Abstract
BackgroundThe 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.MethodsDP 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.ResultsDP 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.ConclusionsThese 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.
Highlights
The mechanisms underlying lesions of dopaminergic (DA) neurons, an essential pathology of Parkinson’s disease (PD), are largely unknown, oxidative stress is recognized as a key factor
Anti-acrolein immunofluorescence staining revealed that the injection of 6-OHDA into the substantia nigra (SN) significantly increased the level of acrolein in both the SN and striatum of 6-OHDA-injected rats compared to the sham rats, when examined at 5 weeks postsurgery (P < 0.01)
Western blotting analysis further showed that both acrolein and αsyn were significantly elevated in the SN of 6-OHDA rats versus sham rats, and the elevation was reversed by DP (P < 0.01) (Fig. 1e)
Summary
The mechanisms underlying lesions of dopaminergic (DA) neurons, an essential pathology of Parkinson’s disease (PD), are largely unknown, 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. While the exact cause is unknown, oxidative stress has been postulated as one of the most important contributors to nigral cell death in PD [9,10,11] To this end, we have previously reported that toxic aldehydes, such as acrolein, may play a key role in PD pathology [11, 12]. We have already shown that the acrolein scavenger HZ has neuroprotective effects by lowering acrolein in 6-OHDA-injected rats [11]
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