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

Abstract

Spinal cord injury (SCI) is a catastrophic condition with few therapeutic options. Astaxanthin (AST), a natural nutritional supplement with powerful antioxidant activities, is finding its new application in the field of SCI. Here, we performed a systematic review to assess the neurological roles of AST in rats following SCI, and assessed the potential for clinical translation. Searches were conducted on PubMed, Embase, Cochrane Library, the Web of Science, China National Knowledge Infrastructure, WanFang data, Vip Journal Integration Platform, and SinoMed databases. Animal studies that evaluated the neurobiological roles of AST in a rat model of SCI were included. A total of 10 articles were included; most of them had moderate-to-high methodological quality, while the overall quality of evidence was not high. Generally, the meta-analyses revealed that rats treated with AST exhibited an increased Basso, Beattie, and Bresnahan (BBB) score compared with the controls, and the weighted mean differences (WMDs) between those two groups showed a gradual upward trend from days 7 (six studies, n = 88, WMD = 2.85, 95% CI = 1.83 to 3.87, p < 0.00001) to days 28 (five studies, n = 76, WMD = 6.42, 95% CI = 4.29 to 8.55, p < 0.00001) after treatment. AST treatment was associated with improved outcomes in spared white matter area, motor neuron survival, and SOD and MDA levels. Subgroup analyses indicated there were differences in the improvement of BBB scores between distinct injury types. The trial sequential analysis then firmly proved that AST could facilitate the locomotor recovery of rats following SCI. In addition, this review suggested that AST could modulate oxidative stress, neuroinflammation, neuron loss, and autophagy via multiple signaling pathways for treating SCI. Collectively, with a protective effect, good safety, and a systematic action mechanism, AST is a promising candidate for future clinical trials of SCI. Nonetheless, in light of the limitations of the included studies, larger and high-quality studies are needed for verification.

Keywords: astaxanthin; clinical translation; locomotor recovery; neuroprotective mechanism; safety; spinal cord injury; systematic review; trial sequential analysis.

Figure 1

Summary of the literature identification and selection process.

Figure 2

Overall analyses of the effects of AST on BBB scores. Meta-analysis of BBB scale at days 21 (A) and 28 (B) after SCI. (C) The WMDs of BBB score between AST and control groups from days 3 to days 28 after SCI. (D) The BBB scores in each group over time. The detailed data at each time point are shown in Table 4.

Figure 3

Subgroup analyses of the effects of AST on BBB scores. (A,B) Subgroup analysis concerning administration route and injury type at days 21 after SCI. The detailed data at each time point are shown in Table 5.

Figure 4

Meta-analysis of the effects of AST on tissue damage in lesion areas. Meta-analysis regarding spared white matter area (A) and the number of surviving motor neurons (B) in lesion areas at days 7 after SCI.

Figure 5

Meta-analysis of the antioxidant effects of AST. Meta-analysis regarding SOD (A) and MDA (B) in rats at day 1 following SCI.

Figure 6

Results of TSA. TSA based on data of BBB scores at days 14 (A), 21 (B), and 28 (C) after SCI.

Figure 7

Potential action mechanisms of AST in treating SCI. The oxidative stress and large generation of ROS are immediately triggered following the insult to the spinal cord, and can lead to the neuroinflammatory response, neuronal apoptosis, and organelle dysfunction. AST shows satisfactory roles on controlling oxidative stress generation in CNS diseases through its unique construction, and modulating NMDAR and Nrf2 signaling pathways. Partly relying on its antioxidant bioactivity, AST then inhibits MAPK, NLRP3 inflammasome, or NF-κB signaling to alleviate the local inflammation, modulate the Bax and caspase family proteins to promote neuron survival, and stabilize the autophagy flux by regulating beclin-1 and mTOR complex 1, finally exerting neuroprotective roles in treating SCI rats.