Riluzole preserves motor function in a transgenic model of familial amyotrophic lateral sclerosis

Gurney, Mark E.; Fleck, Thomas J.; Himes, Carol S.; Hall, Edward D.

doi:10.1212/wnl.50.1.62

Cited by 155 publications

(75 citation statements)

References 3 publications

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“…In our study, E2 treatment extends the lifespan by 8 days in the ovariectomized mice, which approximately corresponds to 27 days in the mice with low copy numbers, suggesting its potential usage as a candidate for combined therapy. Indeed, Riluzole that has been used for the treatment of ALS patients [24] only increases the survival of the hSOD1 G93A mice with high copy number by 12-13 days [25].…”

Section: Discussionmentioning

confidence: 99%

Effects of estrogen on lifespan and motor functions in female hSOD1 G93A transgenic mice

Choi

Lee

Gwag

et al. 2008

Journal of the Neurological Sciences

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Section: Discussionmentioning

confidence: 99%

Effects of estrogen on lifespan and motor functions in female hSOD1 G93A transgenic mice

Choi

Lee

Gwag

et al. 2008

Journal of the Neurological Sciences

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“…Mice were assessed daily for survival and bi-weekly for weighing and stride length analysis starting at 10 weeks of age. The disease end point was determined as previously described (4,(23)(24)(25) based on asymmetrical or symmetrical paralysis of the hind limbs and the inability to right themselves within 15 s after being placed on their side.…”

Section: Methodsmentioning

confidence: 99%

Stabilization of Hyperdynamic Microtubules Is Neuroprotective in Amyotrophic Lateral Sclerosis

Fanara

Banerjee

Hueck

et al. 2007

Journal of Biological Chemistry

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Mutations in copper/zinc superoxide dismutase 1 (SOD1), a genetic cause of human amyotrophic lateral sclerosis, trigger motoneuron death through unknown toxic mechanisms. We report that transgenic SOD1G93A mice exhibit striking and progressive changes in neuronal microtubule dynamics from an early age, associated with impaired axonal transport. Pharmacologic administration of a microtubule-modulating agent alone or in combination with a neuroprotective drug to symptomatic SOD1G93A mice reduced microtubule turnover, preserved spinal cord neurons, normalized axonal transport kinetics, and delayed the onset of symptoms, while prolonging life by up to 26%. The degree of reduction of microtubule turnover was highly predictive of clinical responses to different treatments. These data are consistent with the hypothesis that hyperdynamic microtubules impair axonal transport and accelerate motor neuron degeneration in amyotrophic lateral sclerosis. Measurement of microtubule dynamics in vivo provides a sensitive biomarker of disease activity and therapeutic response and represents a new pharmacologic target in neurodegenerative disorders. Amyotrophic lateral sclerosis (ALS)2 is a late-onset, progressive neurodegenerative disease affecting motoneurons (1). The etiology of the majority of ALS cases is unknown, but ϳ20% of familial disease cases are due to mutations in copper-zinc superoxide dismutase1 (SOD1) (2). This led to the development of SOD1 transgenic mice as models of disease (2-5).Physically, motoneurons are unique, representing the longest cells in the body, with axons of some motoneurons in the spinal cord extending a meter or more to reach an end organ. As a result of this morphology, exceptional demands are placed on motoneurons. Active transport along lengthy axons is required to convey newly made materials from the cell body to the farthest nerve endings, and to convey nutrients and metabolites back to the cell body. Microtubules are an essential component of the neuron's scaffold and represent the "roadway," or conveyer belt, that neurons use to transport nutrients (6 -10). Microtubule-based transport is mandatory for survival of motoneurons and muscle cells; changes in slow axonal transport have been linked to neuropathogenesis in mutant SOD1 transgenic mice (11-13). In addition, the assembly and disassembly of microtubule polymers in motoneurons is highly responsive to cellular insults, such as excitotoxic stimuli (8, 14 -16).The relation between dynamics of microtubules and neuronal pathogenesis has not been explored in detail, in part due to limited techniques for measuring microtubule dynamics in vivo. In most non-neuronal cells, tubulin dimers and microtubule polymers exist in rapid dynamic equilibrium, as we have recently shown in vivo by isotopic labeling (17). In neurons, however, this rapid turnover of axonal and dendritic microtubules is believed to be less dynamic due to their interactions with a specific subclass of microtubule-associated proteins (MAPs) (18 -20). This stability of microtubule...

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“…Mice and rats that carry mutant (MT) SOD1 as a transgene manifest a progressive MN degeneration similar to that in patients with ALS (2)(3)(4). Several lines of evidence suggest that glutamate excitotoxicity is a pathogenic mechanism in both sporadic ALS and FALS (5)(6)(7)(8)(9)(10)(11)(12)(13).…”

mentioning

confidence: 99%

Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models

Ghadge

Slusher

Bodner

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

114

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Approximately 10% of cases of amyotrophic lateral sclerosis (ALS), a progressive and fatal degeneration that targets motor neurons (MNs), are inherited, and Ϸ20% of these cases of familial ALS (FALS) are caused by mutations of copper͞zinc superoxide dismutase type 1. Glutamate excitotoxicity has been implicated as a mechanism of MN death in both ALS and FALS. In this study, we tested whether a neuroprotective strategy involving potent and selective inhibitors of glutamate carboxypeptidase II (GCPII), which converts the abundant neuropeptide N-acetylaspartylglutamate to glutamate, could protect MNs in an in vitro and animal model of FALS. Data suggest that the GCPII inhibitors prevented MN cell death in both of these systems because of the resultant decrease in glutamate levels. GCPII inhibition may represent a new therapeutic target for the treatment of ALS.A myotrophic lateral sclerosis (ALS) is a progressive and fatal degeneration of motor neurons (MNs) in the spinal cord and cerebral cortex. About 10% of ALS cases are inherited in an autosomal dominant fashion, and Ϸ20% of these cases of familial ALS (FALS) are caused by a mutation in copper͞zinc superoxide dismutase type 1 (SOD1) (1). Mice and rats that carry mutant (MT) SOD1 as a transgene manifest a progressive MN degeneration similar to that in patients with ALS (2-4). Several lines of evidence suggest that glutamate excitotoxicity is a pathogenic mechanism in both sporadic .N-acetylaspartylglutamate (NAAG) is one of the most abundant peptides in the mammalian central and peripheral nervous system (14), is present in neuronal vesicles, is released from neurons in a calcium-dependent manner, and functions as a high-affinity agonist at the group II metabotropic glutamate receptor subtype 3 (mGluR3). Activation of mGluR3 by NAAG has been shown to inhibit glutamate release (15), increase release of transforming growth factor ␤ (TGF␤) from glial cells, and provide neuroprotection (16). NAAG is hydrolyzed to N-acetylaspartate and glutamate by glutamate carboxypeptidase II (GCPII) (EC 3.4.17.21; also termed N-acetylated-␣-linked acidic dipeptidase or NAALADase; ref. 17), an enzyme localized on the plasma membrane of glial cells with its catalytic region facing the synapse (18). Therefore, inhibition of GCPII would be expected to provide neuroprotection by means of both decreasing glutamate and increasing NAAG (19).We hypothesized that GCPII inhibition would protect MNs expressing MT SOD1 from cell death, as well as ameliorate the MN degeneration seen in FALS transgenic mouse. For in vitro studies, we used 2-(phosphonomethyl)pentanedioic acid (2-PMPA), a potent and selective GCPII inhibitor (K i ϭ 0.2 nM; ref. 20) that has been shown to selectively reduce ischemic glutamate and provide neuroprotection in cell culture and animal models of ischemia (19), diabetic neuropathy (21), and drug abuse (22, 23). For the animal studies, we used a recently discovered thiol-based GCP II inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA) (24). Unlike 2-PMPA, 2-MPPA is o...

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Riluzole preserves motor function in a transgenic model of familial amyotrophic lateral sclerosis

Cited by 155 publications

References 3 publications

Effects of estrogen on lifespan and motor functions in female hSOD1 G93A transgenic mice

Effects of estrogen on lifespan and motor functions in female hSOD1 G93A transgenic mice

Stabilization of Hyperdynamic Microtubules Is Neuroprotective in Amyotrophic Lateral Sclerosis

Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models

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