GSNOR and ALDH2 alleviate traumatic spinal cord injury

Brain Res. 2021 May 1:1758:147335. doi: 10.1016/j.brainres.2021.147335. Epub 2021 Feb 2.

Abstract

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.

Keywords: ALDH2; Alda-1; BMS score; GSNOR; N6022; Pain; Reactive aldehydes; Reactive oxygen species; S-nitrosylation; SCI.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alcohol Dehydrogenase / metabolism*
  • Aldehyde Dehydrogenase, Mitochondrial / metabolism*
  • Animals
  • Benzamides / pharmacology
  • Benzodioxoles / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pyrroles / pharmacology
  • Recovery of Function / drug effects*
  • Recovery of Function / physiology*
  • Spinal Cord Injuries / enzymology*

Substances

  • Benzamides
  • Benzodioxoles
  • Enzyme Inhibitors
  • N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide
  • N6022
  • Pyrroles
  • Adh5 protein, mouse
  • Alcohol Dehydrogenase
  • ALDH2 protein, mouse
  • Aldehyde Dehydrogenase, Mitochondrial