Mechanism Of Thioredoxin-1 Resisting Methamphetamine-induced Spinal Cord Injury

Spinal cord injury is divided into primary and secondary spinal cord injury and endogenous damage caused by acute viral infection.After the spinal cord injury,axon develops degenerative damage,apoptosis of oligodendrocytes and neurons,as well as demyelination pathological damage and other dysfunction.Inflammation,reactive oxidation,excitotoxicity and dysregulation of metabolic processes are involved in its molecular mechansim.However,the exact molecular mechanisms have not been elucidated.It is essential to explore the molecular mechanism on spinal cord injury.Methamphetamine as illicit drug of spirit excitement has been widely abused. Methamphetamine is a lipophilic compound,after used,it will induce temporarily effects,including enhanced mental acticity,positive mood,euphoria,increased energy levels,reduced appetite and weight loss.It will induce addcition and neurodeg en er ative damage in nerve system after repeat use.The chronic METH abuse can lead excessive growth of white matter,damage gray matter within the nervous system and glial cells apoptosis in the various brain regions through regulating dopamine,sero tonin.Intracellular METH can induce oxidative stress,damage of DNA and protein via destroying oxidative balance.METH also induces excitotoxicity,nerve inflammati on,mitochondrial dysfunction,endoplasmic reticulum stress and finally induces SCI.Thioredxin-1(Trx-1) is a 12kDa,redox regulating protein,and highly conserved in mammalian.It has a conserved active-site sequence:Cys-Gly-Pro-Cys-.Trx-1 can resist oxidative stress damage and the injury caused by excessive ROS,play a protective roles.Trx-1 can protect cells from interference by the neurotoxin,as well as the damages of hydrogen peroxide,ultraviolet radiation and focal cerebral ischemia.Based on the biological functions of Trx-1 and the mechanisms of METH addiction and toxicity,this study constructed Trx-1 transgenic C57BL/6 mice model and wild-type C57BL/6 addiction mice model of METH.By injected the mice with 2.5mg/kg/d of METH every other day for seven days,then addiction behavior were detected. After built model,we will extract spinal cord tissue to test the changes of Trx-1 and related molcules to explore the molecular mechanism of METH inducing SCI and Trx-1 resisting SCI induced by METH.The results of this study are following:(1)Overexpression of Trx-1 could inhibit SCI induced by METH via regulating Erk/CDK5 pathway.Trx-1 could enhance the expression of cyclin-dependent kinase-5 via upregulating phosphorylation extracellular regulated protein kinase in neurons and inhibit the changes of myelin-associated glycoprotein expression.(2)Overexpression of Trx-1 inhibits the apoptosis in SCI induced by METH via supressing endoplasmic reticulum stress pathway.Trx-1 could inhibit cutting and activation of Caspase-3 through supressing calpain 1 expression.(3)Overexpression of Trx-1 inhibited the expression of receptor D2 induced by METH, then regulated glycogen synthase kinase-3β (GSK-3β) pathway and inhibited oxidative stress and inflammation,finally inhibited SCI induced by METH.Conclusion:METH induced SCI; Overexpression of Trx-1 could resist SCI via regulating several pathways and protect the spinal cord.