Metformin’s therapeutic potential in spinal cord injury: a systematic review and meta-analysis on locomotor recovery, neuropathic pain alleviation, and modulation of secondary injury mechanisms

Abstract

Objective

To evaluate metformin’s efficacy in locomotion recovery, alleviating neuropathic pain, and modulating underlying molecular mechanisms in Spinal Cord Injury (SCI) rodent models through a systematic review and meta-analysis.

Methods

We conducted a comprehensive literature search across Medline, Embase, Scopus, and Web of Science from inception to May 2024. We included studies that utilized rodent models of traumatic SCI treated with metformin versus untreated controls. Data on locomotor recovery, neuropathic pain, and molecular mechanisms related to secondary injury were extracted. Standardized mean differences (SMDs) were synthesized as the pooled effect sizes.

Results

Twenty-three studies comprising 1,567 animals met the inclusion criteria. Metformin significantly enhanced locomotor function (SMD = 2.23, 95% CI: 1.74, 2.73, p < 0.001) and improved both mechanical allodynia (SMD = 1.18; 95% CI, 0.35 to 2.00; p = 0.005) and thermal hyperalgesia (SMD = 2.40; 95% CI, 1.65 to 3.16; p < 0.001). It reduces inflammation, oxidative stress, microglial activation, and astrogliosis and promotes myelination and autophagy flux via activating the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. This resulted in decreased apoptosis and lesion size and increased tissue preservation and neuronal survival. Subgroup analyses indicated greater locomotor improvements when metformin was administered in the acute (< 3 days of injury) phase of the injury (meta-regression coefficient = 1.65; 95% CI, 0.37 to 2.93; p = 0.011).

Conclusion

Metformin shows significant therapeutic benefits for SCI in rodent models, promoting locomotor recovery and alleviating neuropathic pain. These results underscore its translational potential for clinical SCI management.