Neuroprotective effects of Alda-1 mitigate spinal cord injury in mice: involvement of Alda-1-induced ALDH2 activation-mediated suppression of reactive aldehyde mechanisms.
Neuroprotective effects of Alda-1 mitigate spinal cord injury in mice: involvement of Alda-1-induced ALDH2 activation-mediated suppression of reactive aldehyde mechanisms.
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DOI：
10.4103/1673-5374.314312
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发表时间：
2022-01
影响因子：
6.1
通讯作者：
Singh I
中科院分区：
文献类型：
--
作者：
Khan M;Qiao F;Kumar P;Touhidul Islam SM;Singh AK;Won J;Singh I
脊髓损伤 (SCI) 与病理性 4-羟基-反式-2-壬烯醛 (4-HNE) 的高产量和过度积累有关，4-HNE 是一种反应性醛，由 SCI 诱导的膜脂代谢失调形成。反应性醛负荷会导致氧化还原改变、神经炎症、神经变性、疼痛样行为和运动缺陷。活性醛的药理清除导致运动和感觉功能的改善有限。在这项研究中，我们针对线粒体乙醛脱氢酶 2 (ALDH2) 的活性来解毒 4-HNE，以加速挫伤 SCI 雄性小鼠模型的功能恢复并改善疼痛样行为。 N-(1,3-苯并二氧杂环戊烯-5-基甲基)-2,6-二氯苯甲酰胺 (Alda-1) 是 ALDH2 的选择性激活剂，被用作抑制 4-HNE 负荷的治疗工具。 SCI 是由 T9-10 椎骨水平的撞击器诱发的。受伤的动物最初在受伤后2小时用Alda-1治疗，随后每天用Alda-1治疗一次，连续30天。通过巴索小鼠量表评估运动功能，通过机械异常性疼痛和热痛觉评估疼痛样行为。通过酶法测定 ALDH2 活性。通过蛋白质印迹分析和组织学/免疫组织化学测定4-HNE蛋白加合物和酶/蛋白表达水平。 SCI 导致 4-HNE 持续且长期超载，这与 ALDH2 活性降低和功能恢复低下同时发生。 SCI 的 Alda-1 治疗可降低 SCI 急性期和慢性期的 4-HNE 负荷并增强 ALDH2 的活性。此外，Alda-1 治疗可减少神经炎症、氧化应激和神经元损失，并增加 5'-三磷酸腺苷水平，刺激神经修复过程并改善运动和感觉功能。总之，结果提供证据表明，通过 Alda-1 治疗 SCI 小鼠增强 ALDH2 活性，可抑制 4-HNE 负荷，从而减轻神经炎症和神经变性，促进神经修复过程，并改善功能结果。因此，我们认为 Alda-1 可能具有治疗人类 SCI 的潜力。动物程序于 2019 年 12 月 21 日获得 MUSC 机构动物护理和使用委员会 (IACUC) 批准 (IACUC-2019-00864)。
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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影响因子：
--
作者：
Ayala A;Muñoz MF;Argüelles S
通讯作者：
Argüelles S
影响因子：
4.2
作者：
Carrico, Kimberly M.;Vaishnav, Radhika;Hall, Edward D.
通讯作者：
Hall, Edward D.
DOI：
10.2147/dddt.s77115
发表时间：
2015
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Khan M;Dhammu TS;Matsuda F;Baarine M;Dhindsa TS;Singh I;Singh AK
通讯作者：
Singh AK
影响因子：
4
作者：
Hagen, Ellen M;Rekand, Tiina
通讯作者：
Rekand, Tiina
影响因子：
6.1
作者：
He, Mengshan;Long, Pan;Wang, Siwang
通讯作者：
Wang, Siwang