The Role Of Thioredoxin-1 In Regulating Environmental Toxicant MPTP-Induced Cognitive Impairment In Mice

Parkinson’s disease(PD)is the common neurodegenerative disorder which is characterized by a loss of dopaminergic neurons in the Substantia nigra pars compacta(SNpc)and the formation of lewy bodies in the neurons.The manifestations include motor and cognitive impairment.The pathogenesis of PD is closely related to genetic and environmental factors.1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)is an environmental toxicant and is often used to construct PD cells and mouse models,which is similar to the pathological characteristics of PD pathological characteristics of PD.Pesticides,herbicides and fungicides which are analogous to MPTP in the environment can increase the incidence of PD.However,the study on PD cognitive dysfunction is few and the molecular mechanism remains unclear.The dopaminergic and glutamatergic systems are closely related to cognitive function of PD.Dopamine receptor 1(D1R)can enhance synaptic plasticity and cognitive ability.N-methyl-D-aspartic acid receptor(NMDAR)subunit NR2 B plays an important role in excitatory synaptic transmission.Extracellular regulated protein kinases(ERK)can activate cAMP response element binding protein(CREB)to participate in the formation of long-term memory.Thioredoxin-1(Trx-1)is a redox regulatory protein.Trx-1 overexpression inhibits MPTP-induced endoplasmic reticulum stress and reduces apoptosis of DA neurons and resists MPTP-induced neurotoxicity.However,it is not clear whether Trx-1 can improve the cognitive function of PD mice.In the present study,we investigated the effects and mechanism of Trx-1 on cognition in MPTP-induced PD mice.The main findings are as follows:(1)Trx-1 overexpression improved the cognitive function of PD mice.The model of PD was established by MPTP.We first examined the PD model by open field,rotarod and grip test.The results showed that the automatic movement and motor coordination ability were significantly reduced,the impairment of limb movement was induced by MPTP,indicating PD model was successfully established.Then,the learning and memory abilities were tested by elevated plus-maze and morris water maze.The retention transfer latency was significantly prolonged in the MPTP group compared to the control group,demonstrating that MPTP induced markedly memory impairment.However,Trx-1 overexpression significantly decreased the retention transfer latency.The navigational experiments in Morris water maze showed that the escape latency in MPTP group mice was longer compared with the control mouse,however,Trx-1 overexpression significantly shortened the escape latency of PD mice.In the spatial probe test,the total number of crossings and the percentage of time spent in the target quadrant were decreased by MPTP,which was significantly increased in overexpression Trx-1 mice with MPTP.These results suggest that Trx-1 overexpression improves memory impairment induced by MPTP.(2)Trx-1 overexpression enhances DA and Glu signaling pathways in the hippocampus.Immunohistochemical and Western Blot results showed that the expressions of TH,D1 R,NR2B,p-ERK and p-CREB were decreased significantly in MPTP mice.Trx-1 overexpression restored the expressions of TH,D1 R,NR2B,p-ERK and p-CREB in PD mice,indicating that Trx-1 regulating cognitive function by regulating DA and Glu systems.(3)Trx-1 downregulation in the substantia nigra aggravated cognitive impairment in PD mice.The mTrx-1 adeno-associated virus was injected into substantia nigra of mice by stereotactic injection to decrease the expression of Trx-1.The learning and memory abilities of mice were tested by the elevated cross maze,morris water maze and new object recognition.The result of elevated plus-maze showed that the retention transfer latency was significantly prolonged compared with the control mouse,after MPTP treatment,the latency was prolonged more,suggesting that the Trx-1 downregulation aggravated the memory impairment induced by MPTP.The navigational experiments in morris water maze showed that the escape latency of Trx-1 downregulation mice with MPTP was significantly longer than that of Trx-1 downregulation mice.Spatial probe results showed that the number of crossing the platform position and the percentage of the target quadrant were decreased significantly in Trx-1 downregulation mice,which were decreased more by MPTP.Novel object recognition showed that the percentage of time spent on novel objects in Trx-1 downregulation mice and MPTP treated mice did not change significantly,however,the number of times touched new object were decreased significantly in Trx-1 downregulation mice and decreased more in Trx-1 downregulation mice by MPTP treatment.These results suggest that Trx-1 downregulation and MPTP treated mice resulted in impairment of the recognition memory.Trx-1 downregulation aggravates MPTP-induced impairment of recognition memory.(4)Trx-1 downregulation reduced DA and Glu signaling pathways in hippocampus.Western Blot results showed that Trx-1 downregulation significantly reduced the expressions of TH,D1 R,NR2B,p-ERK and p-CREB.After MPTP treatment,the expressions of TH,D1 R,NR2B,p-ERK and p-CREB were decreased more.These results suggest that the Trx-1 downregulation may aggravate cognitive impairment in PD mice by down-regulating DA and Glu systems.In conclusion,Trx-1 overexpression improves cognitive impairment induced by MPTP,whereas Trx-1 downregulation aggravates cognitive impairment induced by MPTP.Trx-1 regulates the cognitive impairment induced by MPTP through TH,D1 R and NR2B-ERK-CREB pathways.Trx-1 is an important target for the prevention and treatment of cognitive impairment caused by PD.