title: Excitotoxicity and stroke: identifying novel targets for neuroprotection.
abstract: Excitotoxicity, the specific type of neurotoxicity mediated by glutamate, may be the missing link between ischemia and neuronal death, and intervening the mechanistic steps that lead to excitotoxicity can prevent stroke damage. Interest in excitotoxicity began fifty years ago when monosodium glutamate was found to be neurotoxic. Evidence soon demonstrated that glutamate is not only the primary excitatory neurotransmitter in the adult brain, but also a critical transmitter for signaling neurons to degenerate following stroke. The finding led to a number of clinical trials that tested inhibitors of excitotoxicity in stroke patients. Glutamate exerts its function in large by activating the calcium-permeable ionotropic NMDA receptor (NMDAR), and different subpopulations of the NMDAR may generate different functional outputs, depending on the signaling proteins directly bound or indirectly coupled to its large cytoplasmic tail. Synaptic activity activates the GluN2A subunit-containing NMDAR, leading to activation of the pro-survival signaling proteins Akt, ERK, and CREB. During a brief episode of ischemia, the extracellular glutamate concentration rises abruptly, and stimulation of the GluN2B-containing NMDAR in the extrasynaptic sites triggers excitotoxic neuronal death via PTEN, cdk5, and DAPK1, which are directly bound to the NMDAR, nNOS, which is indirectly coupled to the NMDAR via PSD95, and calpain, p25, STEP, p38, JNK, and SREBP1, which are further downstream. This review aims to provide a comprehensive summary of the literature on excitotoxicity and our perspectives on how the new generation of excitotoxicity inhibitors may succeed despite the failure of the previous generation of drugs.
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, 91 Hsueh-Shih Road, 40402 Taichung, Taiwan; Translational Medicine Research Center, China Medical University Hospital, 2 Yu-De Road, 40447 Taichung, Taiwan. Electronic address: ted.weita@me.com.
authors.forename: Ted Weita
authors.initials: TW
authors.lastname: Lai
authors.affiliation: Translational Medicine Research Center, China Medical University Hospital, 2 Yu-De Road, 40447 Taichung, Taiwan; Brain Research Center, University of British Columbia, 2211 Wesbrook Mall, V6T 2B5 Vancouver, Canada.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Brain Research Center, University of British Columbia, 2211 Wesbrook Mall, V6T 2B5 Vancouver, Canada. Electronic address: ytwang@brain.ubc.ca.
authors.forename: Yu Tian
authors.initials: YT
authors.lastname: Wang
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000209:etiology / Q000517:prevention & control*; D018846:Excitatory Amino Acids / Q000633:toxicity; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000150:complications* / Q000209:etiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000150:complications*
chemical_list: D018846:Excitatory Amino Acids; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate
keywords: Excitotoxicity; Glutamate; Ischemia; NMDA receptor; Neurodegeneration; Stroke