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52 - Current and potential therapeutics in motor neuron diseases

from Part IX - Motor neuron diseases

Published online by Cambridge University Press:  04 August 2010

M. Flint Beal ,
Anthony E. Lang  and
Albert C. Ludolph
By
Clare Wood-Allum  and
Pamela J. Shaw
M. Flint Beal
Affiliation:
Cornell University, New York
Anthony E. Lang
Affiliation:
University of Toronto
Albert C. Ludolph
Affiliation:
Universität Ulm, Germany
Clare Wood-Allum
Affiliation:
Academic Neurology Unit, Sheffield University Medical School, UK
Pamela J. Shaw
Affiliation:
Academic Neurology Unit, Sheffield University Medical School, UK
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Summary

Introduction

This chapter will survey the research underpinning current therapeutic candidates for amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP), Kennedy's disease (SBMA) and spinal muscular atrophy (SMA). It will also review the evidence base and rationale for the use of riluzole in ALS, the only disease-modifying agent currently licensed for use in any neurodegenerative disease of the motor neuron. In the absence of effective therapies to slow disease progression, the focus of management must be on symptomatic therapies aimed at improving quality of life. Guidelines for the symptomatic management of ALS have been generated by the American Academy of Neurology (Miller et al., 1999b) and a number of systematic reviews of the symptomatic management of ALS are also available from the Cochrane library – symptomatic therapies will not be further discussed here (Annane et al., 2000; Langmore et al., 2003). In recent years, improvements in materials science, bioinformatics and the development of exciting new techniques in molecular biology have brought about a revolution in the way that therapeutic candidates are selected and tested. The likely impact of these new techniques on drug development for disorders of motor neurons will also be discussed.

Disease modifying therapies for amyotrophic lateral sclerosis

Aims of therapy

Motor neurons are post-mitotic cells, which make numerous, complex synaptic connections. They are found in the motor cortex, the brainstem and along the entire length of the spinal cord.

Type
Chapter
Information
Neurodegenerative Diseases
Neurobiology, Pathogenesis and Therapeutics
 , pp. 772 - 793
Publisher: Cambridge University Press
Print publication year: 2005

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References

Abel, A., Walcott, J., Woods, J., Duda, J. & Merry, D. E. (2001). Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice. Hum. Mol. Genet., 10, 107–16CrossRefGoogle ScholarPubMed
Acsadi, G., Anguelov, R. A., Yang, H.et al. (2002). Increased survival and function of SOD1 mice after glial cell-derived neurotrophic factor gene therapy. Hum. Gene. Ther., 13, 1047–59CrossRefGoogle ScholarPubMed
Adachi, H., Katsuno, M., Minamiyama, M.et al. (2003). Heat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model by reducing nuclear-localized mutant androgen receptor protein. J. Neurosci., 23, 2203–11CrossRefGoogle ScholarPubMed
Almer, G., Guegan, C., Teismann, P.et al. (2001). Increased expression of the pro-inflammatory enzyme cyclooxygenase-2 in amyotrophic lateral sclerosis. Ann. Neurol., 49, 176–853.0.CO;2-X>CrossRefGoogle ScholarPubMed
Andreassen, O. A., Dedeoglu, A., Klivenyi, P., Beal, M. F. & Bush, A. I. (2000). N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis. Neuroreport, 11, 2491–3CrossRefGoogle Scholar
Andreassi, C., Jarecki, J., Zhou, J.et al. (2001). Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients. Hum. Mol. Genet., 10, 2841–9CrossRefGoogle ScholarPubMed
Andreassi, C., Angelozzi, C., Tiziano, F. D.et al. (2004). Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy. Eur. J. Hum. Genet., 12, 59–65CrossRefGoogle ScholarPubMed
Andrus, P. K., Fleck, T. J., Gurney, M. E. & Hall, E. D. (1998). Protein oxidative damage in a transgenic mouse model of familial amyotrophic lateral sclerosis. J. Neurochem., 71, 2041–8CrossRefGoogle Scholar
Annane, D., Chevrolet, J. C., Chevret, S. & Raphael, J. C. (2000). Nocturnal mechanical ventilation for chronic hypoventilation in patients with neuromuscular and chest wall disorders. Cochrane Database Syst Rev., CD001941CrossRefGoogle ScholarPubMed
Appel, S. H., Alexianu, M., Engelhardt, J. I. et al. (2000). Involvement of immune factors in motor neuron cell injury in amyotrophic lateral sclerosis. In Amyotrophic Lateral Sclerosis, ed. R. H. Brown, V. Meininger & M. Swash, pp. 309–26. London, UK: Martin Dunitz
Ashton, D., Willems, R., Wynants, J.et al. (1997). Altered Na(+)-channel function as an in vitro model of the ischemic penumbra: action of lubeluzole and other neuroprotective drugs. Brain Res., 745, 210–21CrossRefGoogle Scholar
Bailey, C. K., Andriola, I. F., Kampinga, H. H. & Merry, D. E. (2002). Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy. Hum. Mol. Genet., 11, 515–23CrossRefGoogle Scholar
Banks, R. E., Dunn, M. J., Hochstrasser, D. F.et al. (2000). Proteomics: new perspectives, new biomedical opportunities. Lancet, 356, 1749–56CrossRefGoogle ScholarPubMed
Bensimon, G., Lacomblez, L. & Meininger, V. (1994). A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N. Engl. J. Med., 330, 585–91CrossRefGoogle ScholarPubMed
Beretta, S., Sala, G., Mattavelli, L.et al. (2003). Mitochondrial dysfunction due to mutant copper/zinc superoxide dismutase associated with amyotrophic lateral sclerosis is reversed by N-acetylcysteine. Neurobiol. Dis., 13, 213–21CrossRefGoogle ScholarPubMed
Blin, O., Pouget, J., Aubrespy, G.et al. (1992). A double-blind placebo-controlled trial of L-threonine in amyotrophic lateral sclerosis. J. Neurol., 239, 79–81CrossRefGoogle ScholarPubMed
Borasio, G. D., Robberecht, W., Leigh, P. N.et al. (1998). A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I Study Group. Neurology, 51, 583–6CrossRefGoogle ScholarPubMed
Bordet, T., Lesbordes, J. C., Rouhani, S.et al. (2001). Protective effects of cardiotrophin-1 adenoviral gene transfer on neuromuscular degeneration in transgenic ALS mice. Hum. Mol. Genet., 10, 1925–33CrossRefGoogle ScholarPubMed
Borthwick, G. M., Johnson, M. A., Ince, P. G., Shaw, P. J. & Turnbull, D. M. (1999). Mitochondrial enzyme activity in amyotrophic lateral sclerosis: implications for the role of mitochondria in neuronal cell death. Ann. Neurol., 46, 787–903.0.CO;2-8>CrossRefGoogle ScholarPubMed
Brichta, L., Hofmann, Y., Hahnen, E.et al. (2003). Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy. Hum. Mol. Genet., 12, 2481–9CrossRefGoogle ScholarPubMed
Brown, R. H., Hauser, S. L.Jr., Harrington, H. & Weiner, H. L. (1986). Failure of immunosuppression with a ten- to 14-day course of high-dose intravenous cyclophosphamide to alter the progression of amyotrophic lateral sclerosis. Arch. Neurol., 43, 383–4CrossRefGoogle ScholarPubMed
Caroni, P. (1993). Activity-sensitive signaling by muscle-derived insulin-like growth factors in the developing and regenerating of neuromuscular system. Ann. NY Acad. Sci., 692, 209–22CrossRefGoogle ScholarPubMed
Cartegni, L. & Krainer, A. R. (2003). Correction of disease-associated exon skipping by synthetic exon-specific activators. Nat. Struct. Biol., 10, 120–5CrossRefGoogle ScholarPubMed
Cassiman, D., Thomeer, M., Verbeken, E. & Robberecht, W. (2003). Hypersensitivity pneumonitis possibly caused by riluzole therapy in ALS. Neurology, 61, 1150–1CrossRefGoogle ScholarPubMed
Chang, J. G., Hsieh-Li, H. M., Jong, Y. J.et al. (2001). Treatment of spinal muscular atrophy by sodium butyrate. Proc. Natl Acad. Sci., USA, 98, 9808–13CrossRefGoogle ScholarPubMed
Cheramy, A., Barbeito, L., Godeheu, G. & Glowinski, J. (1992). Riluzole inhibits the release of glutamate in the caudate nucleus of the cat in vivo. Neurosci. Lett., 147, 209–12CrossRefGoogle ScholarPubMed
Clement, A. M., Nguyen, M. D., Roberts, E. A.et al. (2003). Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science, 302, 113–17CrossRefGoogle ScholarPubMed
Collins, A. F., Pearson, H. A., Giardina, P.et al. (1995). Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: a clinical trial. Blood, 85, 43–9Google ScholarPubMed
Davenport, R. J., Swingler, R. J., Chancellor, A. M. & Warlow, C. P. (1996). Avoiding false positive diagnoses of motor neuron disease: lessons from the Scottish Motor Neuron Disease Register. J. Neurol. Neurosurg. Psychiatr., 60, 147–51CrossRefGoogle ScholarPubMed
Davidson, B. L., Stein, C. S., Heth, J. A.et al. (2000). Recombinant adeno-associated virus type 2, 4, and 5 vectors: transduction of variant cell types and regions in the mammalian central nervous system. Proc. Natl Acad. Sci., USA, 97, 3428–32CrossRefGoogle ScholarPubMed
Debove, C., Zeisser, P., Salzman, P. M., Powe, L. K. & Truffinet, P. (2001). The Rilutek (riluzole) Global Early Access Programme: an open-label safety evaluation in the treatment of amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Other Motor Neuron Disord., 2, 153–8CrossRefGoogle ScholarPubMed
Desnuelle, C., Dib, M., Garrel, C. & Favier, A. (2001). A double-blind, placebo-controlled randomized clinical trial of alpha-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group. Amyotroph. Lateral Scler. Other Motor Neuron Disord., 2, 9–18CrossRefGoogle ScholarPubMed
Doble, A. (1996). The pharmacology and mechanism of action of riluzole. Neurology, 47, S233–41CrossRefGoogle ScholarPubMed
Doble, A. & Kennel, P. (2000). Animal models of amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Other Motor Neuron Disord., 1, 301–12CrossRefGoogle ScholarPubMed
Drachman, D. B., Frank, K., Dykes-Hoberg, M.et al. (2002). Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS. Ann. Neurol., 52, 771–8CrossRefGoogle Scholar
Drachman, D. B. & Rothstein, J. D. (2000). Inhibition of cyclooxygenase-2 protects motor neurons in an organotypic model of amyotrophic lateral sclerosis. Ann. Neurol., 48, 792–53.0.CO;2-5>CrossRefGoogle Scholar
Ferrante, R. J., Klein, A. M., Dedeoglu, A. & Beal, M. F. (2001). Therapeutic efficacy of EGb761 (Gingko biloba extract) in a transgenic mouse model of amyotrophic lateral sclerosis. J. Mol. Neurosci., 17, 89–96CrossRefGoogle Scholar
Fink, J. K. (2002a). Hereditary spastic paraplegia. Neurol. Clin., 20, 711–26CrossRefGoogle Scholar
Fink, J. K. (2002b). Hereditary spastic paraplegia: the pace quickens. Ann. Neurol., 51, 669–72CrossRefGoogle Scholar
Fournier, J., Steinberg, R., Gauthier, T.et al. (1993). Protective effects of SR 57746A in central and peripheral models of neurodegenerative disorders in rodents and primates. Neuroscience, 55, 629–41CrossRefGoogle ScholarPubMed
Fray, A. E., Ince, P. G., Banner, S. J.et al. (1998). The expression of the glial glutamate transporter protein EAAT2 in motor neuron disease: an immunohistochemical study. Eur. J. Neurosci., 10, 2481–9CrossRefGoogle ScholarPubMed
Fujita, K., Yamauchi, M., Shibayama, K.et al. (1996). Decreased cytochrome c oxidase activity but unchanged superoxide dismutase and glutathione peroxidase activities in the spinal cords of patients with amyotrophic lateral sclerosis. J. Neurosci. Res., 45, 276–813.0.CO;2-A>CrossRefGoogle ScholarPubMed
Gallo, J. M. (2001). Kennedy's disease: a triplet repeat disorder or a motor neuron disease?Brain Res. Bull., 56, 209–14CrossRefGoogle ScholarPubMed
Gil, R. & Neau, J. P. (1992). A double-blind placebo-controlled study of branched chain amino acids and L-threonine for the short-term treatment of signs and symptoms of amyotrophic lateral sclerosis. La semaine des (Paris), 68, 1472–5Google Scholar
Groeneveld, G. J., Veldink, J. H., Tweel, I.et al. (2003). A randomized sequential trial of creatine in amyotrophic lateral sclerosis. Ann. Neurol., 53, 437–45CrossRefGoogle ScholarPubMed
Gurney, M. E., Cutting, F. B., Zhai, P.et al. (1996). Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann. Neurol., 39, 147–57CrossRefGoogle Scholar
Hadano, S., Hand, C. K., Osuga, H.et al. (2001). A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat. Genet., 29, 166–73CrossRefGoogle ScholarPubMed
Haddad, H., Cifuentes-Diaz, C., Miroglio, A.et al. (2003). Riluzole attenuates spinal muscular atrophy disease progression in a mouse model. Muscle Nerve, 28, 432–7CrossRefGoogle ScholarPubMed
Han, D., Williams, E. & Cadenas, E. (2001). Mitochondrial respiratory chain-dependent generation of superoxide anion and its release into the intermembrane space. Biochem. J., 353, 411–16CrossRefGoogle ScholarPubMed
Harrington, M. G., Merril, C. R., Asher, D. M. & Gajdusek, D. C. (1986). Abnormal proteins in the cerebrospinal fluid of patients with Creutzfeldt–Jakob disease. N. Engl. J. Med., 315, 279–83CrossRefGoogle ScholarPubMed
Hedera, P., Williamson, J. A., Rainier, S.et al. (2001). Prenatal diagnosis of hereditary spastic paraplegia. Prenat. Diagn., 21, 202–63.0.CO;2-U>CrossRefGoogle ScholarPubMed
Hofmann, Y., Lorson, C. L., Stamm, S., Androphy, E. J. & Wirth, B. (2000). Htra2-beta 1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2). Proc. Natl Acad. Sci., USA, 97, 9618–23CrossRefGoogle Scholar
Holden, C. (2002). Neuroscience. Versatile cells against intractable diseases. Science, 297, 500–2CrossRefGoogle ScholarPubMed
Hsieh-Li, H. M., Chang, J. G., Jong, Y. J.et al. (2000). A mouse model for spinal muscular atrophy. Nat. Genet., 24, 66–70CrossRefGoogle ScholarPubMed
Hubert, J. P., Delumeau, J. C., Glowinski, J., Premont, J. & Doble, A. (1994). Antagonism by riluzole of entry of calcium evoked by NMDA and veratridine in rat cultured granule cells: evidence for a dual mechanism of action. Br. J. Pharmacol., 113, 261–7CrossRefGoogle ScholarPubMed
Ishihara, K., Yamagishi, N., Saito, Y.et al. (2003). Hsp105 alpha suppresses the aggregation of truncated androgen receptor with expanded CAG repeats and cell toxicity. J. Biol. Chem., 278, 25143–50CrossRefGoogle ScholarPubMed
Ishiyama, T., Ogo, H., Wong, V.et al. (2002). Methionine-free brain-derived neurotrophic factor in wobbler mouse motor neuron disease: dose-related effects and comparison with the methionyl form. Brain Res., 944, 195–9CrossRefGoogle ScholarPubMed
Jaarsma, D., Guchelaar, H. J., Haasdijk, E., Jong, J. M. & Holstege, J. C. (1998). The anti-oxidant N-acetylcysteine does not delay disease onset and death in a transgenic mouse model of amyotrophic lateral sclerosis. Ann. Neurol., 44, 293CrossRefGoogle Scholar
Kaspar, B. K., Llado, J., Sherkat, N., Rothstein, J. D. & Gage, F. H. (2003). Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science, 301, 839–42CrossRefGoogle Scholar
Katsuno, M., Adachi, H., Kume, A.et al. (2002). Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron, 35, 843–54CrossRefGoogle Scholar
Katsuno, M., Adachi, H., Doyu, M.et al. (2003). Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy. Nat. Med., 9, 768–73CrossRefGoogle Scholar
Kelemen, J., Hedlund, W., Orlin, J. B., Berkman, E. M. & Munsat, T. L. (1983). Plasmapheresis with immunosuppression in amyotrophic lateral sclerosis. Arch. Neurol., 40, 752–3CrossRefGoogle ScholarPubMed
Keller, J. N., Mark, R. J., Bruce, A. J.et al. (1997). 4-Hydroxynonenal, an aldehydic product of membrane lipid peroxidation, impairs glutamate transport and mitochondrial function in synaptosomes. Neuroscience, 80, 685–96CrossRefGoogle ScholarPubMed
Khoo, B., Akker, S. A. & Chew, S. L. (2003). Putting some spine into alternative splicing. Trends Biotechnol., 21, 328–30CrossRefGoogle ScholarPubMed
Klivenyi, P., Ferrante, R. J., Matthews, R. T.et al. (1999). Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat. Med., 5, 347–50CrossRefGoogle Scholar
Klivenyi, P., Kiaei, M., Gardian, G., Calingasan, N. Y. & Beal, M. F. (2004). Additive neuroprotective effects of creatine and cyclooxygenase 2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. J. Neurochem., 88, 576–82CrossRefGoogle Scholar
Kobayashi, Y., Kume, A., Li, M.et al. (2000). Chaperones Hsp70 and Hsp40 suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract. J. Biol. Chem., 275, 8772–8CrossRefGoogle ScholarPubMed
Kong, J. & Xu, Z. (1998). Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J. Neurosci., 18, 3241–50CrossRefGoogle ScholarPubMed
Kriz, J., Gowing, G. & Julien, J. P. (2003). Efficient three-drug cocktail for disease induced by mutant superoxide dismutase. Ann. Neurol., 53, 429–36CrossRefGoogle ScholarPubMed
Kriz, J., Nguyen, M. D. & Julien, J. P. (2002). Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiol. Dis., 10, 268–78CrossRefGoogle Scholar
Lacomblez, L., Bensimon, G., Leigh, P. N., Guillet, P. & Meininger, V. (1996). Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet, 347, 1425–31CrossRefGoogle ScholarPubMed
Lai, E. C., Felice, K. J., Festoff, B. W.et al. (1997). Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The North America ALS/IGF-I Study Group. Neurology, 49, 1621–30CrossRefGoogle Scholar
Lange, D. J., Murphy, P. L., Diamond, B.et al. (1998). Selegiline is ineffective in a collaborative double-blind, placebo-controlled trial for treatment of amyotrophic lateral sclerosis. Arch. Neurol., 55, 93–6CrossRefGoogle Scholar
Langmore, S. E., Kasarskis, E. J. K., Manca, M. L. & Olney, R. O. (2003). Enteral feeding for amyotrophic lateral sclerosis/motor neuron disease (Protocol). Cochrane Database Syst. Rev., 3CrossRefGoogle Scholar
Lesbordes, J. C., Cifuentes-Diaz, C., Miroglio, A.et al. (2003). Therapeutic benefits of cardiotrophin-1 gene transfer in a mouse model of spinal muscular atrophy. Hum. Mol. Genet., 12, 1233–9CrossRefGoogle Scholar
Lewis, M. E., Neff, N. T., Contreras, P. C.et al. (1993). Insulin-like growth factor-I: potential for treatment of motor neuronal disorders. Exp. Neurol., 124, 73–88CrossRefGoogle ScholarPubMed
Louwerse, E. S., Weverling, G. J., Bossuyt, P. M., Meyjes, F. E. & Jong, J. M. (1995). Randomized, double-blind, controlled trial of acetylcysteine in amyotrophic lateral sclerosis. Arch. Neurol., 52, 559–64CrossRefGoogle ScholarPubMed
Luo, Z. & Geschwind, D. H. (2001). Microarray applications in neuroscience. Neurobiol. Dis., 8, 183–93CrossRefGoogle ScholarPubMed
Manabe, Y., Nagano, I., Gazi, M. S.et al. (2003). Glial cell line-derived neurotrophic factor protein prevents motor neuron loss of transgenic model mice for amyotrophic lateral sclerosis. Neurol. Res., 25, 195–200CrossRefGoogle ScholarPubMed
Mandlekar, S. & Kong, A. N. (2001). Mechanisms of tamoxifen-induced apoptosis. Apoptosis, 6, 469–77CrossRefGoogle ScholarPubMed
Martin, D., Thompson, M. A. & Nadler, J. V. (1993). The neuroprotective agent riluzole inhibits release of glutamate and aspartate from slices of hippocampal area CA1. Eur. J. Pharmacol., 250, 473–6CrossRefGoogle ScholarPubMed
Martinou, J. C., Martinou, I. & Kato, A. C. (1992). Cholinergic differentiation factor (CDF/LIF) promotes survival of isolated rat embryonic motoneurons in vitro. Neuron, 8, 737–44CrossRefGoogle ScholarPubMed
Matthews, R. T., Yang, L., Browne, S., Baik, M. & Beal, M. F. (1998). Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc. Natl Acad. Sci., USA, 95, 8892–7CrossRefGoogle ScholarPubMed
Matthijs, G., Devriendt, K. & Fryns, J. P. (1998). The prenatal diagnosis of spinal muscular atrophy. Prenat. Diagn., 18, 607–103.0.CO;2-V>CrossRefGoogle ScholarPubMed
Mattiazzi, M., D'Aurelio, M., Gajewski, C. D.et al. (2002). Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice. J. Biol. Chem., 277, 29626–33CrossRefGoogle ScholarPubMed
Mazzini, L., Balzarini, C., Colombo, R.et al. (2001). Effects of creatine supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis: preliminary results. J. Neurol. Sci., 191, 139–44CrossRefGoogle ScholarPubMed
McGeer, P. L. & McGeer, E. G. (2002). Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve, 26, 459–70CrossRefGoogle ScholarPubMed
Meininger, V., Lacomblez, L. & Bensimon, G. (1995). Unpublished report: controlled trial of riluzole in patients with advanced ALS. RP 54272–302Google Scholar
Menzies, F. M., Cookson, M. R., Taylor, R. W.et al. (2002). Mitochondrial dysfunction in a cell culture model of familial amyotrophic lateral sclerosis. Brain, 125, 1522–33CrossRefGoogle Scholar
Mercuri, E., Bertini, E., Messina, S.et al. (2004). Pilot trial of phenylbutyrate in spinal muscular atrophy. Neuromuscul. Disord., 14, 130–5CrossRefGoogle ScholarPubMed
Merlini, L., Estournet-Mathiaud, B., Iannaccone, S.et al. (2002). 90th ENMC international workshop: European Spinal Muscular Atrophy Randomised Trial (EuroSMART) 9–10 February 2001, Naarden, The Netherlands. Neuromuscul. Disord., 12, 201–10CrossRefGoogle ScholarPubMed
Meucci, N., Nobile-Orazio, E. & Scarlato, G. (1996). Intravenous immunoglobulin therapy in amyotrophic lateral sclerosis. J. Neurol., 243, 117–20CrossRefGoogle ScholarPubMed
Miller, R. G., Bryan, W. W., Dietz, M. A.et al. (1996). Toxicity and tolerability of recombinant human ciliary neurotrophic factor in patients with amyotrophic lateral sclerosis. Neurology, 47, 1329–31CrossRefGoogle ScholarPubMed
Miller, R. G., Munsat, T. L., Swash, M. & Brooks, B. R. (1999a). Consensus guidelines for the design and implementation of clinical trials in ALS. World Federation of Neurology Committee on Research. J. Neurol. Sci., 169, 2–12CrossRefGoogle Scholar
Miller, R. G., Rosenberg, J. A., Gelinas, D. F.et al. (1999b). Practice parameter: the care of the patient with amyotrophic lateral sclerosis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology: ALS Practice Parameters Task Force. Neurology, 52, 1311–23CrossRefGoogle Scholar
Miller, R. G., Moore, D. H., 2nd, Gelinas, D. F.et al. (2001a). Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis. Neurology, 56, 843–8CrossRefGoogle Scholar
Miller, R. G., Moore, D. H., Dronsky, V.et al. (2001b). A placebo-controlled trial of gabapentin in spinal muscular atrophy. J. Neurol. Sci., 191, 127–31CrossRefGoogle Scholar
Miller, R. G., Mitchell, J. D., Lyon, M. & Moore, D. H. (2002). Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst. Rev., CD001447CrossRefGoogle Scholar
Mitchell, J. D., Houghton, E., Rostron, G.et al. (1995). Serial studies of free radical and anti-oxidant activity in motor neurone disease and the effect of selegiline. Neurodegeneration, 4, 233–5Google Scholar
Mitchell, J. D., Wokke, J. H. & Borasio, G. D. (2002). Recombinant human insulin-like growth factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst. Rev., CD002064CrossRefGoogle ScholarPubMed
Mitsumoto, H., Ikeda, K., Holmlund, T.et al. (1994a). The effects of ciliary neurotrophic factor on motor dysfunction in wobbler mouse motor neuron disease. Ann. Neurol., 36, 142–8CrossRefGoogle Scholar
Mitsumoto, H., Ikeda, K., Klinkosz, B.et al. (1994b). Arrest of motor neuron disease in wobbler mice cotreated with CNTF and BDNF. Science, 265, 1107–10CrossRefGoogle Scholar
Mizuta, I., Ohta, M., Ohta, K.et al. (2001). Riluzole stimulates nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor synthesis in cultured mouse astrocytes. Neurosci. Lett., 310, 117–20CrossRefGoogle ScholarPubMed
Molina, J. A., Bustos, F., Jimenez-Jimenez, F. J.et al. (2000). Serum levels of coenzyme Q10 in patients with amyotrophic lateral sclerosis. J. Neural Transm., 107, 1021–6CrossRefGoogle ScholarPubMed
Monani, U. R., Coovert, D. D. & Burghes, A. H. (2000). Animal models of spinal muscular atrophy. Hum. Mol. Genet., 9, 2451–7CrossRefGoogle ScholarPubMed
Mora, J. S., Munsat, T. L., Kao, K. P.et al. (1986). Intrathecal administration of natural human interferon alpha in amyotrophic lateral sclerosis. Neurology, 36, 1137–40CrossRefGoogle ScholarPubMed
Nakano, Y., Hirayama, K. & Terao, K. (1987). Hepatic ultrastructural changes and liver dysfunction in amyotrophic lateral sclerosis. Arch. Neurol., 44, 103–6CrossRefGoogle ScholarPubMed
Nakatomi, H., Kuriu, T., Okabe, S.et al. (2002). Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell, 110, 429–41CrossRefGoogle ScholarPubMed
National Institute for Clinical Excellence (2001). Guidance on the use of riluzole (Rilutek) for the treatment of motor neurone disease. Technology Appraisal Guidance, 20
Neff, N. T., Prevette, D., Houenou, L. J.et al. (1993). Insulin-like growth factors: putative muscle-derived trophic agents that promote motoneuron survival. J. Neurobiol., 24, 1578–88CrossRefGoogle ScholarPubMed
Noh, K. M., Hwang, J. Y., Shin, H. C. & Koh, J. Y. (2000). A novel neuroprotective mechanism of riluzole: direct inhibition of protein kinase C. Neurobiol. Dis., 7, 375–83CrossRefGoogle ScholarPubMed
Ochs, G., Penn, R. D., York, M.et al. (2000). A phase I/II trial of recombinant methionyl human brain derived neurotrophic factor administered by intrathecal infusion to patients with amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Other Motor Neuron Disord., 1, 201–6CrossRefGoogle ScholarPubMed
Olarte, M. R. & Shafer, S. Q. (1985). Levamisole is ineffective in the treatment of amyotrophic lateral sclerosis. Neurology, 35, 1063–6CrossRefGoogle ScholarPubMed
Oosthuyse, B., Moons, L., Storkebaum, E.et al. (2001). Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat. Genet., 28, 131–8CrossRefGoogle ScholarPubMed
Orrell, R. W., Lane, R. J. M. & Ross, M. (2003). Anti-oxidant treatment for amyotrophic lateral sclerosis/motor neuron disease (Protocol). Cochrane Database Syst. Rev., 3Google Scholar
Parmar, M. K., Torri, V. & Stewart, L. (1998). Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat. Med., 17, 2815–343.0.CO;2-8>CrossRefGoogle ScholarPubMed
Parton, M., Mitsumoto, H. & Leigh, P. (2003). Amino acids for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst. Rev., 4, CDCrossRefGoogle Scholar
Patel, H., Cross, H., Proukakis, C.et al. (2002). SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nat. Genet., 31, 347–8CrossRefGoogle ScholarPubMed
Patten, B. M. & Klein, L. M. (1988). L-Threonine and the modification of ALS. Neurology, 38, 354–5Google Scholar
Plaitakis, A. & Sivak, M. (1992). Treatment of amyotrophic lateral sclerosis with branched chain amino acids (BCAA): results of a second study. Neurology, 42, 454Google Scholar
Plaitakis, A., Nicklas, W. J. & Desnick, R. J. (1980). Glutamate dehydrogenase deficiency in three patients with spinocerebellar syndrome. Ann. Neurol., 7, 297–303CrossRefGoogle ScholarPubMed
Plaitakis, A., Berl, S. & Yahr, M. D. (1984). Neurological disorders associated with deficiency of glutamate dehydrogenase. Ann. Neurol., 15, 144–53CrossRefGoogle ScholarPubMed
Quality Standards Subcommittee of the American Academy of Neurology (1997). Practice advisory on the treatment of amyotrophic lateral sclerosis with riluzole: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 49, 657–9CrossRef
Rainier, S., Chai, J. H., Tokarz, D., Nicholls, R. D. & Fink, J. K. (2003). NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). Am. J. Hum. Genet., 73, 967–71CrossRefGoogle Scholar
Ramesh, T. M., Buradagunta, S., Thompson, K.et al. (2002). Analysis of critical parameters for preclinical drug screening in the SOD1 G93A mouse model for amyotrophic lateral sclerosis (abstract). Amytroph. Lateral Scler. Other Motor Neuron Disord., 3, 5Google Scholar
Reid, E., Kloos, M., Ashley-Koch, A.et al. (2002). A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am. J. Hum. Genet., 71, 1189–94CrossRefGoogle Scholar
Robberecht, W. L. & de Jong, J. M. B. V. (2000). Oxidative stress in amyotrophic lateral sclerosis: pathogenic mechanism or epiphenomenona? In Amyotrophic Lateral Sclerosis, ed. R. H., Brown, V. Meininger, & M. Swash, pp. 211–22. London, UK: Martin DunitzCrossRef
Rosen, D. R., Siddique, T., Patterson, D.et al. (1993). Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature, 362, 59–62CrossRefGoogle ScholarPubMed
Rothstein, J. D., Kammen, M., Levey, A. I., Martin, L. J. & Kuncl, R. W. (1995). Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann. Neurol., 38, 73–84CrossRefGoogle ScholarPubMed
Russman, B. S., Iannaccone, S. T. & Samaha, F. J. (2003). A phase 1 trial of riluzole in spinal muscular atrophy. Arch. Neurol., 60, 1601–3CrossRefGoogle ScholarPubMed
Shaw, P. J. (2001). Mechanisms of cell death and treatment prospects in motor neuron disease. Hong Kong Med. J., 7, 267–80Google ScholarPubMed
Shaw, P. J. & Ince, P. G. (1997). Glutamate, excitotoxicity and amyotrophic lateral sclerosis. J. Neurol., 244 Suppl 2, S3–14CrossRefGoogle ScholarPubMed
Shaw, P. J., Forrest, V., Ince, P. G., Richardson, J. P. & Wastell, H. J. (1995a). CSF and plasma amino acid levels in motor neuron disease: elevation of CSF glutamate in a subset of patients. Neurodegeneration, 4, 209–16CrossRefGoogle Scholar
Shaw, P. J., Ince, P. G., Falkous, G. & Mantle, D. (1995b). Oxidative damage to protein in sporadic motor neuron disease spinal cord. Ann. Neurol., 38, 691–5CrossRefGoogle Scholar
Shaw, P. J., Chinnery, R. M., Thagesen, H., Borthwick, G. M. & Ince, P. G. (1997). Immunocytochemical study of the distribution of the free radical scavenging enzymes Cu/Zn superoxide dismutase (SOD1) MN superoxide dismutase (MN SOD) and catalase in the normal human spinal cord and in motor neuron disease. J. Neurol. Sci., 147, 115–25CrossRefGoogle ScholarPubMed
Sher, G. D., Ginder, G. D., Little, J.et al. (1995). Extended therapy with intravenous arginine butyrate in patients with beta-hemoglobinopathies. N. Engl. J. Med., 332, 1606–10CrossRefGoogle ScholarPubMed
Siklos, L., Engelhardt, J., Harati, Y.et al. (1996). Ultrastructural evidence for altered calcium in motor nerve terminals in amyotrophic lateral sclerosis. Ann. Neurol., 39, 203–16CrossRefGoogle Scholar
Simpson, M. A., Cross, H., Proukakis, C.et al. (2003). Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. Am. J. Hum. Genet., 73, 1147–56CrossRefGoogle ScholarPubMed
Skordis, L. A., Dunckley, M. G., Yue, B., Eperon, I. C. & Muntoni, F. (2003). Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts. Proc. Natl Acad. Sci., USA, 100, 4114–19CrossRefGoogle ScholarPubMed
Smith, R. G., Henry, Y. K., Mattson, M. P. & Appel, S. H. (1998). Presence of 4-hydroxynonenal in cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis. Ann. Neurol., 44, 696–9CrossRefGoogle ScholarPubMed
Snow, R. J., Turnbull, J., da Silva, S., Jiang, F. & Tarnopolsky, M. A. (2003). Creatine supplementation and riluzole treatment provide similar beneficial effects in copper, zinc superoxide dismutase (G93A) transgenic mice. Neuroscience, 119, 661–7CrossRefGoogle ScholarPubMed
Sobue, G., Sahashi, K., Takahashi, A.et al. (1983). Degenerating compartment and functioning compartment of motor neurons in ALS: possible process of motor neuron loss. Neurology, 33, 654–7CrossRefGoogle ScholarPubMed
Spreux-Varoquaux, O., Bensimon, G., Lacomblez, L.et al. (2002). Glutamate levels in cerebrospinal fluid in amyotrophic lateral sclerosis: a reappraisal using a new HPLC method with coulometric detection in a large cohort of patients. J. Neurol. Sci., 193, 73–8CrossRefGoogle Scholar
Strong, M. J. & Pattee, G. L. (2000). Creatine and coenzyme Q10 in the treatment of ALS. Amyotroph. Lateral Scler. Other Motor Neuron Disord., 1 Suppl 4, 17–20CrossRefGoogle ScholarPubMed
Sumner, C. J., Huynh, T. N., Markowitz, J. A.et al. (2003). Valproic acid increases SMN levels in spinal muscular atrophy patient cells. Ann. Neurol., 54, 647–54CrossRefGoogle ScholarPubMed
Takeyama, K., Ito, S., Yamamoto, A.et al. (2002). Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila. Neuron, 35, 855–64CrossRefGoogle ScholarPubMed
Tarnopolsky, M. A. & Beal, M. F. (2001). Potential for creatine and other therapies targeting cellular energy dysfunction in neurological disorders. Ann. Neurol., 49, 561–74CrossRefGoogle ScholarPubMed
Testa, D., Caraceni, T. & Fetoni, V. (1989). Branched-chain amino acids in the treatment of amyotrophic lateral sclerosis. J. Neurol., 236, 445–7CrossRefGoogle ScholarPubMed
Testa, D., Caraceni, T., Fetoni, V. & Girotti, F. (1992). Chronic treatment with L-threonine in amyotrophic lateral sclerosis: a pilot study. Clin. Neurol. Neurosurg., 94, 7–9CrossRefGoogle ScholarPubMed
The ALS CNTF Treatment Study Group (1996). A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. Neurology, 46, 1244–9CrossRef
The BDNF Study Group (1999). A controlled trial of recombinant methionyl human BDNF in ALS: the BDNF Study Group (Phase III). Neurology, 52, 1427–33CrossRef
Tikka, T. M., Vartiainen, N. E., Goldsteins, G.et al. (2002). Minocycline prevents neurotoxicity induced by cerebrospinal fluid from patients with motor neurone disease. Brain, 125, 722–31CrossRefGoogle ScholarPubMed
Tohgi, H., Abe, T., Yamazaki, K.et al. (1999). Remarkable increase in cerebrospinal fluid 3-nitrotyrosine in patients with sporadic amyotrophic lateral sclerosis. Ann. Neurol., 46, 129–313.0.CO;2-Y>CrossRefGoogle ScholarPubMed
Turner, M. R. & Leigh, P. N. (2003). Disease-modifying therapies in motor neuron disorders: the present position and potential future developments. In Blue Books of Practical Neurology: Motor Neuron Disorders, ed. P. J. Shaw & M. J. Strong, Woburn, UK: Butterworth-HeinemannCrossRef
Turner, M. R., Bakker, M., Sham, P.et al. (2002). Prognostic modelling of therapeutic interventions in amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Other Motor Neuron. Disord., 3, 15–21CrossRefGoogle ScholarPubMed
Turrens, J. F. (1997). Superoxide production by the mitochondrial respiratory chain. Biosci. Rep., 17, 3–8CrossRefGoogle ScholarPubMed
Tzeng, A. C., Cheng, J., Fryczynski, H.et al. (2000). A study of thyrotropin-releasing hormone for the treatment of spinal muscular atrophy: a preliminary report. Am. J. Phys. Med. Rehabil., 79, 435–40CrossRefGoogle ScholarPubMed
Bosch, L., Tilkin, P., Lemmens, G. & Robberecht, W. (2002). Minocycline delays disease onset and mortality in a transgenic model of ALS. Neuroreport, 13, 1067–70CrossRefGoogle Scholar
Vastag, B. (2001). Stem cells step closer to the clinic: paralysis partially reversed in rats with ALS-like disease. J. Am. Med. Assoc., 285, 1691–3Google ScholarPubMed
Vyth, A., Timmer, J. G., Bossuyt, P. M., Louwerse, E. S. & Jong, J. M. (1996). Survival in patients with amyotrophic lateral sclerosis, treated with an array of anti-oxidants. J. Neurol. Sci., 139 Suppl, 99–103CrossRefGoogle Scholar
Werdelin, L., Boysen, G., Jensen, T. S. & Mogensen, P. (1990). Immunosuppressive treatment of patients with amyotrophic lateral sclerosis. Acta. Neurol. Scand., 82, 132–4CrossRefGoogle ScholarPubMed
Westarp, M. E., Westphal, K. P., Kolde, G.et al. (1992). Dermal, serological and CSF changes in amyotrophic lateral sclerosis with and without intrathecal interferon beta treatment. Int. J. Clin. Pharmacol. Ther. Toxicol., 30, 81–93Google ScholarPubMed
Wirth, B. (2002). Spinal muscular atrophy: state-of-the-art and therapeutic perspectives. Amyotroph. Lateral Scler. Other Motor Neuron Disord., 3, 87–95CrossRefGoogle ScholarPubMed
Wood, J. D., Beaujeux, T. P. & Shaw, P. J. (2003). Protein aggregation in motor neurone disorders. Neuropathol. Appl. Neurobiol., 29, 529–45CrossRefGoogle ScholarPubMed
Wood-Allum, C. A. & Shaw, P. J. (2003). Mitochondrial dysfunction in amyotrophic lateral sclerosis (ALS). In Blue Books of Practical Neurology: Motor Neuron Disorders, ed. P. J. Shaw & M. J. Strong, Woburn, UK: Butterworth-HeinemannCrossRef
World Federation of Neurology Research Committee on Motor Neuron Diseases (1998). Revised criteria for the diagnosis of amyotrophic lateral sclerosis. http://wfnals.org/Articles/elescorial1998criteria.htm
Yanagisawa, N., Tashiro, K., Tohgi, H.et al. (1997). Efficacy and safety of riluzole in patients with amyotrophic lateral sclerosis: double-blind placebo-controlled study in Japan. Igakuno Ayumi., 182, 851–66Google Scholar
Yang, Y., Hentati, A., Deng, H. X.et al. (2001). The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat. Genet., 29, 160–5CrossRefGoogle Scholar
Yasojima, K., Tourtellotte, W. W., McGeer, E. G. & McGeer, P. L. (2001). Marked increase in cyclooxygenase-2 in ALS spinal cord: implications for therapy. Neurology, 57, 952–6CrossRefGoogle ScholarPubMed
Zhang, W., Narayanan, M. & Friedlander, R. M. (2003). Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS. Ann. Neurol., 53, 267–70CrossRefGoogle Scholar
Zhu, S., Stavrovskaya, I. G., Drozda, M.et al. (2002). Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature, 417, 74–8CrossRefGoogle ScholarPubMed

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