NMDARs in Cell Survival and Death: Implications in Stroke Pathogenesis and Treatment

Synaptic (mainly GluN2A-containing ) and extrasynaptic (predominantly GluN2B-containing ) NMDARs have opposing roles in mediating neuronal survival and death; GluN2C and GluN2D-containing NMDARs may also promote neuronal survival and death, respectively, and are potentially critical during white matter damage. Whether synaptic and extrasynaptic NMDARs function antagonistically or synergistically during excitotoxic neuronal death is still subject to debate. Several newly discovered neuronal death signaling complexes downstream of NMDAR activation are potential targets for developing neuroprotective stroke therapeutics with reduced adverse effects and prolonged therapeutic windows. With one phase 3 clinical trial completed and another phase 3 trial on-going for neuroprotection against ischemic stroke brain damage, NA-1 may be the first NMDAR-based neuroprotectant to be approved as stroke therapy. Stroke is a leading cause of death and disability in developed countries. N-methyl -D-aspartate glutamate receptors (NMDARs) have important roles in stroke pathology and recovery. Depending on their subtypes and locations, these NMDARs may promote either neuronal survival or death. Recently, the functions of previously overlooked NMDAR subtypes during stroke were characterized, and NMDARs expressed at different subcellular locations were found to have synergistic rather than opposing functions. Moreover, the complexity of the neuronal survival and death signaling pathways following NMDAR activation was further elucidated. In this review, we summarize the recent developments in these areas and discuss how delineating the dual roles of NMDARs in stroke has directed the development of novel neuroprotective therapeutics for stroke. Stroke is a leading cause of death and disability in developed countries. N-methyl -D-aspartate glutamate receptors (NMDARs) have important roles in stroke pathology and recovery. Depending on their subtypes and locations, these NMDARs may promote either neuronal survival or death. Recently, the functions of previously overlooked NMDAR subtypes during stroke were characterized, and NMDARs expressed at different subcellular locations were found to have synergistic rather than opposing functions. Moreover, the complexity of the neuronal survival and death signaling pathways following NMDAR activation was further elucidated. In this review, we summarize the recent developments in these areas and discuss how delineating the dual roles of NMDARs in stroke has directed the development of novel neuroprotective therapeutics for stroke. a proton gated cationic channel activated by a decrease in extracellular pH. This channel may also mediate glutamate-independent calcium (Ca2+) entry into neurons during ischemic brain injury. an enzyme that is responsible for the formation of inflammatory mediator prostaglandins from arachidonic acid. a nonsurgical treatment using microcatheters inserted into the blood clot from the groin or the arm. It is an FDA-approved therapy for ischemic stroke. also known as mitogen-activated protein kinase (MAPK). ERK signaling cascades mediate diverse biological functions, such as cell growth, adhesion, survival, and differentiation. a chemogenetically engineered protein modified from the human M4 muscarinic receptor that permits designer drug-activated G-protein signaling in vivo. an FDA-approved pharmacological stroke therapy involving the use of drugs to break up or dissolve blood clots. occurs when a cerebral blood vessel is blocked by a clot or fatty build-up, resulting in a lack of blood supply to surrounding tissues. a cytosolic protein that is released into the cell culture medium upon damage to the plasma membrane of cells. Measurement of extracellular LDH is often used as a cytotoxic assay. an irreversible NMDAR open channel blocker that can long-lastingly block active NMDARs. Radioactive isotope-label ed MK801 ([3H]-MK801) can be used as a tracer in autoradiography that measures NMDAR activity. refers to protecting neurons from a brain insult, thereby preserving neuronal structure and/or function to some extent. It is commonly measured in vitro with various assays, including the lactose dehydrogenase (LDH) assay, and in vivo using histological methods or behavioral tests. application of NMDA at high concentration (usually >30 μM) for an extended time period (generally >30 min) to induce neuronal death. It is a frequently used in vitro model for neuronal excitotoxicity. a commonly used in vitro model mimicking ischemic stroke involving incubating cells or tissue slices in a glucose-free medium under a deoxygenated atmosphere. an important signaling pathway involved in cellular functions, such as promoting cell growth, proliferation, differentiation, motility, survival, and receptor trafficking. proteins that can link with several other proteins and lipids and, thus, localize signaling complexes close to their targets within subcellular domains. involves the use of an intraluminal suture to temporarily occlude the medial cerebral artery. It is the most frequently used in vivo model to induce focal brain ischemia in rodents. refers to damage to the white matter of the brain. WMD accounts for nearly half of the average infarct volume during stroke.