SyRF

Background: Traumatic brain injury (TBI) remains a leading cause of death and disability worldwide, with limited effective pharmacological treatments currently available. Erythropoietin (EPO) has shown promise as a neuroprotective agent in preclinical models due to its anti-apoptotic, anti-inflammatory, and neurotrophic properties. However, the optimal dose, timing, and route of administration remain unclear.

Methods: We conducted a systematic search of PubMed, Embase, Web of Science, and Scopus databases from inception to December 2023 for controlled studies investigating the neuroprotective effects of EPO in animal models of TBI. Two independent reviewers screened 2,847 records using predefined inclusion and exclusion criteria. Data were extracted on study design, animal species and strain, TBI model type, EPO dose and route, timing of administration, and neurobehavioural and histological outcomes. Risk of bias was assessed using the SYRCLE tool. A dose-response meta-analysis was performed using restricted cubic splines.

Results: Forty-seven studies met the inclusion criteria, encompassing 1,284 animals across 12 species. The pooled standardized mean difference for neurobehavioural outcome was 1.34 (95% CI: 1.12–1.56, p<0.001), indicating a large beneficial effect of EPO treatment. Dose-response analysis revealed a non-linear relationship, with maximal efficacy observed at approximately 5,000 IU/kg. Subgroup analyses showed that intraperitoneal administration within 6 hours of injury produced the largest effect sizes. Significant heterogeneity was observed (I²=72%), partially explained by differences in TBI model, species, and outcome measurement timing. Publication bias was evident on funnel plot inspection and confirmed by Egger's test (p=0.003).

Conclusions: EPO demonstrates robust neuroprotective efficacy in preclinical TBI models, with a dose-response relationship suggesting an optimal dose of approximately 5,000 IU/kg administered intraperitoneally within the first 6 hours post-injury. These findings support the design of appropriately powered clinical trials, though the observed heterogeneity and publication bias warrant cautious interpretation. Future preclinical studies should prioritise blinding, randomisation, and pre-registration to improve translational reliability.