases-1 and -2. Mol Cell Neurosci 16: 724-739. 11. Rasmuson, S., B. Nasman, and T. Olsson. 2011. Increased serum levels of dehydroepiandrosterone (DHEA) and interleukin-6 (IL-6) in women with mild to moderate Alzheimer's disease. Int Psychogeriatr: 1-7. 12. Uslu, S., Z. E. Akarkarasu, D. Ozbabalik, S. Ozkan, O. Colak, E. S. Demirkan, A. Ozkiris, C. Demirustu, and O. Alatas. 2012. Levels of amyloid beta-42, interleukin-6 and tumor necrosis factor-alpha in Alzheimer's disease and vascular dementia. Neurochem Res 37: 1554-1559. 13. Samantaray, S., V. H. Knaryan, D. C. Shields, and N. L. Banik. 2013. Critical role of calpain in spinal cord degeneration in Parkinson's disease. Journal of neurochemistry 127: 880-890. 14. McGeer, P. L., and E. G. McGeer. 2007. NSAIDs and Alzheimer disease: epidemiological, animal model and clinical studies. Neurobiology of aging 28: 639-647. 15. Samad, T. A., K. A. Moore, A. Sapirstein, S. Billet, A. Allchorne, S. Poole, J. V. Bonventre, and C. J. Woolf. 2001. Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 410: 471-475. 16. Brown, J. R., and R. N. DuBois. 2005. COX-2: a molecular target for colorectal cancer prevention. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23: 2840-2855. 17. Temel, S. G., and Z. Kahveci. 2009. Cyclooxygenase-2 expression in astrocytes and microglia in human oligodendroglioma and astrocytoma. Journal of molecular histology 40: 369-377. 18. Teismann, P., M. Vila, D. K. Choi, K. Tieu, D. C. Wu, V. Jackson-Lewis, and S. Przedborski. 2003. COX-2 and neurodegeneration in Parkinson's disease. Ann N Y Acad Sci 991: 272-277. 19. Ejima, K., M. D. Layne, I. M. Carvajal, P. A. Kritek, R. M. Baron, Y. H. Chen, J. Vom Saal, B. D. Levy, S. F. Yet, and M. A. Perrella. 2003. Cyclooxygenase-2-deficient mice are resistant to endotoxin-induced inflammation and death. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17: 1325-1327. 20. Feng, Z. H., T. G. Wang, D. D. Li, P. Fung, B. C. Wilson, B. Liu, S. F. Ali, R. Langenbach, and J. S. Hong. 2002. Cyclooxygenase-2-deficient mice are resistant to 1-methyl-4-phenyl1, 2, 3, 6-tetrahydropyridine-induced damage of dopaminergic neurons in the substantia nigra. Neuroscience letters 329: 354-358. 21. Bartels, A. L., and K. L. Leenders. 2010. Cyclooxygenase and neuroinflammation in Parkinson's disease neurodegeneration. Current neuropharmacology 8: 62-68. 22. Manabe, Y., J. Anrather, T. Kawano, K. Niwa, P. Zhou, M. E. Ross, and C. Iadecola. 2004. Prostanoids, not reactive oxygen species, mediate COX-2-dependent neurotoxicity. Ann Neurol 55: 668-675. 23. Consilvio, C., A. M. Vincent, and E. L. Feldman. 2004. Neuroinflammation, COX-2, and ALS--a dual role? Exp Neurol 187: 1-10. 24. Giovannini, M. G., C. Scali, C. Prosperi, A. Bellucci, G. Pepeu, and F. Casamenti. 2003. Experimental brain inflammation and neurodegeneration as model of Alzheimer's disease: protective effects of selective COX-2 inhibitors. International journal of immunopathology and pharmacology 16: 31-40. 25. O'Banion, M. K. 1999. COX-2 and Alzheimer's disease: potential roles in inflammation and neurodegeneration. Expert opinion on investigational drugs 8: 1521-1536. 26. Teismann, P. 2012. COX-2 in the neurodegenerative process of Parkinson's disease. Biofactors 38: 395-397. 27. Levin, J. R., G. Serrano, and R. Dingledine. 2012. Reduction in delayed mortality and subtle improvement in retrograde memory performance in pilocarpine-treated mice with conditional neuronal deletion of cyclooxygenase-2 gene. Epilepsia 53: 1411-1420. 28. Sanchez-Pernaute, R., A. Ferree, O. Cooper, M. Yu, A. L. Brownell, and O. Isacson. 2004. Selective COX-2 inhibition prevents progressive dopamine neuron degeneration in a rat model of Parkinson's disease. Journal of neuroinflammation 1: 6. 29. Tomimoto, H., I. Akiguchi, H. Wakita, J. X. Lin, and H. Budka. 2000. Cyclooxygenase-2 is induced in microglia during chronic cerebral ischemia in humans. Acta Neuropathol 99: 26-30. 30. Minghetti, L., and M. Pocchiari. 2007. Cyclooxygenase-2, prostaglandin E2, and microglial activation in prion diseases. Int Rev Neurobiol 82: 265-275. 31. Shih, R. H., and C. M. Yang. 2010. Induction of heme oxygenase-1 attenuates lipopolysaccharide-induced cyclooxygenase-2 expression in mouse brain endothelial cells. Journal of neuroinflammation 7: 86. 32. Zhang, B., L. Yan, P. Zhou, Z. Dong, S. Feng, K. Liu, and Z. Gong. 2013. CHP1002, a novel andrographolide derivative, inhibits pro-inflammatory inducible nitric oxide synthase and cyclooxygenase-2 expressions in RAW264.7 macrophages via up-regulation of heme oxygenase-1 expression. International immunopharmacology 15: 289-295. 33. Seledtsov, V. I., and G. V. Seledtsova. 2012. A balance between tissue-destructive and tissue-protective immunities: a role of toll-like receptors in regulation of adaptive immunity. Immunobiology 217: 430-435. 34. Sica, A., and A. Mantovani. 2012. Macrophage plasticity and polarization: in vivo veritas. The Journal of clinical investigation 122: 787-795. 35. Van Ginderachter, J. A., K. Movahedi, G. Hassanzadeh Ghassabeh, S. Meerschaut, A. Beschin, G. Raes, and P. De Baetselier. 2006. Classical and alternative activation of mononuclear phagocytes: picking the best of both worlds for tumor promotion. Immunobiology 211: 487-501. 36. Martinez, F. O. 2011. Regulators of macrophage activation. European journal of immunology 41: 1531-1534. 37. Hanisch, U. K., and H. Kettenmann. 2007. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10: 1387-1394. 38. Gordon, S. 2003. Alternative activation of macrophages. Nature reviews. Immunology 3: 23-35. 39. Schwartz, M., O. Butovsky, W. Bruck, and U. K. Hanisch. 2006. Microglial phenotype: is the commitment reversible? Trends in neurosciences 29: 68-74. 40. Michelucci, A., T. Heurtaux, L. Grandbarbe, E. Morga, and P. Heuschling. 2009. Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: Effects of oligomeric and fibrillar amyloid-beta. Journal of neuroimmunology 210: 3-12. 41. Ponomarev, E. D., K. Maresz, Y. Tan, and B. N. Dittel. 2007. CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 27: 10714-10721. 42. Boillee, S., K. Yamanaka, C. S. Lobsiger, N. G. Copeland, N. A. Jenkins, G. Kassiotis, G. Kollias, and D. W. Cleveland. 2006. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312: 1389-1392. 43. Guerrero, A. R., K. Uchida, H. Nakajima, S. Watanabe, M. Nakamura, W. E. Johnson, and H. Baba. 2012. Blockade of interleukin-6 signaling inhibits the classic pathway and promotes an alternative pathway of macrophage activation after spinal cord injury in mice. Journal of neuroinflammation 9: 40. 44. Weis, N., A. Weigert, A. von Knethen, and B. Brune. 2009. Heme oxygenase-1 contributes to an alternative macrophage activation profile induced by apoptotic cell supernatants. Mol Biol Cell 20: 1280-1288. 45. Sierra-Filardi, E., M. A. Vega, P. Sanchez-Mateos, A. L. Corbi, and A. Puig-Kroger. 2010. Heme Oxygenase-1 expression in M-CSF-polarized M2 macrophages contributes to LPS-induced IL-10 release. Immunobiology 215: 788-795. 46. Louvet, A., F. Teixeira-Clerc, M. N. Chobert, V. Deveaux, C. Pavoine, A. Zimmer, F. Pecker, A. Mallat, and S. Lotersztajn. 2011. Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice. Hepatology 54: 1217-1226. 47. Jazwa, A., and A. Cuadrado. 2010. Targeting heme oxygenase-1 for neuroprotection and neuroinflammation in neurodegenerative diseases. Curr Drug Targets 11: 1517-1531. 48. Jeong, G. S., D. S. Lee, B. Li, H. J. Lee, E. C. Kim, and Y. C. Kim. 2010. Effects of sappanchalcone on the cytoprotection and anti-inflammation via heme oxygenase-1 in human pulp and periodontal ligament cells. Eur J Pharmacol 644: 230-237. 49. Syapin, P. J. 2008. Regulation of haeme oxygenase-1 for treatment of neuroinflammation and brain disorders. Br J Pharmacol 155: 623-640. 50. Boehning, D., L. Sedaghat, T. W. Sedlak, and S. H. Snyder. 2004. Heme oxygenase-2 is activated by calcium-calmodulin. J Biol Chem 279: 30927-30930. 51. Farombi, E. O., and Y. J. Surh. 2006. Heme oxygenase-1 as a potential therapeutic target for hepatoprotection. J Biochem Mol Biol 39: 479-491. 52. Wu, L., and R. Wang. 2005. Carbon monoxide: endogenous production, physiological functions, and pharmacological applications. Pharmacol Rev 57: 585-630. 53. Chopra, V. S., L. E. Chalifour, and H. M. Schipper. 1995. Differential effects of cysteamine on heat shock protein induction and cytoplasmic granulation in astrocytes and glioma cells. Brain Res Mol Brain Res 31: 173-184. 54. Fukuda, K., S. S. Panter, F. R. Sharp, and L. J. Noble. 1995. Induction of heme oxygenase-1 (HO-1) after traumatic brain injury in the rat. Neuroscience letters 199: 127-130. 55. Ewing, J. F., and M. D. Maines. 2006. Regulation and expression of heme oxygenase enzymes in aged-rat brain: age related depression in HO-1 and HO-2 expression and altered stress-response. J Neural Transm 113: 439-454. 56. Ghattas, M. H., L. T. Chuang, A. Kappas, and N. G. Abraham. 2002. Protective effect of HO-1 against oxidative stress in human hepatoma cell line (HepG2) is independent of telomerase enzyme activity. Int J Biochem Cell Biol 34: 1619-1628. 57. Scapagnini, G., D. A. Butterfield, C. Colombrita, R. Sultana, A. Pascale, and V. Calabrese. 2004. Ethyl ferulate, a lipophilic polyphenol, induces HO-1 and protects rat neurons against oxidative stress. Antioxid Redox Signal 6: 811-818. 58. Guzman-Beltran, S., S. Espada, M. Orozco-Ibarra, J. Pedraza-Chaverri, and A. Cuadrado. 2008. Nordihydroguaiaretic acid activates the antioxidant pathway Nrf2/HO-1 and protects cerebellar granule neurons against oxidative stress. Neuroscience letters 447: 167-171. 59. Tsoyi, K., H. J. Jang, Y. S. Lee, Y. M. Kim, H. J. Kim, H. G. Seo, J. H. Lee, J. H. Kwak, D. U. Lee, and K. C. Chang. 2011. (+)-Nootkatone and (+)-valencene from rhizomes of Cyperus rotundus increase survival rates in septic mice due to heme oxygenase-1 induction. J Ethnopharmacol 137: 1311-1317. 60. Choy, C. S., C. M. Hu, W. T. Chiu, C. S. Lam, Y. Ting, S. H. Tsai, and T. C. Wang. 2008. Suppression of lipopolysaccharide-induced of inducible nitric oxide synthase and cyclooxygenase-2 by Sanguis Draconis, a dragon's blood resin, in RAW 264.7 cells. J Ethnopharmacol 115: 455-462. 61. Choi, H. G., D. S. Lee, B. Li, Y. H. Choi, S. H. Lee, and Y. C. Kim. 2012. Santamarin, a sesquiterpene lactone isolated from Saussurea lappa, represses LPS-induced inflammatory responses via expression of heme oxygenase-1 in murine macrophage cells. International immunopharmacology 13: 271-279. 62. Lu, D. Y., Y. Y. Tsao, Y. M. Leung, and K. P. Su. 2010. Docosahexaenoic acid suppresses neuroinflammatory responses and induces heme oxygenase-1 expression in BV-2 microglia: implications of antidepressant effects for omega-3 fatty acids. Neuropsychopharmacology 35: 2238-2248. 63. Chen, J. H., S. M. Huang, T. W. Tan, H. Y. Lin, P. Y. Chen, W. L. Yeh, S. C. Chou, C. F. Tsai, I. H. Wei, and D. Y. Lu. 2012. Berberine induces heme oxygenase-1 up-regulation through phosphatidylinositol 3-kinase/AKT and NF-E2-related factor-2 signaling pathway in astrocytes. International immunopharmacology 12: 94-100. 64. Lu, D. Y., J. H. Chen, T. W. Tan, C. Y. Huang, W. L. Yeh, and H. C. Hsu. 2013. Resistin protects against 6-hydroxydopamine-induced cell death in dopaminergic-like MES23.5 cells. Journal of cellular physiology 228: 563-571. 65. Chang, C. Y., Y. H. Kuan, J. R. Li, W. Y. Chen, Y. C. Ou, H. C. Pan, S. L. Liao, S. L. Raung, C. J. Chang, and C. J. Chen. 2013. Docosahexaenoic acid reduces cellular inflammatory response following permanent focal cerebral ischemia in rats. The Journal of nutritional biochemistry 24: 2127-2137. 66. Lee, D. S., B. Li, S. Keo, K. S. Kim, G. S. Jeong, H. Oh, and Y. C. Kim. 2013. Inhibitory effect of 9-hydroxy-6,7-dimethoxydalbergiquinol from Dalbergia odorifera on the NF-kappaB-related neuroinflammatory response in lipopolysaccharide-stimulated mouse BV2 microglial cells is mediated by heme oxygenase-1. International immunopharmacology 17: 828-835. 67. Le, W. D., W. J. Xie, and S. H. Appel. 1999. Protective role of heme oxygenase-1 in oxidative stress-induced neuronal injury. J Neurosci Res 56: 652-658. 68. Bishop, A., S. F. Yet, M. E. Lee, M. A. Perrella, and B. Demple. 2004. A key role for heme oxygenase-1 in nitric oxide resistance in murine motor neurons and glia. Biochem Biophys Res Commun 325: 3-9. 69. Huang, Y. N., C. H. Wu, T. C. Lin, and J. Y. Wang. 2009. Methamphetamine induces heme oxygenase-1 expression in cortical neurons and glia to prevent its toxicity. Toxicol Appl Pharmacol 240: 315-326. 70. Vinet, J., S. Carra, J. M. Blom, N. Brunello, N. Barden, and F. Tascedda. 2004. Chronic treatment with desipramine and fluoxetine modulate BDNF, CaMKKalpha and CaMKKbeta mRNA levels in the hippocampus of transgenic mice expressing antisense RNA against the glucocorticoid receptor. Neuropharmacology 47: 1062-1069. 71. Schipper, H. M. 1999. Glial HO-1 expression, iron deposition and oxidative stress in neurodegenerative diseases. Neurotox Res 1: 57-70. 72. Lee, I. T., S. F. Luo, C. W. Lee, S. W. Wang, C. C. Lin, C. C. Chang, Y. L. Chen, L. Y. Chau, and C. M. Yang. 2009. Overexpression of HO-1 protects against TNF-alpha-mediated airway inflammation by down-regulation of TNFR1-dependent oxidative stress. Am J Pathol 175: 519-532. 73. Li, L., R. F. Hamilton, Jr., and A. Holian. 2000. Protection against ozone-induced pulmonary inflammation and cell death by endotoxin pretreatment in mice: role of HO-1. Inhal Toxicol 12: 1225-1238. 74. Livingston, G., V. Watkin, B. Milne, M. V. Manela, and C. Katona. 1997. The natural history of depression and the anxiety disorders in older people: the Islington community study. J Affect Disord 46: 255-262. 75. Schrag, A., M. Jahanshahi, and N. Quinn. 2000. What contributes to quality of life in patients with Parkinson's disease? J Neurol Neurosurg Psychiatry 69: 308-312. 76. Shulman, L. M., R. L. Taback, A. A. Rabinstein, and W. J. Weiner. 2002. Non-recognition of depression and other non-motor symptoms in Parkinson's disease. Parkinsonism Relat Disord 8: 193-197. 77. Cummings, J. L. 1992. Depression and Parkinson's disease: a review. Am J Psychiatry 149: 443-454. 78. Reijnders, J. S., U. Ehrt, W. E. Weber, D. Aarsland, and A. F. Leentjens. 2008. A systematic review of prevalence studies of depression in Parkinson's disease. Mov Disord 23: 183-189; quiz 313. 79. Leentjens, A. F., M. Van den Akker, J. F. Metsemakers, R. Lousberg, and F. R. Verhey. 2003. Higher incidence of depression preceding the onset of Parkinson's disease: a register study. Mov Disord 18: 414-418. 80. Shiba, M., J. H. Bower, D. M. Maraganore, S. K. McDonnell, B. J. Peterson, J. E. Ahlskog, D. J. Schaid, and W. A. Rocca. 2000. Anxiety disorders and depressive disorders preceding Parkinson's disease: a case-control study. Mov Disord 15: 669-677. 81. Behr, G. A., J. C. Moreira, and B. N. Frey. 2012. Preclinical and clinical evidence of antioxidant effects of antidepressant agents: implications for the pathophysiology of major depressive disorder. Oxidative medicine and cellular longevity 2012: 609421. 82. Turker, R. K., and P. A. Khairallah. 1967. Demethylimipramine (desipramine), an alpha-adrenergic blocking agent. Experientia 23: 252. 83. Stewart, J. W., F. Quitkin, A. Fyer, A. Rifkin, P. McGrath, M. Liebowitz, L. Rosnick, and D. F. Klein. 1980. Efficacy of desipramine in endogenomorphically depressed patients. J Affect Disord 2: 165-176. 84. Goodnough, D. B., and G. B. Baker. 1994. 5-Hydroxytryptamine2 and beta-adrenergic receptor regulation in rat brain following chronic treatment with desipramine and fluoxetine alone and in combination. Journal of neurochemistry 62: 2262-2268. 85. Wille, S. M., S. G. Cooreman, H. M. Neels, and W. E. Lambert. 2008. Relevant issues in the monitoring and the toxicology of antidepressants. Critical reviews in clinical laboratory sciences 45: 25-89. 86. Roth, S., A. Kinne, and U. Schweizer. 2010. The tricyclic antidepressant desipramine inhibits T3 import into primary neurons. Neuroscience letters 478: 5-8. 87. Huang, Y. Y., C. H. Peng, Y. P. Yang, C. C. Wu, W. M. Hsu, H. J. Wang, K. H. Chan, Y. P. Chou, S. J. Chen, and Y. L. Chang. 2007. Desipramine activated Bcl-2 expression and inhibited lipopolysaccharide-induced apoptosis in hippocampus-derived adult neural stem cells. J Pharmacol Sci 104: 61-72. 88. Bravo, J. A., G. Diaz-Veliz, S. Mora, J. L. Ulloa, V. M. Berthoud, P. Morales, S. Arancibia, and J. L. Fiedler. 2009. Desipramine prevents stress-induced changes in depressive-like behavior and hippocampal markers of neuroprotection. Behav Pharmacol 20: 273-285. 89. Agarwal, S., and A. V. Rao. 2000. Tomato lycopene and its role in human health and chronic diseases. CMAJ 163: 739-744. 90. van Breemen, R. B., and N. Pajkovic. 2008. Multitargeted therapy of cancer by lycopene. Cancer letters 269: 339-351. 91. Karppi, J., T. Nurmi, S. Kurl, T. H. Rissanen, and K. Nyyssonen. 2010. Lycopene, lutein and beta-carotene as determinants of LDL conjugated dienes in serum. Atherosclerosis 209: 565-572. 92. Turk, G., A. O. Ceribasi, F. Sakin, M. Sonmez, and A. Atessahin. 2010. Antiperoxidative and anti-apoptotic effects of lycopene and ellagic acid on cyclophosphamide-induced testicular lipid peroxidation and apoptosis. Reprod Fertil Dev 22: 587-596. 93. Marcotorchino, J., B. Romier, E. Gouranton, C. Riollet, B. Gleize, C. Malezet-Desmoulins, and J. F. Landrier. 2012. Lycopene attenuates LPS-induced TNF-alpha secretion in macrophages and inflammatory markers in adipocytes exposed to macrophage-conditioned media. Mol Nutr Food Res 56: 725-732. 94. Lee, W., S. K. Ku, J. W. Bae, and J. S. Bae. 2012. Inhibitory effects of lycopene on HMGB1-mediated pro-inflammatory responses in both cellular and animal models. Food Chem Toxicol 50: 1826-1833. 95. Hsiao, G., T. H. Fong, N. H. Tzu, K. H. Lin, D. S. Chou, and J. R. Sheu. 2004. A potent antioxidant, lycopene, affords neuroprotection against microglia activation and focal cerebral ischemia in rats. In vivo 18: 351-356. 96. Ramamurthy, S., and G. Ronnett. 2012. AMP-Activated Protein Kinase (AMPK) and Energy-Sensing in the Brain. Exp Neurobiol 21: 52-60. 97. Yang, W., Y. H. Hong, X. Q. Shen, C. Frankowski, H. S. Camp, and T. Leff. 2001. Regulation of transcription by AMP-activated protein kinase: phosphorylation of p300 blocks its interaction with nuclear receptors. J Biol Chem 276: 38341-38344. 98. Greer, E. L., P. R. Oskoui, M. R. Banko, J. M. Maniar, M. P. Gygi, S. P. Gygi, and A. Brunet. 2007. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem 282: 30107-30119. 99. Zhang, Y., J. Qiu, X. Wang, and M. Xia. 2011. AMP-activated protein kinase suppresses endothelial cell inflammation through phosphorylation of transcriptional coactivator p300. Arterioscler Thromb Vasc Biol 31: 2897-2908. 100. Salt, I., J. W. Celler, S. A. Hawley, A. Prescott, A. Woods, D. Carling, and D. G. Hardie. 1998. AMP-activated protein kinase: greater AMP dependence, and preferential nuclear localization, of complexes containing the alpha2 isoform. Biochem J 334 ( Pt 1): 177-187. 101. Turnley, A. M., D. Stapleton, R. J. Mann, L. A. Witters, B. E. Kemp, and P. F. Bartlett. 1999. Cellular distribution and developmental expression of AMP-activated protein kinase isoforms in mouse central nervous system. Journal of neurochemistry 72: 1707-1716. 102. Kodiha, M., J. G. Rassi, C. M. Brown, and U. Stochaj. 2007. Localization of AMP kinase is regulated by stress, cell density, and signaling through the MEK-->ERK1/2 pathway. Am J Physiol Cell Physiol 293: C1427-1436. 103. Ju, T. C., H. M. Chen, J. T. Lin, C. P. Chang, W. C. Chang, J. J. Kang, C. P. Sun, M. H. Tao, P. H. Tu, C. Chang, D. W. Dickson, and Y. Chern. 2011. Nuclear translocation of AMPK-alpha1 potentiates striatal neurodegeneration in Huntington's disease. J Cell Biol 194: 209-227. 104. Hardie, D. G., F. A. Ross, and S. A. Hawley. 2012. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nature reviews. Molecular cell biology 13: 251-262. 105. Zhou, G., R. Myers, Y. Li, Y. Chen, X. Shen, J. Fenyk-Melody, M. Wu, J. Ventre, T. Doebber, N. Fujii, N. Musi, M. F. Hirshman, L. J. Goodyear, and D. E. Moller. 2001. Role of AMP-activated protein kinase in mechanism of metformin action. The Journal of clinical investigation 108: 1167-1174. 106. Anderson, K. A., T. J. Ribar, F. Lin, P. K. Noeldner, M. F. Green, M. J. Muehlbauer, L. A. Witters, B. E. Kemp, and A. R. Means. 2008. Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell metabolism 7: 377-388. 107. Tamas, P., S. A. Hawley, R. G. Clarke, K. J. Mustard, K. Green, D. G. Hardie, and D. A. Cantrell. 2006. Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. The Journal of experimental medicine 203: 1665-1670. 108. Won, J. S., Y. B. Im, J. Kim, A. K. Singh, and I. Singh. 2010. Involvement of AMP-activated-protein-kinase (AMPK) in neuronal amyloidogenesis. Biochem Biophys Res Commun 399: 487-491. 109. Cai, Z., L. J. Yan, K. Li, S. H. Quazi, and B. Zhao. 2012. Roles of AMP-activated protein kinase in Alzheimer's disease. Neuromolecular medicine 14: 1-14. 110. Kim, H. S., M. J. Kim, E. J. Kim, Y. Yang, M. S. Lee, and J. S. Lim. 2012. Berberine-induced AMPK activation inhibits the metastatic potential of melanoma cells via reduction of ERK activity and COX-2 protein expression. Biochem Pharmacol 83: 385-394. 111. Yi, C. O., B. T. Jeon, H. J. Shin, E. A. Jeong, K. C. Chang, J. E. Lee, D. H. Lee, H. J. Kim, S. S. Kang, G. J. Cho, W. S. Choi, and G. S. Roh. 2011. Resveratrol activates AMPK and suppresses LPS-induced NF-kappaB-dependent COX-2 activation in RAW 264.7 macrophage cells. Anat Cell Biol 44: 194-203. 112. Scapagnini, G., S. Vasto, N. G. Abraham, C. Caruso, D. Zella, and G. Fabio. 2011. Modulation of Nrf2/ARE pathway by food polyphenols: a nutritional neuroprotective strategy for cognitive and neurodegenerative disorders. Mol Neurobiol 44: 192-201. 113. Sandberg, M., J. Patil, B. D'Angelo, S. G. Weber, and C. Mallard. 2014. NRF2-regulation in brain health and disease: implication of cerebral inflammation. Neuropharmacology 79: 298-306. 114. Rojo, A. I., N. G. Innamorato, A. M. Martin-Moreno, M. L. De Ceballos, M. Yamamoto, and A. Cuadrado. 2010. Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson's disease. Glia 58: 588-598. 115. Lee, J. M., A. Y. Shih, T. H. Murphy, and J. A. Johnson. 2003. NF-E2-related factor-2 mediates neuroprotection against mitochondrial complex I inhibitors and increased concentrations of intracellular calcium in primary cortical neurons. J Biol Chem 278: 37948-37956. 116. Ramsey, C. P., C. A. Glass, M. B. Montgomery, K. A. Lindl, G. P. Ritson, L. A. Chia, R. L. Hamilton, C. T. Chu, and K. L. Jordan-Sciutto. 2007. Expression of Nrf2 in neurodegenerative diseases. Journal of neuropathology and experimental neurology 66: 75-85. 117. Linker, R. A., D. H. Lee, S. Ryan, A. M. van Dam, R. Conrad, P. Bista, W. Zeng, X. Hronowsky, A. Buko, S. Chollate, G. Ellrichmann, W. Bruck, K. Dawson, S. Goelz, S. Wiese, R. H. Scannevin, M. Lukashev, and R. Gold. 2011. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain : a journal of neurology 134: 678-692. 118. Li, L., X. Zhang, L. Cui, L. Wang, H. Liu, H. Ji, and Y. Du. 2013. Ursolic acid promotes the neuroprotection by activating Nrf2 pathway after cerebral ischemia in mice. Brain research 1497: 32-39. 119. Barone, M. C., G. P. Sykiotis, and D. Bohmann. 2011. Genetic activation of Nrf2 signaling is sufficient to ameliorate neurodegenerative phenotypes in a Drosophila model of Parkinson's disease. Dis Model Mech 4: 701-707. 120. Tufekci, K. U., E. Civi Bayin, S. Genc, and K. Genc. 2011. The Nrf2/ARE Pathway: A Promising Target to Counteract Mitochondrial Dysfunction in Parkinson's Disease. Parkinsons Dis 2011: 314082. 121. Lu, D. Y., C. H. Tang, W. L. Yeh, K. L. Wong, C. P. Lin, Y. H. Chen, C. H. Lai, Y. F. Chen, Y. M. Leung, and W. M. Fu. 2009. SDF-1alpha up-regulates interleukin-6 through CXCR4, PI3K/Akt, ERK, and NF-kappaB-dependent pathway in microglia. Eur J Pharmacol 613: 146-154. 122. Lin, H. Y., C. H. Tang, J. H. Chen, J. Y. Chuang, S. M. Huang, T. W. Tan, C. H. Lai, and D. Y. Lu. 2011. Peptidoglycan induces interleukin-6 expression through the TLR2 receptor, JNK, c-Jun, and AP-1 pathways in microglia. Journal of cellular physiology 226: 1573-1582. 123. Blasi, E., R. Barluzzi, V. Bocchini, R. Mazzolla, and F. Bistoni. 1990. Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. Journal of neuroimmunology 27: 229-237. 124. De Backer, O., E. Elinck, B. Blanckaert, L. Leybaert, R. Motterlini, and R. A. Lefebvre. 2009. Water-soluble CO-releasing molecules reduce the development of postoperative ileus via modulation of MAPK/HO-1 signalling and reduction of oxidative stress. Gut 58: 347-356. 125. Hsu, J. T., W. H. Kan, C. H. Hsieh, M. A. Choudhry, M. G. Schwacha, K. I. Bland, and I. H. Chaudry. 2008. Mechanism of estrogen-mediated intestinal protection following trauma-hemorrhage: p38 MAPK-dependent upregulation of HO-1. Am J Physiol Regul Integr Comp Physiol 294: R1825-1831. 126. Li-ying, Z., X. Zhong-yuan, X. Fang, and C. Bang-chang. 2007. Effect of radix paeoniae rubra on expression of p38 MAPK/iNOS/HO-1 in rats with lipopolysaccharide-induced acute lung injury. Chin J Traumatol 10: 269-274. 127. Zhang, Y., L. Guan, X. Wang, T. Wen, J. Xing, and J. Zhao. 2008. Protection of chlorophyllin against oxidative damage by inducing HO-1 and NQO1 expression mediated by PI3K/Akt and Nrf2. Free Radic Res 42: 362-371. 128. de Vries, H. E., M. Witte, D. Hondius, A. J. Rozemuller, B. Drukarch, J. Hoozemans, and J. van Horssen. 2008. Nrf2-induced antioxidant protection: a promising target to counteract ROS-mediated damage in neurodegenerative disease? Free Radic Biol Med 45: 1375-1383. 129. Surh, Y. J., and H. K. Na. 2008. NF-kappaB and Nrf2 as prime molecular targets for chemoprevention and cytoprotection with anti-inflammatory and antioxidant phytochemicals. Genes Nutr 2: 313-317. 130. Antkiewicz-Michaluk, L., J. Wardas, J. Michaluk, I. Romaska, A. Bojarski, and J. Vetulani. 2004. Protective effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline against dopaminergic neurodegeneration in the extrapyramidal structures produced by intracerebral injection of rotenone. Int J Neuropsychopharmacol 7: 155-163. 131. Betarbet, R., R. M. Canet-Aviles, T. B. Sherer, P. G. Mastroberardino, C. McLendon, J. H. Kim, S. Lund, H. M. Na, G. Taylor, N. F. Bence, R. Kopito, B. B. Seo, T. Yagi, A. Yagi, G. Klinefelter, M. R. Cookson, and J. T. Greenamyre. 2006. Intersecting pathways to neurodegeneration in Parkinson's disease: effects of the pesticide rotenone on DJ-1, alpha-synuclein, and the ubiquitin-proteasome system. Neurobiol Dis 22: 404-420. 132. Perez, V., C. Marin, A. Rubio, E. Aguilar, M. Barbanoj, and J. Kulisevsky. 2009. Effect of the additional noradrenergic neurodegeneration to 6-OHDA-lesioned rats in levodopa-induced dyskinesias and in cognitive disturbances. J Neural Transm 116: 1257-1266. 133. Hurtado-Lorenzo, A., E. Millan, V. Gonzalez-Nicolini, D. Suwelack, M. G. Castro, and P. R. Lowenstein. 2004. Differentiation and transcription factor gene therapy in experimental parkinson's disease: sonic hedgehog and Gli-1, but not Nurr-1, protect nigrostriatal cell bodies from 6-OHDA-induced neurodegeneration. Mol Ther 10: 507-524. 134. Palhagen, S. E., S. Ekberg, J. Walinder, A. K. Granerus, and G. Granerus. 2009. HMPAO SPECT in Parkinson's disease (PD) with major depression (MD) before and after antidepressant treatment. J Neurol 256: 1510-1518. 135. Richard, I. H., K. A. LaDonna, R. Hartman, C. Podgorski, and R. Kurlan. 2007. The patients' perspective: Results of a survey assessing knowledge about and attitudes toward depression in PD. Neuropsychiatr Dis Treat 3: 903-906. 136. Keppel Hesselink, J. M. 1993. Serotonin, depression, and PD. Neurology 43: 1624-1625. 137. Tai, Y. H., R. Y. Tsai, S. L. Lin, C. C. Yeh, J. J. Wang, P. L. Tao, and C. S. Wong. 2009. Amitriptyline suppresses neuroinflammation-dependent interleukin-10-p38 mitogen-activated protein kinase-heme oxygenase-1 signaling pathway in chronic morphine-infused rats. Anesthesiology 110: 1379-1389. 138. Choi, A. M., and J. Alam. 1996. Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol 15: 9-19. 139. Appleby, B. S., P. S. Duggan, A. Regenberg, and P. V. Rabins. 2007. Psychiatric and neuropsychiatric adverse events associated with deep brain stimulation: A meta-analysis of ten years' experience. Mov Disord 22: 1722-1728. 140. Takeshita, S., K. Kurisu, L. Trop, K. Arita, T. Akimitsu, and N. P. Verhoeff. 2005. Effect of subthalamic stimulation on mood state in Parkinson's disease: evaluation of previous facts and problems. Neurosurg Rev 28: 179-186; discussion 187. 141. Temel, Y., A. Blokland, L. Ackermans, P. Boon, V. H. van Kranen-Mastenbroek, E. A. Beuls, G. H. Spincemaille, and V. Visser-Vandewalle. 2006. Differential effects of subthalamic nucleus stimulation in advanced Parkinson disease on reaction time performance. Exp Brain Res 169: 389-399. 142. Richard, I. H. 2000. Depression in Parkinson's Disease. Curr Treat Options Neurol 2: 263-274. 143. Zhang, F., H. Zhou, B. C. Wilson, J. S. Shi, J. S. Hong, and H. M. Gao. 2012. Fluoxetine protects neurons against microglial activation-mediated neurotoxicity. Parkinsonism Relat Disord 18 Suppl 1: S213-217. 144. Lee, T. S., and L. Y. Chau. 2002. Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nat Med 8: 240-246. 145. Minamino, T., H. Christou, C. M. Hsieh, Y. Liu, V. Dhawan, N. G. Abraham, M. A. Perrella, S. A. Mitsialis, and S. Kourembanas. 2001. Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia. Proc Natl Acad Sci U S A 98: 8798-8803. 146. Suttner, D. M., and P. A. Dennery. 1999. Reversal of HO-1 related cytoprotection with increased expression is due to reactive iron. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 13: 1800-1809. 147. Parfenova, H., S. Basuroy, S. Bhattacharya, D. Tcheranova, Y. Qu, R. F. Regan, and C. W. Leffler. 2006. Glutamate induces oxidative stress and apoptosis in cerebral vascular endothelial cells: contributions of HO-1 and HO-2 to cytoprotection. Am J Physiol Cell Physiol 290: C1399-1410. 148. Dwivedi, Y., H. S. Rizavi, H. Zhang, R. C. Roberts, R. R. Conley, and G. N. Pandey. 2009. Aberrant extracellular signal-regulated kinase (ERK)1/2 signalling in suicide brain: role of ERK kinase 1 (MEK1). Int J Neuropsychopharmacol 12: 1337-1354. 149. Quesada, A., J. Ogi, J. Schultz, and A. Handforth. 2011. C-terminal mechano-growth factor induces heme oxygenase-1-mediated neuroprotection of SH-SY5Y cells via the protein kinase C/Nrf2 pathway. J Neurosci Res 89: 394-405. 150. Huang, J. Y., and J. I. Chuang. 2010. Fibroblast growth factor 9 upregulates heme oxygenase-1 and gamma-glutamylcysteine synthetase expression to protect neurons from 1-methyl-4-phenylpyridinium toxicity. Free Radic Biol Med 49: 1099-1108. 151. Oh, G. S., H. O. Pae, B. M. Choi, S. C. Chae, H. S. Lee, D. G. Ryu, and H. T. Chung. 2004. 3-Hydroxyanthranilic acid, one of metabolites of tryptophan via indoleamine 2,3-dioxygenase pathway, suppresses inducible nitric oxide synthase expression by enhancing heme oxygenase-1 expression. Biochem Biophys Res Commun 320: 1156-1162. 152. Krishnan, V., and E. J. Nestler. 2008. The molecular neurobiology of depression. Nature 455: 894-902. 153. Chen, Z., H. Xu, S. Haimano, X. Li, and X. M. Li. 2005. Quetiapine and venlafaxine synergically regulate heme oxygenase-2 protein expression in the hippocampus of stressed rats. Neuroscience letters 389: 173-177. 154. Shin, T. K., M. S. Kang, H. Y. Lee, M. S. Seo, S. G. Kim, C. D. Kim, and W. S. Lee. 2009. Fluoxetine and sertraline attenuate postischemic brain injury in mice. Korean J Physiol Pharmacol 13: 257-263. 155. Chen, G., and H. K. Manji. 2006. The extracellular signal-regulated kinase pathway: an emerging promising target for mood stabilizers. Curr Opin Psychiatry 19: 313-323. 156. Dwivedi, Y., H. S. Rizavi, R. C. Roberts, R. C. Conley, C. A. Tamminga, and G. N. Pandey. 2001. Reduced activation and expression of ERK1/2 MAP kinase in the post-mortem brain of depressed suicide subjects. Journal of neurochemistry 77: 916-928. 157. Feng, P., Z. Guan, X. Yang, and J. Fang. 2003. Impairments of ERK signal transduction in the brain in a rat model of depression induced by neonatal exposure of clomipramine. Brain research 991: 195-205. 158. Valjent, E., C. Pages, D. Herve, J. A. Girault, and J. Caboche. 2004. Addictive and non-addictive drugs induce distinct and specific patterns of ERK activation in mouse brain. The European journal of neuroscience 19: 1826-1836. 159. Sacerdote, P., M. Bianchi, and A. E. Panerai. 1994. Chlorimipramine and nortriptyline but not fluoxetine and fluvoxamine inhibit human polymorphonuclear cell chemotaxis in vitro. General pharmacology 25: 409-412. 160. Boyce-Rustay, J. M., B. Palachick, K. Hefner, Y. C. Chen, R. M. Karlsson, R. A. Millstein, J. Harvey-White, and A. Holmes. 2008. Desipramine potentiation of the acute depressant effects of ethanol: modulation by alpha2-adrenoreceptors and stress. Neuropharmacology 55: 803-811. 161. Simon O'Brien, E., R. Legastelois, H. Houchi, C. Vilpoux, S. Alaux-Cantin, O. Pierrefiche, E. Andre, and M. Naassila. 2011. Fluoxetine, desipramine, and the dual antidepressant milnacipran reduce alcohol self-administration and/or relapse in dependent rats. Neuropsychopharmacology 36: 1518-1530. 162. Maes, M., Z. Fisar, M. Medina, G. Scapagnini, G. Nowak, and M. Berk. 2012. New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates--Nrf2 activators and GSK-3 inhibitors. Inflammopharmacology 20: 127-150. 163. Yuan, X., C. Xu, Z. Pan, Y. S. Keum, J. H. Kim, G. Shen, S. Yu, K. T. Oo, J. Ma, and A. N. Kong. 2006. Butylated hydroxyanisole regulates ARE-mediated gene expression via Nrf2 coupled with ERK and JNK signaling pathway in HepG2 cells. Mol Carcinog 45: 841-850. 164. Xu, C., X. Yuan, Z. Pan, G. Shen, J. H. Kim, S. Yu, T. O. Khor, W. Li, J. Ma, and A. N. Kong. 2006. Mechanism of action of isothiocyanates: the induction of ARE-regulated genes is associated with activation of ERK and JNK and the phosphorylation and nuclear translocation of Nrf2. Mol Cancer Ther 5: 1918-1926. 165. Bianchi, R., I. Giambanco, and R. Donato. 2010. S100B/RAGE-dependent activation of microglia via NF-kappaB and AP-1 Co-regulation of COX-2 expression by S100B, IL-1beta and TNF-alpha. Neurobiology of aging 31: 665-677. 166. Calo, L. A., M. Fusaro, and P. A. Davis. 2010. HO-1 attenuates hypertension-induced inflammation/oxidative stress: support from Bartter's/Gitelman's patients. Am J Hypertens 23: 936; author reply 937. 167. Carter, E. P., C. Garat, and M. Imamura. 2004. Continual emerging roles of HO-1: protection against airway inflammation. Am J Physiol Lung Cell Mol Physiol 287: L24-25. 168. Lu, D. Y., C. H. Tang, Y. H. Chen, and I. H. Wei. 2010. Berberine suppresses neuroinflammatory responses through AMP-activated protein kinase activation in BV-2 microglia. J Cell Biochem 110: 697-705. 169. Jang, E., S. Lee, J. H. Kim, J. W. Seo, W. H. Lee, K. Mori, K. Nakao, and K. Suk. 2013. Secreted protein lipocalin-2 promotes microglial M1 polarization. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27: 1176-1190. 170. Lovren, F., Y. Pan, A. Quan, P. E. Szmitko, K. K. Singh, P. C. Shukla, M. Gupta, L. Chan, M. Al-Omran, H. Teoh, and S. Verma. 2010. Adiponectin primes human monocytes into alternative anti-inflammatory M2 macrophages. Am J Physiol Heart Circ Physiol 299: H656-663. 171. Tsoyi, K., H. J. Jang, I. T. Nizamutdinova, Y. M. Kim, Y. S. Lee, H. J. Kim, H. G. Seo, J. H. Lee, and K. C. Chang. 2011. Metformin inhibits HMGB1 release in LPS-treated RAW 264.7 cells and increases survival rate of endotoxaemic mice. Br J Pharmacol 162: 1498-1508. 172. Giri, S., N. Nath, B. Smith, B. Viollet, A. K. Singh, and I. Singh. 2004. 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside inhibits proinflammatory response in glial cells: a possible role of AMP-activated protein kinase. The Journal of neuroscience : the official journal of the Society for Neuroscience 24: 479-487. 173. Rao, A. V., and L. G. Rao. 2007. Carotenoids and human health. Pharmacol Res 55: 207-216. 174. Magbanua, M. J., R. Roy, E. V. Sosa, V. Weinberg, S. Federman, M. D. Mattie, M. Hughes-Fulford, J. Simko, K. Shinohara, C. M. Haqq, P. R. Carroll, and J. M. Chan. 2011. Gene expression and biological pathways in tissue of men with prostate cancer in a randomized clinical trial of lycopene and fish oil supplementation. PloS one 6: e24004. 175. Puri, T., S. Goyal, P. K. Julka, O. Nair, D. N. Sharma, and G. K. Rath. 2010. Lycopene in treatment of high-grade gliomas: a pilot study. Neurol India 58: 20-23. 176. DeLorenze, G. N., L. McCoy, A. L. Tsai, C. P. Quesenberry, Jr., T. Rice, D. Il'yasova, and M. Wrensch. 2010. Daily intake of antioxidants in relation to survival among adult patients diagnosed with malignant glioma. BMC Cancer 10: 215. 177. Qu, M., Z. Zhou, C. Chen, M. Li, L. Pei, F. Chu, J. Yang, Y. Wang, L. Li, C. Liu, L. Zhang, G. Zhang, Z. Yu, and D. Wang. 2011. Lycopene protects against trimethyltin-induced neurotoxicity in primary cultured rat hippocampal neurons by inhibiting the mitochondrial apoptotic pathway. Neurochem Int 59: 1095-1103. 178. Qu, M., L. Li, C. Chen, M. Li, L. Pei, F. Chu, J. Yang, Z. Yu, D. Wang, and Z. Zhou. 2011. Protective effects of lycopene against amyloid beta-induced neurotoxicity in cultured rat cortical neurons. Neuroscience letters 505: 286-290. 179. Qin, L., X. Wu, M. L. Block, Y. Liu, G. R. Breese, J. S. Hong, D. J. Knapp, and F. T. Crews. 2007. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55: 453-462. 180. Bossu, P., D. Cutuli, I. Palladino, P. Caporali, F. Angelucci, D. Laricchiuta, F. Gelfo, P. De Bartolo, C. Caltagirone, and L. Petrosini. 2012. A single intraperitoneal injection of endotoxin in rats induces long-lasting modifications in behavior and brain protein levels of TNF-alpha and IL-18. Journal of neuroinflammation 9: 101. 181. Franciosi, S., J. K. Ryu, Y. Shim, A. Hill, C. Connolly, M. R. Hayden, J. G. McLarnon, and B. R. Leavitt. 2012. Age-dependent neurovascular abnormalities and altered microglial morphology in the YAC128 mouse model of Huntington disease. Neurobiol Dis 45: 438-449. 182. Cunningham, C., S. Campion, K. Lunnon, C. L. Murray, J. F. Woods, R. M. Deacon, J. N. Rawlins, and V. H. Perry. 2009. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry 65: 304-312.
摘要: 
Neurodegenerative diseases are known as progressive loss of neurons in the central nervous system (CNS). Activation of microglia leads to the production of excessive inflammatory molecules and deleterious consequences leading to neuronal death, which has been thought to contribute to the pathogenesis of neurodegenerative diseases. The precise mechanisms underlying the cause of diseases remained unknown but a well-controlled inflammatory reaction is essential for the integrity and proper function of the CNS. The better understand of the mechanisms involving in neurological disorder and find pharmacologic target to delay the disease progression mediated by the uncontrolled inflammation may be the top priority. We investigated the molecular mechanisms of heme oxygenase-1 (HO-1) in regulation of anti-neuroinflammation and neuroprotection in CNS. Results showed that desipramine protected neuronal cells against rotenone- and 6-hydroxydopamine (6-OHDA)-induced neuronal death via activation of HO-1. Furthermore, we demonstrated that lycopene inhibited lipopolysaccharide (LPS)-induced COX-2 and inflammatory mediators expression through heme HO-1 activation. In a mouse model, lycopene showed significant anti-neuroinflammatory effects on microglial activation and motor behavior deficits. Our results suggested that induction of HO-1 may be useful as a therapeutic target for the treatment of neuroinflammation-associated disorders. Therefore, targeting HO-1 in central nervous system will hold a great value for neuroprotection and anti-neuroinflammation.

神經退化性疾病主要影響人類大腦中的神經細胞或者是神經細胞功能逐漸喪失或神經細胞死亡,目前認為微膠細胞的活化及所形成的發炎反應與神經退化性疾病的發生有關,且有研究指出持續不斷的神經性發炎可能會造成神經細胞退化。但由於目前確切的致病機轉仍不清楚,因此維持中樞神經系統的恆定和避免不當的活化顯得格外重要。了解致病的機轉和減緩或預防神經細胞的退化及開發藥物來改變退化的進行,甚至抑制神經細胞的衰退,成為目前重要的課題。本論文旨在探討第一型血紅素氧化酶heme oxygenase-1 (HO-1)在中樞神經系統的調節作用及其神經保護及抗神經性發炎的分子機轉。在本論文中實驗結果證實desipramine透過活化第一型血紅素氧化酶的表現能夠保護、減緩多巴胺神經細胞對於rotenone毒魚藤和6-OHDA所誘發多巴胺神經細胞的死亡作用。此外,我們也探討茄紅素調節第一型血紅素氧化酶的抗神經性發炎的機轉,研究結果證實茄紅素抑制LPS誘發神經性發炎產生COX-2的表現是透過活化第一型血紅素氧化酶。此外在動物實驗中;我們更進一步證實示茄紅素具有非常好的抗神經性發炎的作用,能夠抑制微膠細胞在大腦的活化和減緩LPS造成的運動功能缺陷。我們的結果顯示透過增加第一型血紅素氧化酶的表現能達到抗神經性發炎的作用。綜合以上結果,我們認為第一型血紅素氧化酶在中樞神經系統的調節作用扮演重要的角色,因此研究第一型血紅素氧化酶在中樞神經系統的神經保護作用及抗神經性發炎,這些結果將有助於瞭解神經退化性疾病形成的機轉及抗神經性發炎藥物發展的基礎。
URI: http://hdl.handle.net/11455/92149
Rights: 同意授權瀏覽/列印電子全文服務,2015-12-16起公開。
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