Glutamate excitotoxicity: Potential therapeutic target for ischemic stroke

May 24, 2022Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

Glutamate Overactivity as a Possible Treatment Target for Stroke

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Abstract

Glutamate-mediated excitotoxicity is a key mechanism contributing to post-stroke damage.

A sudden reduction in cerebral blood flow after acute stroke leads to dysfunction in ion transport proteins.
Disruption of ion balance results in impaired glutamate release and reuptake, which may cause excessive activation of N-methyl-D-aspartate receptors (NMDAR).
Excessive NMDAR stimulation is associated with neuronal death following ischemic stroke.
Current stroke treatments are limited, highlighting the need for new neuroprotective therapeutic agents.
Recent findings on glutamate mechanisms and cellular signaling pathways provide insights for developing new therapeutic targets.

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Glutamate-mediated excitotoxicity is an important mechanism leading to post ischemic stroke damage. After acute stroke, the sudden reduction in cerebral blood flow is most initially followed by ion transport protein dysfunction and disruption of ion homeostasis, which in turn leads to impaired glutamate release, reuptake, and excessive N-methyl-D-aspartate receptor (NMDAR) activation, promoting neuronal death. Despite extensive evidence from preclinical studies suggesting that excessive NMDAR stimulation during ischemic stroke is a central step in post-stroke damage, NMDAR blockers have failed to translate into clinical stroke treatment. Current treatment options for stroke are very limited, and there is therefore a great need to develop new targets for neuroprotective therapeutic agents in ischemic stroke to extend the therapeutic time window. In this review, we highlight recent findings on glutamate release, reuptake mechanisms, NMDAR and its downstream cellular signaling pathways in post-ischemic stroke damage, and review the pathological changes in each link to help develop viable new therapeutic targets. We then also summarize potential neuroprotective drugs and therapeutic approaches for these new targets in the treatment of ischemic stroke.

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