Targeting GluN2B-containing N-methyl-D-aspartic acid receptors to alleviate excitotoxic secondary brain injury after traumatic brain injury.

Excitotoxicity, mediated by overactivation of N-methyl-d-aspartate receptors (NMDARs), is a key pathological mechanism in secondary brain injury following traumatic brain injury (TBI). However, the clinical application of broad-spectrum NMDAR antagonists is often hampered by adverse effects. This study evaluated the therapeutic potential of a novel, orally active GluN2B-selective NMDAR antagonist (GluN2B-NMDAR antagonist-1) in comparison to memantine. In vitro,l-glutamate-induced excitotoxic injury model using PC-12 Adh cells to assess cytoprotective effects. The novel antagonist demonstrated superior efficacy to memantine in maintaining long-term (by 36-h) cell viability and promoting post-injury proliferation. Mechanistically, it effectively inhibited calcium overload, stabilized mitochondrial membrane potential, restored the neuroprotective CREB/BDNF pathway, and modulated apoptosis-related proteins (Bcl-2, Bad). In vivo, a controlled cortical impact mouse model of TBI was employed. Mice received the novel antagonist or memantine (10 mg/kg, p.o.) at designated time points post-injury. The novel antagonist led to greater improvement in locomotor activity (open field tests), and learning/memory (novel object recognition test and Morris water maze tests) than memantine. Histological analysis further suggested its superior efficacy in reducing acute neuronal apoptosis and its potential to promote synaptic reconstruction in the recovery phase. The results indicate that GluN2B-NMDAR antagonist-1 exhibits more pronounced neuroprotective and restorative effects than memantine in experimental TBI models. This study provides important evidence for the development of subunit-selective anti-excitotoxic agents and suggests the potential translational value of this candidate drug for TBI treatment.