The Role And Mechanism Of Thioredoxin-1 Improving Movement Disorders Through Regulating Inflammation In MPTP Parkinson’s Disease Model Mice

Parkinson’s disease(PD)is a neurodegenerative disease characterized by the formation of Lewy body(LB)in substantia nigra pars compacta(SNPC)and the degeneration and loss of dopaminergic(DA)neurons.The main clinical symptoms are divided into two categories:motor symptoms and non-motor symptoms.Motor symptoms mainly include:forbidden tremor,myotonia and bradykinesia.Non-motor symptoms mainly include:olfactory,sleep,cognitive disorders,etc.The pathogenesis of Parkinson’s disease is complexed.At present,studies show that it is related to inflammatory response,immune abnormality,oxidative stress,mitochondria fission/fusion abnormality,endoplasmic reticulum stress and cell apoptosis.Among them,the abnormal inflammatory response plays a key role in Parkinson’s disease.Some studies have shown that inflammation is an important feature of Parkinson’s disease and leads to neurodegeneration.However,its molecular mechanism is not clear.Inflammation is a natural defense response.Most inflammatory mediators are part of the innate immunity of cells.Immune defense cells release inflammatory mediators and other signaling molecules(such as prostaglandins,histamines,leukotrienes,oxygen and nitrogen free radicals,5-hydroxytryptamines)under inflammation.In the brain,both glial cells and neurons participate in inflammatory response.In addition,the expression of inflammatory biomarkers and related factors has been found in peripheral blood circulation in PD.Therefore,to study the role of inflammatory response in the pathogenesis of PD can provide new treatment ideas and targets for PD patients.Immune response is a defense network composed of special cell types and tissues to make defense responses to the alien components from outside or some components that are mutated in the body.The immune system special cells,such as,T lymphocytes(CD8~+,CD4~+)detect antigen peptide binding to Major histocompatibility complex-I/II(MHC-I/II)through T cell receptor(TCR),and release a series of inflammatory cytokines and specific neutralizing antibodies.Thioredoxin-1(Trx-1)is a redox protein.It can not only promote the growth of the cells and inhibit apoptosis,but also participate in the inflammatory response.Trx-1 overexpression can effectively resist the neurotoxicity of1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)and its derivative1-methyl-4-phenylpyridinium(MPP~+),protect dopaminergic neurons in substantia nigra and improve the motor ability of PD mice.However,its specific mechanism is still unclear.Some studies have shown that the abnormal inflammatory immune response plays an important role in the pathogenesis of PD.Therefore,the study on the effect and mechanism of Trx-1 regulating inflammatory immune response can provide a new method for the treatment of PD patients.This paper mainly studies the effect of Trx-1 on the motor ability of PD mice and the role of inflammatory immune response,and explores the mechanism of Trx-1improving Parkinson’s disease by inhibiting inflammation.The research results are as follows:(1)Trx-1 overexpression can effectively improve the motor dysfunction of PD mice.Construction of PD animal model:wild type mice and Trx-1 overexpression transgenic mice(TG)were used to construct the experimental animal model.Three behavioral tests(rotation test,open field test and grab bar test)were used to detect the motor ability of PD mice.The behavioral test showed that the motor ability and autonomous activity of PD mice were obviously weakened.On the contrary,Trx-1overexpression mice after MPTP injection showed the improvement of motor ability and autonomous activity of compared with wild-type PD mice.Trx-1 overexpression can improve the movement disorders of PD mice.(2)Trx-1 downregulation aggravates the dyskinesia of PD mice.To construct low expression of Trx-1 in the substantia nigra in PD mouse model and detect its behaviors.The results showed that the damage of motor ability was significantly increased in MPTP group and Trx-1 downregulation PD group.These results suggest that the Trx-1 downregulation aggravates the movement disorder of PD mice.(3)Overexpression of Trx-1 reversed the decrease of tyrosine hydroxylase(TH)expression in midbrain of PD mice induced by MPTP.Downregulation of Trx-1 could aggravate the decrease of TH expression in midbrain of PD mice induced by MPTP.(4)The effect of Trx-1 overexpression on inflammatory response and its molecular mechanism.The results showed that the expressions of MHC-I and TNF-αwere increased significantly in ventral tegmental area(Midbrain)of PD mice.When Trx-1 was overexpressed,the increases of MHC-I and TNF-αin the midbrain of PD mice were significantly inhibited.The expression of MHC-II and IL-10 in midbrain of PD mice was significantly decreased,which was reversed by Trx-1 overexpression.(5)The effect of Trx-1 downregulation on inflammatory response and its molecular mechanism.The results showed that the expressions of MHC-I and TNF-αwere increased significantly in the midbrain of PD mice.When Trx-1 was downregulation,the increases of MHC-I and TNF-αin the midbrain of PD mice were significantly enhanced,the expressions of MHC-II and IL-10 in midbrain of PD mice was further decreased.These results suggest Trx-1 plays a regulating role in inflammatory response in PD.Summary:Trx-1 overexpression improved the movement disorders in PD mice,whereas Trx-1 downregulation aggravated the movement disorders in PD mice.Trx-1overexpression suppressed the changes of MHC-I,MHC-II,TNF-αand IL-10 in midbrain of PD mice,whereas Trx-1 downregulation enhanced these changes.These results suggested that Trx-1 improved the movement disorders in PD mice through regulating inflammatory response.