Background/Objectives: Traumatic spinal cord injury (SCI) frequently results in permanent motor and sensory deficits. Tumor necrosis factor-α is rapidly upregulated after SCI and contributes to secondary injury cascades, including microglial activation, cytokine amplification, and blood–spinal cord barrier disruption. Etanercept, a TNF-α inhibitor, has been investigated in modulating post-SCI neuroinflammation. This systematic review synthesizes preclinical evidence evaluating the therapeutic role of etanercept in SCI. Methods: A systematic review was conducted in accordance with PRISMA 2020 guidelines. The review was not prospectively registered. PubMed, Scopus, and Web of Science were searched through 9 December 2025. Eligible studies included original investigations of etanercept administered for in vivo mammalian models of SCI. Non-English articles, preprints, conference abstracts, case reports, and reviews were excluded. Risk of bias was assessed independently by at least two reviewers using the SYRCLE tool. Due to heterogeneity in models and dosing strategies, meta-analysis was not performed. Results: Of 119 records identified, 36 duplicates were removed. After screening 83 titles and abstracts, 67 were excluded. One additional study was excluded after full-text retrieval. Thus, 15 articles were included. Primary outcomes varied between studies, including inflammation, histopathology, and functional recovery. Conclusions: Preclinical evidence suggests that etanercept may attenuate early neuroinflammation after SCI; however, methodological heterogeneity and limited data warrant further investigation. This work was supported by the College of Medicine at Central Michigan University, the John G. Kulhavi Professorship in Neuroscience, and the E. Malcolm Field and Gary Leo Dunbar Endowed Chair in Neuroscience at Central Michigan University.
Garmo et al. (Tue,) studied this question.