Alterations in spinal cord excitatory amino acid receptors in amyotrophic lateral sclerosis patients

Allaoua, Horia; Chaudieu, Isabelle; Krieger, Charles; Boksa, Patricia; Privat, Alain; Quirion, Rémi

doi:10.1016/0006-8993(92)90758-2

Cited by 43 publications

(6 citation statements)

References 21 publications

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“…Increased densities of non‐NMDA receptors were indeed found in the spinal cord of ALS patients, as labelled by [ 3 H]CNQX and [ 3 H]kainate (Shaw et al . 1994), while [ 3 H]AMPA binding sites were unaltered (Allaoua et al . 1992).…”

Section: Discussionmentioning

confidence: 99%

Biochemical and pharmacological evidence of a functional role of AMPA receptors in motor neuron dysfunction in mnd mice

Mennini

Cagnotto

Carvelli

et al. 1999

Eur J of Neuroscience

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We studied ionotropic glutamate receptor subtypes and the effect of chronic treatment with NBQX [6-nitro-7-sulphamoyl-benzo(F)quinoxaline-2,3-dione], a selective (rs)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist, in the spinal cord of mnd mice. NBQX (8 mg/kg daily i.p. for 3 weeks starting from 24 weeks old) significantly improved the behavioural scores (hind leg extension reflex, cage rung grasping and gait) in mnd mice, measured after the last drug injection, and increased the number of mice with 'normal' gait (from 50% to 90%, P < 0.05). Receptor binding autoradiography of the competitive N-methyl-D-aspartate (NMDA) antagonist, [3H]CGP 39653, of [3H]AMPA and [3H]kainic acid in spinal cord sections, measured after 1 week of drug washout, were not significantly different in control and mnd mice, and were not modified by NBQX. GluR2/3 immunoreactivity, assessed using Western blotting, was significantly enhanced (by 59%, P < 0.01) in the spinal cord but not in the brain of 28-week-old mnd mice compared to age-matched control mice. NBQX treatment increased GluR2/3 immunoreactivity in the spinal cord of control mice and mnd mice by 327 +/- 74% (P < 0.01) and 212 +/- 52% (P < 0.01), respectively. The changes in GluR2/3 subunits may involve adaptive mechanisms of the receptor and play some role in the protective effect of NBQX. These findings suggest that selective antagonism of ionotropic non-NMDA receptors may be of value in the treatment of motor neuron disease.

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Section: Discussionmentioning

confidence: 99%

Biochemical and pharmacological evidence of a functional role of AMPA receptors in motor neuron dysfunction in mnd mice

Mennini

Cagnotto

Carvelli

et al. 1999

Eur J of Neuroscience

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“…72 Somewhat later, Charles Krieger also worked on excitotoxicity. [73][74][75] Charles Krieger and Andrew Eisen collaborated on many publications, highlighted by a monograph on ALS. 76 When at the Montreal Neurological Institute, he got to know George Karpati, Heather Durham, and Guy Rouleau.…”

Section: Excitotoxicitymentioning

confidence: 99%

Canadian Pioneers of Amyotrophic Lateral Sclerosis: A Brief History

Eisen

Taylor

2020

Can. J. Neurol. Sci.

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This is an historical account of Canadian pioneers working in amyotrophic lateral sclerosis (ALS) in the 1970s and 1980s. Key contributions included the development of specialized clinics, the ALS Society of Canada, human motor unit estimates in vivo, use of transcranial magnetic stimulation (TMS), the dementias of ALS, the importance of neurofilaments and axonal flow, neuroinflammation and immunity related to ALS, use of tissue culture to study pathogenesis, and the story of ALS in Guam. Their work set the stage for future generations of ALS physicians and scientists to bring about meaningful therapies and hopefully a cure for ALS.

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“…An opening argument for abnormal GluR permeability to Ca 2+ in ALS is the observation of Ca 2+ accumulation in MN terminals of ALS patients 175 and in vacuoles of degenerating MNs in SOD1 G93A mice. 176 In ALS patients, a specific reduction of NMDA receptor binding sites and NR-1 mRNA levels was observed in the ventral horn compared with control individuals, 177,178 indicating that the MNs that were lost were expressing NMDA receptors. Reflecting earlier stages of the disease, a postsynaptic decrease of NR2A subunit expression was also recently reported in upper MNs of presymptomatic SOD1 G93A mice.…”

Section: Mn Glur Alteration In Als: Zoom In On Glur2 Loss and Editingmentioning

confidence: 99%

“…211,212 D-serine, a physiological co-agonist of the NMDA receptor, was suggested to amplify ALS MN excitability by increasing the receptor's affinity for glutamate, 213,214 even though the expression of NMDA receptors is kept low in this disease. 142,177 An increase of D-serine was observed in spinal cords of mutant SOD1 mice and in familial and sporadic ALS patients. 215 Further, primary spinal cord neurons from ALS mice were shown to be more vulnerable to NMDA toxicity in a D-serine-dependent manner than those from control mice, and removal of endogenous D-serine from spinal cord cultures of SOD1 mice attenuated NMDA receptor-mediated MN death.…”

Section: Astrocytes: a New Piece In The Excitotoxic Puzzle In Alsmentioning

confidence: 99%

Glutamate pathway implication in amyotrophic lateral sclerosis: what is the signal in the noise?

Verche¹,

Ikiz²,

Jacquier³

et al. 2010

JRLCR

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Abstract:The cause of the fatal motor neuron disease, amyotrophic lateral sclerosis (ALS), remains largely unknown. Most cases of ALS are sporadic and, for ∼20% of familial ALS patients, mutations in the superoxide dismutase-1 (SOD1) gene have been identified. Transgenic rodents overexpressing mutant SOD1 emulate the disease and constitute the best ALS animal model so far. Several lines of evidence suggest that ALS is a multifactorial condition. In this review, we discuss the question of the involvement of the glutamate pathways in ALS-induced motor neuron death. As such, we review the data implicating glutamate metabolism alterations, glutamatergic environmental toxins, glutamate transporter/receptor defects, and Ca 2+ -mediated glutamate toxicity in the etiopathogenesis of ALS. Given the published data, we contend that glutamate-induced neurotoxicity more likely precipitates motor neuron degeneration rather than being the initiating factor of ALS. Furthermore, we propose that glutamate-induced neurotoxicity participates in the ALS deadly molecular cascade only as an executioner to put an end to a series of molecular perturbations that have irreversibly compromised motor neuron function. This could provide an explanation for the modest effect of therapeutic strategies targeting the glutamatergic system, including the only currently FDA-approved ALS treatment, riluzole. As in diseased motor neurons, overwhelming Ca 2+ overload may be the converging point for glutamate, endoplasmic reticulum stress, and mitochondrial dysfunctional pathways, and only therapies targeting these simultaneously or targeting the earliest alterations initiating this deleterious cascade may have a real impact on halting ALS progression.

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Alterations in spinal cord excitatory amino acid receptors in amyotrophic lateral sclerosis patients

Cited by 43 publications

References 21 publications

Biochemical and pharmacological evidence of a functional role of AMPA receptors in motor neuron dysfunction in mnd mice

Biochemical and pharmacological evidence of a functional role of AMPA receptors in motor neuron dysfunction in mnd mice

Canadian Pioneers of Amyotrophic Lateral Sclerosis: A Brief History

Glutamate pathway implication in amyotrophic lateral sclerosis: what is the signal in the noise?

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