A new specific GluN2B partial antagonist ameliorates brain injury caused by ischemic stroke in rats.

Ischemic stroke is one of the top-ranked causes of death and disability in the world, but still lacking efficacy treatment options. Excitotoxicity caused by NMDA receptors (NMDARs) hyperactivation plays a key role in brain injury after ischemic stroke. GluN2B, the regulatory subunit of NMDARs, plays an important role in brain injury induced by ischemic stroke, and specific antagonists of GluN2B can ameliorate brain damage induced by ischemic stroke in rats. However, over half a century after Memantine (the first NMDA partial inhibitor for Alzheimer's clinical treatment) was identified, only a few additional NMDA partial inhibitors, especially those specifically targeting GluN2B, have been discovered. In this study, by using whole patch-clamp technique and multiple molecular biological methods, we discovered a new specific GluN2B partial antagonist, named FLY26, and further determined its effects on alleviating the brain injury caused by ischemic stroke in rats. Our experiment results showed FLY26 suppressed the excitotoxicity caused by overactivation of NMDARs in SH-SY5Y cells, and ameliorated brain damage of middle cerebral artery occlusion (MACO) rats, within the dosage range of 1.5-6.0 mg/kg, via BDNF/TrkB signaling pathway. Our results indicated that FLY26 is a promising lead compound for the development of novel, specific GluN2B partial antagonist. Our results indicated that FLY26 is a promising lead compound for the development of novel, specific GluN2B partial antagonist, which may offer better safety profile as a therapeutic intervention for ischemic stroke.