The Efficacy of Rapamycin in Spinal Cord Injury: A Systematic Review and Meta-Analysis of preclinical studies

Abstract

Background Rapamycin has shown a potential role in functional and neurological recovery after neurodegenerative disease. The current study evaluates the efficacy of Rapamycin in preclinical spinal cord injury (SCI). Methods A systematic literature search was conducted in Medline, Embase, Scopus, and Web of Science databases until April 2023. Inclusion criteria were preclinical studies comparing Rapamycin treatment to a control group in animal models of SCI and reporting outcomes including locomotion, apoptosis, autophagy, inflammation, astrogliosis, neuronal counts, and signaling proteins related to the mechanistic target of Rapamycin in Akt/mTOR/p70S6K pathway. Two independent reviewers performed study screening and data extraction. For meta-analyses, a standardized mean difference (SMD) with a 95% confidence interval (CI) was calculated for each experiment and a pooled effect size was reported. The risk of bias and certainty of evidence was assessed using SYRCLE and GRADE tools, respectively. Results 18 papers were included in the study. Rapamycin significantly decreased apoptosis (TUNEL: SMD − 3.44, 95% CI -5.41 to -1.47; Caspase-3: SMD − 3.85, 95% CI -7.57 to -0.13), inflammation (TNF-α: SMD − 3.26, 95% CI -5.56 to -0.97), astrogliosis (GFAP: SMD − 0.76, 95% CI -1.28 to -0.25), and inhibited Akt/mTOR/p70S6K signaling pathway (SMD − 3.74, 95% CI -6.31 to -1.18). It increased autophagy markers (Beclin-1: SMD 1.42, 95% CI 0.51 to 2.33; LC3-II: SMD 1.09, 95% CI 0.35 to 1.82) and neuronal counts (SMD 1.18, 95% CI 0.44 to 1.91). Locomotion was not significantly influenced by the short-term effects of Rapamycin. However, treatment had significant long-term improvements in locomotion (SMD 0.74–1.54 from 1–6 weeks). Conclusion The current study indicates Rapamycin provides neuroprotection, reduces inflammation, enhances autophagy, and improves long-term locomotion in rodent SCI models.