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Opposing roles of NMDA receptor subtypes in neuronal fate and novel treatments for ischemic brain injury Liu, Yitao


Ischemic brain damage is largely due to excitotoxicity mediated by glutamate receptors, notably the N-methyl-D-aspartate-type receptors (NMDARs); however, to date none of the NMDAR antagonists have shown therapeutic benefits in treating stroke. Moreover, recent studies indicate blockade of NMDARs may even cause neuronal death. An explanation of the molecular mechanisms underlying this paradox is urgently required in order to develop new, effective stroke therapeutics. In this doctoral thesis project, we hypothesized that different NMDAR subtypes have opposing roles in neuronal fate and effective treatment of ischemic brain injury may be achieved through selective activation of the NMDAR subtype mediating neuronal survival and/or blockage of the NMDAR subtype mediating neuronal death. We first determined whether the two major NMDAR subtypes in mature cortical neurons, NR2A- and NR2B-containing NMDARs play differential roles in neuronal apoptosis. The results showed that NR2B-containing NMDARs are coupled to neuronal death whereas NR2A-containing receptors mediate neuronal survival. Further investigation revealed that the subcellular location (synaptic versus extrasynaptic) of NMDARs has little effect on their roles in neuronal fate. We then tested whether selective activation of NR2A-mediated neuronal survival signaling [i.e. neuronal survival signalling] or inhibition of NR2B-mediated neuronal death pathway is neuroprotective in stroke models. The data showed that blockade of NR2B is neuroprotective but has a relatively narrow therapeutic window. In contrast, selective activation of NR2A attenuates ischemic brain injury even when delivered 4.5 h post stoke onset. These findings suggest for the first time that selective stimulation of NR2A-containing NMDARs may constitute a promising therapy for stroke. Due to the critical role of NR2B in neuronal death and the narrow time window of NR2B antagonists, we examined whether disrupting the excitotoxic signaling [i.e. excitotoxic signalling] pathway downstream of NR2B activation was efficacious in treating ischemic damage. We found that post-ischemic administration of an interference peptide derived from the carboxyl tail of NR2B remarkably reduces stroke-induced brain injury. Thus, perturbing protein-protein interaction downstream of NR2B activation may represent another novel therapy for stroke. This research project provides a molecular basis for the dual roles of NMDARs in neuronal survival and demise and thereby suggests a number of clinically relevant new stroke therapies.

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