CSF and Plasma Amino Acid Levels in Motor Neuron Disease: Elevation of CSF Glutamate in a Subset of Patients

Shaw, Pamela J.; Forrest, V.; Ince, Paul G.; Richardson, Julian; Wastell, H.

doi:10.1006/neur.1995.0026

Cited by 232 publications

(110 citation statements)

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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).…”

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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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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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“…Despite the role of glutamate role in neurotransmission, it is itself highly toxic to neurons. Elevated levels of glutamate have been observed in the CSF of ALS patients, suggesting a role of excitotoxicity in ALS pathogenesis [42]. Further evidence implicating excitotoxicity in ALS is the fact that the drug riluzole acts to ameliorate excitotoxicity at least in part through reduction in presynaptic glutamate release [43].…”

Section: 24mentioning

confidence: 99%

Current developments in gene therapy for amyotrophic lateral sclerosis

Scarrott

Herranz-Martín

Alrafiah

et al. 2015

Expert Opinion on Biological Therapy

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Article highlights: Types of ALS and the recent genetic discoveries. No effective treatment for ALS is available. Gene therapy approaches to modulate mutant ALS genes by using siRNA or antisense oligonucleotide (ASO) therapy. AAV or LV-based vectors driving the expression of neurotrophic factors to support motor neuron survival. A summary of the previous and the ongoing gene therapy clinical trials for ALS.3

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“…Based on the reduction of glutamate transporter-1 (GLT1 in rodents and excitatory amino acid transporter 2 or EAAT2 in human) content detected post-mortem in motor cortex and spinal cord of ALS patients (Rothstein et al, 1992;Rothstein et al, 1995) and on the increase of glutamate concentration in the cerebrospinal fluid (CSF) of about 40% of ALS patients (Shaw et al, 1995b;Spreux-Varoquaux et al, 2002), one proposed mechanism to explain www.intechopen.com motor neuron death in ALS is glutamate-mediated excitotoxicity. This hypothesis has been generally accepted, although some data from our laboratory do not support it because a chronic increase in extracellular glutamate due to glutamate transport inhibition in the spinal cord in vivo was innocuous for motor neurons (Tovar-y-Romo et al, 2009b).…”

Section: Excitotoxicitymentioning

confidence: 99%