AMPA Receptor Antagonists in Preclinical Models of Traumatic Brain Injury: A Systematic Review and Meta-analysis of...

Traumatic brain injury (TBI) is a major cause of death and long-term disability, yet no pharmacological neuroprotective strategy has shown clear clinical benefit. Because excitotoxicity is a key mechanism of secondary brain injury, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists have emerged as promising candidates in preclinical research. We aimed to evaluate whether AMPA receptor antagonists improve neurobehavioural outcomes and reduce brain lesion severity, mortality and inflammatory biomarkers in in vivo animal models of TBI.

We conducted a systematic review and meta-analysis of preclinical animal studies, searching MEDLINE, Embase and Web of science. We included mammalian in vivo TBI studies evaluating AMPA receptor antagonists administered after injury, compared with vehicle, no treatment, or an alternative intervention. Two reviewers independently screened studies, extracted data and assessed methodological quality and risk of bias using the Collaborative Approach to Meta-analysis and Review of Animal Data from Experimental Studies (CAMARADES) checklist and the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. The primary outcome was neurobehavioural performance across three domains: neurological deficit, cognition and memory and motor coordination. Secondary outcomes included brain lesion severity, mortality and inflammatory biomarkers. Random-effects meta-analyses used standardized mean differences (SMDs).

Of 410 records, 11 studies were included. Compared with controls, AMPA receptor antagonists improved neurological deficit scores [SMD 1.28, 95% confidence intervals (CI) 0.05-2.50; I² = 78%; four studies] and cognition and memory (SMD 1.53, 95% CI 1.06-2.01; I² = 3%; five studies), but not motor coordination (SMD - 1.00, 95% CI - 2.96 to 0.96; I² = 83%; two studies). Brain lesion severity was significantly reduced (SMD - 1.39, 95% CI - 2.07 to - 0.71; I² = 53%; seven studies). Mortality showed no significant effect. Inflammatory biomarkers were consistently reduced with AMPA receptor antagonists.

In preclinical TBI models, AMPA receptor antagonists improved neurological and cognitive outcomes and reduced brain lesion severity, but not motor coordination or mortality, supporting the biological plausibility of AMPA-targeted neuroprotection, although some results should be interpreted with caution.