The effect of metformin on ameliorating neurological function deficits and tissue damage in rats following spinal cord injury: A systematic review and network meta-analysis

Abstract

Spinal cord injury (SCI) is a devastating condition with few treatment options. Metformin, a classical antidiabetic and antioxidant, has extended its application to experimental SCI treatment. Here, we performed a systematic review to evaluate the neurobiological roles of metformin for treating SCI in rats, and to assess the potential for clinical translation. PubMed, Embase, China National Knowledge Infrastructure, WanFang data, SinoMed, and Vip Journal Integration Platform databases were searched from their inception dates to October 2021. Two reviewers independently selected controlled studies evaluating the neurobiological roles of metformin in rats following SCI, extracted data, and assessed the quality of methodology and evidence. Pairwise meta-analyses, subgroup analyses and network analysis were performed to assess the roles of metformin in neurological function and tissue damage in SCI rats. Twelve articles were included in this systematic review. Most of them were of moderate-to-high methodological quality, while the quality of evidence from those studies was not high. Generally, Basso, Beattie, and Bresnahan scores were increased in rats treated with metformin compared with controls, and the weighted mean differences (WMDs) between metformin and control groups exhibited a gradual upward trend from the 3rd (nine studies, n = 164, WMD = 0.42, 95% CI = −0.01 to 0.85, P = 0.06) to the 28th day after treatment (nine studies, n = 136, WMD = 3.48, 95% CI = 2.04 to 4.92, P < 0.00001). Metformin intervention was associated with improved inclined plane scores, tissue preservation ratio and number of anterior horn motor neurons. Subgroup analyses indicated an association between neuroprotection and metformin dose. Network meta-analysis showed that 50 mg/kg metformin exhibited greater protection than 10 and 100 mg/kg metformin. The action mechanisms behind metformin were associated with activating adenosine monophosphate-activated protein kinase signaling, regulating mitochondrial function and relieving endoplasmic reticulum stress. Collectively, this review indicates that metformin has a protective effect on SCI with satisfactory safety and we demonstrate a rational mechanism of action; therefore, metformin is a promising candidate for future clinical trials. However, given the limitations of animal experimental methodological and evidence quality, the findings of this pre-clinical review should be interpreted with caution.

Efficacy of metformin in prevention of paclitaxel-induced peripheral neuropathy in breast cancer patients: a randomized controlled trial

“…The main mechanisms for paclitaxel-induced PN are impairment to the function of the microtubules and breakdown of the transport process in peripheral nerves (Andersen Hammond et al, 2019). The existing solid evidence of the role of metformin in the modulation of these processes stimulates the interest in testing the hypothesis that metformin protects against chemotherapy-induced PN (Mao-Ying et al, 2014;Wang et al, 2020;Zhou et al, 2022). Frontiers in Pharmacology frontiersin.org This is the first randomized study that demonstrates the preventive efficacy of metformin against paclitaxel-induced PN in breast cancer patients.…”

Astaxanthin promotes locomotor function recovery and attenuates tissue damage in rats following spinal cord injury: a systematic review and trial sequential analysis

“…No pre-registration was performed for this study. The design of this study followed the methods of previous studies ( Yao et al, 2015 ; Sng et al, 2022 ; Zhou et al, 2022 ).…”

“…A systematic literature search was performed in the PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, WanFang data, Vip Journal Integration Platform, and SinoMed databases from their inception date to May 2023 ( Sng et al, 2022 ; Zhou et al, 2022 ). Key words included “spinal cord injuries,” “spinal cord injury,” “spinal cord contusion,” “spinal cord compression,” “spinal cord trauma,” “astaxanthine,” “astaxanthin,” “E-astaxanthin’, “rats,” “rat,” and “murinae.” The bibliographies of the included studies were also screened to identify any additional relevant studies.…”

“…This scale is a well-documented tool widely applied in evaluating the locomotor function recovery of rats following SCI ( Basso et al, 1995 ). To reduce the risk of data heterogeneity, only data at the same time points were used in the analyses of BBB scores and the following outcomes ( Zhou et al, 2022 ).…”

Effects of early adjunctive pharmacotherapy on serum levels of brain injury biomarkers in patients with traumatic brain injury: a systematic review of randomized controlled studies

“…Suppressing the pro-inflammatory microglial cells has been recently targeted to attenuate the rate of inflammation and consequent neurological deficit in animal models (DiBona et al, 2021;Bourget et al, 2022). Apart from suppressing microglial activation, a growing body of evidence proves that metformin neuroprotective effects are attributable to AMP-activated protein kinase activation (Rahimi et al, 2020;Zhang et al, 2022;Zhou et al, 2022). The efficacy of metformin therapy was investigated in one RCT.…”