Neuroprotection by Acrolein Sequestration through Exogenously Applied Scavengers and Endogenous Enzymatic Enabling Strategies in mouse EAE model

We have previously shown that the pro-oxidative aldehyde acrolein is a critical factor in MS pathology, and the acrolein scavenger hydralazine (HZ) can suppress acrolein and alleviate motor deficits in a mouse experimental autoimmune encephalomyelitis (EAE) model. In this study, we found that in addition to hydralazine (HZ), phenelzine and dimercaprol, two structurally distinct acrolein scavengers, can mitigate motor and/or sensory deficits in EAE when applied immediately post-induction. This suggests that the chief factor of neuroprotection offered by three structurally distinct acrolein scavengers in EAE is their common feature of acrolein neutralization, not other functions unique to each compound. Furthermore, HZ can alleviate motor deficits when applied after the emergence of MS symptoms, making anti-acrolein treatment a more clinically relevant strategy. In addition, HZ can reduce both acrolein and MPO, suggesting a causative interaction between acrolein and inflammation. Finally, up-and-down regulation of ALDH2 function in EAE mice using either a pharmacological or genetic strategy led to correspondent motor and sensory changes. This data indicates a key role of ALDH2 in influencing oxidative stress, inflammation, and behavior in EAE. 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.