Neurotoxic effects of excitatory amino acids in the mouse spinal cord: quisqualate and kainate but not N-methyl-l-aspartate induce permanent neural damage

Urca, Gideon; Urca, Rivka

doi:10.1016/0006-8993(90)90805-l

Cited by 64 publications

(22 citation statements)

References 23 publications

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“…This contrasts with previous studies reporting glutamate-or kainic acidmediated neuronal cell loss in vitro (Regan and Choi, 1991;Regan, 1996;Simonian et al, 1996) and in vivo (Urca and Urca, 1990;Pollard et al, 1994;PorteraCailliau et al, 1997;Liu et al, 1999). The reasons for this discrepancy may be related to the dose of kainic acid and the mode of delivery used in our study.…”

Section: Discussioncontrasting

confidence: 84%

Temporal and spatial distribution of activated caspase‐3 after subdural kainic acid infusions in rat spinal cord

Nottingham

Springer

2003

J of Comparative Neurology

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The molecular events initiating apoptosis following traumatic spinal cord injury (SCI) remain poorly understood. Soon after injury, the spinal cord is exposed to numerous secondary insults, including elevated levels of glutamate, that contribute to cell dysfunction and death. In the present study, we attempted to mimic the actions of glutamate by subdural infusion of the selective glutamate receptor agonist, kainic acid, into the uninjured rat spinal cord. Immunohistochemical colocalization studies revealed that activated caspase-3 was present in ventral horn motor neurons at 24 hours, but not 4 hours or 96 hours, following kainic acid treatment. However, at no time point examined was there evidence of significant neuronal loss. Kainic acid resulted in caspase-3 activation in several glial cell populations at all time points examined, with the most pronounced effect occurring at 24 hours following infusion. In particular, caspase-3 activation was observed in a significant number of oligodendroglia in the dorsal and ventral funiculi, and there was a pronounced loss of oligodendroglia at 96 hours following treatment. The results of these experiments indicate a role for glutamate as a mediator of oligodendroglial apoptosis in traumatic SCI. In addition, understanding the apoptotic signaling events activated by glutamate will be important for developing therapies targeting this cell death process.

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Section: Discussioncontrasting

confidence: 84%

Temporal and spatial distribution of activated caspase‐3 after subdural kainic acid infusions in rat spinal cord

Nottingham

Springer

2003

J of Comparative Neurology

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“…38 A large number of studies assert that glutamate and its structural analogues could have both short and long-term poisonous impacts on cortical and motor neurons. [46][47][48] The exposure of neurons to abnormally high concentrations of glutamate results from the defective clearance of glutamate from the extracellular space. 38 Glutamate neurotransmission is greatly regulated, mainly via glutamate transporters.…”

Section: Discussionmentioning

confidence: 99%

Comparative Study on the Effects of Ceftriaxone and Monocytes on Recovery after Spinal Cord Injury in Rat

et al. 2015

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“…For instance, the single intrathecal injection of a high concentration of NMDA, contrary to AMPA agonists, had no effect on spinal MNs. 145 Likewise, in a model of organotypic rat spinal cord culture and in vivo, larger MNs were shown to be relatively well preserved against NMDA exposure, 146 but considerably more sensitive to AMPA/KA mediated toxicity. [147][148][149] In addition, AMPA/KA receptor activation, through the continuous infusion of KA into the rat spinal subarachnoid space, induces a progressive and motor-selective behavioral deficit associated with a late loss of spinal MNs.…”

Section: Differential Glur Expression and Vulnerability To Excitotoximentioning

confidence: 96%

“…179 Although these observations suggest that NMDA receptors could be involved in MN degeneration in ALS, intrathecal application of NMDA had no impact on MN survival in mice. 145 In contrast, memantine, a noncompetitive NMDA receptor antagonist, significantly but quite modestly prolongs the survival of ALS mice (∼7%) without affecting disease onset. 180 However, because memantine is also a potent serotonin-3 180 and alpha7 nicotinic acetylcholine receptor 181 antagonist and an agonist of dopamine D2 receptors, 182 it is difficult to attribute its therapeutic effect to a selective action on NMDA receptors.…”

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

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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Neurotoxic effects of excitatory amino acids in the mouse spinal cord: quisqualate and kainate but not N-methyl-l-aspartate induce permanent neural damage

Cited by 64 publications

References 23 publications

Temporal and spatial distribution of activated caspase‐3 after subdural kainic acid infusions in rat spinal cord

Temporal and spatial distribution of activated caspase‐3 after subdural kainic acid infusions in rat spinal cord

Comparative Study on the Effects of Ceftriaxone and Monocytes on Recovery after Spinal Cord Injury in Rat

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

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