Glial Cells in ALS: The Missing Link?

Elsa Raibon1, Lisa Marie Todd2, Thomas Möller1
1Department of Neurology, University of Washington, Box 356465, 1959 NE Pacific Street, Seattle, WA 98195, USA
2Department of Rehabilitation Medicine, University of Washington, Box 356490, 1959 NE Pacific Street, Seattle, WA 98195, USA

Tài liệu tham khảo

Rowland, 2001, How amyotrophic lateral sclerosis got its name: the clinical-pathologic genius of Jean-Martin Charcot, Arch Neurol, 58, 512, 10.1001/archneur.58.3.512 Brown, 2000, Amyotrophic lateral sclerosis Bruijn, 2004, Unraveling the mechanisms involved in motor neuron degeneration in ALS, Annu Rev Neurosci, 27, 723, 10.1146/annurev.neuro.27.070203.144244 Strong, 2003, Amyotrophic lateral sclerosis: a review of current concepts, Amyotroph Lateral Scler Other Motor Neuron Disord, 4, 136, 10.1080/14660820310011250 Cleveland, 2001, From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS, Nat Rev Neurosci, 2, 806, 10.1038/35097565 Ludolph, 2000, The role of excitotoxicity in ALS—what is the evidence?, J Neurol, 247, I7, 10.1007/s004150050552 Robberecht, 2000, Oxidative stress in amyotrophic lateral sclerosis, J Neurol, 247, I1, 10.1007/s004150050551 Shaw, 2000, Molecular factors underlying selective vulnerability of motor neurons to neurodegeneration in amyotrophic lateral sclerosis, J Neurol, 247, I17, 10.1007/BF03161151 Weydt, 2005, Neuroinflammation in the pathogenesis of amyotrophic lateral sclerosis, Neuroreport, 16, 527, 10.1097/00001756-200504250-00001 Eisen, 1995, Amyotrophic lateral sclerosis is a multifactorial disease, Muscle Nerve, 18, 741, 10.1002/mus.880180711 Strong, 2005, The pathobiology of amyotrophic lateral sclerosis: a proteinopathy?, J Neuropathol Exp Neurol, 64, 649, 10.1097/01.jnen.0000173889.71434.ea Dhib-Jalbut, 2006, Neurodegeneration and neuroprotection in multiple sclerosis and other neurodegenerative diseases, J Neuroimmunol, 176, 198, 10.1016/j.jneuroim.2006.03.027 Kreutzberg, 1996, Microglia: a sensor for pathological events in the CNS, Trends Neurosci, 19, 312, 10.1016/0166-2236(96)10049-7 Streit, 2006, Microglial senescence: does the brain's immune system have an expiration date?, Trends Neurosci, 29, 506, 10.1016/j.tins.2006.07.001 Streit, 1999, Reactive microgliosis, Prog Neurobiol, 57, 563, 10.1016/S0301-0082(98)00069-0 McGeer, 1999, Brain inflammation in Alzheimer disease and the therapeutic implications, Curr Pharm Des, 5, 821, 10.2174/1381612805666230111212056 2002 Streit, 2002, Microglia as neuroprotective, immunocompetent cells of the CNS, Glia, 40, 133, 10.1002/glia.10154 Nimmerjahn, 2005, Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo, Science, 308, 1314, 10.1126/science.1110647 Hanisch, 2001, Microglia as a source and target of cytokines activities in the brain Wyss-Coray, 2002, Inflammation in neurodegenerative disease—a double-edged sword, Neuron, 35, 419, 10.1016/S0896-6273(02)00794-8 Brown, 2007, Astrocyte glycogen and brain energy metabolism, Glia, 55, 1263, 10.1002/glia.20557 Abbott, 2006, Astrocyte-endothelial interactions at the blood-brain barrier, Nat Rev Neurosci, 7, 41, 10.1038/nrn1824 Haydon, 2006, Astrocyte control of synaptic transmission and neurovascular coupling, Physiol Rev, 86, 1009, 10.1152/physrev.00049.2005 Montana, 2006, Vesicular transmitter release from astrocytes, Glia, 54, 700, 10.1002/glia.20367 Sattler, 2006, Regulation and dysregulation of glutamate transporters, Handb Exp Pharmacol, 175, 277, 10.1007/3-540-29784-7_14 Dong, 2001, Immune function of astrocytes, Glia, 36, 10.1002/glia.1107 Farina, 2007, Astrocytes are active players in cerebral innate immunity, Trends Immunol, 28, 138, 10.1016/j.it.2007.01.005 Tilleux, 2007, Neuroinflammation and regulation of glial glutamate uptake in neurological disorders, J Neurosci Res, 85, 2059, 10.1002/jnr.21325 de Haas, 2007, Neuronal chemokines: versatile messengers in central nervous system cell interaction, Mol Neurobiol, 36, 137, 10.1007/s12035-007-0036-8 Ince, 1996, Familial amyotrophic lateral sclerosis with a mutation in exon 4 of the Cu/Zn superoxide dismutase gene: pathological and immunocytochemical changes, Acta Neuropathol (Berl), 92, 395, 10.1007/s004010050535 Kawamata, 1992, Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue, Am J Pathol, 140, 691 Ince, 2000, Neuropathology of ALS, 83 Turner, 2004, Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study, Neurobiol Dis, 15, 601, 10.1016/j.nbd.2003.12.012 Alexianu, 2001, Immune reactivity in a mouse model of familial ALS correlates with disease progression, Neurology, 57, 1282, 10.1212/WNL.57.7.1282 Hall, 1998, Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS, Glia, 23, 249, 10.1002/(SICI)1098-1136(199807)23:3<249::AID-GLIA7>3.0.CO;2-# Olsen, 2001, Disease mechanisms revealed by transcription profiling in SOD1-G93A transgenic mouse spinal cord, Ann Neurol, 50, 730, 10.1002/ana.1252 Yoshihara, 2002, Differential expression of inflammation- and apoptosis-related genes in spinal cords of a mutant SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis, J Neurochem, 80, 158, 10.1046/j.0022-3042.2001.00683.x Elliott, 2001, Cytokine upregulation in a murine model of familial amyotrophic lateral sclerosis, Brain Res Mol Brain Res, 95, 172, 10.1016/S0169-328X(01)00242-X Nguyen, 2001, Induction of proinflammatory molecules in mice with amyotrophic lateral sclerosis: no requirement for proapoptotic interleukin-1beta in neurodegeneration, Ann Neurol, 50, 630, 10.1002/ana.1256 Hensley, 2002, Temporal patterns of cytokine and apoptosis-related gene expression in spinal cords of the G93A-SOD1 mouse model of amyotrophic lateral sclerosis, J Neurochem, 82, 365, 10.1046/j.1471-4159.2002.00968.x Almer, 2001, Increased expression of the pro-inflammatory enzyme cyclooxygenase-2 in amyotrophic lateral sclerosis, Ann Neurol, 49, 176, 10.1002/1531-8249(20010201)49:2<176::AID-ANA37>3.0.CO;2-X Chen, 2004, Temporal gene expression patterns in G93A/SOD1 mouse, Amyotroph Lateral Scler Other Motor Neuron Disord, 5, 164, 10.1080/14660820410017091 Xie, 2004, Expression of neuroinflammatory mediators and growth factors in the spinal cord of the G93A SOD1 transgenic rats, Neuroreport, 15, 2513, 10.1097/00001756-200411150-00016 Moreau, 2005, Elevated IL-6 and TNF-alpha levels in patients with ALS: inflammation or hypoxia?, Neurology, 65, 1958, 10.1212/01.wnl.0000188907.97339.76 Dengler, 2005, Amyotrophic lateral sclerosis: new developments in diagnostic markers, Neurodegener Dis, 2, 177, 10.1159/000089623 Raoul, 2002, Motoneuron death triggered by a specific pathway downstream of Fas. potentiation by ALS-linked SOD1 mutations, Neuron, 35, 1067, 10.1016/S0896-6273(02)00905-4 Figlewicz, 2000, Culture models of neurodegenerative disease, Ann N Y Acad Sci, 919, 106, 10.1111/j.1749-6632.2000.tb06873.x Wen, 2006, Activated microglial supernatant induced motor neuron cytotoxicity is associated with upregulation of the TNFR1 receptor, Neurosci Res, 55, 87, 10.1016/j.neures.2006.02.004 Engelhardt, 1993, Lymphocytic infiltrates in the spinal cord in amyotrophic lateral sclerosis, Arch Neurol, 50, 30, 10.1001/archneur.1993.00540010026013 Holmoy, 2008, T cells in amyotrophic lateral sclerosis, Eur J Neurol, 15, 360, 10.1111/j.1468-1331.2008.02065.x Villoslada, 2004, Role of nerve growth factor and other trophic factors in brain inflammation, Prog Brain Res, 146, 403, 10.1016/S0079-6123(03)46025-1 Beck, 2001, Motoneuron cell death and neurotrophic factors: basic models for development of new therapeutic strategies in ALS, Amyotroph Lateral Scler Other Motor Neuron Disord, 2, S55, 10.1080/146608201300079454 Oosthuyse, 2001, Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration, Nat Genet, 28, 131, 10.1038/88842 Markus, 2002, Neurotrophic factors and axonal growth, Curr Opin Neurobiol, 12, 523, 10.1016/S0959-4388(02)00372-0 Lambrechts, 2004, VEGF: necessary to prevent motoneuron degeneration, sufficient to treat ALS?, Trends Mol Med, 10, 275, 10.1016/j.molmed.2004.04.004 Greenberg, 2004, VEGF and ALS: the luckiest growth factor?, Trends Mol Med, 10, 1, 10.1016/j.molmed.2003.11.006 Clement, 2003, Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice, Science, 302, 113, 10.1126/science.1086071 Boillee, 2006, Onset and progression in inherited ALS determined by motor neurons and microglia, Science, 312, 1389, 10.1126/science.1123511 Beers, 2006, Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis, Proc Natl Acad Sci U S A, 103, 16021, 10.1073/pnas.0607423103 Weydt, 2004, Increased cytotoxic potential of microglia from ALS-transgenic mice, Glia, 48, 179, 10.1002/glia.20062 Xiao, 2007, Mutant SOD1(G93A) microglia are more neurotoxic relative to wild-type microglia, J Neurochem, 102, 2008, 10.1111/j.1471-4159.2007.04677.x Urushitani, 2006, Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis, Nat Neurosci, 9, 108, 10.1038/nn1603 Knott, 2007, ALS: astrocytes take center stage, but must they share the spotlight?, Cell Death Differ, 14, 1985, 10.1038/sj.cdd.4402241 Holden, 2007, Neuroscience. Astrocytes secrete substance that kills motor neurons in ALS, Science, 316, 353, 10.1126/science.316.5823.353a Julien, 2007, ALS: astrocytes move in as deadly neighbors, Nat Neurosci, 10, 535, 10.1038/nn0507-535 Rothstein, 1995, Excitotoxicity and neurodegeneration in amyotrophic lateral sclerosis, Clin Neurosci, 3, 348 Van Den Bosch, 2006, The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis, Biochim Biophys Acta, 1762, 1068, 10.1016/j.bbadis.2006.05.002 Nagai, 2007, Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons, Nat Neurosci, 10, 615, 10.1038/nn1876 Als-Tdf Turner, 2001, Clinical trials in ALS: an overview, Semin Neurol, 21, 167, 10.1055/s-2001-15262 Carri, 2006, Targets in ALS: designing multidrug therapies, Trends Pharmacol Sci, 27, 267, 10.1016/j.tips.2006.03.009 Traynor, 2006, Neuroprotective agents for clinical trials in ALS: a systematic assessment, Neurology, 67, 20, 10.1212/01.wnl.0000223353.34006.54 Miller, 2003, Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND), Amyotroph Lateral Scler Other Motor Neuron Disord, 4, 191, 10.1080/14660820310002601 McGeer, 2002, Inflammatory processes in amyotrophic lateral sclerosis, Muscle Nerve, 26, 459, 10.1002/mus.10191 Jankowsky, 2002, Transgenic mouse models of neurodegenerative disease: opportunities for therapeutic development, Curr Neurol Neurosci Rep, 2, 457, 10.1007/s11910-002-0073-7 Julien, 2006, Transgenic mouse models of amyotrophic lateral sclerosis, Biochim Biophys Acta, 1762, 1013, 10.1016/j.bbadis.2006.03.006 Benatar, 2007, Lost in translation: treatment trials in the SOD1 mouse and in human ALS, Neurobiol Dis, 26, 1, 10.1016/j.nbd.2006.12.015 Rothstein, 2003, Of mice and men: reconciling preclinical ALS mouse studies and human clinical trials, Ann Neurol, 53, 423, 10.1002/ana.10561 Weydt, 2002, Neuro-inflammation as a therapeutic target in amyotrophic lateral sclerosis, Curr Opin Investig Drugs, 3, 1720 Dimayuga, 2007, SOD1 overexpression alters ROS production and reduces neurotoxic inflammatory signaling in microglial cells, J Neuroimmunol, 182, 89, 10.1016/j.jneuroim.2006.10.003 Rocca, 2002, Cyclooxygenases and prostaglandins: shaping up the immune response, Int Immunopharmacol, 2, 603, 10.1016/S1567-5769(01)00204-1 FitzGerald, 2003, COX-2 and beyond: approaches to prostaglandin inhibition in human disease, Nat Rev Drug Discov, 2, 879, 10.1038/nrd1225 Kaufmann, 1996, COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex, Proc Natl Acad Sci U S A, 93, 2317, 10.1073/pnas.93.6.2317 Consilvio, 2004, Neuroinflammation, COX-2, and ALS—a dual role?, Exp Neurol, 187, 1, 10.1016/j.expneurol.2003.12.009 Engblom, 2002, Prostaglandins as inflammatory messengers across the blood-brain barrier, J Mol Med, 80, 5, 10.1007/s00109-001-0289-z Takadera, 2002, Prostaglandin E(2) induces caspase-dependent apoptosis in rat cortical cells, Neurosci Lett, 317, 61, 10.1016/S0304-3940(01)02449-1 Wang, 2004, Role of reactive oxygen species in LPS-induced production of prostaglandin E2 in microglia, J Neurochem, 88, 939, 10.1046/j.1471-4159.2003.02242.x Ilzecka, 2003, Prostaglandin E2 is increased in amyotrophic lateral sclerosis patients, Acta Neurol Scand, 108, 125, 10.1034/j.1600-0404.2003.00102.x Almer, 2002, Increased levels of the pro-inflammatory prostaglandin PGE2 in CSF from ALS patients, Neurology, 58, 1277, 10.1212/WNL.58.8.1277 Yokota, 2004, Increased expression of neuronal cyclooxygenase-2 in the hippocampus in amyotrophic lateral sclerosis both with and without dementia, Acta Neuropathol, 107, 399, 10.1007/s00401-004-0826-2 Yasojima, 2001, Marked increase in cyclooxygenase-2 in ALS spinal cord: implications for therapy, Neurology, 57, 952, 10.1212/WNL.57.6.952 Drachman, 2002, Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS, Ann Neurol, 52, 771, 10.1002/ana.10374 Pompl, 2003, A therapeutic role for cyclooxygenase-2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis, FASEB J, 17, 725, 10.1096/fj.02-0876fje Klivenyi, 2003, Additive neuroprotective effects of creatine and a cyclooxygenase 2 inhibitor against dopamine depletion in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease, J Mol Neurosci, 21, 191, 10.1385/JMN:21:3:191 Cudkowicz, 2006, Trial of celecoxib in amyotrophic lateral sclerosis, Ann Neurol, 60, 22, 10.1002/ana.20903 Yrjanheikki, 1998, Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia, Proc Natl Acad Sci U S A, 95, 15769, 10.1073/pnas.95.26.15769 Yrjanheikki, 1999, A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window, Proc Natl Acad Sci U S A, 96, 13496, 10.1073/pnas.96.23.13496 Teng, 2004, Minocycline inhibits contusion-triggered mitochondrial cytochrome c release and mitigates functional deficits after spinal cord injury, Proc Natl Acad Sci U S A, 101, 3071, 10.1073/pnas.0306239101 Tikka, 2001, Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia, J Neurosci, 21, 2580, 10.1523/JNEUROSCI.21-08-02580.2001 Tikka, 2001, Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia, J Immunol, 166, 7527, 10.4049/jimmunol.166.12.7527 Wu, 2002, Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease, J Neurosci, 22, 1763, 10.1523/JNEUROSCI.22-05-01763.2002 Kriz, 2002, Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis, Neurobiol Dis, 10, 268, 10.1006/nbdi.2002.0487 Van Den Bosch, 2002, Minocycline delays disease onset and mortality in a transgenic model of ALS, Neuroreport, 13, 1067, 10.1097/00001756-200206120-00018 Zhu, 2002, Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice, Nature, 417, 74, 10.1038/417074a Gordon, 2004, Placebo-controlled phase I/II studies of minocycline in amyotrophic lateral sclerosis, Neurology, 62, 1845, 10.1212/01.WNL.0000125321.92112.7E Pontieri, 2005, Minocycline in amyotrophic lateral sclerosis: a pilot study, Neurol Sci, 26, 285, 10.1007/s10072-005-0474-x Butler, 2006, Histone deacetylase inhibitors as therapeutics for polyglutamine disorders, Nat Rev Neurosci, 7, 784, 10.1038/nrn1989 Saha, 2006, HATs and HDACs in neurodegeneration: a tale of disconcerted acetylation homeostasis, Cell Death Differ, 13, 539, 10.1038/sj.cdd.4401769 Ryu, 2005, Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice, J Neurochem, 93, 1087, 10.1111/j.1471-4159.2005.03077.x Tremolizzo, 2005, Valproate and HDAC inhibition: a new epigenetic strategy to mitigate phenotypic severity in ALS?, Amyotroph Lateral Scler Other Motor Neuron Disord, 6, 185, 10.1080/14660820510033614 Blanchard, 2005, Histone deacetylase inhibitors: new drugs for the treatment of inflammatory diseases?, Drug Discov Today, 10, 197, 10.1016/S1359-6446(04)03309-4 Kelly, 2005, Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer, J Clin Oncol, 23, 3923, 10.1200/JCO.2005.14.167 Adcock, 2006, Histone deacetylase inhibitors as novel anti-inflammatory agents, Curr Opin Investig Drugs, 7, 966 Leoni, 2002, The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines, Proc Natl Acad Sci U S A, 99, 2995, 10.1073/pnas.052702999 Franks, 2004, Thalidomide, Lancet, 363, 1802, 10.1016/S0140-6736(04)16308-3 Teo, 2005, Thalidomide as a novel therapeutic agent: new uses for an old product, Drug Discov Today, 10, 107, 10.1016/S1359-6446(04)03307-0 Kiaei, 2006, Thalidomide and Lenalidomide extend survival in a transgenic mouse model of amyotrophic lateral sclerosis, J Neurosci, 26, 2467, 10.1523/JNEUROSCI.5253-05.2006 ALS-TDI. ALS TDI Animal Studies: CoQ10 I. 2003. Available at: http://www.als.net/research/studies/animalStudyDetail.asp?studyType=internal&studyID=44. ALS-TDI. ALS TDI Animals studies: Prednisolone I. 2003. Available at: http://www.als.net/research/studies/animalStudyDetail.asp?studyType=internal&studyID=170. Werdelin, 1990, Immunosuppressive treatment of patients with amyotrophic lateral sclerosis, Acta Neurol Scand, 82, 132, 10.1111/j.1600-0404.1990.tb01602.x ALS-TDI. ALS TDI Animals studies: Minocycline I II III. 2003. Available at: http://www.als.net/research/treatments/treatmentDetail.asp?studyType=all&treatmentId=459. Diguet, 2004, Rise and fall of minocycline in neuroprotection: need to promote publication of negative results, Exp Neurol, 189, 1, 10.1016/j.expneurol.2004.05.016 Zhang, 2003, Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS, Ann Neurol, 53, 267, 10.1002/ana.10476 Gordon, 2007, Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial, Lancet Neurol, 6, 1045, 10.1016/S1474-4422(07)70270-3 ALS-TDI. ALS TDI Animals studies: Thalidomide I–IV. 2001–2005. Available at: http://www.als.net/research/treatments/treatmentDetail.asp?studyType=internal&treatmentId=707. ALS-TDI. ALS TDI Animal Studies: Celebrex I–III. 2001–2005. Available at: http://www.als.net/research/treatments/treatmentDetail.asp?studyType=internal&treatmentId=137. 1996, A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. ALS CNTF Treatment Study Group, Neurology, 46, 1244, 10.1212/WNL.46.5.1244 Aebischer, 1996, Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients, Nat Med, 2, 696, 10.1038/nm0696-696 Suzuki, 2007, GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial ALS, PLoS ONE, 2, e689, 10.1371/journal.pone.0000689 Li, 2007, Muscle-derived but not centrally derived transgene GDNF is neuroprotective in G93A-SOD1 mouse model of ALS, Exp Neurol, 203, 457, 10.1016/j.expneurol.2006.08.028 Azzouz, 2004, VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model, Nature, 429, 413, 10.1038/nature02544 Zheng, 2007, VEGF reduces astrogliosis and preserves neuromuscular junctions in ALS transgenic mice, Biochem Biophys Res Commun, 363, 989, 10.1016/j.bbrc.2007.09.088 Storkebaum, 2005, Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS, Nat Neurosci, 8, 85, 10.1038/nn1360 Karlsson, 2004, Life span extension and reduced neuronal death after weekly intraventricular cyclosporin injections in the G93A transgenic mouse model of amyotrophic lateral sclerosis, J Neurosurg, 101, 128, 10.3171/jns.2004.101.1.0128 Kirkinezos, 2004, An ALS mouse model with a permeable blood-brain barrier benefits from systemic cyclosporine A treatment, J Neurochem, 88, 821, 10.1046/j.1471-4159.2003.02181.x Appel, 1988, A double-blind study of the effectiveness of cyclosporine in amyotrophic lateral sclerosis, Arch Neurol, 45, 381, 10.1001/archneur.1988.00520280027011 Anneser, 2001, Immunosuppressant FK506 does not exert beneficial effects in symptomatic G93A superoxide dismutase-1 transgenic mice, Neuroreport, 12, 2663, 10.1097/00001756-200108280-00015 ALS-TDI. ALS TDI Animals studies: Sodium Valproate I. 2001. Available at: http://www.als.net/research/studies/animalStudyDetail.asp?studyType=internal&studyID=215. UMC Utrecht Clinical Trials Phase III. Sodium Valproate. 2005. Available at: http://www.als.net/research/studies/currentClinicalTrialDetail.asp?studyID=18. ALS-TDI. ALS TDI Animals studies: Trichostatin A I. 2002. Available at: http://www.als.net/research/studies/animalStudyDetail.asp?studyType=internal&studyID=238.