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Melatonin and Other Neuroprotective Agents Target Molecular Mechanisms of Disease in Amyotrophic Lateral Sclerosis

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Melatonin, Neuroprotective Agents and Antidepressant Therapy

Abstract

Amyotrophic lateral sclerosis (ALS) is a debilitating disease characterized by progressive loss of voluntary motor neurons leading to muscle atrophy, weakness, weight loss, and respiratory failure. Evidence suggests that various molecular mechanisms including oxidative stress, mitochondrial dysfunction, apoptosis, glutamate excitotoxicity, proteasomal dysfunction, and inflammation are responsible for ALS pathogenesis. In this chapter we summarize the various therapies tested on animal models targeting the above molecular mechanisms and compare their effects on body weight loss, muscle damage, disease onset, duration, and survival. We also review drugs that prevent body weight loss in animal models of ALS and analyze their structure-activity relationship.

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References

  1. Rosen DR, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;362(6415):59–62.

    Article  CAS  PubMed  Google Scholar 

  2. Wood H. Amyotrophic lateral sclerosis: a hexanucleotide repeat expansion in C9ORF72 links amyotrophic lateral sclerosis and frontotemporal dementia. Nat Rev Neurol. 2011;7(11):595.

    Article  PubMed  Google Scholar 

  3. Tanner CM, Goldman SM, Ross GW, Grate S. The disease intersection of susceptibility and exposure: Chemical exposures and degenerative disease risk. Alzheimers Dement. 2014;10(3):S213–25.

    Google Scholar 

  4. Miller RG, et al. Clinical trials of riluzole in patients with ALS. Neurology. 1996;47(4 Suppl 2):S86–92.

    Article  CAS  PubMed  Google Scholar 

  5. Eisen A, et al. Duration of amyotrophic lateral sclerosis is age dependent. Muscle Nerve. 1993;16(1):27–32.

    Article  CAS  PubMed  Google Scholar 

  6. Loureiro MPS, et al. Clinical aspects of amyotrophic lateral sclerosis in Rio de Janeiro/Brazil. J Neurol Sci. 2012;316(1):61–6.

    Article  PubMed  Google Scholar 

  7. Potemkowski A, Honczarenko K, Fabian A. Clinical course and epidemiological analysis of amyotrophic lateral sclerosis in Szczecin in 1986–1995. Neurol Neurochir Pol. 1999;33(1):71–8.

    CAS  PubMed  Google Scholar 

  8. Logroscino G, et al. Incidence of amyotrophic lateral sclerosis in Europe. J Neurol Neurosurg Psychiatry. 2010;81(4):385–09.

    Article  PubMed  Google Scholar 

  9. Weijs PJM. Hypermetabolism, is it real? The example of amyotrophic lateral sclerosis. J Am Diet Assoc. 2011;111(11):1670–3.

    Article  PubMed  Google Scholar 

  10. Genton L, et al. Nutritional state, energy intakes and energy expenditure of amyotrophic lateral sclerosis (ALS) patients. Clin Nutr. 2011;30(5):553–9.

    Article  CAS  PubMed  Google Scholar 

  11. Dupuis L, et al. Energy metabolism in amyotrophic lateral sclerosis. Lancet Neurol. 2011;10(1):75–82.

    Article  CAS  PubMed  Google Scholar 

  12. Silva LB, et al. Amyotrophic lateral sclerosis: combined nutritional, respiratory and functional assessment. Arq Neuropsiquiatr. 2008;66(2B):354–9.

    Article  PubMed  Google Scholar 

  13. Jawaid A, et al. A decrease in body mass index is associated with faster progression of motor symptoms and shorter survival in ALS. Amyotroph Lateral Scler. 2010;11(6):542–8.

    Article  PubMed  Google Scholar 

  14. Paganoni S, et al. Body mass index, not dyslipidemia, is an independent predictor of survival in amyotrophic lateral sclerosis. Muscle Nerve. 2011;44(1):20–4.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kuhle J, et al. Increased levels of inflammatory chemokines in amyotrophic lateral sclerosis. Eur J Neurol. 2009;16(6):771–4.

    Article  CAS  PubMed  Google Scholar 

  16. McCombe AP, Henderson RD. The role of immune and inflammatory mechanisms in ALS. Curr Mol Med. 2011;11(3):246–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Glass CK, et al. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140(6):918–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Aziz NA, et al. Weight loss in neurodegenerative disorders. J Neurol. 2008;255(12):1872–80.

    Article  CAS  PubMed  Google Scholar 

  19. Lennie TA. Relationship of body energy status to inflammation-induced anorexia and weight loss. Physiol Behav. 1998;64(4):475–81.

    Article  CAS  PubMed  Google Scholar 

  20. Clement K, et al. Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects. FASEB J. 2004;18(14):1657–69.

    Article  CAS  PubMed  Google Scholar 

  21. Forsythe LK, Wallace J, Livingstone M. Obesity and inflammation: the effects of weight loss. Nutr Res Rev. 2008;21(2):117–33.

    Article  CAS  PubMed  Google Scholar 

  22. Lee CD, et al. Muscle ultrasound quantifies the rate of reduction of muscle thickness in amyotrophic lateral sclerosis. Muscle Nerve. 2010;42(5):814–9.

    Article  PubMed  Google Scholar 

  23. Dalbello-Haas V, Florence JM, Krivickas LS. Therapeutic exercise for people with amyotrophic lateral sclerosis or motor neuron disease. Cochrane Database Syst Rev. 2008;2:CD005229.

    Google Scholar 

  24. Pandya RS, et al. Neuroprotection for amyotrophic lateral sclerosis: role of stem cells, growth factors, and gene therapy. Cent Nerv Syst Agents Med Chem. 2012;12(1):15–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gurney ME, et al. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science. 1994;264(5166):1772–5.

    Article  CAS  PubMed  Google Scholar 

  26. Deng HX, et al. Amyotrophic lateral sclerosis and structural defects in Cu, Zn superoxide dismutase. Science. 1993;261(5124):1047–51.

    Article  CAS  PubMed  Google Scholar 

  27. Martin N, et al. A missense mutation in Tbce causes progressive motor neuronopathy in mice. Nat Genet. 2002;32(3):443–7.

    Article  CAS  PubMed  Google Scholar 

  28. Ludolph AC, et al. Guidelines for preclinical animal research in ALS/MND: a consensus meeting. Amyotroph Lateral Scler. 2010;11(1–2):38–45.

    Article  PubMed  Google Scholar 

  29. Bederson JB, et al. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke. 1986;17(3):472–6.

    Article  CAS  PubMed  Google Scholar 

  30. Feeney DM, Gonzalez A, Law WA. Amphetamine, haloperidol, and experience interact to affect rate of recovery after motor cortex injury. Science. 1982;217(4562):855–7.

    Article  CAS  PubMed  Google Scholar 

  31. Suzuki M, et al. Sexual dimorphism in disease onset and progression of a rat model of ALS. Amyotroph Lateral Scler. 2007;8(1):20–5.

    Article  PubMed  Google Scholar 

  32. Weydt P, et al. Assessing disease onset and progression in the SOD1 mouse model of ALS. Neuroreport. 2003;14(7):1051–4.

    Article  PubMed  Google Scholar 

  33. Combs DJ, D’Alecy LG. Motor performance in rats exposed to severe forebrain ischemia: effect of fasting and 1,3-butanediol. Stroke. 1987;18(2):503–11.

    Article  CAS  PubMed  Google Scholar 

  34. Willing AE, et al. hNT neurons delay onset of motor deficits in a model of amyotrophic lateral sclerosis. Brain Res Bull. 2001;56(6):525–30.

    Article  CAS  PubMed  Google Scholar 

  35. Garbuzova-Davis S, et al. Intravenous administration of human umbilical cord blood cells in a mouse model of amyotrophic lateral sclerosis: distribution, migration, and differentiation. J Hematother Stem Cell Res. 2003;12(3):255–70.

    Article  CAS  PubMed  Google Scholar 

  36. Morita E, et al. A novel cell transplantation protocol and its application to an ALS mouse model. Exp Neurol. 2008;213(2):431–8.

    Article  CAS  PubMed  Google Scholar 

  37. Basso DM, Beattie MS, Bresnahan JC. A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma. 1995;12(1):1–21.

    Article  CAS  PubMed  Google Scholar 

  38. Ferrante RJ, et al. Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem. 1997;69(5):2064–74.

    Article  CAS  PubMed  Google Scholar 

  39. Wang X. The antiapoptotic activity of melatonin in neurodegenerative diseases. CNS Neurosci Ther. 2009;15(4):345–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang X, et al. The melatonin MT1 receptor axis modulates mutant Huntingtin-mediated toxicity. J Neurosci. 2011;31(41):14496–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang X, et al. Inhibitors of cytochrome c release with therapeutic potential for Huntington’s disease. J Neurosci. 2008;28(38):9473–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang X, et al. Methazolamide and melatonin inhibit mitochondrial cytochrome C release and are neuroprotective in experimental models of ischemic injury. Stroke. 2009;40(5):1877–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang Y, et al. Melatonin inhibits the caspase-1/cytochrome c/caspase-3 cell death pathway, inhibits MT1 receptor loss and delays disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiol Dis. 2013;55:26–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rival T, et al. Decreasing glutamate buffering capacity triggers oxidative stress and neuropil degeneration in the drosophila brain. Curr Biol. 2004;14(7):599–605.

    Article  CAS  PubMed  Google Scholar 

  45. Weishaupt JH, et al. Reduced oxidative damage in ALS by high-dose enteral melatonin treatment. J Pineal Res. 2006;41(4):313–23.

    Article  CAS  PubMed  Google Scholar 

  46. Dardiotis E, et al. Intraperitoneal melatonin is not neuroprotective in the G93ASOD1 transgenic mouse model of familial ALS and may exacerbate neurodegeneration. Neurosci Lett. 2013;548:170–5.

    Article  CAS  PubMed  Google Scholar 

  47. Rogério F, et al. Superoxide dismutase isoforms 1 and 2 in lumbar spinal cord of neonatal rats after sciatic nerve transection and melatonin treatment. Dev Brain Res. 2005;154(2):217–25.

    Article  CAS  Google Scholar 

  48. Das A, et al. The inhibition of apoptosis by melatonin in VSC4. 1 motoneurons exposed to oxidative stress, glutamate excitotoxicity, or TNF‐α toxicity involves membrane melatonin receptors. J Pineal Res. 2010;48(2):157–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Jacob S, et al. Melatonin as a candidate compound for neuroprotection in amyotrophic lateral sclerosis (ALS): high tolerability of daily oral melatonin administration in ALS patients. J Pineal Res. 2002;33(3):186–7.

    Article  CAS  PubMed  Google Scholar 

  50. Gurney ME, et al. Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann Neurol. 1996;39(2):147–57.

    Article  CAS  PubMed  Google Scholar 

  51. Wang H, et al. Vitamin E intake and risk of amyotrophic lateral sclerosis: a pooled analysis of data from 5 prospective cohort studies. Am J Epidemiol. 2011;173(6):595–602.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Petri S, et al. Cell-permeable peptide antioxidants as a novel therapeutic approach in a mouse model of amyotrophic lateral sclerosis. J Neurochem. 2006;98(4):1141–8.

    Article  CAS  PubMed  Google Scholar 

  53. Wu AS, et al. Iron porphyrin treatment extends survival in a transgenic animal model of amyotrophic lateral sclerosis. J Neurochem. 2003;85(1):142–50.

    Article  CAS  PubMed  Google Scholar 

  54. Petri S, et al. The lipophilic metal chelators DP-109 and DP-460 are neuroprotective in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurochem. 2007;102(3):991–1000.

    Article  CAS  PubMed  Google Scholar 

  55. Durham HD, Dahrouge S, Cashman NR. Evaluation of the spinal cord neuron X neuroblastoma hybrid cell line NSC-34 as a model for neurotoxicity testing. Neurotoxicology. 1993;14(4):387–95.

    CAS  PubMed  Google Scholar 

  56. Kupershmidt L, et al. Neuroprotective and neuritogenic activities of novel multimodal iron-chelating drugs in motor-neuron-like NSC-34 cells and transgenic mouse model of amyotrophic lateral sclerosis. FASEB J. 2009;23(11):3766–79.

    Article  CAS  PubMed  Google Scholar 

  57. Kupershmidt L, et al. Novel molecular targets of the neuroprotective/neurorescue multimodal iron chelating drug M30 in the mouse brain. Neuroscience. 2011;189:345–58.

    Article  CAS  PubMed  Google Scholar 

  58. Henderson JT, et al. Reduction of lower motor neuron degeneration in wobbler mice by N-acetyl-L-cysteine. J Neurosci. 1996;16(23):7574–82.

    CAS  PubMed  Google Scholar 

  59. Andreassen OA, et al. N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis. Neuroreport. 2000;11(11):2491–3.

    Article  CAS  PubMed  Google Scholar 

  60. Vyth A, et al. Survival in patients with amyotrophic lateral sclerosis, treated with an array of antioxidants. J Neurol Sci. 1996;139(Suppl):99–103.

    Article  CAS  PubMed  Google Scholar 

  61. Jung C, et al. Synthetic superoxide dismutase/catalase mimetics reduce oxidative stress and prolong survival in a mouse amyotrophic lateral sclerosis model. Neurosci Lett. 2001;304(3):157–60.

    Article  CAS  PubMed  Google Scholar 

  62. Crow JP, et al. Manganese porphyrin given at symptom onset markedly extends survival of ALS mice. Ann Neurol. 2005;58(2):258–65.

    Article  CAS  PubMed  Google Scholar 

  63. Petri S, et al. Additive neuroprotective effects of a histone deacetylase inhibitor and a catalytic antioxidant in a transgenic mouse model of amyotrophic lateral sclerosis. Neurobiol Dis. 2006;22(1):40–9.

    Article  CAS  PubMed  Google Scholar 

  64. Khiat A, et al. MRS study of the effects of minocycline on markers of neuronal and microglial integrity in ALS. Magn Reson Imaging. 2010;28(10):1456–60.

    Article  CAS  PubMed  Google Scholar 

  65. Crompton M. The mitochondrial permeability transition pore and its role in cell death. Biochem J. 1999;341(Pt 2):233–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Leung AW, Varanyuwatana P, Halestrap AP. The mitochondrial phosphate carrier interacts with cyclophilin D and may play a key role in the permeability transition. J Biol Chem. 2008;283(39):26312–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Vieira HL, et al. The adenine nucleotide translocator: a target of nitric oxide, peroxynitrite, and 4-hydroxynonenal. Oncogene. 2001;20(32):4305–16.

    Article  CAS  PubMed  Google Scholar 

  68. Wang H, et al. Nortriptyline delays disease onset in models of chronic neurodegeneration. Eur J Neurosci. 2007;26(3):633–41.

    Article  PubMed  Google Scholar 

  69. Karlsson J, et al. Life span extension and reduced neuronal death after weekly intraventricular cyclosporin injections in the G93A transgenic mouse model of amyotrophic lateral sclerosis. J Neurosurg. 2004;101(1):128–37.

    Article  CAS  PubMed  Google Scholar 

  70. Keep M, et al. Intrathecal cyclosporin prolongs survival of late-stage ALS mice. Brain Res. 2001;894(2):327–31.

    Article  CAS  PubMed  Google Scholar 

  71. Gribkoff VK, Bozik ME. KNS-760704 [(6R)-4,5,6,7-tetrahydro-N6-propyl-2, 6-benzothiazole-diamine dihydrochloride monohydrate] for the treatment of amyotrophic lateral sclerosis. CNS Neurosci Ther. 2008;14(3):215–26.

    Article  CAS  PubMed  Google Scholar 

  72. Danzeisen R, et al. Targeted antioxidative and neuroprotective properties of the dopamine agonist pramipexole and its nondopaminergic enantiomer SND919CL2x [(+)2-amino-4,5,6,7-tetrahydro-6-Lpropylamino-benzathiazole dihydrochloride]. J Pharmacol Exp Ther. 2006;316(1):189–99.

    Article  CAS  PubMed  Google Scholar 

  73. Bozik ME, et al. Safety, tolerability, and pharmacokinetics of KNS-760704 (dexpramipexole) in healthy adult subjects. J Clin Pharmacol. 2011;51(8):1177–85.

    Article  CAS  PubMed  Google Scholar 

  74. Bordet T, et al. Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exp Ther. 2007;322(2):709–20.

    Article  CAS  PubMed  Google Scholar 

  75. Martin LJ. Olesoxime, a cholesterol-like neuroprotectant for the potential treatment of amyotrophic lateral sclerosis. IDrugs. 2010;13(8):568–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Rovini A, et al. Olesoxime prevents microtubule-targeting drug neurotoxicity: selective preservation of EB comets in differentiated neuronal cells. Biochem Pharmacol. 2010;80(6):884–94.

    Article  CAS  PubMed  Google Scholar 

  77. Andreassen OA, et al. Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation. J Neurochem. 2001;77(2):383–90.

    Article  CAS  PubMed  Google Scholar 

  78. Choi JK, et al. Magnetic resonance spectroscopy of regional brain metabolite markers in FALS mice and the effects of dietary creatine supplementation. Eur J Neurosci. 2009;30(11):2143–50.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Klivenyi P, et al. Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med. 1999;5(3):347–50.

    Article  CAS  PubMed  Google Scholar 

  80. Snow RJ, et al. Creatine supplementation and riluzole treatment provide similar beneficial effects in copper, zinc superoxide dismutase (G93A) transgenic mice. Neuroscience. 2003;119(3):661–7.

    Article  CAS  PubMed  Google Scholar 

  81. Rosenfeld J, et al. Creatine monohydrate in ALS: effects on strength, fatigue, respiratory status and ALSFRS. Amyotroph Lateral Scler. 2008;9(5):266–72.

    Article  CAS  PubMed  Google Scholar 

  82. Kriz J, Nguyen MD, Julien JP. Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiol Dis. 2002;10(3):268–78.

    Article  CAS  PubMed  Google Scholar 

  83. Martin LJ. Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible contribution of a programmed cell death mechanism. J Neuropathol Exp Neurol. 1999;58(5):459–71.

    Article  CAS  PubMed  Google Scholar 

  84. Mattson MP. Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol. 2000;1(2):120–30.

    Article  CAS  PubMed  Google Scholar 

  85. Kostic V, et al. Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis. Science. 1997;277(5325):559–63.

    Article  CAS  PubMed  Google Scholar 

  86. Zhu S, et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature. 2002;417(6884):74–8.

    Article  CAS  PubMed  Google Scholar 

  87. Van Den Bosch L, et al. Minocycline delays disease onset and mortality in a transgenic model of ALS. Neuroreport. 2002;13(8):1067–70.

    Article  Google Scholar 

  88. Zhang W, Narayanan M, Friedlander RM. Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS. Ann Neurol. 2003;53(2):267–70.

    Google Scholar 

  89. Gordon PH, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol. 2007;6(12):1045–53.

    Article  CAS  PubMed  Google Scholar 

  90. Wang X, et al. Characterization of a p75(NTR) apoptotic signaling pathway using a novel cellular model. J Biol Chem. 2001;276(36):33812–20.

    Article  CAS  PubMed  Google Scholar 

  91. Turner BJ, et al. Opposing effects of low and high-dose clozapine on survival of transgenic amyotrophic lateral sclerosis mice. J Neurosci Res. 2003;74(4):605–13.

    Article  CAS  PubMed  Google Scholar 

  92. Yi H, et al. N-Propargylamine protects SH-SY5Y cells from apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, through stabilization of mitochondrial membrane and induction of anti-apoptotic Bcl-2. J Neural Transm. 2006;113(1):21–32.

    Article  CAS  PubMed  Google Scholar 

  93. Waibel S, et al. Rasagiline alone and in combination with riluzole prolongs survival in an ALS mouse model. J Neurol. 2004;251(9):1080–4.

    Google Scholar 

  94. Li M, et al. Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science. 2000;288(5464):335–9.

    Article  CAS  PubMed  Google Scholar 

  95. Sagot Y, et al. An orally active anti-apoptotic molecule (CGP 3466B) preserves mitochondria and enhances survival in an animal model of motoneuron disease. Br J Pharmacol. 2000;131(4):721–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Groeneveld GJ, et al. CGP 3466B has no effect on disease course of (G93A) mSOD1 transgenic mice. Amyotroph Lateral Scler. 2004;5(4):220–5.

    CAS  Google Scholar 

  97. Olanow CW, et al. TCH346 as a neuroprotective drug in Parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol. 2006;5(12):1013–20.

    Article  CAS  PubMed  Google Scholar 

  98. Rothstein JD. Excitotoxicity and neurodegeneration in amyotrophic lateral sclerosis. Clin Neurosci. 1995;3(6):348–59.

    PubMed  Google Scholar 

  99. Bruijn LI, et al. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron. 1997;18(2):327–38.

    Article  CAS  PubMed  Google Scholar 

  100. Trotti D, et al. SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter. Nat Neurosci. 1999;2(9):427–33.

    Article  CAS  PubMed  Google Scholar 

  101. Rothstein JD. Excitotoxic mechanisms in the pathogenesis of amyotrophic lateral sclerosis. Adv Neurol. 1995;68:7–20.

    CAS  PubMed  Google Scholar 

  102. Miller RG, et al. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2007;1:CD001447.

    Google Scholar 

  103. Scott S, et al. Design, power, and interpretation of studies in the standard murine model of ALS. Amyotroph Lateral Scler. 2008;9(1):4–15.

    Google Scholar 

  104. Joo IS, et al. Oral administration of memantine prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis. J Clin Neurol. 2007;3(4):181–6.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Wang R, Zhang D. Memantine prolongs survival in an amyotrophic lateral sclerosis mouse model. Eur J Neurosci. 2005;22(9):2376–80.

    Google Scholar 

  106. Lv L, et al. Therapeutic application of histone deacetylase inhibitors for stroke. Cent Nerv Syst Agents Med Chem. 2011;11(2):138–49.

    Google Scholar 

  107. Monti B, et al. Valproic acid is neuroprotective in the rotenone rat model of Parkinson’s disease: involvement of alpha-synuclein. Neurotox Res. 2010;17(2):130–41.

    Article  CAS  PubMed  Google Scholar 

  108. Sugai F, et al. Benefit of valproic acid in suppressing disease progression of ALS model mice. Eur J Neurosci. 2004;20(11):3179–83.

    Article  PubMed  Google Scholar 

  109. Feng HL, et al. Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model. Neuroscience. 2008;155(3):567–72.

    Google Scholar 

  110. Del Signore SJ, et al. Combined riluzole and sodium phenylbutyrate therapy in transgenic amyotrophic lateral sclerosis mice. Amyotroph Lateral Scler. 2009;10(2):85–94.

    Article  CAS  PubMed  Google Scholar 

  111. Rouaux C, et al. Sodium valproate exerts neuroprotective effects in vivo through CREB-binding protein-dependent mechanisms but does not improve survival in an amyotrophic lateral sclerosis mouse model. J Neurosci. 2007;27(21):5535–45.

    Article  CAS  PubMed  Google Scholar 

  112. Crochemore C, et al. Long-term dietary administration of valproic acid does not affect, while retinoic acid decreases, the lifespan of G93A mice, a model for amyotrophic lateral sclerosis. Muscle Nerve. 2009;39(4):548–52.

    Article  CAS  PubMed  Google Scholar 

  113. Yoo YE, Ko CP. Treatment with trichostatin A initiated after disease onset delays disease progression and increases survival in a mouse model of amyotrophic lateral sclerosis. Exp Neurol. 2011;231(1):147–59.

    Article  CAS  PubMed  Google Scholar 

  114. Maragakis NJ, et al. Topiramate protects against motor neuron degeneration in organotypic spinal cord cultures but not in G93A SOD1 transgenic mice. Neurosci Lett. 2003;338(2):107–10.

    Article  CAS  PubMed  Google Scholar 

  115. Paizs M, et al. Talampanel reduces the level of motoneuronal calcium in transgenic mutant SOD1 mice only if applied presymptomatically. Amyotroph Lateral Scler. 2011;12(5):340–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Rothstein JD, et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature. 2005;433(7021):73–7.

    Article  CAS  PubMed  Google Scholar 

  117. Guo H, et al. Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice. Hum Mol Genet. 2003;12(19):2519–32.

    Article  CAS  PubMed  Google Scholar 

  118. Morimoto RI, Santoro MG. Stress-inducible responses and heat shock proteins: new pharmacologic targets for cytoprotection. Nat Biotechnol. 1998;16(9):833–8.

    Article  CAS  PubMed  Google Scholar 

  119. Kalmar B, Lu C-H, Greensmith L. The role of heat shock proteins in amyotrophic lateral sclerosis: the therapeutic potential of arimoclomol. Pharmacol Ther. 2014;141(1):40–54.

    Article  CAS  PubMed  Google Scholar 

  120. Kakkar V, et al. Barcoding heat shock proteins to human diseases: looking beyond the heat shock response. Dis Model Mech. 2014;7(4):421–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Amm I, Sommer T, Wolf DH. Protein quality control and elimination of protein waste: the role of the ubiquitin–proteasome system. Biochim Biophys Acta (BBA)-Mol Cell Res. 2014;1843(1):182–96.

    Article  CAS  Google Scholar 

  122. Wang J, et al. Progressive aggregation despite chaperone associations of a mutant SOD1-YFP in transgenic mice that develop ALS. Proc Natl Acad Sci. 2009;106(5):1392–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Kieran D, et al. Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nat Med. 2004;10(4):402–5.

    Article  CAS  PubMed  Google Scholar 

  124. Wen J, et al. Edaravone inhibits JNK-c-Jun pathway and restores anti-oxidative defense after ischemia-reperfusion injury in aged rats. Biol Pharm Bull. 2006;29(4):713–8.

    Article  CAS  PubMed  Google Scholar 

  125. Song Y, et al. Edaravone protects PC12 cells from ischemic-like injury via attenuating the damage to mitochondria. J Zhejiang Univ Sci B. 2006;7(9):749–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Yamashita T, et al. The free-radical scavenger, edaravone, augments NO release from vascular cells and platelets after laser-induced, acute endothelial injury in vivo. Platelets. 2006;17(3):201–6.

    Article  CAS  PubMed  Google Scholar 

  127. Qi X, et al. Edaravone protects against hypoxia/ischemia-induced endoplasmic reticulum dysfunction. J Pharmacol Exp Ther. 2004;311(1):388–93.

    Article  CAS  PubMed  Google Scholar 

  128. Green AR, Ashwood T. Free radical trapping as a therapeutic approach to neuroprotection in stroke: experimental and clinical studies with NXY-059 and free radical scavengers. Curr Drug Targets CNS Neurol Disord. 2005;4(2):109–18.

    Article  CAS  PubMed  Google Scholar 

  129. Onimaru S, et al. Inhibitory effects of edaravone on the production of tumor necrosis factor-alpha in the isolated heart undergoing ischemia and reperfusion. Heart Vessels. 2006;21(2):108–15.

    Google Scholar 

  130. Ito H, et al. Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice. Exp Neurol. 2008;213(2):448–55.

    Google Scholar 

  131. Chen RW, et al. Regulation of c-Jun N-terminal kinase, p38 kinase and AP-1 DNA binding in cultured brain neurons: roles in glutamate excitotoxicity and lithium neuroprotection. J Neurochem. 2003;84(3):566–75.

    Google Scholar 

  132. Caldero J, et al. Lithium prevents excitotoxic cell death of motoneurons in organotypic slice cultures of spinal cord. Neuroscience. 2010;165(4):1353–69.

    Google Scholar 

  133. Boillee S, Vande Velde C, Cleveland DW. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron. 2006;52(1):39–59.

    Article  CAS  PubMed  Google Scholar 

  134. Wang S, et al. Role of Wnt1 and Fzd1 in the spinal cord pathogenesis of amyotrophic lateral sclerosis-transgenic mice. Biotechnol Lett. 2013;35(8):1199–207.

    Article  CAS  PubMed  Google Scholar 

  135. Chen Y, et al. Activation of the Wnt/beta-catenin signaling pathway is associated with glial proliferation in the adult spinal cord of ALS transgenic mice. Biochem Biophys Res Commun. 2012;420(2):397–403.

    Article  CAS  PubMed  Google Scholar 

  136. Chen Y, et al. Wnt signaling pathway are involved in pathogenesis of amyotrophic lateral sclerosis in adult transgenic mice. Neurol Res. 2012;34(4):390–9.

    Article  CAS  PubMed  Google Scholar 

  137. Howland DS, et al. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci U S A. 2002;99(3):1604–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Schiffer D, et al. Reactive astrogliosis of the spinal cord in amyotrophic lateral sclerosis. J Neurol Sci. 1996;139:27–33.

    Article  PubMed  Google Scholar 

  139. Okamoto Y, et al. An autopsy case of SOD1-related ALS with TDP-43 positive inclusions. Neurology. 2011;77(22):1993–5.

    Article  CAS  PubMed  Google Scholar 

  140. McGeer PL, McGeer EG. Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve. 2002;26(4):459–70.

    Article  CAS  PubMed  Google Scholar 

  141. Sekizawa T, et al. Cerebrospinal fluid interleukin 6 in amyotrophic lateral sclerosis: immunological parameter and comparison with inflammatory and non-inflammatory central nervous system diseases. J Neurol Sci. 1998;154(2):194–9.

    Article  CAS  PubMed  Google Scholar 

  142. Meissner F, Molawi K, Zychlinsky A. Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis. Proc Natl Acad Sci U S A. 2010;107(29):13046–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Kiaei M, et al. Thalidomide and lenalidomide extend survival in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurosci. 2006;26(9):2467–73.

    Article  CAS  PubMed  Google Scholar 

  144. Trott A, et al. Activation of heat shock and antioxidant responses by the natural product celastrol: transcriptional signatures of a thiol-targeted molecule. Mol Biol Cell. 2008;19(3):1104–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Kiaei M, et al. Celastrol blocks neuronal cell death and extends life in transgenic mouse model of amyotrophic lateral sclerosis. Neurodegener Dis. 2005;2(5):246–54.

    Article  CAS  PubMed  Google Scholar 

  146. Maresz K, et al. Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli. J Neurochem. 2005;95(2):437–45.

    Article  CAS  PubMed  Google Scholar 

  147. Ehrhart J, et al. Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation. J Neuroinflammation. 2005;2:29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Shoemaker JL, et al. The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis when initiated at symptom onset. J Neurochem. 2007;101(1):87–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Kim K, et al. AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis. Eur J Pharmacol. 2006;542(1–3):100–5.

    Article  CAS  PubMed  Google Scholar 

  150. Bilsland LG, et al. Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice. FASEB J. 2006;20(7):1003–5.

    Article  CAS  PubMed  Google Scholar 

  151. Weydt P, et al. Cannabinol delays symptom onset in SOD1 (G93A) transgenic mice without affecting survival. Amyotroph Lateral Scler. 2005;6(3):182–4.

    Article  CAS  Google Scholar 

  152. Neymotin A, et al. Lenalidomide (Revlimid) administration at symptom onset is neuroprotective in a mouse model of amyotrophic lateral sclerosis. Exp Neurol. 2009;220(1):191–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Breidert T, et al. Protective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson’s disease. J Neurochem. 2002;82(3):615–24.

    Article  CAS  PubMed  Google Scholar 

  154. Schütz B, et al. The oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-G93A transgenic mice. J Neurosci. 2005;25(34):7805–12.

    Google Scholar 

  155. Cacabelos R. Pharmacogenomics and therapeutic prospects in Alzheimer’s disease. Expert Opin Pharmacother. 2005;6(12):1967–87.

    Google Scholar 

  156. Van der Schyf CJ, Geldenhuys WJ, Youdim MB. Multifunctional drugs with different CNS targets for neuropsychiatric disorders. J Neurochem. 2006;99(4):1033–48.

    Article  CAS  PubMed  Google Scholar 

  157. Youdim MB. Multi target neuroprotective and neurorestorative anti-Parkinson and anti-Alzheimer drugs ladostigil and m30 derived from rasagiline. Exp Neurobiol. 2013;22(1):1–10.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Berk M, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder – a double-blind randomized placebo-controlled trial. Biol Psychiatry. 2008;64(6):468–75.

    Article  CAS  PubMed  Google Scholar 

  159. Berk M, et al. N-acetyl cysteine as a glutathione precursor for schizophrenia – a double-blind, randomized, placebo-controlled trial. Biol Psychiatry. 2008;64(5):361–8.

    Article  CAS  PubMed  Google Scholar 

  160. Grant JE, Odlaug BL, Kim SW. N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study. Arch Gen Psychiatry. 2009;66(7):756–63.

    Article  CAS  PubMed  Google Scholar 

  161. Kano O, et al. Beneficial effect of pramipexole for motor function and depression in Parkinson’s disease. Neuropsychiatr Dis Treat. 2008;4(4):707.

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Fujiwara S, et al. Anhedonia in Japanese patients with Parkinson’s disease. Geriatr Gerontol Int. 2011;11(3):275–81.

    Article  PubMed  Google Scholar 

  163. Oguro H, et al. Efficacy of pramipexole for treatment of apathy in Parkinson’s disease. Int J Clin Med. 2014;5(15):885.

    Article  CAS  Google Scholar 

  164. Clemens L, et al. Olesoxime improves specific features of the HD pathology. J Neurol Neurosurg Psychiatry. 2012;83 Suppl 1:A53–4.

    Article  Google Scholar 

  165. Roitman S, et al. Creatine monohydrate in resistant depression: a preliminary study. Bipolar Disord. 2007;9(7):754–8.

    Article  CAS  PubMed  Google Scholar 

  166. Watanabe A, Kato N, Kato T. Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation. Neurosci Res. 2002;42(4):279–85.

    Article  CAS  PubMed  Google Scholar 

  167. Verbessem P, et al. Creatine supplementation in Huntington’s disease a placebo-controlled pilot trial. Neurology. 2003;61(7):925–30.

    Article  CAS  PubMed  Google Scholar 

  168. Miyaoka T, et al. Possible antipsychotic effects of minocycline in patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(1):304–7.

    Article  CAS  PubMed  Google Scholar 

  169. Miyaoka T, et al. Minocycline as adjunctive therapy for schizophrenia: an open-label study. Clin Neuropharmacol. 2008;31(5):287–92.

    Article  CAS  PubMed  Google Scholar 

  170. Levkovitz Y, et al. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry. 2010;71(2):138.

    Article  CAS  PubMed  Google Scholar 

  171. Kumra S, et al. Childhood-onset schizophrenia: a double-blind clozapine-haloperidol comparison. Arch Gen Psychiatry. 1996;53(12):1090–7.

    Article  CAS  PubMed  Google Scholar 

  172. Frazier JA, et al. An open trial of clozapine in 11 adolescents with childhood-onset schizophrenia. J Am Acad Child Adolesc Psychiatry. 1994;33(5):658–63.

    Article  CAS  PubMed  Google Scholar 

  173. Hanagasi HA, et al. The effects of rasagiline on cognitive deficits in Parkinson’s disease patients without dementia: a randomized, double‐blind, placebo‐controlled, multicenter study. Mov Disord. 2011;26(10):1851–8.

    Article  PubMed  Google Scholar 

  174. Group PS. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol. 2002;59(12):1937.

    Article  Google Scholar 

  175. Tariot PN, et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004;291(3):317–24.

    Article  CAS  PubMed  Google Scholar 

  176. Muhonen LH, et al. Double-blind, randomized comparison of memantine and escitalopram for the treatment of major depressive disorder comorbid with alcohol dependence. J Clin Psychiatry. 2008;69(3):392–9.

    Article  CAS  PubMed  Google Scholar 

  177. Aboujaoude E, Barry JJ, Gamel N. Memantine augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. J Clin Psychopharmacol. 2009;29(1):51–5.

    Article  CAS  PubMed  Google Scholar 

  178. Orgogozo J-M, et al. Efficacy and safety of memantine in patients with mild to moderate vascular dementia a randomized, placebo-controlled trial (MMM 300). Stroke. 2002;33(7):1834–9.

    Article  CAS  PubMed  Google Scholar 

  179. Aarsland D, et al. Memantine in patients with Parkinson’s disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial. Lancet Neurol. 2009;8(7):613–8.

    Article  CAS  PubMed  Google Scholar 

  180. Kastner T, Finesmith R, Walsh K. Long-term administration of valproic acid in the treatment of affective symptoms in people with mental retardation. J Clin Psychopharmacol. 1993;13(6):448–51.

    Article  CAS  PubMed  Google Scholar 

  181. Kinrys G, et al. Valproic acid for the treatment of social anxiety disorder. Int Clin Psychopharmacol. 2003;18(3):169–72.

    PubMed  Google Scholar 

  182. Abel T, Zukin RS. Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders. Curr Opin Pharmacol. 2008;8(1):57–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Rudenko A, Tsai L-H. Epigenetic regulation in memory and cognitive disorders. Neuroscience. 2014;264:51–63.

    Article  CAS  PubMed  Google Scholar 

  184. McIntyre RS, et al. Topiramate versus Bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single‐blind study. Bipolar Disord. 2002;4(3):207–13.

    Article  CAS  PubMed  Google Scholar 

  185. Claudino AM, et al. Double-blind, randomized, placebo-controlled trial of topiramate plus cognitive-behavior therapy in binge-eating disorder. J Clin Psychiatry. 2007;68(9):1324–32.

    Article  CAS  PubMed  Google Scholar 

  186. Aujla PK, Fetell MR, Jensen FE. Talampanel suppresses the acute and chronic effects of seizures in a rodent neonatal seizure model. Epilepsia. 2009;50(4):694–701.

    Article  PubMed  PubMed Central  Google Scholar 

  187. Bowers MS, Chen BT, Bonci A. AMPA receptor synaptic plasticity induced by psychostimulants: the past, present, and therapeutic future. Neuron. 2010;67(1):11–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Finsterer J. Psychosis as a manifestation of cerebral involvement in mitochondrial disorders. In: Recent advances in clinical medicine. Proceedings of the International Conferences on Medical Pharmacology/Medical Histology and Embryology/Psychiatry and Psychotherapy/International Conference on Oncology. 2010.

    Google Scholar 

  189. Claude Desport PMP, Truong CT, Courat L, Vallat JM, Couratier PJ. Nutritional assessment and survival in ALS patients. Amyotroph Lateral Scler. 2000;1(2):91–6.

    Google Scholar 

  190. Vera G, et al. WIN 55,212-2 prevents mechanical allodynia but not alterations in feeding behaviour induced by chronic cisplatin in the rat. Life Sci. 2007;81(6):468–79.

    Article  CAS  PubMed  Google Scholar 

  191. Pagano C, et al. The endogenous cannabinoid system stimulates glucose uptake in human fat cells via phosphatidylinositol 3-kinase and calcium-dependent mechanisms. J Clin Endocrinol Metab. 2007;92(12):4810–9.

    Article  CAS  PubMed  Google Scholar 

  192. Stommel EW, et al. Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: a phase II open label clinical trial. Amyotroph Lateral Scler. 2009;10(5–6):393–404.

    Article  CAS  PubMed  Google Scholar 

  193. Lenglet T, et al. A phase II–III trial of olesoxime in subjects with amyotrophic lateral sclerosis. Eur J Neurol. 2014;21(3):529–36.

    Article  CAS  PubMed  Google Scholar 

  194. Dupuis L, et al. A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis. PLoS One. 2012;7(6):e37885.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Pandya RS, et al. Therapeutic neuroprotective agents for amyotrophic lateral sclerosis. Cell Mol Life Sci. 2013;70(24):4729–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Liang H, et al. PGC-1α protects neurons and alters disease progression in an amyotrophic lateral sclerosis mouse model. Muscle Nerve. 2011;44(6):947–56.

    Article  CAS  PubMed  Google Scholar 

  197. Da Cruz S, et al. Elevated PGC-1α activity sustains mitochondrial biogenesis and muscle function without extending survival in a mouse model of inherited ALS. Cell Metab. 2012;15(5):778–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Holzbaur EL, et al. Myostatin inhibition slows muscle atrophy in rodent models of amyotrophic lateral sclerosis. Neurobiol Dis. 2006;23(3):697–707.

    Article  CAS  PubMed  Google Scholar 

  199. Morrison BM, et al. A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis. Exp Neurol. 2009;217(2):258–68.

    Article  CAS  PubMed  Google Scholar 

  200. Zhu Y, et al. Neuroprotective agents target molecular mechanisms of disease in ALS. Drug Discov Today. 2014.

    Google Scholar 

  201. Jan JE, O’Donnell ME. Use of melatonin in the treatment of paediatric sleep disorders. J Pineal Res. 1996;21(4):193–9.

    Article  CAS  PubMed  Google Scholar 

  202. Dolberg OT, Hirschmann S, Grunhaus L. Melatonin for the treatment of sleep disturbances in major depressive disorder. Am J Psychiatry. 1998;155(8):1119–21.

    Article  CAS  PubMed  Google Scholar 

  203. Uher R, Mors O, McGuffin P. Antidepressant effects of nortriptyline and escitalopram in the GENDEP study: is one better than the other? Acta Psychiatr Scand. 2013;127(4):330.

    Article  CAS  PubMed  Google Scholar 

  204. Buysse DJ, et al. Longitudinal effects of nortriptyline on EEG sleep and the likelihood of recurrence in elderly depressed patients. Neuropsychopharmacology. 1996;14(4):243–52.

    Article  CAS  PubMed  Google Scholar 

  205. Andrews J. Amyotrophic lateral sclerosis: clinical management and research update. Curr Neurol Neurosci Rep. 2009;9(1):59–68.

    Article  CAS  PubMed  Google Scholar 

  206. Coric V, et al. Riluzole augmentation in treatment-resistant obsessive–compulsive disorder: an open-label trial. Biol Psychiatry. 2005;58(5):424–8.

    Article  CAS  PubMed  Google Scholar 

  207. Zarate Jr CA, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry. 2005;57(4):430–2.

    Article  CAS  PubMed  Google Scholar 

  208. Grant P, et al. An open-label trial of riluzole, a glutamate antagonist, in children with treatment-resistant obsessive-compulsive disorder. J Child Adolesc Psychopharmacol. 2007;17(6):761–7.

    Google Scholar 

  209. Goodman WK, et al. Obsessive-compulsive disorder. Psychiatr Clin N Am. 2014;37(3): 257–67.

    Google Scholar 

  210. Ryu H, et al. Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice. J Neurochem. 2005;93(5):1087–98.

    Google Scholar 

  211. Sedel F, et al. Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults. J Inherit Metab Dis. 2007;30(5):631–41.

    Article  CAS  PubMed  Google Scholar 

  212. Bachmann C. Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr. 2003;162(6):410–6.

    PubMed  Google Scholar 

  213. Krupp L, et al. Study and treatment of post Lyme disease (STOP-LD) A randomized double masked clinical trial. Neurology. 2003;60(12):1923–30.

    Article  CAS  PubMed  Google Scholar 

  214. Mineur YS, Picciotto MR, Sanacora G. Antidepressant-like effects of ceftriaxone in male C57BL/6J mice. Biol Psychiatry. 2007;61(2):250–2.

    Article  CAS  PubMed  Google Scholar 

  215. Guler E, Leyhe T. A late form of neurosyphilis manifesting with psychotic symptoms in old age and good response to ceftriaxone therapy. Int Psychogeriatr. 2011;23(4):666–9.

    Article  PubMed  Google Scholar 

  216. Kalmar B, et al. Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1 mouse model of ALS. J Neurochem. 2008;107(2):339–50.

    Article  CAS  PubMed  Google Scholar 

  217. Shin JH, et al. Concurrent administration of Neu 2000 and lithium produces marked improvement of motor neuron survival, motor function, and mortality in a mouse model of amyotrophic lateral sclerosis. Mol Pharmacol. 2007;71(4):965.

    Article  CAS  PubMed  Google Scholar 

  218. Fornai F, et al. Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci. 2008;105(6):2052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Macritchie K, et al. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev. 2001;3:CD003196.

    Google Scholar 

  220. Goodwin GM, et al. A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry. 2004;65(3):432–41.

    Article  CAS  PubMed  Google Scholar 

  221. Siegel M, et al. Preliminary investigation of lithium for mood disorder symptoms in children and adolescents with autism spectrum disorder. J Child Adolesc Psychopharmacol. 2014;24(7):399–402.

    Google Scholar 

  222. Geddes JR, et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet. 2010;375(9712):385–95.

    Article  CAS  PubMed  Google Scholar 

  223. Allison AC, et al. Celastrol, a potent antioxidant and anti-inflammatory drug, as a possible treatment for Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 2001;25(7):1341–57.

    Article  CAS  PubMed  Google Scholar 

  224. Gamaleddin I, et al. Effects of a selective cannabinoid CB2 agonist and antagonist on intravenous nicotine self administration and reinstatement of nicotine seeking. PLoS One. 2012;7(1):e29900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Pamplona FA, et al. The cannabinoid receptor agonist WIN 55,212-2 facilitates the extinction of contextual fear memory and spatial memory in rats. Psychopharmacology (Berl). 2006;188(4):641–9.

    Article  CAS  Google Scholar 

  226. Haller J, et al. CB1 cannabinoid receptors mediate anxiolytic effects: convergent genetic and pharmacological evidence with CB1-specific agents. Behav Pharmacol. 2004;15(4):299–304.

    Article  CAS  PubMed  Google Scholar 

  227. Imai K, et al. Psychological and mental health problems in patients with thalidomide embryopathy in Japan. Psychiatry Clin Neurosci. 2014;68(6):479–86.

    Article  PubMed  Google Scholar 

  228. Anagnostou E, et al. Autism spectrum disorder: advances in evidence-based practice. Can Med Assoc J. 2014;186(7):509–19.

    Google Scholar 

  229. Chez M, et al. Safety and observations in a pilot study of lenalidomide for treatment in autism. Autism Res Treat. 2012;2012:291601.

    PubMed  PubMed Central  Google Scholar 

  230. West M, et al. The arachidonic acid 5-lipoxygenase inhibitor nordihydroguaiaretic acid inhibits tumor necrosis factor alpha activation of microglia and extends survival of G93A-SOD1 transgenic mice. J Neurochem. 2004;91(1):133–43.

    Google Scholar 

  231. Kiaei M, et al. Peroxisome proliferator-activated receptor-gamma agonist extends survival in transgenic mouse model of amyotrophic lateral sclerosis. Exp Neurol. 2005;191(2):331–6.

    Google Scholar 

  232. Kemp DE, et al. Use of insulin sensitizers for the treatment of major depressive disorder: a pilot study of pioglitazone for major depression accompanied by abdominal obesity. J Affect Disord. 2012;136(3):1164–73.

    Article  CAS  PubMed  Google Scholar 

  233. Edlinger M, et al. Treatment of antipsychotic-associated hyperglycemia with pioglitazone: a case series. J Clin Psychopharmacol. 2007;27(4):403–4.

    Article  PubMed  Google Scholar 

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Acknowledgments

Authors thank Drs. Rachna S. Pandya and Wei (David) Li for review discussion. This work is supported by grants from the MDA (to X. W.), the ALS Therapy Alliance (to X. W.), the Brigham and Women’s Hospital Biomedical Research Institute Fund to Sustain Research Excellence (to X. W.), the Bill & Melinda Gates Foundation (to X. W.), and the National Natural Science Foundation of China (81271413 to Y. G.).

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    Authors and Affiliations

    1. Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

      Anastasios Fotinos, Yongjin Zhu, Edward W. Zhou & Xin Wang PhD

    2. Aimcan Pharma Research and Technologies Inc., 398 Laird Rd, Guelph, ON, N1G 3X7, Canada

      Lilly L. J. Mao & Sarfraz Ahmad

    3. Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

      Nazem Atassi, James D. Berry & Merit E. Cudkowicz

    4. Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong, China

      Yingjun Guan

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    1. Vice-Rectorate for Research and Sci, Camilo José Cela University Vice-Rectorate for Research and Sci, Madrid, Spain

      Francisco López-Muñoz

    2. International Medical Sciences Research Study Center, Sri Sathya Sai Medical Educational & Research Foundation, Coimbatore, India

      Venkataramanujam Srinivasan

    3. Department of Neurosciences and Ima, University of Chieti Department of Neurosciences and Ima, Italy, Italy

      Domenico de Berardis

    4. Department of Biomedical Sciences (Pharmacology Area), University of Alcalá, Madrid, Spain

      Cecilio Álamo

    5. Department of Neuropsychiatry, Kyushu University, Fukuoka, Japan

      Takahiro A. Kato

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    Fotinos, A. et al. (2016). Melatonin and Other Neuroprotective Agents Target Molecular Mechanisms of Disease in Amyotrophic Lateral Sclerosis. In: López-Muñoz, F., Srinivasan, V., de Berardis, D., Álamo, C., Kato, T. (eds) Melatonin, Neuroprotective Agents and Antidepressant Therapy. Springer, New Delhi. https://doi.org/10.1007/978-81-322-2803-5_51

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