GSNOR and ALDH2 alleviate traumatic spinal cord injury.
GSNOR and ALDH2 alleviate traumatic spinal cord injury.
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DOI：
10.1016/j.brainres.2021.147335
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发表时间：
2021-05-01
期刊：
影响因子：
2.9
通讯作者：
Singh I
中科院分区：
文献类型：
--
作者：
Khan M;Qiao F;Islam SMT;Dhammu TS;Kumar P;Won J;Singh AK;Singh I
创伤性脊髓损伤（SCI）可增强S-亚硝基谷胱甘肽还原酶（GSNOR）的活性并抑制线粒体醛脱氢酶2（ALDH 2）的活性，导致长期持续的疼痛和功能缺陷。本研究的目的是测试GSNOR的特异性抑制剂N6022在SCI小鼠模型中减轻疼痛和改善功能恢复的假设。此外，通过ALDH 2活化剂Alda-1提高了恢复程度并加速了恢复速率。使用野生型和GSNOR−/−小鼠，在T9-T10椎骨水平上部署SCI模型。测定GSNOR和ALDH 2的酶活性，并通过蛋白质印迹分析测定GSNOR和ALDH 2的表达。通过运动、感觉运动和疼痛样行为测试评估实验动物的功能改善。野生型SCI动物具有增强的GSNOR活性和降低的ALDH 2活性，导致神经血管功能障碍、水肿和恶化的功能结果，包括运动缺陷和疼痛。与野生型SCI小鼠相比，GSNOR−/−小鼠具有更好的功能结果。通过N6022抑制GSNOR或通过Alda-1增强ALDH 2活性的单药治疗与功能恢复和疼痛减轻密切相关。然而，与单药治疗相比，联合治疗提供了协同的疼痛缓解作用和更显著的功能恢复。总之，GSNOR和ALDH 2的失调是SCI损伤的致病机制之一。抑制GSNOR或激活ALDH 2都能改善SCI。将GSNOR的特异性抑制剂（N6022）与ALDH 2的选择性激活剂（Alda-1）组合提供对神经血管单元的更大保护并赋予更大的功能恢复。该研究是新颖的，联合治疗（N6022+Alda-1）具有转化潜力。在SCI中，N6022与Alda-1的组合比N6022或Alda-1的单一疗法提供更大的功能恢复。
Traumatic spinal cord injury (SCI) enhances the activity of S-nitrosoglutathione reductase (GSNOR) and inhibits the mitochondrial aldehyde dehydrogenase 2 (ALDH2) activity, resulting in prolonged and sustained pain and functional deficits. This study's objective was to test the hypotheses that GSNOR’s specific inhibitor N6022 mitigates pain and improves functional recovery in a mouse model of SCI. Furthermore, the degree of recovery is enhanced and the rate of recovery is accelerated by an ALDH2 activator Alda-1. Using both wild-type and GSNOR−/− mice, the SCI model deployed for groups was contusion at the T9-T10 vertebral level. The enzymatic activity of GSNOR and ALDH2 was measured, and the expression of GSNOR and ALDH2 was determined by western blot analysis. Functional improvements in experimental animals were assessed with locomotor, sensorimotor, and pain-like behavior tests. Wild-type SCI animals had enhanced GSNOR activity and decreased ALDH2 activity, leading to neurovascular dysfunction, edema, and worsened functional outcomes, including locomotor deficits and pain. Compared to wild-type SCI mice, GSNOR−/− mice had better functional outcomes. Monotherapy with either GSNOR inhibition by N6022 or enhanced ALDH2 activity by Alda-1 correlated well with functional recovery and lessened pain. However, combination therapy provided synergistic pain-relieving effects and more significant functional recovery compared with monotherapy. Conclusively, dysregulations in GSNOR and ALDH2 are among the causative mechanisms of SCI injury. Either inhibiting GSNOR or activating ALDH2 ameliorates SCI. Combining the specific inhibitor of GSNOR (N6022) with the selective activator of ALDH2 (Alda-1) provides greater protection to the neurovascular unit and confers greater functional recovery. The study is novel, and the combination therapy (N6022+Alda-1) possesses translational potential. Combining N6022 with Alda-1 provides greater functional recovery than monotherapy with N6022 or Alda-1 in SCI.
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