Excitatory and inhibitory amino acid neurotransmitters in stroke: from neurotoxicity to ischemic tolerance

The search for neuroprotection in acute ischemic stroke has been dramatically disappointing, with virtually all clinical trials failed for excessive toxicity or lack of efficacy of the tested drug; whereby, current treatments are exclusively based on reperfusion. Given the crucial role of amino acid neurotransmission in ischemic pathobiology, numerous failed strategies were aimed at blocking ionotropic glutamate receptor-mediated excitotoxicity or potentiating GABA-mediated inhibition. Recent work has revived the interest of pharmacologists toward glutamate and GABA receptors, due to a better understanding of subtype-specific toxicity and their involvement in ischemic tolerance. Thus, blocking receptor stimulation through glutamate grabbing, inhibiting downstream transduction pathways or selectively antagonizing detrimental NMDA receptor subpopulations represent promising strategies to rescue ischemic brain injury with limited side effects.