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

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 via 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.