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
Repurposing small molecule drugs and drug candidates is considered as a promising approach to revolutionise the treatment of snakebite envenoming.In this study,we investigated the inhibiting effects of the small molec...Repurposing small molecule drugs and drug candidates is considered as a promising approach to revolutionise the treatment of snakebite envenoming.In this study,we investigated the inhibiting effects of the small molecules varespladib(nonspecific phospholipase A2 inhibitor),marimastat(broad spectrum matrix metalloprotease inhibitor)and dimercaprol(metal ion chelator)against coagulopathic toxins found in Crotalinae(pit vipers)snake venoms.Venoms from Bothrops asper,Bothrops jararaca,Calloselasma rhodostoma and Deinagkistrodon acutus were separated by liquid chromatography,followed by nanofractionation and mass spectrometry identification undertaken in parallel.Nanofractions of the venom toxins were then subjected to a high-throughput coagulation assay in the presence of different concentrations of the small molecules under study.Anticoagulant venom toxins were mostly identified as phospholipases A2,while procoagulant venom activities were mainly associated with snake venom metalloproteinases and snake venom serine proteases.Varespladib was found to effectively inhibit most anticoagulant venom effects,and also showed some inhibition against procoagulant toxins.Contrastingly,marimastat and dimercaprol were both effective inhibitors of procoagulant venom activities but showed little inhibitory capability against anticoagulant toxins.The information obtained from this study aids our understanding of the mechanisms of action of toxin inhibitor drug candidates,and highlights their potential as future snakebite treatments.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.
基金funded by a China Scholarship Council(CSC)fellowship(201706250035)support from a UK Medical Research Council(MRC)Research Grant(MR/S00016X/1)+1 种基金Confidence in Concept Award(Ci C19017,UK)a Sir Henry Dale Fellowship(200517/Z/16/Z,UK)jointly funded by the Wellcome Trust and Royal Society
文摘Repurposing small molecule drugs and drug candidates is considered as a promising approach to revolutionise the treatment of snakebite envenoming.In this study,we investigated the inhibiting effects of the small molecules varespladib(nonspecific phospholipase A2 inhibitor),marimastat(broad spectrum matrix metalloprotease inhibitor)and dimercaprol(metal ion chelator)against coagulopathic toxins found in Crotalinae(pit vipers)snake venoms.Venoms from Bothrops asper,Bothrops jararaca,Calloselasma rhodostoma and Deinagkistrodon acutus were separated by liquid chromatography,followed by nanofractionation and mass spectrometry identification undertaken in parallel.Nanofractions of the venom toxins were then subjected to a high-throughput coagulation assay in the presence of different concentrations of the small molecules under study.Anticoagulant venom toxins were mostly identified as phospholipases A2,while procoagulant venom activities were mainly associated with snake venom metalloproteinases and snake venom serine proteases.Varespladib was found to effectively inhibit most anticoagulant venom effects,and also showed some inhibition against procoagulant toxins.Contrastingly,marimastat and dimercaprol were both effective inhibitors of procoagulant venom activities but showed little inhibitory capability against anticoagulant toxins.The information obtained from this study aids our understanding of the mechanisms of action of toxin inhibitor drug candidates,and highlights their potential as future snakebite treatments.