Efficacy of N-Methyl-D-Aspartate (NMDA) Receptor Antagonists in Treating Traumatic Brain Injury-Induced Brain Edema: A Systematic Review and Meta-analysis of Animal Studies.

Abstract

Traumatic brain injury leads to glutamate release, which overstimulates N-methyl-D-aspartate (NMDA) receptors, leading to neurotoxicity and cytotoxic edema. NMDA receptor antagonists may offer neuroprotection by blocking this pathway. The objective of this systematic review is to assess the efficacy of NMDA receptor antagonists for traumatic brain injury-induced brain edema in rodent models. This systematic review followed Cochrane Handbook guidelines and registered its protocol in PROSPERO (ID: CRD42023440934). Here, we included controlled rodent animal models comparing NMDA antagonist use with a placebo treatment. Outcome measures included the reduction of cerebral edema, Neurobehavioral Severity Scale, and adverse effects. The search strategy used Medical Subject Headings terms related to traumatic brain injury and NMDA receptor antagonists. The Collaborative Approach to Meta Analysis and Review of Animal Experimental Studies (CAMARADES) checklist and Systematic Review Centre for Laboratory Animal Experimentation's (SYRCLE's) tools were used to measure the quality and bias of included studies. The synthesis of results was presented in a meta-analysis of standard mean difference. Sixteen studies were included, with the predominant drugs being ifenprodil, MK-801, magnesium, and HU-211. The subjects consisted of Sprague-Dawley or Sabra rats. The analysis showed a significant reduction in brain edema with NMDA antagonist treatment (Standardized mean difference [SMD] - 1.17, 95% confidence interval [CI] - 1.59 to - 0.74, p < 0.01), despite high heterogeneity (I2 = 72%). Neurobehavioral Severity Scale also significantly improved (mean difference - 3.32, 95% CI - 4.36 to - 2.28, p < 0.01) in animals receiving NMDA antagonists. Administration within 1h after injury showed a modest enhancement in reducing brain edema compared with the baseline (SMD - 1.23, 95% CI - 1.69 to - 0.77, p < 0.01). Studies met standards for animal welfare and model appropriateness. Although baseline comparability and selective reporting bias were generally addressed, key biases such as randomization, allocation concealment, and blinding were often unreported. Overall, NMDA antagonists exhibit promising efficacy in the treatment of traumatic brain injury. Notably, our systematic review consistently demonstrated a significant reduction in brain edema with compounds including HU-211 and NPS 150.