Valproic Acid, a Drug with Multiple Molecular Targets Related to Its Potential Neuroprotective Action

Abstract

Valproic acid (VA) is used worldwide as an antiepileptic drug and a mood stabilizer. Recently, VA was shown to act on cell growth, differentiation and apoptosis, by regulating gene expression at the molecular level, through epigenetic mechanisms. Thus, VA was demonstrated to act on the chromatin remodeling what is a consequence of the drug inhibition of histone deacetylases (HDACs) activity. Other studies uncovered the potential of VA to interfere with multiple regulatory mechanisms besides HDACs, as the GSK3 alpha and beta, Akt, ERK and phosphoinositol pathways, tricarboxylic acid cycle, GABA and OXPHOS system. The review focuses on the mechanisms of action of VA, showing that HDAC inhibitors, as VA, can be successfully used in the treatment of neurodegenerative disorders. This molecule, whose biological activities range from interactions with receptors and ion channels to the regulation of many catalytic reactions, has a central role in cellular cascades that regulate gene expression. Thus, inhibitors of HDACs, by positively affecting both neuronal degeneration and cognitive deficits, appear as promising drugs against various pathological conditions and neurodegenerative diseases. VA is known to present anti-inflammatory and antioxidative properties. And, since inflammation and oxidative stress are common links in neurodegeneration, VA is a drug that, from a clinical point of view, shows a great potential as a candidate for the treatment of neurodegenerative diseases related to excitotoxic events.

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J. Christian Machado Ximenes, E. Crisóstomo Lima Verde, M. da Graça Naffah-Mazzacoratti and G. Socorro de Barros Viana, "Valproic Acid, a Drug with Multiple Molecular Targets Related to Its Potential Neuroprotective Action," Neuroscience and Medicine, Vol. 3 No. 1, 2012, pp. 107-123. doi: 10.4236/nm.2012.31016.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] H. Meunier, G. Carraz, Y. Meunier, P. Eymard and P. Aimard, “Propriétés Pharmacodynamiques de L`acide n-Dipropylacétique,” Therapie, Vol. 18, 1963, pp. 435-438.
[2] T. R. Henry, “The History of Valproate in Clinical Neuroscience,” Psychopharmacology Bulletin, Vol. 37, Suppl. 2, 2003, pp. 5-16.
[3] M. J. Owens and C. B. Nemeroff, “Pharmacology of Valproate,” Psychopharmacology Bulletin, Vol. 37, Suppl. 2, 2003, pp. 17-24.
[4] E. M. Cornford, C. P. Diep and W. M. Pardridge, “Blood- Brain Barrier Transport of Valproic Acid,” Journal of Neurochemistry, Vol. 44, No. 5, 1985, pp. 1541-1550. doi:10.1111/j.1471-4159.1985.tb08793.x
[5] B. Monti, E. Polazzi and A. Contestabile, “Biochemical, Molecular and Epigenetic Mechanisms of Valproic Acid Neuroprotection,” Current Molecular Pharmacology, Vol. 2, No. 1, 2009, pp. 95-109. doi:10.2174/1874467210902010095
[6] E. Perucca, “Pharmacological and Therapeutic Properties of Valproate: A Summary after 35 Years of Clinical Experience,” CNS Drugs, Vol. 16, No. 10, 2002, pp. 695- 714. doi:10.2165/00023210-200216100-00004
[7] O. A. Petroff, D. L. Rothman, K. L. Behar, F. Hyder and R. H. Mattson, “Effects of Valproate and Other Antiepileptic Drugs on Brain Glutamate, Glutamine and GABA in Patients with Refractory Complex Partial Seizures,” Seizure, Vol. 8, No. 2, 1999, pp. 120-127. doi:10.1053/seiz.1999.0267
[8] A. M. Vandongen, M. G. Vanerp, R. A. Voskuyl, “Valproate Reduces Excitability by Blockade of Sodium and Potassium Conductance,” Epilepsia, Vol. 27, No. 3, 1986, pp. 177-182. doi:10.1111/j.1528-1157.1986.tb03525.x
[9] E. P. Chronicl and W. M Mulleners, “Anticonvulsant Drugs for Migraine Prophylaxis,” Cochrane Database of Systematic Reviews, No. 3, 2009, p. CD003226.
[10] M. J. Morrell, “Reproductive and Metabolic Disorders in Women with Epilepsy,” Epilepsia, Vol. 44, No. S4, 2003, pp. 11-20. doi:10.1046/j.1528-1157.44.s4.2.x
[11] R. Sreedhar and S. V. Gadhinglajkar, “Pharmacological Neuroprotection,” Indian Journal of Anaesthesia, Vol. 47, No. 1, 2003, pp. 8-22.
[12] E. C. Lauterbach, J. Victoroff, K. L. Coburn, S. D. Shillcutt, et al., “Psychopharmacological Neuroprotection in Neurodegenerative Disease: Assessing the Preclinical Data,” The Journal of Neuropsychiatry & Clinical Neurosciencesi, Vol. 22, No. 1, 2010, pp. 8-18. doi:10.1176/appi.neuropsych.22.1.8
[13] C. Costa, G. Martella, B. Picconi, C. Prosperetti, et al., “Multiple Mechanisms Underlying the Neuroprotective Effects of Antiepileptic Drugs against in Vitro Ischemia,” Stroke, Vol. 37, 2006, pp. 1319-1326. doi:10.1161/01.STR.0000217303.22856.38
[14] P. Calabresi, L. M. Cupini, D. Centonze, F. Pisani and G. Bernardi, “Antiepileptic Drugs as a Possible Neuroprotective Strategy in Brain Ischemia,” Annals of Neurology, Vol. 53, No. 6, 2003, pp. 693-702. doi:10.1002/ana.10603
[15] R. R. Leker and M. Y. Neufeld, “Anti-Epileptic Drugs as Possible Neuroprotectants in Cerebral Ischemia,” Brain Research Reviews, Vol. 42, No. 3, 2003, pp. 187-203. doi:10.1016/S0165-0173(03)00170-X
[16] D. Centonze, G. A. Marfia, A. Pisani and B. Picconi, “Ionic Mechanisms Underlying Differential Vulnerability to Ischemia in Striatal Neurons,” Progress in Neurobiology, Vol. 63, No. 6, 2001, pp. 687-696. doi:10.1016/S0301-0082(00)00037-X
[17] P. Calabresi, E. Saulle, D. Centonzed and A. Pisani, “Post-Ischaemic Long-Term Synaptic Potentiation in the Striatum: A Putative Mechanism for Cell Type-Specific Vulnerability,” Brain, Vol. 125, No. 4, 2002, pp. 844-860. doi:10.1093/brain/awf073
[18] M. A. Rogawski and W. Loscher, “The Neurobiology of Antiepileptic Drugs,” Nature Reviews Neuroscience, Vol. 5, 2004, pp. 553-564. doi:10.1038/nrn1430
[19] P. Calabresi, B. Picconi, E. Saulle and D. Centonze, “Is Pharmacological Neuroprotection Dependent on Reduced Glutamate Release?” Stroke, Vol. 31, 2000, pp. 766-772. doi:10.1161/01.STR.31.3.766
[20] M. Ren, Y. Leng, M. Jeong, P. R. Leeds, D. M. Chuang, “Valproic Acid Reduces Brain Damage Induced by Transient Focal Cerebral Ischemia in Rats: Potential Roles of Histone Deacetylase Inhibition and Heat Shock Protein Induction,” Journal of Neurochemistry, Vol. 89, No. 6, 2004, pp. 1358-1367. doi:10.1111/j.1471-4159.2004.02406.x
[21] A. Mora, R. A. González-Polo, J. M. Fuentes, G. Soler and F. Centeno, “Different Mechanisms of Protection against Apoptosis by Valproate and Li+,” European Journal of Biochemistry, Vol. 266, No. 3, 1999, pp. 886-891. doi:10.1046/j.1432-1327.1999.00919.x
[22] S. Eyal, B. Yagen, E. Sobol, Y. Altschuler, M. Shmuel and M. Bialer, “The Activity of Antiepileptic Drugs as Histone Deacetylase Inhibitors,” Epilepsia, Vol. 45, No. 7, 2004, pp. 737-744. doi:10.1111/j.0013-9580.2004.00104.x
[23] H. J. Kim, M. Rowe, M. Ren, J. S. Hong, P. S. Chen and D. M. Chuang, “Histone Deacetylase Inhibitors Exhibit Anti-Inflammatory and Neuroprotective Effects in a Rat Permanent Ischemic Model of Stroke: Multiple Mechanisms of Action,” Journal of Pharmacology and Experimental Therapeutics, Vol. 321, No. 3, 2007, pp. 892-901. doi:10.1124/jpet.107.120188
[24] B. N. Frey, S. S. Val-vassori, G. Z. Réus and M. R. Martins, “Changes in Antioxidant Defense Enzymes after d-Amphetamine Exposure: Implications as an Animal Model of Mania,” Neurochemical Research, Vol. 31, No. 5, 2006, pp. 699-703. doi:10.1007/s11064-006-9070-6
[25] J. F. Wang, J. E. Azzam and L. T. Young, “Valproate Inhibits Oxidative Damage to Lipid and Protein in Primary Cultured Rat Cerebrocortical Cells,” Neuroscience, Vol. 116, No. 2, 2003, pp. 485-489. doi:10.1016/S0306-4522(02)00655-3
[26] R. Hashimoto, N. Takei, K. Shimazu, L. Christ, B. Lu and D. M. Chuang, “Lithium Induces Brain-Derived Neurotrophic Factor and Activates TrkB in Rodent Cortical Neurons: An Essential Step for Neuroprotection against Glutamate Excitotoxicity,” Neuropharmacology, Vol. 43, No. 7, 2002, pp. 1173-1179. doi:10.1016/S0028-3908(02)00217-4
[27] G. Alvarez, J. R. Mu?oz-Monta?o, J. Satrústegui, J. Avila, E. Bogónez and J. Díaz-Nido, “Lithium Protects Cultured Neurons against Beta-Amyloid-Induced Neurodegenera- tion,” FEBS Letters, Vol. 453, No. 3, 1999, pp. 260-264. doi:10.1016/S0014-5793(99)00685-7
[28] S. Jakopec, D. Karlovic, K. Dubravcic and D. Batinic, “Lithium Effect on Glutamate Induced Damage in Glioblastoma Cells,” Collegium Antropologicum, Vol. 32, Suppl. 1, 2008, pp. 87-91.
[29] L. Shao, L. T. Young and J. F. Wang, “Chronic Treatment with Mood Stabilizers Lithium and Valproate Prevents Excitotoxicity by Inhibiting Oxidative Stress in Rat Cerebral Cortical Cells,” Biological Psychiatry, Vol. 58, No. 11, 2005, pp. 879-884. doi:10.1016/j.biopsych.2005.04.052
[30] Q. Bian, T. Shi, D. M. Chuang and Y. Qian, “Lithium Reduces Ischemia-Induced Hippocampal CA1 Damage and Behavioral Deficits in Gerbils,” Brain Research, Vol. 1184, 2007, pp. 270-276. doi:10.1016/j.brainres.2007.09.054
[31] M. K. Rowe and D. M. Chuang, “Lithium Neuroprotection: Molecular Mechanisms and Clinical Implications,” Expert Reviews in Molecular Medicine, Vol. 6, 2004, pp. 1-18. doi:10.1017/S1462399404008385
[32] H. Eldar-Filkelman, “Glycogen Synthase Kinase 3: An Emerging Therapeutic Target,” Trends in Molecular Medicine, Vol. 8, No. 3, 2002, pp.126-132. doi:10.1016/S1471-4914(01)02266-3
[33] C. A. Grimes and R. S. Jope, “The Multifaceted Roles of Glycogen Synthase Kinase 3Beta in Cellular Signaling,” Progress in Neurobiology, Vol. 65, No. 4, 2001, pp. 391- 426. doi:10.1016/S0301-0082(01)00011-9
[34] J. R. Woodgett, “Judging a Protein by More Than Its Name: GSK-3,” Science’s STKE, Vol. 2011, No. 100, 2001, p. RE12.
[35] G. N. Bijur, P. De Sarno and R. S. Jope, “Glycogen Synthase Kinase-3b Facilitates Staurosporine and Heat Shock-Induced Apoptosis: Protection by Li-thium,” Journal of Biological Chemistry, Vol. 275, 2000, pp. 7583-7590. doi:10.1074/jbc.275.11.7583
[36] R. H. Lenox and C. Hahn, “Overview of the Mechanism of Action of Lithium in the Brain: Fifty year Update,” Journal of Clinical Psychiatry, Vol. 61, Suppl. 9, 2000, pp. 5-15.
[37] O. Kaidanovich-Beilin, A. Milman, A. Weizman, C. G. Pick and H. Eldar-Finkelman, “Rapid Antidepressive-Like Activity of Specific Glycogen Synthase Kinase-3 Inhibitor and Its Effect on β-Catenin in Mouse Hippocampus,” Biological Psychiatry, Vol. 55, No. 8, 2004, pp. 781-784. doi:10.1016/j.biopsych.2004.01.008
[38] N. Gurvich and P. S. Klein, “Lithium and Valproic Acid: Parallels and Contrasts in Diverse Signaling Contexts,” Pharmacology & Therapeutics, Vol. 96, No. 1, 2002, pp. 45-66. doi:10.1016/S0163-7258(02)00299-1
[39] A. Brunet, S. R. Datta and M. E. Greenberg, “Transcription-Dependent and-Independent Control of Neuronal Survival by the PI3K-Akt Signaling Pathway,” Current Opinion in Neurobiology, Vol. 11, No. 3, 2001, pp. 297- 305. doi:10.1016/S0959-4388(00)00211-7
[40] V. Duronio, “The Life of a Cell: Apoptosis Regulation by the PI3K/PKB Pathway,” Biochemical Journal, Vol. 415, 2008, pp. 333-344. doi:10.1042/BJ20081056
[41] T. K. Creson, P. Yuan, H. K. Manji and G. Chen, “Evidence for Involvement of ERK, PI3K and RSK in Induction of Bcl-2 by Valproate,” Journal of Molecular Neuroscience, Vol. 37, No. 2, 2008, pp. 123-134. doi:10.1007/s12031-008-9122-2
[42] C. A. Bondy and C. M. Cheng, “Signaling by Insulin-Like Growth Factor 1 in Brain,” European Journal of Pharmacology, Vol. 490, No. 1-3, 2004, pp. 25-31. doi:10.1016/j.ejphar.2004.02.042
[43] E. Chaleck-a-Franaszek and De-Maw Chuang, “Lithium Activates the Serine/Threonine Kinase Akt-1 and Suppresses Glutamate-Induced Inhibition of Akt-1 Activity in Neurons,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 15, 1999, pp. 8745-8750. doi:10.1073/pnas.96.15.8745
[44] A. Mora, G. Sabio, J. C. Alonso, G. Soler and F. Centeno, “Different Dependence of Lithium and Valproate on PI3K/ PKB Pathway,” Bipolar Disorders, Vol. 4, No. 3, 2002, pp. 195-200. doi:10.1034/j.1399-5618.2002.40301.x
[45] J. Chen, F. M. Ghazawi, W. Bakkar and Q. Li, “Valproate Acid and Butyrate Induce Apoptosis in Human Cancer Cells through Inhibition of Gene Expression of Akt/Protein Kinase B,” Molecular Cancer, Vol. 5, 2006, p. 71. doi:10.1186/1476-4598-5-71
[46] J. M. Beaulieu, T. D. Sotnikova, W. D. Yao, L. Kockeritz, et al., “Lithium Antagonizes Dopamine-Dependent Behaviors Mediated by na AKT/Glycogen Synthase Kinase 3 Signaling Cascade,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 14, 2004, pp. 5099-5104. doi:10.1073/pnas.0307921101
[47] T. Pan, X. Li, W. Xie, J. Jankovic and W. Le, “Valproic Acid Mediated Hsp70 Induction and Antiapoptotic Neuroprotection in SH-SY5Y Cells,” FEBS Letters, Vol. 579, No. 30, 2005, pp. 6716-6720. doi:10.1016/j.febslet.2005.10.067
[48] M. Kostrouchová, Z. Kostrouch and M. Kostrouchová, “Valproic Acid, a Molecular Lead to Multiple Regulatory Pathways” Folia Biologica (Praha), Vol. 53, 2007, pp. 37-49.
[49] M. H. Liang, J. R. Wendland and D. M. Chuang, “Lithium Inhibits Smad3/4 Transactivation via Increased CREB Activ-ity induced by PKA and Akt Signaling,” Molecular and Cellular Neuroscience, Vol. 37, No. 3, 2008, pp. 440-453. doi:10.1016/j.mcn.2007.10.017
[50] M. Miloso, A. Scu-teri, D. Foudah and G. Tredici, “MAPKs as Mediators of Cell Fate Determination: An Approach to Neurodegenerative Diseases,” Current Medicinal Chemistry, Vol. 15, No. 6, 2008, pp. 538-548. doi:10.2174/092986708783769731
[51] M. C. Lawrence, A. Jivan, C. Shao and L. Duan, “The Roles of MAPKs in Diseases,” Cell Research, Vol. 18, 2008, pp. 436-442. doi:10.1038/cr.2008.37
[52] M. Cargnello and P. P. Roux, “Activation and Function of MAPs and Their Substrates, the MAPK-Activated Protein Kinases,” Microbiology and Molecular Biology Reviews, Vol. 75, No. 1, 2011, pp. 50-83. doi:10.1128/MMBR.00031-10
[53] F. Zhang, C. J. Phiel, L. Spece, N. Gurvich and P. S. Klein, “Inhibitory Phos-phorylation of Glycogen Synthase Kinase-3 (GSK-3) in Response to Lithium. Evidence for Autoregulation of GSK-3,” Journal of Biological Chemistry, Vol. 278, 2003, pp. 33067-33077. doi:10.1074/jbc.M212635200
[54] H. Einat, P. Yuan, T. D. Gould, J. Li, et al., “The Role of the Extracellular Signal-Regulated Kinase Signaling Pathway in Mood Modulation,” Journal of Neuroscience, Vol. 23, No. 19, 2003, pp. 7311-7316.
[55] X. Li, G. N. Bijur and R. S. Jope, “Glycogen Synthase Kinase-3beta, Mood Stabilizers, and Neuroprotection,” Bipolar Disorders, Vol. 4, No. 2, 2002, pp. 137-144. doi:10.1034/j.1399-5618.2002.40201.x
[56] T. D. Gould and H. K. Manji, “Glycogen Synthase Kinase-3: A Putative Molecular Target for Lithium Mimetic Drugs,” Neuropsychopharmacology, Vol. 30, No. 7, 2005, pp. 1223-1237.
[57] J. T. Coyle and H. K. Manji, “Getting Balance: Drugs for Bipolar Disorder Share Target,” Nature Medicine, Vol. 8, 2002, pp. 557-558. doi:10.1038/nm0602-557
[58] G. Chen, H. K. Manji, D. B. Hawver, C. B. Wright and W. Z. Potter, “Chronic Sodium Valproate Selectively Decreases Protein Kinase C Alpha and Epsilon in Vitro,” Journal of Neurochemistry, Vol. 63, No. 6, 1994, pp. 2361- 2364. doi:10.1046/j.1471-4159.1994.63062361.x
[59] S. G. Birbaum, P. X. Yuan, M. Wang and S. Vijayraghavan, “Protein Kinase C Overactivity Impairs Prefrontal Cortical Regulation of Working Memory,” Science, Vol. 306, No. 5697, 2004, pp. 882-884. doi:10.1126/science.1100021
[60] S. Chateauvieux, F. Morceau, M. Dicato and M. Diederich, “Molecular and Therapeutic Potential and Toxicity of Valproic Acid,” Journal of Biomedicine and Biotechnology, Vol. 2010, 2010, p. 479364. doi:10.1155/2010/479364
[61] D. Marchion and P. Münster, “Development of Histone Deacetylase Inhibitors for Cancer Treatment,” Expert Review of Anticancer Therapy, Vol. 7, No. 4, 2007, pp. 583- 598. doi:10.1586/14737140.7.4.583
[62] C. M. Marson, “Histone Deacetylase Inhibitors: Design, Structure-Activity Relationships and Therapeutic Implications for Cancer,” Anti-Cancer Agents in Medicinal Chemistry, Vol. 9, No. 6, 2009, pp. 661-692.
[63] M. Bantscheff, C. Hopf, M. M. Savitski, A. Dittmann, et al., “Chemoproteomics Profiling of HDAC Inhibitors Reveals Selective Targeting of HDAC Complexes,” Nature Biotechnology, Vol. 29, 2011, pp. 255-265. doi:10.1038/nbt.1759
[64] J. E. Bolden, M. J. Peart and R. W. Johnstone, “Anticancer Activities of Histone Deacetylase Inhibitors,” Nature Reviews Drug Discovery, Vol. 5, 2006, pp. 769-784. doi:10.1038/nrd2133
[65] R. J. Ferrante, J. K. Kubilus, J. Lee and H. Ryu, “Histone Deacetylase Inhibition by Sodium Butyrate Chemotherapy Ameliorates the Neurodegenerative Phenotype in Huntington’s Disease Mice,” Journal of Neuroscience, Vol. 23, No. 28, 2003, pp. 9418-9427.
[66] M. R. Jeong, R. Hashimoto, W. Senatorov, K. Fujimakik, et al., “Valproic Acid, a Mood Stabilizer and Anticonvulsant, Protects Rat Cerebral Cortical Neurons from Spontaneous Cell Death: A Role of Histone Deacetylase Inhibition,” FEBS Letters, Vol. 542, No. 1, 2003, pp. 74-78. doi:10.1016/S0014-5793(03)00350-8
[67] G. Gardian, L. Yang, C. Cleren and N. Y. Calingasan, “Neuroprotective Effects of Phenylbutyrate AGAINST MPTP Neurotoxicity,” Neuromolecular Medicine, Vol. 5, No. 23, 2004, pp. 235-241. doi:10.1385/NMM:5:3:235
[68] G. Gardian, S. E. Browne, D. K. Choi and P. Klivenyi, “Neuroprotective Effects of Phenylbutyrate in the N171- 82Q Transgenic Mouse Model of Huntington’s Disease,” Journal of Biological Chemistry, Vol. 280, No. 1, 2005, pp. 556-563.
[69] M. Minamiyama, M. Katsuno, H. Adachi and M. Waza, “Sodium Butyrate Ameliorates Phenotypic Expression in a Transgenic Mouse Model of Spinal and Bulbar Muscular Atrophy,” Human Molecular Genetics, Vol. 13, No. 11, 2004, pp. 1183-1192. doi:10.1093/hmg/ddh131
[70] G. S. Peng, G. Li, N. S. Tzengc and P. S. Chen, “Valproate Pretreatment Protects Dopaminergic Neurons from LPS-Induced Neurotoxicity in Rat Primary Midbrain Cultures: Role of Microglia,” Molecular Brain Research, Vol. 134, No. 1, 2005, pp. 162-169. doi:10.1016/j.molbrainres.2004.10.021
[71] S. Petri, M. Kiaei, K. Kipian and J. Chen, “Additive Neuroprotective Effects of a Histone Deacetylase Inhibitor and a Catalytic Antioxidant in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis,” Neurobiology of Disease, Vol. 22, No. 1, 2006, pp. 40-49. doi:10.1016/j.nbd.2005.09.013
[72] P. S. Chen, C. C. Wang, C. D. Bortner and G. S. Peng, “Valproic Acid and Other HDAC Inhibitors Induce Microglial Apoptosis and Attenuate Lipopolysaccharide-Induced Dopaminergic Neurotoxicity,” Neuroscience, Vol. 149, No. 1, 2007, pp. 203-212. doi:10.1016/j.neuroscience.2007.06.053
[73] G. Raivich and A. Behrens, “Role of the AP-1 Transcription Factor c-JUN in Developing, Adult and Injured Brain,” Progress in Neurobiology, Vol. 78, No. 6, 2006, pp. 347-363. doi:10.1016/j.pneurobio.2006.03.006
[74] J. A. Williams, C. J. Barreiro, L. U. Nwakanma and M. S. Lange, “Valproic Acid Prevents Brain Injury in a Canine Model of Hypothermic Circulatory Arrest: A Promising New Approach to Neuroprotection during Cardiac Surgery,” The Annals of Thoracic Surgery, Vol. 81, No. 6, 2006, pp. 2235-2242. doi:10.1016/j.athoracsur.2005.12.060
[75] H. Dou, K. Birusingh, J. Faraci, S. Gorantia, et al., “Neuroprotective Activities of Sodium Valproate in a Murine Model of Human Immunodeficiency Virus-1 Encephalitis,” Journal of Neuroscience, Vol. 23, No. 27, 2003, pp. 9162- 9170.
[76] H. Kanai, A. Sawa, R. W. Chen, P. Leeds and D. M. Chuang, “Valproic Acid Inhibits Histone Deacetylase Activity and Suppresses Excitotoxicity-Induced GAPDH Nuclear Accumulation and Apoptotic Death in Neurons,” The Pharmacogenomics Journal, Vol. 4, 2004, pp. 336- 344. doi:10.1038/sj.tpj.6500269
[77] P. S. Chen, G. S. Peng, G. Li, S. Yang, et al., “Valproate Protects Dopaminergic Neurons in Midbrain Neuron/Glia Cultures by Stimulating the Release of Neurotrophic Factors from Astrocytes,” Molecular Psychiatry, Vol. 11, No. 12, 2006, pp. 1116-1125. doi:10.1038/sj.mp.4001893
[78] Y. Leng and De-Maw Chuang, “Endogenous α-Synuclein Is Induced by Valproic Acid through Histone Deacetylase Inhibition and Participates in Neuroprotection against Glutamate-Induced Excitotoxicity,” Journal of Neuroscience, Vol. 26, No. 28, 2006, pp. 7502-7512. doi:10.1523/JNEUROSCI.0096-06.2006
[79] D. I. Sinn, S. J. Kim, K. H. Jung and S. T. Lee, “Valproic acid-Mediated Neuroprotection in Intracerebral Hemorrhage via Histone Deacetylase Inhibition and Transcriptional Activation,” Neurobiology of Disease, Vol. 26, No. 2, 2007, pp. 464-472. doi:10.1016/j.nbd.2007.02.006
[80] Y. Leng, M. H. Liang, M. Ren, et al., “Synergistic Neuroprotective Effects of Lithium and Valproic Acid or other Histone Deacetylase Inhibitors in Neurons: Roles of Glycogen Synthase Kinase-3 Inhibition,” Journal of Neuroscience, Vol. 28, No. 10, 2008, pp. 2576-2588. doi:10.1523/JNEUROSCI.5467-07.2008
[81] S. R. D’Mello, “Histone Deacetylases as Targets for the Treatment of Human Neurodegenerative Diseases,” Drug News & Perspectives, Vol. 22, No. 9, 2009, pp. 513-524. doi:10.1358/dnp.2009.22.9.1437959
[82] B. Monti, V. Gatta, F. Piretti, S. S. Rafaelli, M. Virgili and A. Contestabile, “Valproic Acid Is Neuroprotective in the Rotenone Rat Model of Parkinson’s Disease: In- volvement of Al-pha-Synuclein,” Neurotoxicity Research, Vol. 17, No. 2, 2010, pp. 130-141. doi:10.1007/s12640-009-9090-5
[83] X. N. Li, Q. Shu, J. M. F. Su, L. Perlaky, S. M. Blaney and C. C. Lau, “Val-proic Acid Induces Growth Arrest, Apoptosis, and Se-nescence in Medulloblastomas by Increasing Histone Hyperacetylation and Regulating Expression of p21Cip1, CDK4, and CMYC,” Molecular Cancer Therapeutics, Vol. 4, No. 12, 2005, pp. 1912- 1922. doi:10.1158/1535-7163.MCT-05-0184
[84] T. Akiama, “Wnt/Beta-Catenin Signaling,” Cytokine Grow- th Factor Review, Vol. 11, No. 4, 2000, pp. 273-282. doi:10.1016/S1359-6101(00)00011-3
[85] M. Barbacid, “Ras Genes,” Annual Review of Biochemistry, Vol. 56, 1987, pp. 779-827. doi:10.1146/annurev.bi.56.070187.004023
[86] G.-A. Jung, J.-Y. Yoon, B.-S. Moon, D.-H. Yang, et al., “Valproic Acid Induces Differentiation and Inhibition of Proliferation in Neural Progenitor Cells via the Beta-Catenin-Ras-ERK-p21Cip/WAF1 Pathway,” BMC Cell Biology, Vol. 9, 2008, p. 66. doi:10.1186/1471-2121-9-66
[87] D. Bar-Sagi and A. Hall, “Ras and Rho GRTases: A Family Reunion,” Cell, Vol. 103, No. 2, 2000, pp. 227- 238. doi:10.1016/S0092-8674(00)00115-X
[88] P. V. Nunes, P. Wacker, O. V. Forlenza and W. F. Gattaz, “O Uso do Lítio em Idosos: Evidências de Sua A??o Neuroprotetora,” Revista de Psiquiatria Clínica, Vol. 29, 2002, pp. 248-255.
[89] P. X. Yuan, L. D. Huang, Y. M. Jiang, J. S. Gutkind, et al., “The Mood Stabilizer Valproic Acid Activates Mitogen-Activated Protein Kinases and Promotes Neurite Growth,” Journal of Biological Chemistry, Vol. 276, 2001, pp. 31674-31683. doi:10.1074/jbc.M104309200
[90] P. De Sarno, X. Li and R. S. Jope, “Regulation of Akt and Glycogen Synthase Kinase-3 Beta Phosphorylation by Sodium Valproate and Lithium,” Neuropharmacology, Vol. 43, No. 7, 2002, pp. 1158-1164. doi:10.1016/S0028-3908(02)00215-0
[91] Y. Hao, T. Creson, L. Zhang, P. Li, et al., “Mood Stabilizer Valproate, Promotes ERK Pathway-Dependent Cortical Neuronal Growth and Neurogenesis,” Journal of Neuroscience, Vol. 24, No. 29, 2004, pp. 6590-6599. doi:10.1523/JNEUROSCI.5747-03.2004
[92] J. Hsieh, K. Nakashima, T. Kuwabara, E. Mejia and F.H. Gage, “Histone Deacetylase Inhibition-Mediated Neuronal Differentiation of Multipotent Adult Neural Progenitor Cells,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 47, 2004, pp. 16659-16664. doi:10.1073/pnas.0407643101
[93] G. Chen, L. D. Huang, Y. M. Jiang and H. K. Manji, “The Mood Stabilizing Agent Valproate Inhibits the Activity of Glycogen Synthase Kinase-3,” Journal of Neurochemistry, Vol. 72, No. 3, 1999, pp. 1327-1330. doi:10.1046/j.1471-4159.2000.0721327.x
[94] J. W. Kim, J. E. Lee. M. J. Kim, E. G. Cho, et al., “Glycogen Synthase Kinase 3 Beta Is a Natural Activator of Mitogen-Activated Protein Kinase/Extracellular Signal- Regulated Kinase Kinase 1 (MEKK1),” Journal of Biological Chemistry, Vol. 278, 2003, pp. 13995-14001. doi:10.1074/jbc.M300253200
[95] V. Stambolic, L. Ruel and J. R. Woodgett, “Lithium Inhibits Glycogen Synthase Kinase-3 Activity and Mimics Wingless Signalling in Intact Cells,” Current Biology, Vol. 6, No. 12, 1996, pp. 1664-1668. doi:10.1016/S0960-9822(02)70790-2
[96] D. M. Chuang, Z. Wang and C. T. Chiu, “GSK-3 as a Target for Lithium-Induced Neuroprotection against Excitotoxicity in Neuronal Cultures and Animal Models of Ischemic Stroke,” Frontiers in Molecular Neuroscience, Vol. 4, 2011, p. 15. doi:10.3389/fnmol.2011.00015
[97] A. M. Corral, “Mecanismos Implicados en la Protección de la Apoptosis Neuronal en céLulas Granulares de Cerebelo por Litio y Valproato,” Tesis Doctoral Dirigida por Fran-cisco Centeno Velázquez, Universidad de Extre- madura, Mérida, 2001.
[98] J. Dupont, M. Karas and D. Leroith, “The Cyclin-Dependent Kinase Inhibitor p21CIP/WAF Is a Positive Regulator of Insulin-Like Growth Factor 1-Induced Cell Proliferation in MCF-7 Human Breast Cancer Cells,” Journal of Biological Chemistry, Vol. 278, 2003, pp. 37256-37264. doi:10.1074/jbc.M302355200
[99] J. M. Levenson, K. J. O’Riordan, K. D. Brown, M. A. Trinh, et al., “Regulation of Histone Acetylation during Memory Formation on the Hippocampus,” Journal of Biological Chemistry, Vol. 279, 2004, pp. 40545-40559. doi:10.1074/jbc.M402229200
[100] T. W. Bredy, H. Wu, C. Crego, J. Zellhoefer, Y. E. Sun and M. Barad, “Histone Modifications around Individual BDNF Gene Promotors in Prefrontal Cortex Are Associated with Extinction of Conditioned Fear,” Learning & Memory, Vol. 14, 2007, pp. 268-276. doi:10.1101/lm.500907
[101] M. Cammarota, L. R. M. Bevilaqua, M. R. M. Vianna, J. H. Medina and I. Iz-quierdo, “The Extinction of Conditioned Fear: Structural and Molecular Basis and Therapeutic Use,” Revista Brasileira de Psiquiatria, Vol. 29, No. 1, 2007, pp. 80-85. doi:10.1590/S1516-44462006005000022
[102] K. M. Lattal, R. M. Barrett and M. A. Wood, “Systemic or Intrahippocampal Delivery of Histone Deacetylase Inhibitors Facilitates Fear Extinction,” Behavioral Neuroscience, Vol. 121, No. 5, 2007, pp. 1125-1131. doi:10.1037/0735-7044.121.5.1125
[103] G. Raivich and A. Behrens, “Role of the AP-1 Transcription Factor c-Jun in Developing, Adult and Injured brain,” Progress in Neurobiology, Vol. 78, No. 6, 2006, pp. 347- 363. doi:10.1016/j.pneurobio.2006.03.006
[104] P. K. Dash, S. A. Orsi, Min Zhang, R. J. Grill, et al., “Valproate Administered after Traumatic Brain Injury Provides Neuroprotection and Improves Cognitive Function in Rats,” Plos ONE, Vol. 5, No. 6, 2010, p. e11383.
[105] E. A. Thomas, “Focal Nature of Neurological Disorders Necessitates Isotype-Selective Histone Deacetylase (HDAC) Inhibitors,” Molecular Neurobiology, Vol. 40, No. 1, 2009, pp. 33-45. doi:10.1007/s12035-009-8067-y
[106] N. N. Nalivaeva, N. D. Belyaev and A. J. Turner, “Sodium Valproate: An Old Drug with New Roles,” Trends in Pharmacological Sciences, Vol. 30, No. 10, 2009, pp. 509-514. doi:10.1016/j.tips.2009.07.002
[107] C. Morland, K. A. Boldingh, E. G. Iversen and B. Hassel, “Valproate Is Neuroprotective against Malonate Toxicity in Rat Striatum: An Association with Augmentation of High-Affinity Glutamate Uptake,” Journal of Cerebral Blood Flow and Metabolism, Vol. 24, 2004, pp. 1226- 1234. doi:10.1097/01.WCB.0000138666.25305.A7
[108] R. S. Williams, L. Cheng, A. W. Mudge and A. J. Har- wood, “A Common Mechanism of Action for Three Mood- Stabilizing Drugs,” Nature, Vol. 417, 2002, pp. 292-295. doi:10.1038/417292a
[109] C. J. Phiel, F. Zhang, E. Y. Huang and M. G. Guenther, “Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen,” Journal of Biological Chemistry, Vol. 276, 2001, pp. 36734-36741. doi:10.1074/jbc.M101287200
[110] M. Gottlicher, S. Minucci, P. Zhu and O. H. Kramer, “Valproic Acid Defines a Novel Class of HDAC Inhibitors Inducing Differentiation of Transformed Cells,” The EMBO Journal, Vol. 20, 2001, pp. 6969-7698. doi:10.1093/emboj/20.24.6969
[111] N. Detich, V. Bo-venzi and M. Szyf, “Valproate Induces Replication-Independent Active DNA Demetylation,” Journal of Biological Chemistry, Vol. 278, 2003, pp. 27586- 27592. doi:10.1074/jbc.M303740200
[112] S. Milutinovic, A. C. Dálessio, N. Detich and M. Szyf, “Valproate Reduces Widespread Epigenetic Reprogramming Which Involves Demethylation of Specific Genes,” Carcinogenesis, Vol. 28, No. 3, 2007, pp. 560-571. doi:10.1093/carcin/bgl167
[113] L. M. Castro, M. Gallant and L. P. Niles, “Novel Targets for Valproic Acid and Upregulation of Melatonin Receptors and Neurotrophic Factors in C6 Glioma Cells,” Journal of Neurochemistry, Vol. 95, No. 5, 2005, pp. 1227-1236. doi:10.1111/j.1471-4159.2005.03457.x
[114] X. Wu, P. S. Chen, S. Dallas and B. Wilson, “Histone Deacetylase In-hibitors Upregulate Astrocyte GDNF and BDNF Gene Transcription and Protect Dopaminergic Neurons” International Journal of Neuropsychopharmacology, Vol. 9, No. 3, 2008, pp. 1-12.
[115] N. Gurvich, M. G. Berman, B. S. Wittner and R. C. Gentleman, “Association of Valproate-Induced Teratogenenesis with Histone Deacetylase Inhibition in Vivo,” FASEB Journal, Vol. 19, No. 9, 2005, pp. 1166-1168.
[116] B. H. Maskrey, I. L. Megson, P. D. Whitfield and A. G. Rossi, “Mechanisms of Resolution of Inflammation, a Focus on Cardiovascular Disease,” Arteriosclerosis, Thrombosis and Vascular Biology, Vol. 31, 2011, pp. 1001-1006. doi:10.1161/ATVBAHA.110.213850
[117] D. Bayarsaihan, “Epigenetic Mechanisms in Inflammation,” Journal of Dental Research, Vol. 90, No. 1, 2011, pp. 9-17. doi:10.1177/0022034510378683
[118] L. A. B. Joosten, F. Leoni, S. Meghji and P. Mascagni, “Inhibition of HDAC Activity by ITF2357 Ameliorates Joint Inflammation and Prevents Cartilage and Bone Destruction in Experimental Arthritis,” Molecular Medicine, Vol. 17, No. 5-6, 2011, pp. 391-396. doi:10.2119/molmed.2011.00058
[119] S. Shuttlewort and S. Kerry, “HDAC Inhibitors: New Promise in the Treatment of Immune and Inflammatory Disease,” Innovations in Pharmaceutical Technology, 2011. http://www.Iptonline.com/articles/public/pg/nonprint.pdf
[120] J. C. Ximenes, D. O. Gon?alves, R. Siqueira and L. K. A. M. Leal, “Valproic Acid Reduces Polymorphonuclear Cell Migration and Myeloperoxidase Release: An in Vivo and in Vitro Study,” XXVI Annual Meeting of the Brazilian Federation of Biological Societies (FESBE), Rio de Janeiro, Brazil, 2011.
[121] J. C. Ximenes, E. C. Lima-Verde, R. S. Pinheiro, K. R. T. Neves, D. O. Gon?alves and G. S. B. Viana, “Avalia??o dos Efeitos Anti-Inflamatórios e Antinociceptivos do ácido valpróIco (AV) em Modelos Experimentais de Edema de pata e no Teste da Formalina, em Roedores,”. XXXIV Annual Congress of the Brazilian Society of Neuro- science and Behavior, Caxambu, Brazil, 2010.
[122] K. S. Figueiredo, M. L. A. Oliveira Sales, J. B. Fontenele, G. S.B.Viana and F. H. C. Félix, “Valproate Effect in Carrageenan-Induced Thermal Hyperalgesia in Female Rats Has A Bimodal Dose-Response Curve,” to be sub- mitted.
[123] I. M. Adcock, “Histone Deacetylase Inhibitors as Novel Anti-Inflammatory Agents,” Current Opinion in Investigational Drugs, Vol. 7, No. 11, 2006, pp. 966-973.
[124] C. A. Dinarello, G. Fossati and P. Mascagni, “Histone Deacetylase Inhibitors for Treating a Spectrum of Diseases Not Related to Cancer,” Molecular Medicine, Vol. 17, No. 5-6, 2011, pp. 333-352. doi:10.2119/molmed.2011.00116
[125] G. Faraco, M. Pittelli, L. Cavone and S. Fossati, “Histone Deacetylase (HDAC) Inhibitors Reduce the Glial Inflammatory Response in Vitro and in Vivo,” Neurobiology of Disease, Vol. 36, No. 2, 2009, pp. 269-279. doi:10.1016/j.nbd.2009.07.019
[126] T. Suuronen, J. Huuskonen, R. Pihlaja, S. Kyrylenko and A. Salminen, “Regulation of Microglial Inflammatory Response by Histone Deacetylase Inhibitors,” Journal of Neurochemi-stry, Vol. 87, No. 2, 2003, pp. 407-416. doi:10.1046/j.1471-4159.2003.02004.x
[127] J. Huuskonen, T. Suuronen, T. Nuutinen, S. Kyrylenko and A. Sal-minen, “Regulation of Microglial Inflammatory Response by Sodium Butyrate and Short-Chain Fatty Acids,” Pharmacology & Pharmaceutical Medicine, Vol. 141, No. 5, 2004, pp. 874-880. doi:10.1038/sj.bjp.0705682
[128] M. Dragunow, J. M. Greenwood, R. E. Cameron, P. J. Narayan, et al., “Val-proic Acid Induces Caspase 3-Mediated Apoptosis in Microglial Cells,” Neuroscience, Vol. 140, No. 4, 2006, pp. 1149-1156. doi:10.1016/j.neuroscience.2006.02.065
[129] H. Kan-kaanranta, M. Janka, P. Ilmarinen-Salo and K. Ito, “Histone Deacetylase Inhibitors Induce Apoptosis in Human Eosinophils and Neutrophils,” Journal of Inflam- mation, Vol. 7, 2010, pp. 1-15. doi:10.1186/1476-9255-7-9
[130] T. Abel and S. Zukin, “Epigenetic Targets of HDAC Inhibition in Neurodegenerative and Psychiatric Disorders,” Current Opinion in Pharmacology, Vol. 8, No. 1, 2008, pp. 57-64. doi:10.1016/j.coph.2007.12.002
[131] S. J. K. M. Haggarty, J. C. Koeler, J. C. Wong, C. M. Grozinger, et al., “Domain-Selective Small Molecule In- hibitor of Histone Deacetylase 6 (HDAC6)-Mediated Tubulin Deacetylation,” Proceedings of the National Acad- emy of Sciences of the United States of America, Vol. 100, No. 8, 2003, pp. 4389-4394. doi:10.1073/pnas.0430973100
[132] J. S. Guan, S. J. Haggart, E. Giacometti and J. H. Dannenberg, “HDAC2 Negatively Regulates Memory Formation and Synaptic Plasticity,” Nature, Vol. 459, 2009, pp. 55-60. doi:10.1038/nature07925
[133] M. Kilgore, C. A. Miller, D. M. Fass and K. M. Henning, “Inhibitors of Class 1 Histone Deacetylases Reverse Contextual Memory Deficits in a Mouse Model of Alzheimer’s Disease,” Neuropsychopharmacology, Vol. 35, 2010, pp. 870-880. doi:10.1038/npp.2009.197
[134] E. Costa, Y. Chen, E. Dong and D. R. Grayson, “GAB-Aergic Promoter Hypermethylation as a Model to Study the Neurochemistry of Schizophrenia Vulnerability,” Expert Review of Neurotherapeutics, Vol. 9, No. 1, 2009, pp. 87-98. doi:10.1586/14737175.9.1.87
[135] P. N. Tariot, L. S. Schneider, J. Cummings, R. G. Thomas, et al., “Chronic Divalproex Sodium to Attenuate Agitation and Clinical Progression of Alzheimer Disease,” Ar- chives of General Psychiatry, Vol. 68, No. 8, 2011, pp. 853-861. doi:10.1001/archgenpsychiatry.2011.72
[136] A. S. Fleischer, D. Truran, J. T. Mai and J. B. Langbaum, “Chronic Divalproex Sodium Use and Brain Atrophy in Alzheimer Disease,” Neurology, Vol. 77, No. 13, 2011, pp. 1263-1271. doi:10.1212/WNL.0b013e318230a16c
[137] M. K. Tripathy and D. Mitra, “Differential Modulation of Mitochondrial OXPHOS System during HIV-1-Induced T Cell Apoptosis: Up Regulation of Complex-IV Subunit and Its Possible Implications,” Apoptosis, Vol. 15, No. 1, 2010, pp. 28-40. doi:10.1007/s10495-009-0408-9
[138] T. Nonaka and M. Hasegawa, “In Vitro Recapitulation of Aberrant Protein Inclusions in Neurodegenerative Diseases,” Communicative & Integrative Biology, Vol. 4, No. 4, 2011, pp. 501-502.
[139] S. A. Lipton, Z. Gu and T. Nakamura, “Inflammatory Mediators Leading to Protein Misfolding and Uncompetitive/Fast Off-Rate Drug Therapy for Neurodegenerative Disorders,” International Review of Neurobiology, Vol. 82, 2007, pp. 1-27. doi:10.1016/S0074-7742(07)82001-0
[140] A. T. Welzel and D. M. Walsh, “Aberrant Protein Structure and Diseases of the Brain,” Irish Journal of Medical Science, Vol. 180, No. 1, 2011, pp. 15-22. doi:10.1007/s11845-010-0606-z
[141] S. Oddo, “The Ubiquitin-Proteosome System in Azheimer’s Diseases,” Journal of Cellular and Molecular Medicine, Vol. 12, No. 2, 2008, pp. 363-373. doi:10.1111/j.1582-4934.2008.00276.x
[142] C. W. Olanow and K. S. McNaught, “Ubiquitin-Proteosome System and Parkinson’s Disease,” Movement Disorders, Vol. 21, No. 11, 2006, pp. 1006-1023.
[143] C. A. Ross and C. M. Pickar, “The Ubiquitin-Proteosome Pathway in Parkinson’s Disease and Other Neurodegenerative Diseases,” Trends in Cell Biology, Vol. 14, No. 12, 2004, pp. 703-711. doi:10.1016/j.tcb.2004.10.006
[144] B. J. Tabner, S. Tumbull, O. El-Agnaf and D. Allsop, “Production of Reactive Oxygen Species from Aggregating Proteins Implicated in Alzheimer’s Disease, Parkinson’s Disease and Other Neurodegenerative Diseases,” Current Topics in Medicinal Chemistry, Vol. 1, 2001, pp. 507-517. doi:10.2174/1568026013394822
[145] K. Sas, H. Robotka, J. Toldi and L. Vécsei, “Mitochon- dria, Metabolic Disturbances, Oxidative Stress and the Kinure-Nine System, with Focus on Neurodegenerative Diseases,” Journal of Neuroscience, Vol. 257, 2007, pp. 221-239.
[146] J. Emerit, M. Edeas and F. Bricaire, “Neurodegenerative Diseases and Oxidative Stress,” Biomedicine & Pharmacotherapy, Vol. 58, No. 1, 2004, pp. 39-46. doi:10.1016/j.biopha.2003.11.004
[147] N. Shibata and M. Kobayashi, “The Role for Oxidative Stress in Neurode-generative Diseases,” Brain Nerve, Vol. 60, No. 2, 2008, pp. 157-170.
[148] M. M. Esiri, “The Interplay between Inflammation and Neurodegeneration in CNS Disease,” Journal of Neuroimmunology, Vol. 184, No. 1-2, 2007, pp. 4-16.
[149] T. Wyss-Coray and L. Mucke, “Inflamma-tion in Neurodegenerative Disease: A Doble-Edged Sword,” Neuron, Vol. 35, No. 3, 2002, pp. 419-432. doi:10.1016/S0896-6273(02)00794-8
[150] F. Zipp and O. Aktas, “The Brain as Target of Inflammation: Common Pathways Link Inflammatory and Neurodegenerative Diseases,” Trends in Biochemical Sciences, Vol. 29, No. 9, 2010, pp. 518-527.
[151] G. C. Brown and J. J. Neher, “Inflammatory Neurodegeneration and Mechanisms of MicróGlial Killing of Neurons,” Molecular Neurobiology, Vol. 41, No. 2-3, 2010, pp. 242-247. doi:10.1007/s12035-010-8105-9
[152] B. Liu, J.-S. Hong, “Role of Microglia in Inflammation-Mediated Neurode-generative Diseases: Mechanisms and Strategies for The-rapeutic Intervention,” Journal of Pharmacology and Experimental Therapeutics, Vol. 304, No. 1, 2003, pp. 1-7. doi:10.1124/jpet.102.035048
[153] A. Cagnin, M. Kassiou, S. R. Meikle and R. B. Banati, “In Vivo Evidence for micróGlial Activation in Neurode-generative Dementia,” Acta Neurologica Scandinavica, Vol. 114, No. S185, 2006, pp. 107-114. doi:10.1111/j.1600-0404.2006.00694.x
[154] L.-F. Lue, Y.-M. Kuo, T. Beach and D. G. Walker, “Microglia Activation and Anti-Inflammatory Regulation in Alzheimer’s Disease,” Molecular Neurobiology, Vol. 41, No. 2-3, 2010, pp. 115-128. doi:10.1007/s12035-010-8106-8
[155] M. A. Burguillos, T. Deierborg, E. Kavanagh, A. Persson, et al., “Caspase Signalling Controls Microglia Activation and Neurotoxicity,” Nature, Vol. 472, No. 7343, 2011, pp. 319-324. doi:10.1038/nature09788
[156] J. A. Beller, G. G. Gurkoff, R. F. Berman and B. G. Lyeth, “Pharmacological Enhancement of Glutamate Transport Reduces Excitotoxicity in Vitro,” Restorative Neurology and Neuroscience, Vol. 29, No. 5, 2011, pp. 331-346.
[157] K. Kim, S. G. Lee, T. P. Kegelman, Z. Z. Su, et al., “Role of Excitatory Amino Acid Transporter-2 (EAAT2) and Glutamate in Neurodegeneration: Opportunities for Developing Novel Therapeutics,” Journal of Cellular Physiology, Vol. 226, No. 10, 1011, pp. 2484-2493.
[158] S. K. Kidd and J. S. Schneider, “Protective Effects of Valproic Acid on the Nigrostriatal Dopamine System in a 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson’s Disease,” Neuroscience, Vol. 194, 2011, pp. 189-194. doi:10.1016/j.neuroscience.2011.08.010
[159] M. T. Lin and M. F. Beal, “Mitochondrial Dysfunction and Oxidative Stress in Neurodegenerative Diseases,” Nature, Vol. 443, 2006, pp. 787-795. doi:10.1038/nature05292
[160] M. B. Moura, L. S. Santos and B. V. Houten, “Mitochondrial Dysfunction in Neu-rodegenerative Diseases and Cancer,” Environmental and Molecular Mutagenesis, Vol. 51, No. 5, 2010, pp. 395-405.
[161] S. Hammed and G.-Y. R. Hsung, “The Role of Mito- chondria in Aging, Neurodegenerative Disease, and Future Therapeutic Options,” BC Medical Journal, Vol. 53, No. 4, 2011, pp. 188-192.
[162] H. Du, L. Guo and S. S. Yan, “Synaptic Mitochondrial Pathology in Alzheimer’s Disease,” Antioxidants & Redox Signaling, 2011, Ahead of Print.

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