Therapeutic developments in the treatment of amyotrophic lateral sclerosis

Bibliography

• SIDDIQUE T, NIJHAWAN D, HENTATI A: Molecular genetic basis of familial ALS. Neurology (1996) 47(4: Suppl. 2):S27–S34.
   Google Scholar
• GAUDETTE M, HIRANO M, SIDDIQUE T: Current status of SOD1 mutations in familial amyotrophic lateral sclerosis. Anyotroph. Lateral. Scler. Other Motor Neuron Disord. (2000) 1(2):83–89.
   PubMed Web of Science ®Google Scholar
• HADANO S, HAND CK, OSUGA H et al.: A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat. Genet. (2001) 29(2):166–173.
   PubMed Web of Science ®Google Scholar
• ••Identification of a second gene responsiblefor juvenile ALS.
   Google Scholar
• YANG Y, HENTATI A, DENG HX et al.: 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. (2001) 29(2):160–165.
   PubMed Web of Science ®Google Scholar
• ••Identification of a second gene responsiblefor juvenile ALS.
   Google Scholar
• ROSEN DR, SIDDIQUE T, PATTERSON D et al.: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature (1993) 362(6415):59–62.
   PubMed Web of Science ®Google Scholar
• ••First report of SOD1 mutations that are aprimary cause of ALS.
   Google Scholar
• GURNEY ME, PU H, CHIU AY et al.: Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science (1994) 264(5166):1772–1775.
   PubMed Web of Science ®Google Scholar
• •Mouse model provides the first evidence that disease is not caused by a loss of SOD1 activity.
   Google Scholar
• WONG PC, PARDO CA, BORCHELT DR et al.: An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron (1995) 14(6):1105–1116.
   PubMed Web of Science ®Google Scholar
• TU PH, RAJU P, ROBINSON KA, GURNEY ME, TROJANOWSKI JQ, LEE VM: Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions. Proc. Nati Acad. Sci. USA (1996) 93(7):3155–3160.
   PubMed Web of Science ®Google Scholar
• RIPPS ME, HUNTLEY GW, HOF PR, MORRISON JH, GORDON JW: Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA (1995) 92(3):689–693.
   PubMed Web of Science ®Google Scholar
• REAUME AG, ELLIOTT JL, HOFFMAN EK et al.: Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat. Genet. (1996) 13(1):43–47.
   PubMed Web of Science ®Google Scholar
• FUKADA K, NAGANO S, SATOH M et al.: Stabilization of mutant Cu/Zn superoxide dismutase (SOD1) protein by coexpressed wild SOD1 protein accelerates the disease progression in familial amyotrophic lateral sclerosis mice. Eur. Neurosci. (2001) 14(12):2032–2036.
   PubMed Web of Science ®Google Scholar
• WIEDAU-PAZOS M, GOTO JJ, RABIZADEH S et al.: Altered reactivity of superoxide dismutase in familial amyotrophic lateral sclerosis. Science (1996) 271(5248):515–518.
   PubMed Web of Science ®Google Scholar
• BECKMAN JS, CARSON M, SMITH CD, KOPPENOL WH: ALS, SOD and peroxynitrite. Nature (1993) 364(6438):584.
   PubMed Web of Science ®Google Scholar
• SUBRAMANIAM JR, LYONS WE, LIU J et al.: Mutant SOD1 causes motor neuron disease independent of copper chaperone-mediated copper loading. Nat. Neurosci. (2002) 5(4):301–307.
   PubMed Web of Science ®Google Scholar
• NAGANO S, SATOH M, SUMI H et al.: Reduction of metallothioneins promotes the disease expression of familial amyotrophic lateral sclerosis mice in a dose-dependent manner. Eur.J Neurosci. (2001) 13(7):1363–1370.
   PubMed Web of Science ®Google Scholar
• BRUIJN LI, BECHER MW, LEE MK et al.: ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron (1997) 18(2):327–338.
   PubMed Web of Science ®Google Scholar
• WATANABE M, DYKES-HOBERG M, CULOTTA VC, PRICE DL, WONG PC, ROTHSTEIN JD: Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues. Neurobiol. Dis. (2001) 8(6):933–941.
   PubMed Web of Science ®Google Scholar
• BRUENING W, ROY J, GIASSON B, FIGLEWICZ DA, MUSHYNSKI WE, DURHAM HD: Up-regulation of protein chaperones preserves viability of cells expressing toxic Cu/Zn-superoxide dismutase mutants associated with amyotrophic lateral sclerosis. Neurochein. (1999) 72(2):693–699.
   PubMed Web of Science ®Google Scholar
• LINO MM, SCHNEIDER C, CARONI P: Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease. Neurosci. (2002) 22(12):4825–4832.
   PubMed Web of Science ®Google Scholar
• ••Specific expression of SOD1 in neuronsdoes not cause motor neuron pathology.
   Google Scholar
• KONG J, XU Z: Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. j Neurosci. (1998) 18(9):3241–3250.
   PubMed Web of Science ®Google Scholar
• OKAMOTO K, HIRAI S, SHOJI M, SENOH Y, YAMAZAKI T: Axonal swellings in the corticospinal tracts in amyotrophic lateral sclerosis. Acta Neuropathol. (Berl) (1990) 80(2):222–226.
   PubMed Web of Science ®Google Scholar
• STURTZ LA, DIEKERT K, JENSEN LT, LILL R, CULOTTA VC: A fraction of yeast Cu,Zn-superoxide dismutase and its metallochaperone, CCS, localize to the intermembrane space of mitochondria. A physiological role for SOD1 in guarding against mitochondrial oxidative damage. Eta Chem. (2001) 276(41):38084–38089.
   Google Scholar
• JAARSMA D, ROGNONI F, VAN DUIJN W, VERSPAGET HW, HAASDIJK ED, HOLSTEGE JC: CuZn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations. Acta Neuropathol. (Ben) (2001) 102(4):293–305.
   PubMed Web of Science ®Google Scholar
• GONG YH, PARSADANIAN AS, ANDREEVA A, SNIDER WD, ELLIOTT JL: Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration. Neurosci. (2000) 20(2):660–665.
   PubMed Web of Science ®Google Scholar
• ••Specific expression of mutant SOD1 inastrocytes demonstrates that although astrocytic dysfunction is observed early on in disease it is not sufficient for motor neuron degeneration.
   Google Scholar
• PRAMATAROVA A, LAGANIERE J, ROUSSEL J, BRISEBOIS K, ROULEAU GA: Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. Neurosci. (2001) 21(10):3369–3374.
   PubMed Web of Science ®Google Scholar
• •Specific expression of SOD1 in neurons does not cause motor neuron pathology.
   Google Scholar
• OLNEY JW: Glutamate-induced neuronal necrosis in the infant mouse hypothalamus. An electron microscopic study. Neuropathol. Exp. Neurol. (1971) 30(1):75–90.
   PubMed Web of Science ®Google Scholar
• ROTHSTEIN JD, TSAI G, KUNCL RW et al.: Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann. Neurol. (1990) 28(1):18–25.
   PubMed Web of Science ®Google Scholar
• SHAW PJ, FORREST V, INCE PG, RICHARDSON JP, WASTELL HJ: CSF and plasma amino acid levels in motor neuron disease: elevation of CSF glutamate in a subset of patients. Neurodegeneration (1995) 4(2):209–216.
   PubMedGoogle Scholar
• ROTHSTEIN JD, MARTIN LJ, KUNCL RW: Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl. I Med. (1992) 326(22):1464–1468.
   PubMed Web of Science ®Google Scholar
• ROTHSTEIN JD, VAN KAMMEN M, LEVEY Al, MARTIN LJ, KUNCL RW: Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann. Neurol. (1995) 38(1):73–84.
   PubMed Web of Science ®Google Scholar
• FERRARESE C, SALA G, RIVA R et al.:Decreased platelet glutamate uptake in patients with amyotrophic lateral sclerosis. Neurology (2001) 56(2):270–272.
   PubMed Web of Science ®Google Scholar
• SASAKI S, KOMORI T, IWATA M: Excitatory amino acid transporter 1 and 2 immunoreactivity in the spinal cord in amyotrophic lateral sclerosis. Acta Neuropathol. 04 (2000) 100(2):138–144.
   Google Scholar
• HOWLAND DS, LIU J, SHE Y 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. Sri. USA (2002) 99(3):1604–1609.
   PubMed Web of Science ®Google Scholar
• GINSBERG SD, MARTIN LJ, ROTHSTEIN JD: Regional deafferentation down-regulates subtypes of glutamate transporter proteins. Neurochem. (1995) 65(6):2800–2803.
   PubMed Web of Science ®Google Scholar
• LIN CL, BRISTOL LA, JIN L et al.: Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron (1998) 20(3):589–602.
   PubMed Web of Science ®Google Scholar
• MEYER T, FROMM A, MUNCH C et al.: The RNA of the glutamate transporter EAAT2 is variably spliced in amyotrophic lateral sclerosis and normal individuals. Neurol. Sri. (1999) 170(1):45–50.
   Web of Science ®Google Scholar
• HONIG LS, CHAMBLISS DD, BIGIO EH, CARROLL SL, ELLIOTT JL: Glutamate transporter EAAT2 splice variants occur not only in ALS, but also in AD and controls. Neurology (2000) 55(8):1082–1088.
   PubMed Web of Science ®Google Scholar
• FLOWERS JM, POWELL JF, LEIGH PN, ANDERSEN P, SHAW CE: Intron 7 retention and exon 9 skipping EAAT2 mRNA variants are not associated with amyotrophic lateral sclerosis. Ann. Neurol. (2001) 49(5):643–649.
   PubMed Web of Science ®Google Scholar
• JACKSON M, MORRISON KE, AL CHALABI A, BAKKER M, LEIGH PN: Analysis of chromosome 5q13 genes in amyotrophic lateral sclerosis: homozygous NAIP deletion in a sporadic case. Ann. Neurol. (1996) 39(6):796–800.
   PubMed Web of Science ®Google Scholar
• TROTTI D, ROLES A, DANBOLT NC, BROWN RH Jr, HEDIGER MA: SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter. Nat. Neurosci. (1999) 2(5):427–433.
   PubMed Web of Science ®Google Scholar
• ROTHSTEIN JD, JIN L, DYKES-HOBERG M, KUNCL RW: Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity. Proc. Nati Acad. Sci. USA (1993) 90(14):6591–6595.
   PubMed Web of Science ®Google Scholar
• ROTHSTEIN JD, DYKES-HOBERG M, PARDO CA et al.: Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron (1996) 16(3):675–686.
   PubMed Web of Science ®Google Scholar
• •Study indicates that there is a close link between the loss of glutamate transporters and the degeneration of motor neurons.
   Google Scholar
• COURATIER P, HUGON J, SINDOU P, VALLAT JM, DUMAS M: Cell culture evidence for neuronal degeneration in amyotrophic lateral sclerosis being linked to glutamate AMPA/kainate receptors. Lancet (1993) 341(8840):265–268.
   PubMed Web of Science ®Google Scholar
• CARPENTER S: Proximal axonal enlargement in motor neuron disease. Neurology (1968) 18(9):841–851.
   PubMed Web of Science ®Google Scholar
• HIRANO A, DONNENFELD H, SASAKI S, NAKANO I: Fine structural observations of neurofilamentous changes in amyotrophic lateral sclerosis. Neuropathol. Exp. Neurol. (1984) 43(5):461–470.
   PubMed Web of Science ®Google Scholar
• WILLIAMSON TL, BRUIJN LI, ZHU Q et al.: Absence of neurofilaments reduces the selective vulnerability of motor neurons and slows disease caused by a familial amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutant. Proc. Natl. Acad. Sci. USA (1998) 95(16):9631–9636.
   PubMed Web of Science ®Google Scholar
• •Neuroprotection conferred by loss of neurofilarnents identifies a new therapeutic approach.
   Google Scholar
• KONG J, XU Z: Overexpression of neurofilament subunit NF-L and NF-H extends survival of a mouse model for amyotrophic lateral sclerosis. Neurosci. Lett. (2000) 281(1):72–74.
   PubMed Web of Science ®Google Scholar
• COUILLARD-DESPRES S, ZHU Q, WONG PC, PRICE DL, CLEVELAND DW, JULIEN JP: Protective effect of neurofilament heavy gene overexpression in motor neuron disease induced by mutant superoxide dismutase. Proc. Natl. Acad. Sci. US.A (1998) 95(16):9626–9630.
   PubMed Web of Science ®Google Scholar
• XU Z, CORK LC, GRIFFIN JW, CLEVELAND DW: Increased expression of neurofilament subunit NF-L produces morphological alterations that resemble the pathology of human motor neuron disease. Cell (1993) 73(1):23–33.
   PubMed Web of Science ®Google Scholar
• COTE F, COLLARD JF, JULIEN JP: Progressive neuronopathy in transgenic mice expressing the human neurofilament heavy gene: a mouse model of amyotrophic lateral sclerosis. Cell (1993) 73(1):35–46.
   PubMed Web of Science ®Google Scholar
• LEE MK, MARSZALEK JR, CLEVELAND DW: A mutant neurofilament subunit causes massive, selective motor neuron death: implications for the pathogenesis of human motor neuron disease. Neuron (1994) 13(4):975–978.
   PubMed Web of Science ®Google Scholar
• LEFEBVRE S, MUSHYNSKI WE: Calcium binding to untreated and dephosphorylated porcine neurofilaments. Biochem. Biophys. Res. Commun. (1987) 145(3):1006–1011.
   PubMed Web of Science ®Google Scholar
• ZHANG B, TU P, ABTAHIAN F, TROJANOWSKI JQ, LEE VM: Neurofilaments and orthograde transport are reduced in ventral root axons of transgenic mice that express human SOD1 with a G93A mutation. J. Cell Biol. (1997) 139(5):1307–1315.
   PubMed Web of Science ®Google Scholar
• WILLIAMSON TL, CLEVELAND DW: Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat. Neurosci. (1999) 2(1):50–56.
   PubMed Web of Science ®Google Scholar
• BEAULIEU JM, JACOMY H, JULIEN JP: Formation of intermediate filament protein aggregates with disparate effects in two transgenic mouse models lacking the neurofilament light subunit. Neurosci. (2000) 20(14):5321–5328.
   PubMed Web of Science ®Google Scholar
• FIGLEWICZ DA, KRIZUS A, MARTINOLI MG et al.: Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. Hum. MM. Genet. (1994) 3(10):1757–1761.
   PubMed Web of Science ®Google Scholar
• AL CHALABI A, ANDERSEN PM, NILSSON P et al: Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis. Hum. MM. Genet. (1999) 8(2):157–164.
   PubMed Web of Science ®Google Scholar
• TOMKINS J, USHER P, SLADE JY et al.: Novel insertion in the KSP region of the neurofilament heavy gene in amyotrophic lateral sclerosis (ALS). Neuroreport (1998) 9(17):3967–3970.
   PubMed Web of Science ®Google Scholar
• VECHIO JD, BRUIJN LI, XU Z, BROWN RH Jr., CLEVELAND DW: Sequence variants in human neurofilament proteins: absence of linkage to familial amyotrophic lateral sclerosis. Ann. Neural. (1996) 40(4):603–610.
   Google Scholar
• KAWAMURA Y, DYCK PJ, SHIM ONO M, OKAZAKI H, TATEISHI J, DOI H: Morphometric comparison of the vulnerability of peripheral motor and sensory neurons in amyotrophic lateral sclerosis. Neuropathol Exp. Nemo]. (1981) 40(6):667–675.
   PubMed Web of Science ®Google Scholar
• ANAND P, PARRETT A, MARTIN J et al.: Regional changes of ciliary neurotrophic factor and nerve growth factor levels in post mortem spinal cord and cerebral cortex from patients with motor disease. Nat. Med. (1995) 1(2):168–172.
   PubMed Web of Science ®Google Scholar
• GIESS R, HOLTMANN B, BRAGA M et al.: Early onset of severe familial amyotrophic lateral sclerosis with a SOD- 1 mutation: potential impact of CNTF as a candidate modifier gene. Am. J. Hum. Genet. (2002) 70(5):1277–1286.
   PubMed Web of Science ®Google Scholar
• BEZZI P, CARMIGNOTO G, PASTI L et al.: Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature (1998) 391(6664):281–285.
   PubMed Web of Science ®Google Scholar
• O'BANION MK, MILLER JC, CHANG JVV, KAPLAN MD, COLEMAN PD: Interleukin-1 beta induces prostaglandin G/ H synthase-2 (cyclooxygenase- 2) in primary murine astrocyte cultures. Neurochem. (1996) 66(6):2532–2540.
   PubMed Web of Science ®Google Scholar
• LI M, ONA VO, GUEGAN C et a/.: Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science (2000) 288(5464):335–339.
   Google Scholar
• •First publication showing the potential use of pharmacological inhibition of caspases to prevent neurodegeneration.
   Google Scholar
• ALMER G, GUEGAN C, TEISMANN P et al.: Increased expression of the pro-inflammatory enzyme cyclooxygenase-2 in amyotrophic lateral sclerosis. Ann. Neurol (2001) 49(2):176–185.
   PubMed Web of Science ®Google Scholar
• YASOJIMA K, TOURTELLOTTE WW, MCGEER EG, MCGEER PL: Marked increase in cyclooxygenase-2 in ALS spinal cord: implications for therapy. Neurology (2001) 57(6):952–956.
   PubMed Web of Science ®Google Scholar
• ALMER G, TEISMANN P, STEVIC Z et al.: Increased levels of the pro-inflammatory prostaglandin PGE2 in CSF from ALS patients. Neurology (2002) 58(8):1277–1279.
   PubMed Web of Science ®Google Scholar
• ALEXIANU ME, KOZOVSKA M, APPEL SH: Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology (2001) 57(7):1282–1289.
   PubMed Web of Science ®Google Scholar
• HALL ED, OOSTVEEN JA, GURNEY ME: Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia (1998) 23(3):249–256.
   PubMed Web of Science ®Google Scholar
• YOSHIHARA T, ISHIGAKI S, YAMAMOTO M et al: 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. (2002) 80(1):158–167.
   PubMed Web of Science ®Google Scholar
• MALASPINA A, KAUSHIK N, DE BELLEROCHE J: Differential expression of 14 genes in amyotrophic lateral sclerosis spinal cord detected using gridded cDNA arrays. J. Neurochem. (2001) 77(1):132–145.
   PubMed Web of Science ®Google Scholar
• ALEXIANU ME, HO BK, MOHAMED AH, LA BELLA V, SMITH RG, APPEL SH: The role of calcium-binding proteins in selective motoneuron vulnerability in amyotrophic lateral sclerosis. Ann. Neural. (1994) 36(6):846–858.
   PubMed Web of Science ®Google Scholar
• BEERS DR, HO BK, SIKLOS L et al: Parvalbumin overexpression alters immune-mediated increases in intracellular calcium, and delays disease onset in a transgenic model of familial amyotrophic lateral sclerosis. J. Neurochem. (2001) 79(3):499–509.
   PubMed Web of Science ®Google Scholar
• BAR-PELED 0, O'BRIEN RJ, MORRISON JH, ROTHSTEIN JD: Cultured motor neurons possess calcium-permeable AMPA/kainate receptors. Neuroreport (1999) 10(4):855–859.
   PubMed Web of Science ®Google Scholar
• PRUSS RM, AKESON RL, RACKE MM, WILBURN JL: Agonist-activated cobalt uptake identifies divalent cation-permeable kainate receptors on neurons and glial cells. Neuron (1991) 7(3):509–518.
   PubMed Web of Science ®Google Scholar
• HUME RI, DINGLEDINE R, HEINEMANN SF: Identification of a site in glutamate receptor subunits that controls calcium permeability. Science (1991) 253(5023):1028–1031.
   PubMed Web of Science ®Google Scholar
• WILLIAMS TL, INCE PG, OAKLEY AE, SHAW PJ: An immunocytochemical study of the distribution of AMPA selective glutamate receptor subunits in the normal human motor system. Neuroscience (1996) 74(1):185–198.
   PubMed Web of Science ®Google Scholar
• TAKUMA H, KWAK S, YOSHIZAWA T, KANAZAWA I: Reduction of G1uR2 RNA editing, a molecular change that increases calcium influx through AMPA receptors, selective in the spinal ventral gray of patients with amyotrophic lateral sclerosis. Ann. Neural. (1999) 46(6):806–815.
   PubMed Web of Science ®Google Scholar
• TSUDA T, MUNTHASSER S, FRASER PE et al.: Analysis of the functional effects of a mutation in SOD1 associated with familial amyotrophic lateral sclerosis. Neuron (1994) 13(3):727–736.
   PubMed Web of Science ®Google Scholar
• OOSTHUYSE B, MOONS L, STORKEBAUM E et al.: Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat. Genet. (2001) 28(2):131–138.
   PubMed Web of Science ®Google Scholar
• •Raised the possibility that motor neurons are especially sensitive to hypoxia and identified a possible risk factor.
   Google Scholar
• EYMARD-PIERRE E, LESCA G, DOLLET S et al.: Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. Am. j Hum. Genet. (2002) 71(3):518–527.
   PubMed Web of Science ®Google Scholar
• AL CHALABI A, ANDERSEN PM, CHIOZA B et al.: Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor. Hum. MM. Genet. (1998) 7(13):2045–2050.
   PubMed Web of Science ®Google Scholar
• KUNST CB, MESSER L, GORDON J, HAINES J, PATTERSON D: Genetic mapping of a mouse modifier gene that can prevent ALS onset. Genomics (2000) 70 (2):181–189.
   PubMed Web of Science ®Google Scholar
• CORCIA P, MAYEUX-PORTAS V, KHORIS J et al.: Abnormal SMN1 gene copy number is a susceptibility factor for amyotrophic lateral sclerosis. Ann. Neurol (2002) 51(2):243–246.
   PubMed Web of Science ®Google Scholar
• RABIZADEH S, GRALLA EB, BORCHELT DR et al.: Mutations associated with amyotrophic lateral sclerosis convert superoxide dismutase from an anti-apoptotic gene to a proapoptotic gene: studies in yeast and neural cells. Proc. Nati Acad. Sci. USA (1995) 92(7):3024–3028.
   PubMed Web of Science ®Google Scholar
• MARTIN LJ: Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible contribution of a programmed cell death mechanism. I Neuropathol Exp. Neurol (1999) 58(5):459–471.
   PubMed Web of Science ®Google Scholar
• •This paper suggests that neuronal degeneration structurally resembles apoptosis.
   Google Scholar
• EMBACHER N, KAUFMANN WA, BEER R et al.: Apoptosis signals in sporadic amyotrophic lateral sclerosis: an immunocytochemical study. Acta Neuropathol. (Ber) (2001) 102(5):426–434.
   PubMed Web of Science ®Google Scholar
• MIGHELI A, ATZORI C, PIVA R et al:Lack of apoptosis in mice with ALS. Nat. Med. (1999) 5(9):966–967.
   PubMed Web of Science ®Google Scholar
• MARTIN LJ, PRICE AC, KAISER A, SHAIKH AY, LIU Z: Mechanisms for neuronal degeneration in amyotrophic lateral sclerosis and in models of motor neuron death (Review). Lit. I Ma Med. (2000) 5(1):3–13.
   PubMed Web of Science ®Google Scholar
• GUEGAN C, VILA M, ROSOKLIJA G, HAYS AP, PRZEDBORSKI S: Recruitment of the mitochondrial-dependent apoptotic pathway in amyotrophic lateral sclerosis. j. Neurosci. (2001) 21(17):6569–6576.
   PubMed Web of Science ®Google Scholar
• •Shows the sequential activation of mitochondrial and cytosolic molecular components in the cell death pathway.
   Google Scholar
• PASINELLI P, HOUSE WEART MK, BROWN RH Jr., CLEVELAND DW: Caspase-1 and -3 are sequentially activated in motor neuron death in Cu,Zn superoxide dismutase-mediated familial amyotrophic lateral sclerosis. Proc. Nati Acad. Sci. USA (2000) 97(25):13901–13906.
   Google Scholar
• VUKOSAVIC S, STEFANIS L, JACKSON-LEWIS V et al.: Delaying caspase activation by Bc1-2: A clue to disease retardation in a transgenic mouse model of amyotrophic lateral sclerosis. j. Neurosci. (2000) 20(24):9119–9125.
   PubMed Web of Science ®Google Scholar
• KOSTIC V, JACKSON-LEWIS V, DE BILBAO F, DUBOIS-DAUPHIN M, PRZEDBORSKI S: Bc1-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis. Science (1997) 277(5325):559–562.
   PubMed Web of Science ®Google Scholar
• ••Suggests a role for intervention in the celldeath pathway using antiapoptotic gene products of the Bd-2 family.
   Google Scholar
• VUKOSAVIC S, DUBOIS-DAUPHIN M, ROMERO N, PRZEDBORSKI S: Bax and Bc1-2 interaction in a transgenic mouse model of familial amyotrophic lateral sclerosis. J. Neurochem. (1999) 73(6):2460–2468.
   PubMed Web of Science ®Google Scholar
• FRIEDLANDER RM, BROWN RH, GAGLIARDINI V, WANG J, YUAN J: Inhibition of ICE slows ALS in mice. Nature (1997) 388(6637):31.
   PubMed Web of Science ®Google Scholar
• •This publication shows that the dominant negative inhibition of a cell death gene is able to slow the progression of ALS and delay mortality in SOD 1 mice.
   Google Scholar
• PUTCHA GV, KNUDSON CM, JOHNSON EMJ, KORSMEYER SJ: Bax deletion delays mortality in a murine model of familial ALS and neuronal cell death in SOD1-deficient mice. Soc. Neurosci. Abs. (1998) 24:477.
   Google Scholar
• WHITE FA, KELLER-PECK CR, KNUDSON CM, KORSMEYER SJ, SNIDER WD: Widespread elimination of naturally occurring neuronal death in Bax-deficient mice. Neurosci. (1998) 18(4):1428–1439.
   PubMed Web of Science ®Google Scholar
• GONZALEZ DE AGUILAR JL, GORDON JW, RENE F et al.: Alteration of the Bcl-x/Bax ratio in a transgenic mouse model of amyotrophic lateral sclerosis: evidence for the implication of the p53 signaling pathway. Neurobiol Dis. (2000) 7(4):406–415.
   PubMed Web of Science ®Google Scholar
• KUNTZ C, KINOSHITA Y, BEAL ME DONEHOWER LA, MORRISON RS: Absence of p53: no effect in a transgenic mouse model of familial amyotrophic lateral sclerosis. Exp. Neurol (2000) 165 (1) :184–190.
   PubMed Web of Science ®Google Scholar
• PRUDLO J, KOENIG J, GRASER J et al.: Motor neuron cell death in a mouse model of FALS is not mediated by the p53 cell survival regulator. Brain Res. (2000) 879 (1-2):183–187.
   PubMed Web of Science ®Google Scholar
• ALS CNTF TREATMENT STUDY GROUP: 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(1996) 46(5): 1244–1249.
   PubMed Web of Science ®Google Scholar
• MILLER RG,PETAJAN JH, BRYAN WW et al.: A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. rhCNTF ALS Study Group. Ann. Neural. (1996) 39(2):256–260.
   Google Scholar
• KASARSKIS EJ, SHEFNER JM, MILLER R et al.: A controlled trial of recombinant methionyl human BDNF in ALS. Neurology (1999) 52:1427–1433.
   PubMed Web of Science ®Google Scholar
• CARONI P, GRANDES P: Nerve sprouting in innervated adult skeletal muscle induced by exposure to elevated levels of insulin-like growth factors. j. Cell Biol. (1990) 110(4):1307–1317.
   PubMed Web of Science ®Google Scholar
• LEWIS ME, NEFF NT, CONTRERAS PC et al.: Insulin-like growth factor-I: potential for treatment of motor neuronal disorders. Exp. Neural. (1993) 124(1):73–88.
   PubMed Web of Science ®Google Scholar
• VERGANI L, DI GIULIO AM, LOSA M, ROSSONI G, MULLER EE, GORIO A: Systemic administration of insulin-like growth factor decreases motor neuron cell death and promotes muscle reinnervation.j. Neurosci. Res. (1998) 54(6):840–847.
   Google Scholar
• LANGE DJ, FELICE KJ, FESTOFF BW et al.: Recombinant human insulin-like growth factor-I in ALS: description of a double-blind, placebo-controlled study. North American ALS/IGF-I Study Group. Neurology(1996) 47(4, Suppl. 2):593–594.
   Google Scholar
• LAI EC, FELICE KJ, FESTOFF BW et al.: 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(1997) 49(6):1621–1630.
   Google Scholar
• BORASIO GD, ROBBERECHT W, LEIGH PN et al.: A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I Study Group. Neurology (1998) 51(2):583–586.
   Google Scholar
• MITCHELL JD, WOKKE JHJ, BORASIO GD: Recombinant human insulin-like growth Factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron disease (Cochrane Review). In: The Cochrane Library (Volume 3). Oxford Software (2002).
   Google Scholar
• GURNEY ME, CUTTING FB, ZHAI P et al.: Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann. Neurol. (1996) 39(2):147–157.
   PubMed Web of Science ®Google Scholar
• ••First preclinical trial in the ALS transgenicmouse model to show a significant beneficial effect.
   Google Scholar
• MILLER RG, BOUCHARD JP, DUQUETTE P et al.: Clinical trials of riluzole in patients with ALS. ALS/Riluzole Study Group-II. Neurology (1996) 47(4 Suppl. 2):S86–S90.
   Google Scholar
• ••Human clinical trials showed that riluzolecould significantly alter the disease progression and resulted in the first drug being approved and marketed for the treatment of ALS.
   Google Scholar
• MILLER R, MITCHELL JD, LYON M, MOORE DH: Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND) (Cochrane Review). In: The Cochrane Library (Volume 3). Oxford Software (2002).
   Google Scholar
• •Review of all human clinical trials with riluzole.
   Google Scholar
• MEININGER V, BENSIMON G, LACOMBLEZ L, SALACHAS F: Natural history of amyotrophic lateral sclerosis. A discussion. Adv. Neurol. (1995) 68:199–207.
   PubMed Web of Science ®Google Scholar
• MILLER RG, MOORE D, YOUNG LA et al.: Placebo-controlled trial of gabapentin in patients with amyotrophic lateral sclerosis. WALS Study Group. Western Amyotrophic Lateral Sclerosis Study Group. Neurology(1996) 47(6):1383–1388.
   Google Scholar
• MAZZINI L, MORA G, BALZARINI C et al.: The natural history and the effects of gabapentin in amyotrophic lateral sclerosis. Neurol. Sci. (1998) 160 (Suppl. 1):557–S63.
   Google Scholar
• MILLER RG, MOORE DH, GELINAS DF et al.: Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis. Neurology(2001) 56(7):843–848.
   PubMed Web of Science ®Google Scholar
• NOH KM, HWANG JY, SHIN HC, KOH JY: A novel neuroprotective mechanism of riluzole: direct inhibition of protein kinase C. Neurobiol. Dis. (2000) 7(4):375–383.
   PubMed Web of Science ®Google Scholar
• KOH JY, KIM DK, HWANG JY, KIM YH, SEO JH: Antioxidative and proapoptotic effects of riluzole on cultured cortical neurons. Neurochem. (1999) 72(2):716–723.
   PubMed Web of Science ®Google Scholar
• REINHOLZ MM, MERKLE CM, PODUSLO JF: Therapeutic benefits of putrescine-modified catalase in a transgenic mouse model of familial amyotrophic lateral sclerosis. Exp. Neurol. (1999) 159(1):204–216.
   PubMed Web of Science ®Google Scholar
• PODUSLO JF, WHELAN SL, CURRAN GL, WENGENACK TM: Therapeutic benefit of polyamine-modified catalase as a scavenger of hydrogen peroxide and nitric oxide in familial amyotrophic lateral sclerosis transgenics. Ann. Neurol. (2000) 48(6)943–947.
   Google Scholar
• DUGAN LL, TURETSKY DM, DU C et al.: Carboxyfullerenes as neuroprotective agents. Proc. Nati Acad. ScL USA (1997) 94(17)9434–9439.
   Google Scholar
• BARNEOUD P, CURET 0: Beneficial effects of lysine acetylsalicylate, a soluble salt of aspirin, on motor performance in a transgenic model of amyotrophic lateral sclerosis. Exp. Neurol. (1999) 155(2):243–251.
   PubMed Web of Science ®Google Scholar
• ANDREASSEN OA, DEDEOGLU A, FRIEDLICH A et al.: Effects of an inhibitor of poly(ADP-ribose) polymerase, desmethylselegiline, trientine, and lipoic acid in transgenic ALS mice. Exp. Neurol. (2001) 168(2):419–424.
   PubMed Web of Science ®Google Scholar
• HARNETT JJ, AUGUET M, VIOSSAT I, DOLO C, BIGG D, CHABRIER PE: Novel lipoic acid analogues that inhibit nitric oxide synthase. Bioorg. Med. Chem. Lett. (2002) 12(11):1439–1442.
   PubMed Web of Science ®Google Scholar
• FACCHINETTI F, SASAKI M, CUTTING FB et al.: Lack of involvement of neuronal nitric oxide synthase in the pathogenesis of a transgenic mouse model of familial amyotrophic lateral sclerosis. Neuroscience (1999) 90(4):1483–1492.
   PubMed Web of Science ®Google Scholar
• HOTTINGER AF, FINE EG, GURNEY ME, ZURN AD, AEBISCHER P: The copper chelator d-penicillamine delays onset of disease and extends survival in a transgenic mouse model of familial amyotrophic lateral sclerosis. Ear. Neurosci. (1997) 9(7):1548–1551.
   PubMed Web of Science ®Google Scholar
• NAGANO S, OGAWA Y, YANAGIHARA T, SAKODA S: Benefit of a combined treatment with trientine and ascorbate in familial amyotrophic lateral sclerosis model mice. Neurosci. Lett. (1999) 265(3):159–162.
   PubMed Web of Science ®Google Scholar
• DESNUELLE C, DIB M, GARREL C, FAVIER A: 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. Arnyotroph. Lateral Scler. Other Motor Neuron Disord. (2001) 2(1):9–18.
   PubMed Web of Science ®Google Scholar
• CANTON T, BOHME GA, BOIREAU A et al.: RPR 119990, a novel alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist: synthesis, pharmacological properties, and activity in an animal model of amyotrophic lateral sclerosis. Pharmacol. Exp. The]: (2001) 299(1):314–322.
   PubMed Web of Science ®Google Scholar
• SUTHERLAND ML, MARTINOWICK K, ROTHSTEIN JD: EAAT2 overexpression plays a neuroprotective role in the SOD1 G93A model of amyotrophic lateral sclerosis (ALS). Soc. Neurosci. Abs. (2001) 27:607.6
   Google Scholar
• GANEL R, HOT, COCCIA C et al.: Excitotoxicity and neurodegeneration - a novel therapeutic approach. Soc. Neurosci. Abs. (1998) 24:2069
   Google Scholar
• ROTHSTEIN JD, JACKSON M, SAKAL C, SPICER DM, KIM BD, STEINER JP: GPI-1046, a novel non-immunosuppressant immunophilin ligand, delays the appearance of motor deficits in a transgenic mouse model of amyotrophic lateral sclerosis. Soc. Neurosci. Abs. (1999) 25:1592
   Google Scholar
• JACKSON M, SONG W, LIU MY et al: Modulation of the neuronal glutamate transporter EAAT4 by two interacting proteins. Nature (2001) 410(6824):89–93.
   PubMed Web of Science ®Google Scholar
• LIN CI, ORLOV I, RUGGIERO AM et al.: Modulation of the neuronal glutamate transporter EAAC1 by the interacting protein GTRAP3-18. Nature (2001) 410(6824):84–88.
   PubMed Web of Science ®Google Scholar
• SLUSHER BS, WOZNIAK KM, HARTMAN T, JADA P, CHADRAN M, DALCANTO M: NAALADase inhibition increases survival and delays clinicalsymptoms in SOD transgenic model of ALS. Soc. Neurosci. Abs. (2000) 26:110
   Google Scholar
• ALEXIANU ME, ROBBINS E, CARSWELL S, APPEL SH: lAlpha, 25 dihydroxyvitamin D3-dependent up-regulation of calcium- binding proteins in motoneuron cells. Neurosci. Res. (1998) 51(1):58–66.
   Web of Science ®Google Scholar
• VAN DEN BOSCH L, VAN DAMME P, VLEMINCKX V et al: An alpha-mercaptoacrylic acid derivative (PD150606) inhibits selective motor neuron death via inhibition of kainate-induced Ca(2+) influx and not via calpain inhibition. Neuropharmacology (2002) 42(5):706–713.
   PubMed Web of Science ®Google Scholar
• AEBISCHER P, SCHLUEP M, DEGLON N et al.: Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients. Nat. Med. (1996) 2(6):696–699.
   PubMed Web of Science ®Google Scholar
• •Presents the novelty and safety of polymer-encapsulated delivery of neurotrophic factors in humans.
   Google Scholar
• HENDERSON CE, PHILLIPS HS, POLLOCK RA et al.: GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle. Science (1994) 266(5187):1062–1064.
   PubMed Web of Science ®Google Scholar
• OPPENHEIM RW, HOUENOU LJ, JOHNSON JE et al.: Developing motor neurons rescued from programmed and axotomy-induced cell death by GDNF. Nature (1995) 373(6512):344–346.
   PubMed Web of Science ®Google Scholar
• MOHAJERI MH, FIGLEWICZ DA, BOHN MC: Intramuscular grafts of myoblasts genetically modified to secrete glial cell line-derived neurotrophic factor prevent motoneuron loss and disease progression in a mouse model of familial amyotrophic lateral sclerosis. Hum. Gene Ther. (1999) 10(11):1853–1866.
   PubMed Web of Science ®Google Scholar
• HOTTINGER AF, AZZOUZ M, DEGLON N, AEBISCHERP, ZURN AD: Complete and long-term rescue of lesioned adult motoneurons by lentiviral-mediated expression of glial cell line-derived neurotrophic factor in the facial nucleus. Neurosci. (2000) 20(15)5587–5593.
   Google Scholar
• ACSADI G, ANGUELOV RA, YANG H et al.: Increased survival and function of SOD1 mice after glial cell-derived neurotrophic factor gene therapy. Hum. Gene Ther. (2002) 13(9):1047–1059.
   PubMed Web of Science ®Google Scholar
• •This study shows that GDNF gene delivery to muscle and motor neurons is a potential tool for neurodegenerative diseases.
   Google Scholar
• WANG LJ, LU YY, MURAMATSU Set al.: Neuroprotective effects of glial cell line-derived neurotrophic factor mediated by an adeno-associated virus vector in a transgenic animal model of amyotrophic lateral sclerosis. J. Neurosci. (2002) 22(16):6920–6928.
   Google Scholar
• •This study shows that GDNF gene delivery to muscle and motor neurons is a potential tool for neurodegenerative diseases.
   Google Scholar
• BORDET T, LESBORDES JC, ROUHANI S et al.: Protective effects of cardiotrophin-1 adenoviral gene transfer on neuromuscular degeneration in transgenic ALS mice. Hum. Ma Genet. (2001) 10(18):1925–1933.
   PubMed Web of Science ®Google Scholar
• PENNICA D, ARCE V, SWANSON TA et al.: Cardiotrophin-1, a cytokine present in embryonic muscle, supports long- term survival of spinal motoneurons. Neuron (1996) 17(1):63–74.
   PubMed Web of Science ®Google Scholar
• OPPENHEIM RW, WIESE S, PREVETTE D et al.: Cardiotrophin-1, a muscle-derived cytokine, is required for the survival of subpopulations of developing motoneurons. Neurosci. (2001) 21(4):1283–1291.
   PubMed Web of Science ®Google Scholar
• HAASE G, KENNEL P, PETTMANN B et al.: Gene therapy of murine motor neuron disease using adenoviral vectors for neurotrophic factors. Nat. Med. (1997) 3(4):429–436.
   PubMed Web of Science ®Google Scholar
• MARTINOU JC, MARTINOU I, KATO AC: Cholinergic differentiation factor (CDF/LIF) promotes survival of isolated rat embryonic motoneurons in vitro. Neuron (1992) 8(4):737–744.
   PubMed Web of Science ®Google Scholar
• CHEEMA SS, ARUMUGAM D, MURRAY SS, BARTLETT PF: Leukemia inhibitory factor maintains choline acetyltransferase expression in vivo. Neuroreport (1998) 9(3):363–366.
   PubMed Web of Science ®Google Scholar
• CURTIS R, SCHERER SS, SOMOGYI R et al.: Retrograde axonal transport of LIF is increased by peripheral nerve injury: correlation with increased LIF expression in distal nerve. Neuron (1994) 12(1):191–204.
   PubMed Web of Science ®Google Scholar
• SENDTNER M, GOTZ R, HOLTMANN B et al.: Cryptic physiological trophic support of motoneurons by LIF revealed by double gene targeting of CNTF and LIE Curl-. Biol. (1996) 6(6):686–694.
   Google Scholar
• AZARI ME GALLE A, LOPES EC, KUREK J, CHEEMA SS: Leukemia inhibitory factor by systemic administration rescues spinal motor neurons in the SOD1 G93A murine model of familial amyotrophic lateral sclerosis. Brad) Res. (2001) 922(1):144–147.
   PubMed Web of Science ®Google Scholar
• GIESS R, BECK M, GOETZ R, NITSCH RM, TOYKA KV, SENDTNER M: Potential role of LIF as a modifier gene in the pathogenesis of amyotrophic lateral sclerosis. Neurology(2000) 54(4):1003–1005.
   PubMed Web of Science ®Google Scholar
• IWASAKI Y, SHIOJIMA T, KINOSHITA M, IKEDA K: 5R57746A: a survival factor for motor neurons in vivo. J. Neurol (1998) 160\(Suppl. 1):592–596.
   Google Scholar
• DUONG F, FOURNIER J, KEANE PE et al.: The effect of the nonpeptide neurotrophic compound SR 57746A on the progression of the disease state of the pmn mouse. Br. J. Pharmacol (1998) 124(4):811–817.
   PubMed Web of Science ®Google Scholar
• GOLD BG: Neuroimmunophilin ligands: evaluation of their therapeutic potential for the treatment of neurological disorders. Expert Opin. Investig. Drugs (2000) 9(10):2331–2342.
   PubMed Web of Science ®Google Scholar
• SHEFNERJM, BROWN RH Jr, COLE D et al.: Effect of neurophilin ligands on motor units in mice with SOD1 ALS mutations. Neurology (2001) 57(10):1857–1861.
   PubMed Web of Science ®Google Scholar
• APPEL SH, STEWART SS, APPEL V et al.: A double-blind study of the effectiveness of cyclosporine in amyotrophic lateral sclerosis. Arch. Neurol (1988) 45(4):381–386.
   PubMed Web of Science ®Google Scholar
• KEEP M, ELMER E, FONG KS, CSISZAR K: Intrathecal cyclosporin prolongs survival of late-stage ALS mice. Brain Res. (2001) 894(2):327–331.
   PubMed Web of Science ®Google Scholar
• ANNESER JM, GMEREK A, GERKRATH J, BORASIO GD, HEUMANN R: Immunosuppressant FK506 does not exert beneficial effects in symptomatic G93A superoxide dismutase-1 transgenic mice. Neuroreport (2001) 12(12):2663–2665.
   PubMed Web of Science ®Google Scholar
• ZHU S, STAVROVSKAYA IG, DROZDA M et al.: Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature (2002) 417(6884):74–78.
   PubMed Web of Science ®Google Scholar
• ••Identifies minocydine through the inhibition of cytochrome c release as a new therapeutic tool for ALS.
   Google Scholar
• VAN DEN BOSCH L, TILKIN P, LEMMENS G, ROBBERECHT W: Minocycline delays disease onset and mortality in a transgenic model of ALS. Neuromport (2002) 13(8):1067–1070.
   PubMed Web of Science ®Google Scholar
• TIKKA TM, VARTIAINEN NE, GOLDSTEINS G et al.: Minocycline prevents neurotoxicity induced by cerebrospinal fluid from patients with motor neurone disease. Brant (2002) 125\(Part 4):722–731.
   Google Scholar
• TIKKA TM, KOISTINAHO JE: Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia..1. Immunol. (2001) 166(12):7527–7533.
   Google Scholar
• SAGOT Y, TONI N, PERRELET D et al.: An orally active anti-apoptotic molecule (CGP 3466B) preserves mitochondria and enhances survival in an animal model of motoneuron disease. Br. .1. Pbarmacol. (2000) 131(0721–728.
   Google Scholar
• MACGOWAN DJ, SCELSA SN, WALDRON M: An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy. Neurology (2001) 57(6):1094–1097.
   PubMed Web of Science ®Google Scholar
• AZZOUZ M, HOTTINGER A, PATERNA JC, ZURN AD, AEBISCHER P, BUELER H: Increased motoneuron survival and improved neuromuscular function in transgenic ALS mice after intraspinal injection of an adeno-associated virus encoding Bc1-2. Hum. Mol. Genet. (2000) 9(5):803–811.
   PubMed Web of Science ®Google Scholar
• YAMASHITA S, MITA S, ARIMA T et al: Bc1-2 expression by retrograde transport of adenoviral vectors with Cre- loxP recombination system in motor neurons of mutant SOD1 transgenic mice. Gene net: (2001) 8(13):977–986.
   Web of Science ®Google Scholar
• KASPAR BK, VISSEL B, BENGOECHEA T et al.: Adeno-associated virus effectively mediates conditional gene modification in the brain. Proc. Natl. Acad. Sci. USA (2002) 99(4):2320–2325.
   PubMed Web of Science ®Google Scholar
• DRACHMAN DB, ROTHSTEIN JD: Inhibition of cyclooxygenase-2 protects motor neurons in an organotypic model of amyotrophic lateral sclerosis. Ann. Neurol. (2000) 48(5):792–795.
   PubMed Web of Science ®Google Scholar
• DRACHMAN DB, FRANK K, DYKES-HOBERG M et al.: COX-2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS. Ann. Neurol. (2002): In Press.
   Google Scholar
• WENDT S, DEDEOGLU A, SPEER 0, WALLIMANN T, BEAL ME ANDREASSEN OA: Reduced creatine kinase activity in transgenic amyotrophic lateral sclerosis mice. Free Radic. Biol. Med. (2002) 32(9):920–926.
   PubMed Web of Science ®Google Scholar
• KLIVENYI P, FERRANTE RJ, MATTHEWS RT et al.: Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat. Med. (1999) 5(3):347–350.
   PubMed Web of Science ®Google Scholar
• ••Successful predinical trial using creatinesupports the theory that mitochondrial dysfunction and energy production are factors in ALS and led to the initiation of a human trial.
   Google Scholar
• LAWLER JM, BARNES WS, WU G, SONG W, DEMAREE S: Direct antioxidant properties of creatine. Biotbem. Biophys. Res. Commun. (2002) 290(1):47–52.
   PubMed Web of Science ®Google Scholar
• ANDREASSEN OA, JENKINS BG, DEDEOGLU A et al.: Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation. Neurochem. (2001) 77(2):383–390.
   PubMed Web of Science ®Google Scholar
• MAZZINI L, BALZARINI C, COLOMBO R et al.: Effects of creatine Supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis: preliminary results. Neurol. Sci. (2001) 191(1-2):139–144.
   Web of Science ®Google Scholar
• BEAL MF: Coenzyme Q10 as a possible treatment for neurodegenerative diseases. Free Radic. Res. (2002) 36(4):455–460.
   PubMed Web of Science ®Google Scholar
• TENG YD, BINGAMAN M, TAVEIRA-DASILVA AM, PACE PP, GILLIS RA, WRATHALL JR: Treatment with 5HT1A receptor agonists reverses respiratory abnormalities in spinal cord injured rats. (1999) 25:1333
   Google Scholar
• TENG YD, CUDCOWICZ MRJD, SNYDER EY, BROWN RHJ: Treatment with 5HT1A receptor agonists ameliorates respiratory abnormalities in SOD1 mice. Soc. NeuroscL Abs. (2001) 27:106.9
   Google Scholar
• TRIEU VN, UCKUN FM: Genistein is neuroprotective in murine models of familial amyotrophic lateral sclerosis and stroke. Biotbem. Biophys. Res. Commun. (1999) 258(3):685–688.
   PubMed Web of Science ®Google Scholar
• TRIEU VN, LIU R, LIU XP, UCKUN FM: A specific inhibitor of janus kinase-3 increases survival in a transgenic mouse model of amyotrophic lateral sclerosis. Biotbem. Biophys. Res. Commun. (2000) 267(1):22–25.
   PubMed Web of Science ®Google Scholar
• BROOKS BR, SZUREK PF, VANN JM: Tamoxifen delays disease onset and progression in a mouse model of amyotrophic lateral sclerosis. Soc. Neurosci. Abs. (2001) 27:626.8.
   Google Scholar
• WICHTERLE H, LIEBERAM I, PORTER J, JESSELL T: Directed differentiation of embryonic stem cells into motor neurons. Cell (2002) 110(3):385–397.
   PubMed Web of Science ®Google Scholar
• KIM JH, AUERBACH JM, RODRIGUEZ-GOMEZ JA et al.: Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature (2002) 418(6893):50–56.
   PubMed Web of Science ®Google Scholar
• SHIHABUDDIN LS, HORNER PJ, RAY J, GAGE FH: Adult spinal cord stem cells generate neurons after transplantation in the adult dentate gyrus. Neurosci. (2000) 20(23):8727–8735.
   PubMed Web of Science ®Google Scholar
• KONDZIOLKA D, WECHSLER L, GOLDSTEIN S et al.: Transplantation of cultured human neuronal cells for patients with stroke. Neurology (2000) 55(4):565–569.
   PubMed Web of Science ®Google Scholar
• GARBUZOVA-DAVIS S, WILLING AE, MILLIKEN M et al.: Positive effect of transplantation of hNT neurons (NTera 2/ D1 cell- line) in a model of familial amyotrophic lateral sclerosis. Exp. Neurol. (2002) 174(2):169–180.
   PubMed Web of Science ®Google Scholar
• WILLING AE, GARBUZOVA-DAVIS S, SANBERG PR, SAPORTA S: Routes of stem cell administration in the adult rodent. Methods Mol. Biol. (2002) 198:357–374.
   PubMedGoogle Scholar
• ENDE N, WEINSTEIN F, CHEN R, ENDE M: Human umbilical cord blood effect on sod mice (amyotrophic lateral sclerosis). Life Sci. (2000) 67(1):53–59.
   PubMed Web of Science ®Google Scholar
• NAGAI M, AOKI M, MIYOSHI I et al.: Rats expressing human cytosolic copper-zinc superoxide dismutase transgenes with amyotrophic lateral sclerosis: associated mutations develop motor neuron disease. Neurosci. (2001) 21(23):9246–9254.
   PubMed Web of Science ®Google Scholar
• ROSSI F, CATTANEO E: Opinion: neural stem cell therapy for neurological diseases: dreams and reality. Nat. Rev Neurosci. (2002) 3(5):401–409.
   PubMed Web of Science ®Google Scholar
• •A thorough review of the potential use of neural stem cells that points out the main obstacles that we need to overcome.
   Google Scholar
• WILDA M, FUCHS U, WOSSMANN W, BORKHARDT A: Killing of leukemic cells with a BCR/ABL fusion gene by RNA interference (RNAi). Oncogene (2002) 21(37):5716–5724.
   PubMed Web of Science ®Google Scholar
• COBURN GA, CULLEN BR: Potent and specific inhibition of human immunodeficiency virus Type 1 replication by RNA interference.j Virol. (2002) 76(18):9225–9231.
   PubMed Web of Science ®Google Scholar
• KRICHEVSKY AM, KOSIK KS: RNAi functions in cultured mammalian neurons. Proc. Natl. Acad. Sci. USA (2002) 99(18):11926–9.
   PubMed Web of Science ®Google Scholar
• LOUWERSE ES, WEVERLING GJ, BOSSUYT PM, MEYJES FE, DE JONG JM: Randomized, double-blind, controlled trial of acetylcysteine in amyotrophic lateral sclerosis. Arch. Neurol. (1995) 52(6):559–564.
   PubMed Web of Science ®Google Scholar
• JOSSAN SS, EKBLOM J, GUDJONSSON 0, HAGBARTH KE, AQUILONIUS SM: Double blind cross over trial with deprenyl in amyotrophic lateral sclerosis. j Neural Transm. Suppl. (1994) 41:237–241.
   PubMedGoogle Scholar
• LANGE DJ, MURPHY PL, DIAMOND B et al.: Selegiline is ineffective in a collaborative double-blind, placebo-controlled trial for treatment of amyotrophic lateral sclerosis. Arch. Neurol. (1998) 55(1):93–96.
   PubMed Web of Science ®Google Scholar
• MAZZINI L, TESTA D, BALZARINI C, MORA G: An open-randomized clinical trial of selegiline in amyotrophic lateral sclerosis. Neurol. (1994) 241(4):223–227.
   Web of Science ®Google Scholar
• KWIECINSKI H, JANIK P, JAMROZIK Z, OPUCHLIK A: The effect of selegiline and vitamin E in the treatment of ALS: an open randomized clinical trials. Neurol. Neurochic Poi (2001) 35\(Suppl. 1):101–106.
   Google Scholar
• PLAITAKIS A, SMITH J, MANDELI J, YAHR MD: Pilot trial of branched-chain aminoacids in amyotrophic lateral sclerosis. Lancet (1988) 1(8593):1015–1018.
   PubMed Web of Science ®Google Scholar
• PLAITAKIS A, SIVAK M, FESDIJAN CO, MANDELI J: Treatment of amyotrophic lateral sclerosis with branched chain amino acids (BCAA): Results of a second study. Neurology (1992) 42\(Suppl. 3):454.
   Google Scholar
• TESTA D, CARACENI T, FETONI V: Branched-chain amino acids in the treatment of amyotrophic lateral sclerosis. j. Neurol. (1989) 236(8):445–447.
   PubMed Web of Science ®Google Scholar
• THE ITALIAN ALS STUDY GROUP: Branched-chain amino acids and amyotrophic lateral sclerosis: a treatment failure? Neurology (1993) 43(12):2466–2470.
   PubMed Web of Science ®Google Scholar
• STEINER TJ: Multinational trial of branched-chain amino acids in amyotrophic lateral sclerosis. Muscle Nerve (1994) 1 (Suppl. 166).
   Google Scholar
• ASKMARK H, AQUILONIUS SM, GILLBERG PG, LIEDHOLM LJ, STALBERG E, WUOPIO R: A pilot trial of dextromethorphan in amyotrophic lateral sclerosis.j Neurol. Neurosurg. Psychiatry (1993) 56(2):197–200.
   Google Scholar
• APPELBAUM JS, SALAZAR-GRUESO EF, RICHMAN JG, SHANAHAN M, ROSS RP: Dextromethorphan in the treatment of ALS: A pilot study. Neurology (1991) 41\(Suppl. 1):393.
   Google Scholar
• BLIN 0, AZULAY JP, DESNUELLE C et al.: A controlled one-year trial of dextromethorphan in amyotrophic lateral sclerosis. Clio. Neurophannacol. (1996) 19(2):189–192.
   Google Scholar
• GREDAL 0, PAKKENBERG B, NIELSEN M: Muscarinic, N-methyl-D-aspartate (NMDA) and benzodiazepine receptor binding sites in cortical membranes from amyotrophic lateral sclerosis patients. Neurol. Sci. (1996) 143(1-2):121–125.
   Web of Science ®Google Scholar
• HOLLANDER D, PRADAS J, KAPLAN R, MCLEOD HL, EVANS WE, MUNSAT TL: High-dose dextromethorphan in amyotrophic lateral sclerosis: Phase I safety and pharmacokinetic studies. Ann. Neurol. (1994) 36(6):920–924.
   PubMed Web of Science ®Google Scholar
• EISEN A, STEWART H, SCHULZER M, CAMERON D: Anti-glutamate therapy in amyotrophic lateral sclerosis: a trial using lamotrigine. Can. J. Neurol. Sci. (1993) 20(4):297–301.
   PubMed Web of Science ®Google Scholar
• MILLER RG, SHEPHERD R, DAO H et al.: Controlled trial of nimodipine in amyotrophic lateral sclerosis. Neuromuscul. Disord. (1996) 6(2):101–104.
   PubMed Web of Science ®Google Scholar
• MILLER RG, SMITH SA, MURPHY JR et al.: A clinical trial of verapamil in amyotrophic lateral sclerosis. Muscle Nerve (1996) 19(4):511–515.
   PubMed Web of Science ®Google Scholar
• MUNSAT TL, TAFT J, JACKSON IM et al.: Intrathecal thyrotropin-releasing hormone does not alter the progressive course of ALS: experience with an intrathecal drug delivery system. Neurology (1992) 42(5):1049–1053.
   PubMed Web of Science ®Google Scholar
• PATRIGNANI J, PROANO J, MORALES MD: Treatment of amyotrophic lateral sclerosis with daily intrathecal TRH. A year's experience. Pilot study II. Neurologia (1992) 7(1):4–9.
   Google Scholar
• CONGIA S, TRONCI S, LEDDA M, PORCELLA A, COPPOLA G: Low doses of TRH in amyotrophic lateral sclerosis and in other neurological diseases. Ital. J. Neurol. Sci. (1991) 12(2):193–198.
   PubMedGoogle Scholar
• DRACHMAN DB, CHAUDHRY V, CORNBLATH D et al.: Trial of immunosuppression in amyotrophic lateral sclerosis using total lymphoid irradiation. Ann. Neurol. (1994) 35(2):142–150.
   PubMed Web of Science ®Google Scholar
• MORA JS, MUNSAT TL, KAO KP et al: Intrathecal administration of natural human interferon alpha in amyotrophic lateral sclerosis. Neurology (1986) 36(8):1137–1140.
   PubMed Web of Science ®Google Scholar
• HARRINGTON H, HALLETT M, TYLER HR: Ganglioside therapy for amyotrophic lateral sclerosis: a double-blind controlled trial. Neurology (1984) 34(8):1083–1085.
   PubMed Web of Science ®Google Scholar
• BROWN RH Jr, HAUSER SL, HARRINGTON H, WEINER HL: 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. (1986) 43(4):383–384.
   PubMed Web of Science ®Google Scholar
• GOURIE-DEVI M, NALINI A, SUBBAKRISHNA DK: Temporary amelioration of symptoms with intravenous cyclophosphamide in amyotrophic lateral sclerosis. I Neurol. Sci. (1997) 150(2):167–172.
   PubMed Web of Science ®Google Scholar
• DALAKAS MC, STEIN DP, OTERO C, SEKUL E, CUPLER EJ, MCCROSKY S: Effect of high-dose intravenous immunoglobulin on amyotrophic lateral sclerosis and multifocal motor neuropathy. Arch. Neurol. (1994) 51(9):861–864.
   PubMed Web of Science ®Google Scholar
• MEUCCI N, NOBILE-ORAZIO E, SCARLATO G: Intravenous immunoglobulin therapy in amyotrophic lateral sclerosis. I Neurol. (1996) 243(2):117–120.
   PubMed Web of Science ®Google Scholar
• NORRIS FH, DENYS EH, FALLAT RJ: Trial of octacosanol in amyotrophic lateral sclerosis. Neurology (1986) 36(9):1263–1264.
   PubMed Web of Science ®Google Scholar
• MUNSAT TL, EASTERDAY CS, LEVY S, WOLFF SM, HIATT R: Amantadine and guanidine are ineffective in ALS. Neurology (1981) 31(8):1054–1055.
   PubMed Web of Science ®Google Scholar
• OLARTE MR, GERSTEN JC, ZABRISKIE J, ROWLAND LP: Transfer factor is ineffective in amyotrophic lateral sclerosis. Ann. Neurol (1979) 5(4):385–388.
   PubMed Web of Science ®Google Scholar
• OLSON WH, SIMONS JA, HALAAS GW: Therapeutic trial of tilorone in ALS: lack of benefit in a double- blind, placebo-controlled study. Neurology (1978) 28(12):1293–1295.
   PubMed Web of Science ®Google Scholar
• FAREED GC, TYLER HR: The use of isoprinosine in patients with amyotrophic lateral sclerosis. Neurology (1971) 21(9):937–940.
   PubMed Web of Science ®Google Scholar
• ANDREASSEN OA, DEDEOGLU A, KLIVENYI P, BEAL MF, BUSH AT: N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis. Neuroreport (2000) 11(11):2491–2493.
   PubMed Web of Science ®Google Scholar
• JIANG F, DESILVA S, TURNBULL J: Beneficial effect of ginseng root in SOD-1 (G93A) transgenic mice. Neurol (2000) 180(1-2):52–54.
   Google Scholar