Therapeutic effect of regulating autophagy in spinal cord injury: a network meta-analysis of direct and indirect comparisons

Objective: An increasing number of studies indicate that autophagy plays an important role in the pathogenesis of spinal cord injury, and that regulating autophagy can enhance recovery from spinal cord injury. However, the effect of regulating autophagy and whether autophagy is detrimental or beneficial after spinal cord injury remain unclear. Therefore, in this study we evaluated the effects of autophagy regulation on spinal cord injury in rats by direct and indirect comparison, in an effort to provide a basis for further research. Data source: Relevant literature published from inception to February 1, 2018 were included by searching Wanfang, CNKI, Web of Science, MEDLINE (OvidSP), PubMed and Google Scholar in English and Chinese. The keywords included "autophagy", "spinal cord injury", and "rat". Data selection: The literature included in vivo experimental studies on autophagy regulation in the treatment of spinal cord injury (including intervention pre- and post-spinal cord injury). Meta-analyses were conducted at different time points to compare the therapeutic effects of promoting or inhibiting autophagy, and subgroup analyses were also conducted. Outcome measure: Basso, Beattie, and Bresnahan scores. Results: Of the 622 studies, 33 studies of median quality were included in the analyses. Basso, Beattie, and Bresnahan scores were higher at 1 day (MD = 1.80, 95% CI: 0.81-2.79, P = 0.0004), 3 days (MD = 0.92, 95% CI: 0.72-1.13, P < 0.00001), 1 week (MD = 2.39, 95% CI: 1.85-2.92, P < 0.00001), 2 weeks (MD = 3.26, 95% CI: 2.40-4.13, P < 0.00001), 3 weeks (MD = 3.13, 95% CI: 2.51-3.75, P < 0.00001) and 4 weeks (MD = 3.18, 95% CI: 2.43-3.92, P < 0.00001) after spinal cord injury with upregulation of autophagy compared with the control group (drug solvent control, such as saline group). Basso, Beattie, and Bresnahan scores were higher at 1 day (MD = 6.48, 95% CI: 5.83-7.13, P < 0.00001), 2 weeks (MD = 2.43, 95% CI: 0.79-4.07, P = 0.004), 3 weeks (MD = 2.96, 95% CI: 0.09-5.84, P = 0.04) and 4 weeks (MD = 4.41, 95% CI: 1.08-7.75, P = 0.01) after spinal cord injury with downregulation of autophagy compared with the control group. Indirect comparison of upregulation and downregulation of autophagy showed no differences in Basso, Beattie, and Bresnahan scores at 1 day (MD = -4.68, 95% CI: -5.840 to -3.496, P = 0.94644), 3 days (MD = -0.28, 95% CI: -2.231-1.671, P = 0.99448), 1 week (MD = 1.83, 95% CI: 0.0076-3.584, P = 0.94588), 2 weeks (MD = 0.81, 95% CI: -0.850-2.470, P = 0.93055), 3 weeks (MD = 0.17, 95% CI: -2.771-3.111, P = 0.99546) or 4 weeks (MD = -1.23, 95% CI: -4.647-2.187, P = 0.98264) compared with the control group. Conclusion: Regulation of autophagy improves neurological function, whether it is upregulated or downregulated. There was no difference between upregulation and downregulation of autophagy in the treatment of spinal cord injury. The variability in results among the studies may be associated with differences in research methods, the lack of clearly defined autophagy characteristics after spinal cord injury, and the limited autophagy monitoring techniques. Thus, methods should be standardized, and the dynamic regulation of autophagy should be examined in future studies.