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

Spreux‐Varoquaux, Odile; Bensimon, Gilbert; Lacomblez, Lucette; Salachas, François; Pradat, Pierre; Forestier, Nadine Le; Marouan, Abdellatif; Dib, Michel; Meininger, Vincent

doi:10.1016/s0022-510x(01)00661-x

Cited by 249 publications

(142 citation statements)

References 19 publications

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“…The glutamate concentrations in the media from our organotypic culture controls are identical to the 176 nM glutamate reported in the CSF of control human subjects (Spreux-Varoquaux et al, 2002). With PDC treatment, the glutamate concentrations in culture increase to the range of CSF glutamate levels reported in a subset of ALS patients of 80 nM to 1.43 μM (SpreuxVaroquaux et al, 2002).…”

Section: Neurotoxicity In Organotypic Cortical Cultures In Response Tsupporting

confidence: 74%

Glutamate receptor expression and chronic glutamate toxicity in rat motor cortex

Young¹,

McGehee

Brorson³

2007

Neurobiology of Disease

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In addition to the loss of spinal motor neurons, amyotrophic lateral sclerosis (ALS) is also associated with degeneration of corticospinal layer V pyramidal neurons and decreased glutamate transport in the cortex. We characterized the glutamate receptors on corticospinal neurons in acutely isolated rat motor cortex slices and found that the synaptic inputs to the corticospinal layer V neurons had a lesser proportional contribution from NMDA receptors relative to AMPA receptors than did layer II/III pyramidal neurons. The synaptic I AMPA was also more inwardly rectified, indicating a greater Ca 2+ -permeable component, in layer V. In a cortical organotypic slice culture model, blockade of glutamate transporters elevated glutamate in the media and led to pyramidal neuron loss in both layers. The loss of layer V pyramidal neurons was attenuated by antagonists of AMPA/kainate or Ca 2+ -permeable AMPA receptors, suggesting their therapeutic potential in the protection of the motor cortex in ALS.

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Section: Neurotoxicity In Organotypic Cortical Cultures In Response Tsupporting

confidence: 74%

Glutamate receptor expression and chronic glutamate toxicity in rat motor cortex

Young¹,

McGehee

Brorson³

2007

Neurobiology of Disease

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“…Therefore, it is reasonable to hypothesize that increased levels of extracellular glutamate could contribute to the progression of ALS. This has been addressed in previous studies where increased levels of glutamate were observed in the CSF of patients with ALS compared with controls [77][78][79][80][81][82]. In contrast to these findings, others have also demonstrated similar glutamate levels in CSF from patients with ALS and controls [83,84].…”

Section: Metabolic Biomarkersmentioning

confidence: 96%

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Bowser

2017

Neurotherapeutics

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Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease with no effective treatment. Drug development has been hampered by the lack of biomarkers that aid in early diagnosis, demonstrate target engagement, monitor disease progression, and can serve as surrogate endpoints to assess the efficacy of treatments. Fluid-based biomarkers may potentially address these issues. An ideal biomarker should exhibit high specificity and sensitivity for distinguishing ALS from control (appropriate disease mimics and other neurologic diseases) populations and monitor disease progression within individual patients. Significant progress has been made using cerebrospinal fluid, serum, and plasma in the search for ALS biomarkers, with urine and saliva biomarkers still in earlier stages of development. A few of these biomarker candidates have demonstrated use in patient stratification, predicting disease course (fast vs slow progression) and severity, or have been used in preclinical and clinical applications. However, while ALS biomarker discovery has seen tremendous advancements in the last decade, validating biomarkers and moving them towards the clinic remains more elusive. In this review, we highlight biomarkers that are moving towards clinical utility and the challenges that remain in order to implement biomarkers at all stages of the ALS drug development process.

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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.

115

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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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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

Cited by 249 publications

References 19 publications

Glutamate receptor expression and chronic glutamate toxicity in rat motor cortex

Glutamate receptor expression and chronic glutamate toxicity in rat motor cortex

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

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

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