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Neuroprotective effects of Alda-1 mitigate spinal cord injury in mice: involvement of Alda-1-induced ALDH2 activation-mediated suppression of reactive aldehyde mechanisms

Mushfiquddin Khan  Fei Qiao  Pavan Kumar  S.M.Touhidul Islam  Avtar K.Singh  Jeseong Won  Inderjit Singh  
【摘要】:Spinal cord injury(SCI) is associated with high production and excessive accumulation of pathological 4-hydroxy-trans-2-nonenal(4-HNE), a reactive aldehyde, formed by SCI-induced metabolic dysregulation of membrane lipids. Reactive aldehyde load causes redox alteration, neuroinflammation, neurodegeneration, pain-like behaviors, and locomotion deficits. Pharmacological scavenging of reactive aldehydes results in limited improved motor and sensory functions. In this study, we targeted the activity of mitochondrial enzyme aldehyde dehydrogenase 2(ALDH2) to detoxify 4-HNE for accelerated functional recovery and improved pain-like behavior in a male mouse model of contusion SCI. N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide(Alda-1), a selective activator of ALDH2, was used as a therapeutic tool to suppress the 4-HNE load. SCI was induced by an impactor at the T9–10 vertebral level. Injured animals were initially treated with Alda-1 at 2 hours after injury, followed by once-daily treatment with Alda-1 for 30 consecutive days. Locomotor function was evaluated by the Basso Mouse Scale, and pain-like behaviors were assessed by mechanical allodynia and thermal algesia. ALDH2 activity was measured by enzymatic assay. 4-HNE protein adducts and enzyme/protein expression levels were determined by western blot analysis and histology/immunohistochemistry. SCI resulted in a sustained and prolonged overload of 4-HNE, which parallels with the decreased activity of ALDH2 and low functional recovery. Alda-1 treatment of SCI decreased 4-HNE load and enhanced the activity of ALDH2 in both the acute and the chronic phases of SCI. Furthermore, the treatment with Alda-1 reduced neuroinflammation, oxidative stress, and neuronal loss and increased adenosine 5′-triphosphate levels stimulated the neurorepair process and improved locomotor and sensory functions. Conclusively, the results provide evidence that enhancing the ALDH2 activity by Alda-1 treatment of SCI mice suppresses the 4-HNE load that attenuates neuroinflammation and neurodegeneration, promotes the neurorepair process, and improves functional outcomes. Consequently, we suggest that Alda-1 may have therapeutic potential for the treatment of human SCI. Animal procedures were approved by the Institutional Animal Care and Use Committee(IACUC) of MUSC(IACUC-2019-00864) on December 21, 2019.

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