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image of Non-excitatory Amino Acids Worsen Synaptic Transmission under Ischemia-like Conditions: Hypoxia and Hypoglycemia

Abstract

Introduction

Stroke is the leading cause of adult disability and the second leading cause of death worldwide. Understanding mechanisms of neuronal damage and developing new treatments to stop its progression are key goals in brain ischemia research. We previously showed that a mixture of non-excitatory amino acids at plasma concentrations (PlasmaAA: L-alanine, glycine, L-glutamine, L-histidine, L-serine, taurine, L-threonine) worsens the deleterious effects on synaptic transmission caused by hypoxia.

Method

We hypothesized that this amino acid combination could be especially harmful in the ischemic penumbra, a region potentially recoverable. We used a hypoxia-hypoglycemia model (20 min hypoxia-5 mM glucose) that allows recovery of synaptic transmission after normoxia.

Results

In this model, PlasmaAA induced complete and irreversible depression of excitatory synaptic potentials through activation of NMDA-type glutamate receptors. The effect was mimicked by glutamate application (110 μM) during hypoxia-hypoglycemia.

Discussion

Our data demonstrate that non-excitatory amino acids, at physiological plasma levels, irreversibly aggravate hippocampal synaptic damage under hypoxia-hypoglycemia NMDA receptor activation. As seen under hypoxia alone, this damage is linked to intracellular amino acid accumulation, cell swelling, and excessive glutamate release. We propose that amino acids released in the ischemic core spread to cells in the penumbra, fostering cytotoxic edema and expanding damage.

Conclusion

These findings suggest that targeting cellular uptake of non-excitatory amino acids could represent a novel neuroprotective strategy for stroke.

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2026-02-23
2026-02-26

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Non-excitatory Amino Acids Worsen Synaptic Transmission under Ischemia-like Conditions: Hypoxia and Hypoglycemia
Bentham Science Publishers ; https://doi.org/10.2174/011570159X404794251006154011
/content/journals/cn/10.2174/011570159X404794251006154011
/content/journals/cn/10.2174/011570159X404794251006154011
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  • Article Type:     Research Article
Keywords: NMDA receptor ; cell swelling ; Ischemia ; non-excitatory amino acids ; synaptic transmission

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