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...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.展开更多
基金This work was supported by the National Institutes of Health(Grant#NS090244 and NS115094 to RS)as well as grants from the National Key Technology Support Program(2014BAI03B01 to Z.C)Sichuan International Science and Technology Innovation Cooperation Project(2020YFH0148 to Z.C).
文摘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.
