Mitochondria-Targeted Antioxidant SS-31 Attenuates Mitochondrial Dysfunction, Reduces Pyroptosis and Improves Locomotor Functional Recovery After Spinal Cord Injury

Abstract

Background: Oxidative stress, neuroinflammation, neuronal loss, and demyelination contribute to mechanisms of s pinal cord injury (SCI). Reactive oxygen species (ROS) have been reported to be associated with SCI , which can trigger the pathways toward cellular pyroptosis. Accumulating evidence has suggested that oxidative stress caused by mitochondrial dysfunction play a vital role in the pathophysiology of SCI. In the present study, we explore the effects and mechanisms of SS-31, a mitochondria-targeted antioxidant , on SCI in vivo and vitro. Methods: Functional recovery was assessed using Basso Mouse Scale (BMS) and BMS subscore. Oxidative stress was evaluated using detection of malonaldehyde (MDA) and 3-nitrotyrosine(3-NT). Neuronal loss was evaluated by immunochemistry staining of NeuN. Pyroptosis was assessed by flow cytometry and western blot. Findings: Administration of SS-31 to mice significantly improved locomotor functional recovery up to 28 days after SCI and suppressed neuronal loss and demyelination in mice. Moreover, SS-31 attenuated oxidative stress, inhibited nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome activation and pyroptosis occurrence, and decreased proinflammatory cytokines levels in mice. Furthermore, SS-31 in oxygen-glucose deprivation neurons promoted the survival , alleviated mitochondrial dysfunction, decreased oxidative stress, and suppressed NLRP3 inflammasome activation and pyroptosis . Interpretations: Together, our findings reveal that mitochondria-targeted antioxidant SS-31 can improves locomotor functional recovery in mice after SCI and that SS-31-mediated neuroprotection presumably depends on the attenuation of pyroptosis, mitochondrial dysfunction, neuroinflammation and oxidative stress. Funding Statement: This study was supported by National Natural Science Foundation of China (grant.81702163), Zhejiang Provincial Public Welfare Research Project (grant.LGF20H060014), Zhejiang Provincial Medical and Health Technology Project (grant.2020KY699), Science and Technology Development Project of Hangzhou (grant.20170533838), Zhejiang Provincial Public Welfare Research Project (grant.LGF21H060004). Declaration of Interests: The authors declare no competing financial interest. Ethics Approval Statement: All animal studies (including the mice euthanasia procedure) were done in compliance with the regulations and guidelines of Hangzhou First People's Hospital's institutional animal care and conducted according to the Association for Assessment and Accreditation of Laboratory Animal Care international (AAALAC) and the Institutional Animal Care and Use Committee (IACUC) guidelines.