Acrolein scavenger dimercaprol offers neuroprotection in an animal model of Parkinson’s disease: implication of acrolein and TRPA1

Abstract

Background The mechanisms underlying lesions of dopaminergic (DA) neurons, an essential pathology of Parkinson’s disease (PD), are largely unknown, although oxidative stress is recognized as a key factor. We have previously shown that the pro-oxidative aldehyde acrolein is a critical factor in PD pathology, and that acrolein scavenger hydralazine can reduce the elevated acrolein, mitigate DA neuron death, and alleviate motor deficits in a 6-hydroxydopamine (6-OHDA) rat model. As such, we hypothesize that a structurally distinct acrolein scavenger, dimercaprol (DP), can also offer neuroprotection and behavioral benefits. Methods DP was used to lower the elevated levels of acrolein in the basal ganglia of 6-OHDA rats. The acrolein levels and related pathologies were measured by immunohistochemistry. Locomotor and behavioral effects of 6-OHDA injections and DP treatment were examined using the open field test and rotarod test. Pain was assessed using mechanical allodynia, cold hypersensitivity, and plantar tests. Finally, the effects of DP were assessed in vitro on SK-N-SH dopaminergic cells exposed to acrolein. Results DP reduced acrolein and reversed the upregulation of pain-sensing transient receptor potential ankyrin 1 (TRPA1) channels in the substantia nigra, striatum, and cortex. DP also mitigated both motor and sensory deficits typical of PD. In addition, DP lowered acrolein and protected DA-like cells in vitro. Acrolein’s ability to upregulate TRPA1 was also verified in vitro using cell lines. Conclusions These results further elucidated the acrolein-mediated pathogenesis and reinforced the critical role of acrolein in PD while providing strong arguments for anti-acrolein treatments as a novel and feasible strategy to combat neurodegeneration in PD. Considering the extensive involvement of acrolein in various nervous system illnesses and beyond, anti-acrolein strategies may have wide applications and broad impacts on human health.

Diisocyanates influence models of atopic dermatitis through direct activation of TRPA1

“…Our data is also consistent with prior reports linking dopaminergic responses with TRPA1 activity [40,41]. Glucocorticoids, the most common AD treatment class, has been shown to upregulate dopamine beta-hydroxylase, which converts dopamine to epinephrine and norepinephrine [42].…”

The contribution of initial concussive forces and resulting acrolein surge to β-amyloid accumulation and functional alterations in neuronal networks using a TBI-on-a-chip model

“…While hydralazine was selected to suppress acrolein with these experiments, there are multiple other known effective acrolein scavengers, such as phenelzine and dimercaprol, that are available for further investigating the role of acrolein in post-TBI. 75–77 In addition to sequestration as an anti-acrolein strategy, there are also several models of transgenic mice with an AD predisposition that could be used for a similar purpose. 78–81…”

A high-affinity cocaine binding site associated with the brain acid soluble protein 1

“…Rabbit anti-TH was purchased from BioLegend, catalog no. 818002 ( 84 , 85 ). Mouse anti-FLAG antibody was purchased from Sigma Aldrich, catalog no.…”