The relationship between Parkin-mediated autophagy and manganese-induced neurotoxicity in mice
Objective To explore the relationship between Parkin-mediated autophagy and manganese-induced neurotoxicity in mice.Methods Eighty 8-week-old SPF grade C57 B6 male mice were randomly divided into four groups:Control group and low,medium and high dose group,20 mice in each group.MnCl2·4H2O solution was injected intraperitoneally for 4 weeks.After exposure,the exercise,learning and memory abilities of mice were detected by behavioral experiments,manganese accumulation in whole blood and midbrain of mice was de-tected by inductively coupled plasma mass spectrometry,mitochondrial damage in cerebral striatum of mice was observed by transmission electron microscopy,dopamine level in brain was detected by enzyme-linked immu-nosorbent assay,and Parkin and LC3 protein levels were detected by Western blot.Results Manganese accumu-lation in midbrain and whole blood of mice were increased after exposure to Mn,and Mn accumulation in middle and high dose group was significantly higher than that in control group(P<0.05).Compared with the control group,the motor,learning and memory functions of the mice in the high dose group were impaired,the rod rota-tion residence time,the autonomous alternation rate and the first quadrant residence time were all reduced(P<0.05),and the incubation period escape time was increased(P<0.05).Compared with the control group,the level of dopamine in the high dose group was decreased(P<0.05).With the increase of manganese concentra-tion,the damage of mitochondria in the striatum cells of mice aggravated.Compared with the control group,the outer membrane of mitochondria in the striatum cells of mice in the high dose group was uneven,and the inner membrane cristae was reduced and blurred,observedby transmission electron microscopy.With the increase of manganese concentration,the level of autophagy in the hippocampus of mice increased first and then decreased.Compared with the control group,the Parkin protein content in the medium and high dose groups decreased(P<0.05).With the increase of manganese concentration,the ratio of LC3Ⅱ/Ⅰincreased first and then decreased,which was significantly lower in the high dose group than in the control group(P<0.05).The content of α-syn protein increased gradually with the increase of manganese concentration.Compared with the control group,the content of α-syn protein in the middle and high dose groups increased significantly(P<0.05).Conclusion Manganese-induced nervous system injury in mice may be related to the obstruction of autophagy pathway media-ted by Parkin.
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