Ischemic stroke is a major cause of death and disability in Taiwan and around the world. The only therapy for stroke is tPA, a thrombolytic agent, which has a narrow therapeutic window and modest efficacy. tPA therapy is associated with 10-fold increase in the risk of developing serious intracerebral hemorrhage. The primary mechanism of ischemic brain injury is caused by excessive release of glutamate, a major neurotransmitter in the brain, to cause excitotoxicity. Glutamate-induced excitotoxicity is mediated primarily by N-methyl-D-Aspartate receptors (NMDARs). NMDAR blockade has been the major target for developing neuroprotective strategies. Prior works on neutralizing excitotoxicity to reduce ischemic brain injury has been compounded by serious adverse events caused by non-specific blocade of NMDARs. This PPG is on cutting-edge research to explore differential mechanisms of NMDAR subtypes based on recent novel discoveries by members in this PPG team. Emerging evidence suggests that different subtypes of NMDARs mediate different functions by binding to different downstream NMDAR signaling complex. Novel discoveries made by Prof. YT Wang’s group in this PPG team show NR2AR (NR2A-subunit containing NMDAR) binds to NSC (NMDAR Survival signaling Complex). NR2AR is the major NMDAR subtype in the synapses of the adult forebrain. Prof. YT Wang’s group also found that NR2BR (NR2B-subunit containing NMDAR) bind to NDC (NMDAR Death signaling Complex). NR2BR is the major NMDAR subtype in the extrasynaptic sites. These findings raise the possibility that selective NR2BR blockade is neuroprotective and selective NR2AR blockade is detrimental (for overview see Lai TW, Wang YT, Nature Med, 2010 and Martin HG, Wang YT, Cell, 2010). This PPG features 4 senior stroke researchers at China Medical University (CMU) and Prof. YT Wang, an outstandting stroke investigator at the University of Britich Columbia (UBC). These 5 PIs will lead respectively 5 subprojects. Sub-project 1 directed by Prof. CY Hsu is on synaptic NR2A NMDAR activation of the survival signaling complex, aiming to establish the causal role of NR2A subtype of the NMDARs in sustaining neuronal viability. Sub-project 2 directed by Prof. YT Wang is on extrasynaptic NR2B NMDAR activation of the death signaling complex aiming to confirm the pivotal role of NR2B in causing ischemic neuronal death. Sub-project 3 directed by Prof. SD Lee is on GABA receptor endocytosis in excitotoxic depolarization with the major goal of establishing a novel cellular event involving an inhibitory neurotransmitter in an excitotary pathophysiological process. Sub-project 4 directed by Prof. SZ Lin is on AMPA receptor interacting proteins in AMPA receptor-mediated calcium overload, exploring a group of novel proteins in AMPA receptor mechanisms of excitotoxicity. Sub-project 5 directed by Prof. WC Shyu is on regenerative glutamate release during ischemic spreading depression. These 5 inter-related sub-projects are highly focused on glutamate receptor mechanisms in ischemic brain injury covering differential NMDAR subtypes but converging on a common final pathway of excitotoxicity and ischemic neuronal death. Results derived from these highly integrated subprojects will provide novel insights into the development of preventive and therapeutic strategies for stroke.
