Abstract
Interest in excitotoxicity expanded following its implication in the pathogenesis of ischemic brain injury in the 1980s, but waned subsequent to the failure of N-methyl-D-aspartate (NMDA) antagonists in high profile clinical stroke trials. Nonetheless there has been steady progress in elucidating underlying mechanisms. This review will outline the historical path to current understandings of excitotoxicity in the ischemic brain, and suggest that this knowledge should be leveraged now to develop neuroprotective treatments for stroke.
Highlights
It has been 63 years since Lucas and Newhouse (1957) discovered the ability of parenterally administered glutamate to kill central neurons in the rodent retina, and 51 years since Olney (1969) extended this observation to neurons in the hypothalamus and hippocampus
Consistent with the effects of glutamate + APV, kainate induced immediate excitotoxic neuronal swelling, but if exposure was terminated at 5 m, most cells recovered and survived (Koh et al, 1990). We considered it likely that this more slowly triggered neurotoxicity mediated by kainate or amino-3-methyl-4-isoxazoleproprionic acid (AMPA) receptors (KARs, AMPARs) was mediated by slower Ca2+ overload secondary to excessive Na+ entry, involving voltage-gated Ca2+ channels and reverse operation of the electrogenic Na+/Ca2+ exchanger, NCX (Choi, 1988)
Later we showed that net cellular 45Ca2+ accumulation induced by NMDA or glutamate was much larger/faster than that induced by high K+, kainate, or AMPA (Hartley et al, 1993), and Hyrc et al (1997) found a similar relationship for [Ca2+]i
Summary
It has been 63 years since Lucas and Newhouse (1957) discovered the ability of parenterally administered glutamate to kill central neurons in the rodent retina, and 51 years since Olney (1969) extended this observation to neurons in the hypothalamus and hippocampus. Finding that a series of structurally related neuroexcitatory amino acids exhibited similar neurotoxicity, with potencies corresponding to known neuroexcitant potencies, Olney et al (1974) proposed that the “necrotizing effect is, in essence, an exaggeration of the excitatory effect” and coined the term “excitotoxic amino acids” These seminal observations remained relatively fallow until the 1980s, when advances in excitatory amino acid (EAA) pharmacology led to widespread recognition of glutamate’s neurotransmitter function and scientific interest in EAAs burgeoned. Recent reviews on the topic have appeared (Wu and Tymianski, 2018; Fern and Matute, 2019; Hardingham, 2019; Ge et al, 2020) Other articles in this issue will likely discuss the possible contribution of excitotoxicity to neurodegeneration in chronic diseases such as amyotrophic lateral sclerosis or Alzheimer’s disease
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