The Effect And Its Mechanism Of Oxidative Stress Induced By Alpha-synuclein In Parkinson's Disease

Parkinson's disease(PD)is the second most common neurodegenerative disease after Alzheimer's disease.The majority of PD are middle-aged and elderly people.PD is related to age,and the incidence increases with the age of the person.Epidemiological investigation shows that the global prevalence of PD is about 0.3%,the prevalence rate of the elder over 65 years old is about 2%,and the prevalence rate of the elder over 85 years old is about 5%.According to its pathogenic mechanism,there are two types of PD,hereditary PD and sporadic PD.Hereditary PD only accounts for 5%-10%,and sporadic PD reaches 90%,Currently the cause of PD is unclear.Typical clinical symptoms of PD include resting tremor,muscle stiffness,bradykinesia,and posture balance disorders.PD imposes a heavy burden on patients' families and society.The drugs and surgical treatments now we have can not do much to treat clinical symptoms or delay the progression of PD disease.The symptoms of PD will gradually become severe,until the patients couldn't move anymore and they would not take care of themselves,which affecting the quality of their life,and eventually the patients will die due to many complications of PD.With the increase of the aging population,the incidence of Parkinson's disease is increasing year by year,and PD will become one of the most serious diseases that threaten human beings in the 21 st century.The classic pathological changes of PD are mainly the selective degeneration of dopaminergic neurons(DN)containing melanin in the dense part of the substantia nigra,and the formation of Lewy bodies with ?-synuclein(?-Syn)as the main component in the remaining neurons.Rotenone is a common mitochondrial complex I inhibitor and is widely used in the manufacture of environmental toxin PD models.The cytotoxicity of ?-Syn oligomers is currently considered to be an important cause of DN degeneration and death,but its specific biological mechanism is not fully understood.In this study,a PD mouse model was prepared by continuous intragastric administration of low-dose rotenone.It is hoped that the possible biological mechanism of ?-Syn oligomers leading to loss of DN degeneration can be further studied.Objective: To explore the mechanisms of the impairment of dopaminergic neurons by alpha-synuclein oligomers in the Parkinson's disease mouse model established by gavage with constant low-dose rotenone.Methods: A total of 48 elderly male C57 mice were randomly divided into the rotenone group and control group with 24 mice per group.Mice in the rotenone group were administered 0.01 mL/g rotenone by gavage while mice in the control group were administered chloroform.Mice were sacrificed before and after 12 weeks of continuous treatment.In mice brains harvested after treatment,electron microscopy was used to observe the ultrastructure of substantia nigra neurons in the midbrain;immunohistochemical staining of tyrosine hydroxylase(TH)was performed to examine the density of TH-positive neurons in the substantia nigra.In mice brains harvested before and after treatment,western blotting were carried out to detect ?-Syn expression levels,and amount of superoxide dismutase(SOD),glutathione peroxidase(GSH-PX),and malondialdehyde(MDA)in the brain tissue were determined.Results: After the 12-week treatment,electron microscopy showed swollen mitochondria and Golgi in the substantia nigra of the rotenone group mice.Immunohistochemistry showed that there was a significant decrease in TH-positive neurons in the midbrain of the rotenone group mice compared with that of the control group mice(P<0.05).Western blotting demonstrated that ?-Syn expression in the midbrain of the rotenone group mice was significantly higher than that of the control group mice(P<0.05).Compared to the control group,the rotenone group showed significantly decreased amount of SOD and GSH-PX(P<0.05)and significantly increased amount of MDA(P<0.05).Conclusion: ?-Syn oligomers can form in the brain after continuous intragastric administration of low-dose rotenone.?-Syn oligomers in the midbrain might impair dopaminergic neurons via oxidative stress.