Traumatic brain injury is among the most common causes of death and disability in youth and young adults.In addition to the acute risk of morbidity with moderate to severe injuries,traumatic brain injury is associated...Traumatic brain injury is among the most common causes of death and disability in youth and young adults.In addition to the acute risk of morbidity with moderate to severe injuries,traumatic brain injury is associated with a number of chronic neurological and neuropsychiatric sequelae including neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.However,despite the high incidence of traumatic brain injuries and the established clinical correlation with neurodegeneration,the causative factors linking these processes have not yet been fully elucidated.Apart from removal from activity,few,if any prophylactic treatments against post-traumatic brain injury neurodegeneration exist.Therefore,it is imperative to understand the pathophysiological mechanisms of traumatic brain injury and neurodegeneration in order to identify potential factors that initiate neurodegenerative processes.Oxidative stress,neuroinflammation,and glutamatergic excitotoxicity have previously been implicated in both secondary brain injury and neurodegeneration.In particular,reactive oxygen species appear to be key in mediating molecular insult in neuroinflammation and excitotoxicity.As such,it is likely that post injury oxidative stress is a key mechanism which links traumatic brain injury to increased risk of neurodegeneration.Consequently,reactive oxygen species and their subsequent byproducts may serve as novel fluid markers for identification and monitoring of cellular damage.Furthermore,these reactive species may further serve as a suitable therapeutic target to reduce the risk of post-injury neurodegeneration and provide long term quality of life improvements for those suffering from traumatic brain injury.展开更多
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
Background:It is increasingly clear that in addition to myelin disruption,axonal degeneration may also represent a key pathology in multiple sclerosis(MS).Hence,elucidating the mechanisms of axonal degeneration may no...Background:It is increasingly clear that in addition to myelin disruption,axonal degeneration may also represent a key pathology in multiple sclerosis(MS).Hence,elucidating the mechanisms of axonal degeneration may not only enhance our understanding of the overall MS pathology,but also elucidate additional therapeutic targets.The objective of this study is assess the degree of axonal membrane disruption and its significance in motor deficits in EAE mice.Methods:Experimental Autoimmune Encephalomyelitis was induced in mice by subcutaneous injection of myelin oligodendrocyte glycoprotein/complete Freud’s adjuvant emulsion,followed by two intraperitoneal injections of pertussis toxin.Behavioral assessment was performed using a 5-point scale.Horseradish Peroxidase Exclusion test was used to quantify the disruption of axonal membrane.Polyethylene glycol was prepared as a 30%(w/v)solution in phosphate buffered saline and injected intraperitoneally.Results:We have found evidence of axonal membrane disruption in EAE mice when symptoms peak and to a lesser degree,in the pre-symptomatic stage of EAE mice.Furthermore,polyethylene glycol(PEG),a known membrane fusogen,significantly reduces axonal membrane disruption in EAE mice.Such PEG-mediated membrane repair was accompanied by significant amelioration of behavioral deficits,including a delay in the emergence of motor deficits,a delay of the emergence of peak symptom,and a reduction in the severity of peak symptom.Conclusions:The current study is the first indication that axonal membrane disruption may be an important part of the pathology in EAE mice and may underlies behavioral deficits.Our study also presents the initial observation that PEG may be a therapeutic agent that can repair axolemma,arrest axonal degeneration and reduce motor deficits in EAE mice.展开更多
文摘Traumatic brain injury is among the most common causes of death and disability in youth and young adults.In addition to the acute risk of morbidity with moderate to severe injuries,traumatic brain injury is associated with a number of chronic neurological and neuropsychiatric sequelae including neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.However,despite the high incidence of traumatic brain injuries and the established clinical correlation with neurodegeneration,the causative factors linking these processes have not yet been fully elucidated.Apart from removal from activity,few,if any prophylactic treatments against post-traumatic brain injury neurodegeneration exist.Therefore,it is imperative to understand the pathophysiological mechanisms of traumatic brain injury and neurodegeneration in order to identify potential factors that initiate neurodegenerative processes.Oxidative stress,neuroinflammation,and glutamatergic excitotoxicity have previously been implicated in both secondary brain injury and neurodegeneration.In particular,reactive oxygen species appear to be key in mediating molecular insult in neuroinflammation and excitotoxicity.As such,it is likely that post injury oxidative stress is a key mechanism which links traumatic brain injury to increased risk of neurodegeneration.Consequently,reactive oxygen species and their subsequent byproducts may serve as novel fluid markers for identification and monitoring of cellular damage.Furthermore,these reactive species may further serve as a suitable therapeutic target to reduce the risk of post-injury neurodegeneration and provide long term quality of life improvements for those suffering from traumatic brain injury.
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This work was supported by the State of Indiana and the Indiana Clinical and Translational Sciences Institute(PHS NCCR#TL1RR025759 and#RR025761).
文摘Background:It is increasingly clear that in addition to myelin disruption,axonal degeneration may also represent a key pathology in multiple sclerosis(MS).Hence,elucidating the mechanisms of axonal degeneration may not only enhance our understanding of the overall MS pathology,but also elucidate additional therapeutic targets.The objective of this study is assess the degree of axonal membrane disruption and its significance in motor deficits in EAE mice.Methods:Experimental Autoimmune Encephalomyelitis was induced in mice by subcutaneous injection of myelin oligodendrocyte glycoprotein/complete Freud’s adjuvant emulsion,followed by two intraperitoneal injections of pertussis toxin.Behavioral assessment was performed using a 5-point scale.Horseradish Peroxidase Exclusion test was used to quantify the disruption of axonal membrane.Polyethylene glycol was prepared as a 30%(w/v)solution in phosphate buffered saline and injected intraperitoneally.Results:We have found evidence of axonal membrane disruption in EAE mice when symptoms peak and to a lesser degree,in the pre-symptomatic stage of EAE mice.Furthermore,polyethylene glycol(PEG),a known membrane fusogen,significantly reduces axonal membrane disruption in EAE mice.Such PEG-mediated membrane repair was accompanied by significant amelioration of behavioral deficits,including a delay in the emergence of motor deficits,a delay of the emergence of peak symptom,and a reduction in the severity of peak symptom.Conclusions:The current study is the first indication that axonal membrane disruption may be an important part of the pathology in EAE mice and may underlies behavioral deficits.Our study also presents the initial observation that PEG may be a therapeutic agent that can repair axolemma,arrest axonal degeneration and reduce motor deficits in EAE mice.
