Excitotoxicity in the embryonic chick spinal cord

Stewart, Gregory R.; Olney, John W.; Pathikonda, Maya; Snider, William D.

doi:10.1002/ana.410300604

Cited by 58 publications

(25 citation statements)

References 48 publications

(11 reference statements)

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“…1 and 2). Similar morphological changes have been reported using a number of different in vivo and in vitro models (Ikonomidou et al, 1996;Nag and Riopelle, 1990;Stewart et al, 1991). These findings suggest that a direct toxicity mediated by the NMDA receptor is an unlikely mechanism for the pathogenesis of ALS or other motor neuron diseases.…”

Section: Relevance To Alssupporting

confidence: 71%

“…Previous studies have demonstrated NMDA toxicity to cortical, hippocampal (Choi, 1987(Choi, , 1988Rothman, 1985) and spinal cord (Ikonomidou et al, 1996;Nag and Riopelle, 1990;Regan et al, 1990;Stewart et al, 1991;Wells et al, 1994) neurons. Our studies provide information on the specific effects of NMDA on spinal cord cholinergic enzymes.…”

Section: Relevance To Alsmentioning

confidence: 98%

“…In an identical culture system, Wells et al (1994) reported similar toxic effects exerted by NMDA, KA and glutamate. Although a number of additional investigations have studied changes in spinal cord caused by excitotoxins (Hugon et al, 1989;Ikonomidou et al, 1996;Nag and Riopelle, 1990;Rothstein et al, 1993;Rothstein and Kuncl, 1995;Stewart et al, 1991), no studies are available on the effects of EAAs on the acetylcholinesterase (AChE)-positive ventral horn neurons (VHANs).…”

Section: Introductionmentioning

confidence: 99%

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Effects of NMDA and its antagonists on ventral horn cholinergic neurons in organotypic roller tube spinal cord cultures

Delfs

Saroff

Nishida

et al. 1997

J. Neural Transmission

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Neurotoxic effects of excitatory amino acid (EAA) receptor agonist N-methyl-D-aspartic acid (NMDA) and its antagonists on ventral horn cholinergic neurons were studied in organotypic rollertube cultures of spinal cord (OTC-SCs) using biochemical assays of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activity, and AChE histochemistry. NMDA exposure decreased ChAT and AChE activity by 83% and 66%, respectively. Cultures treated with NMDA also showed a marked loss of AChE staining in both dorsal and ventral horns and a significant, dose-dependent decrease in the number of ventral horn AChE-positive neurons (VHANs). NMDA treatment primarily resulted in the loss of small VHANs (< 300 microns2). VHANs with a size and distribution typical of alpha-motoneurons were relatively well preserved. The effects of NMDA on OTC-SCs appeared to be independent of the age of the cultures. The NMDA antagonist DL-AP5 completely prevented the NMDA-induced loss of ChAT activity, but only attenuated the effect of NMDA on ChE activity. The antagonists DL-AP5, D-AP5 and MK-801, used alone, caused significant loss and/or shrinkage of VHANs. These effects appeared to be distinct from the NMDA mediated toxicity. The results indicate that NMDA and its antagonists exert powerful toxic effects on ventral horn cholinergic neurons. The large cholinergic alpha-motoneurons, however, appear to be relatively immune to these toxic effects.

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Section: Relevance To Alssupporting

confidence: 71%

Section: Relevance To Alsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of NMDA and its antagonists on ventral horn cholinergic neurons in organotypic roller tube spinal cord cultures

Delfs

Saroff

Nishida

et al. 1997

J. Neural Transmission

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“…However, NMDA antagonists were not neuroprotective, and NMDA itself was not toxic to motor neurons. Acute non-NMDA-mediated toxicity affecting motor neurons has been suggested by studies of chicken spinal cord in vitro (26) and neonatal rats in vivo (27). In contrast, our model clearly demonstrates selective non-NMDAmediated slow neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity.

Rothstein

Jin

Dykes-Hoberg

et al. 1993

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

567

350

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ABSTRACTprior to the addition of drugs. To produce chronic toxicity, long-term inhibition of glutamate uptake was effected by incubating slices with culture medium containing various concentrations of THA or PDC (5, 6). At very high concentrations (>1 mM), THA can have weak actions at the N-methyl-D-aspartate (NMDA) receptor, a property not shared by PDC (5). Transport inhibitors were maintained in cultures by replenishing them at each change in culture medium. In all experiments, potentially neuroprotective drugs were added repeatedly, either in the presence or absence of a glutamate transport inhibitor, again beginning after 8 days in culture. Motor-neuron toxicity was monitored by two methods: (i) biochemical analysis of tissue choline acetyltransferase activity (ChAT) and (ii) microscopic morphology. ChAT activity is largely restricted to ventral motor neurons in rat lumbar spinal cord, and assays of ChAT activity have been used as a reliable marker for motor neurons (7-9). Motor neurons were also visualized in organotypic cultures by histological analysis of stained semithin plastic sections and by immunohistochemistry.Organotypic Spinal Cord Cultures. Organotypic spinal cord cultures were prepared using lumbar spinal cord slices from 8-day-old rat pups. Neonatal rat pups were decapitated, and the spinal cords were rapidly harvested and cultured by a modification of described methods (10, 11). Lumbar spinal cords were collected under sterile conditions and sectioned transversely at 350-,um intervals with a McIlwain tissue chopper (Mickle Laboratory Engineering, Gomshall, Surrey, U.K.). Sections were then transferred to sterile Gey's balanced salt solution (GIBCO) containing glucose (6.4 mg/ml) and gently separated at room temperature. Slices were carefully placed on the surface of 30-mm Millipore Millicell-CM porous (0.4 ,um) membranes (five slices per membrane). Such tissue grows optimally at an air/fluid interface, so it was important to remove any excess medium on the membrane surface around slices. The membranes were placed in 35-mm culture wells (Nunc) containing 1 ml of incubation medium [50% (vol/vol) minimal essential medium-25 mM Hepes/ 25% (vol/vol) heat-inactivated horse serum/25% (vol/vol) Hanks' balanced salt solution (GIBCO) supplemented with D-glucose (25.6 mg/ml) and glutamine (2 mM), at a final pH of 7.2]. Initial studies using pH 7.4 or 7.8 revealed similar results. Antibiotic and antifungal agents were not used.Cultures were incubated at 37°C in a 5% C02/95% air humidified environment (Forma Scientific, Marietta, OH). Culture medium, along with any added pharmacological agents, was changed twice weekly. By using this technique, >95% of the explants can be maintained in culture for >3 months with excellent organotypic cellular organization.

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“…None of these studies revealed a major effect on motor neuron (MN) survival or animal life span. [135][136][137] and are more vulnerable than other neuronal subsets to excitoxicity induced by influx of Ca 2+ through GluRs. [138][139][140] Most of the studies investigating the possible implication of GluRs in ALS pathogenesis are therefore particularly focused on ionotropic GluR NMDA and on GluR2 subunit expression and editing, which confer Ca 2+ impermeability to the AMPA/KA GluR.…”

Section: Astrocytementioning

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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Excitotoxicity in the embryonic chick spinal cord

Cited by 58 publications

References 48 publications

Effects of NMDA and its antagonists on ventral horn cholinergic neurons in organotypic roller tube spinal cord cultures

Effects of NMDA and its antagonists on ventral horn cholinergic neurons in organotypic roller tube spinal cord cultures

Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity.

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

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