Targeting harmful effects of non-excitatory amino acids as an alternative therapeutic strategy to reduce ischemic damage

The involvement of the excitatory amino acids glutamate and aspartate in cerebral ischemia and excitotoxicity is well-documented. Nevertheless, the role of non-excitatory amino acids in brain damage following a stroke or brain trauma remains largely understudied. The release of amino acids by necrotic cells in the ischemic core may contribute to the expansion of the penumbra. Our findings indicated that the reversible loss of field excitatory postsynaptic potentials caused by transient hypoxia became irreversible when exposed to a mixture of just four non-excitatory amino acids (L-alanine, glycine, L-glutamine, and L-serine) at their plasma concentrations. These amino acids induce swelling in the somas of neurons and astrocytes during hypoxia, along with permanent dendritic damage mediated by N-methyl-D-aspartate receptors. Blocking N-methyl-D-aspartate receptors prevented neuronal damage in the presence of these amino acids during hypoxia. It is likely that astroglial swelling caused by the accumulation of these amino acids via the alanine-serine-cysteine transporter 2 exchanger and system N transporters activates volume-regulated anion channels, leading to the release of excitotoxins and subsequent neuronal damage through N-methyl-D-aspartate receptor activation. Thus, previously unrecognized mechanisms involving non-excitatory amino acids may contribute to the progression and expansion of brain injury in neurological emergencies such as stroke and traumatic brain injury. Understanding these pathways could highlight new therapeutic targets to mitigate brain injury.