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.

Keywords: action mechanism; clinical translation; metformin; neurological function; safety; spinal cord injury; systematic review.

Figure 1

Summary of the literature identification and selection process.

Figure 2

Overall analyses of the effects of metformin on dynamic changes of neurological function. (A,B) BBB scale, inclined plane test meta-analysis at 28th day after SCI. (C) The BBB scores and inclined plane scores in each group over time. (D) The WMDs of BBB score between metformin and control groups from 3rd to 28th day after SCI.

Figure 3

Overall analyses of the effects of metformin on tissue damage in lesion area. (A,B) Tissue preservation area ratio, number of survival motor neuron meta-analysis in lesion area and the effect sizes line chart.

Figure 4

BBB scale subgroup analysis concerning rat gender and injury model type. (A,B) Subgroup analysis concerning rat gender and injury model type at 28th day after SCI and the WMDs of BBB score over time in different subgroups.

Figure 5

BBB scale subgroup analysis concerning administration details. (A–C) Subgroup analysis concerning administration timing, injection numbers and administration dose at 28th day after SCI and the WMDs of BBB score over time in different subgroups. *p < 0.05.

Figure 6

Network analysis of the effects of metformin at different doses. (A) Forest plot of effect size in different metformin doses according to data on 28th day. (B) Forest plot of effect size in different metformin doses according to data on 21th day. a, Control; b, 10 mg/kg metformin; c, 50 mg/kg metformin; d, 100 mg/kg metformin; e, 200 mg/kg metformin; f, 320 mg/kg metformin.

Figure 7

The SUCRA value and probabilities of each treatment doses. (A) SUCRA value ranking of different administration doses according to data on 28th day. (B) Histogram of ranking probability of each treatment dose according to data on 28th day. (C) SUCRA value ranking of different administration doses according to data on 21th day. (D) Histogram of ranking probability of each treatment dose according to data on 21th day. a, control; b, 10 mg/kg metformin; c, 50 mg/kg metformin; d, 100 mg/kg metformin, e, 200 mg/kg metformin; f, 320 mg/kg metformin.

Figure 8

Potential action mechanisms of metformin against SCI. Following the primary insult, structural damage and a loss of homeostasis trigger the disturbance of energy metabolism, oxidative stress, mitochondrial disorder, endoplasmic reticulum stress, and increased mTORC1 expression. Metformin, the activator of AMPK and well-antioxidant, can modulate the AMPK and reverse electron flow in mitochondria to suppress the ROS generation and activation of NLRP3 inflammasome or NF-κB signaling, ameliorate endoplasmic reticulum stress to regulate the Bcl-2 and caspase-3, attenuate mTORC1 activation to induce the autophagosome formation, thereby exerting a satisfactory neuroprotective role in SCI rat.