Alford : Up and Down Regulation of Aldehyde Expression by External and Internal Mechanisms and their Therapeutic Value in EAE Mice
Up and down Regulation of Aldehyde Expression by External and Internal Mechanisms and their Therapeutic Value in EAE Mice
Anna Alford2,3, Jonathan Tang1,2,3, Gary Leung1,3, Melissa Tully2,3,4, Riyi Shi1,2,3
1 Department of Basic Medical Sciences, College of Veterinary Medicine
2 Weldon School of Biomedical Engineering
3 Center for Paralysis Research Purdue University, West Lafayette, IN 47907
4 MSTP program, Indiana University School of Medicine, Indianapolis, IN, USA
Acrolein, a pro-inflammatory aldehyde, has been shown as a critical factor in MS pathology. It has been demonstrated that the acrolein scavenger hydralazine (HZ) can suppress acrolein as well as alleviate motor deficits in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). We therefore hypothesize that the up and down regulation of aldehyde dehydrogenase 2 (ALDH2), an enzyme capable of metabolizing aldehydes, could instigate behavioral changes in EAE.
We used three acrolein scavengers to mitigate behavioral deficits in EAE mice. The levels of acrolein and myeloperoxidase (MPO) were measured by immunohistochemistry. The mRNA of TRPA1 was assessed using RT-PCR. Motor function was determined using a 5-point system; mechanical hyperreflexia was evaluated using von Frey filaments. ALDH2 was down-regulated through a genetically modified mouse model, and activated using Alda-1, an ALDH2-activator.
Application of acrolein scavengers decreased motor and sensory deficits in EAE mice when applied post-induction. Particularly, HZ could alleviate motor deficits when applied following symptom emergence. This additionally corresponded to a reduction in both acrolein and inflammatory markers in EAE mice.
Furthermore, we observed that ALDH2*2 mice not only display more severe behavioral deficits, but also heightened levels of acrolein, inflammation, and demyelination markers in EAE compared to wild-type mice. In addition, treatment with Alda-1, an activator of ALDH2, can lower acrolein and inflammation in EAE.
We have shown that three structurally distinct acrolein scavengers can behavioral and immunohistochemical deficits in EAE mice. Additionally, up- and down-regulation of ALDH2 corresponded to marked behavioral and biological changes in EAE, underscoring the critical involvement of acrolein in EAE pathogenesis.
Translational/Human Health Impact:
These findings further consolidate the critical role of aldehydes in the pathology of EAE and its mechanisms of regulation. This is expected to reinforce and expand the possible therapeutic targets of anti-aldehyde treatment to achieve neuroprotection through both endogenous and exogenous manners.
|2023-08-30T09:47:53-04:00August 30th, 2023|2023 Annual Meeting Presentations, Annual Meeting|Comments Off on Alford : Up and Down Regulation of Aldehyde Expression by External and Internal Mechanisms and their Therapeutic Value in EAE Mice