The role of glutamate in neuronal ischemic injury: the role of spark in fire

Abstract

Although being a physiologically important excitatory neurotransmitter, glutamate plays a pivotal role in various neurological disorders including ischemic neurological diseases. Its level is increased during cerebral ischemia with excessive neurological stimulation causing the glutamate-induced neuronal toxicity, excitotoxicity, and this is considered the triggering spark in the ischemic neuronal damage. The glutamatergic stimulation will lead to rise in the intracellular sodium and calcium, and the elevated intracellular calcium will lead to mitochondrial dysfunction, activation of proteases, accumulation of reactive oxygen species and release of nitric oxide. Interruption of the cascades of glutamate-induced cell death during ischemia may provide a way to prevent, or at least reduce, the ischemic damage. Various therapeutic options are suggested interrupting the glutamatergic pathways, e.g., inhibiting the glutamate synthesis or release, increasing its clearance, blocking of its receptors or preventing the rise in intracellular calcium. Development of these strategies may provide future treatment options in the management of ischemic stroke.

N-Stearoyltyrosine Protects Against Glutamate-Induced Oxidative Toxicity by an Apoptosis-Inducing Factor (AIF)-Mediated Caspase-Independent Cell Death Pathway

“…The underlying mechanisms of NsTyr were proved to intervene in multiple injuries, such as antagonizing against OGD induced neuronal injury, inhibiting the inflammatory response, and regulating neuronal plasticity (10 -12). Glutamate neurotoxicity plays an important role in neuronal death under stroke/cerebral ischemia conditions (2). In the present study, we verified that NsTyr exerts its neuroprotective effects by acting on glutamate toxicity in PC12 cells.…”

“…Disturbance of glutamate levels is the primary cause of neuronal death in stroke/cerebral ischemia through excitotoxicity triggered by the over activation of glutamate ionotropic receptors and oxida tive toxicity initiated by the blockade of the cysteine/ glutamate antiporter (2). The oxidative toxicity is an important component of glutamate neurotoxicity during cerebral ischemia (3).…”

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

“…Activation of NMDA receptors plays a role in neuronal death induced by transient OGD in different neuronal culture systems (Martinez-Sanchez et al, 2004;Bonde et al, 2005;Ahlgren et al, 2011;Caldeira et al, 2013), similarly to the role of glutamate receptors in neuronal damage in the ischemic brain [for review (Kostandy, 2012)]. The activation of NMDA-type glutamate receptors is likely to be a mediator in OGD and ischemia-induced downregulation of the proteasome activity, as shown in experiments where cultured hippocampal neurons were subjected to excitotoxic stimulation with glutamate or with NMDA (Caldeira et al, 2013).…”

Nanofiber mat spinal cord dressing-released glutamate impairs blood-spinal cord barrier

“…An excessive glutamate level can cause damage and death of CNS cells and is also known as an important contributing factor in many CNS disorders [21,33]. Glutamate-damaged neurons show definite morphological alterations.…”