| Background: Cerebral palsy(CP)describes a group of permanent disorders of the development of movement and posture,causing activity limitation,thoese are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain.The motor disorders of cerebral palsy are often accompanied by disturbances of sensation,perception,cognition,communication and behaviour,by epilepsy,and by secondary musculoskeletal problems.The dyskinesia of CP is often accompanied by disturbances in perception,cognition,communication and behavior,with epilepsy and secondary musculoskeletal problems.With the improvement of obstetric and neonatal intensive care techniques,the survival rate of newborns has increased significantly,but the proportion of newborns with brain damage has increased accordingly.CP seriously affects the child's ability of normal growth and development,social interaction,learning and survival,and imposes a heavy economic burden on families and society.CP,with a high incidence and low cure rate,is mainly assisted by rehabilitation training with drugs,but there is no perfect treatment strategy,clinically.?-Mangostin is a major xanthone purified from the mangosteen,which has been reported to have anti-inflammatory,antioxidant and antibacterial effects.Its use in the treatment of skin infections,dysentery and chronic wounds has a long history.In recent years,it has been found that its derivatives(AMG1)has biological activity against Alzheimer's disease and vascular dementia,and it can penetrate the blood-brain barrier with low cytotoxicity.So it can be one of the potential candidate compound for the treatment of CP.Objective: In this study,a CP animal model of neonatal rat,with hypoxia-ischemia combined infection,was used to explore the intervention effect and possible mechanism of ?-mangostin derivative on CP,which provided a new idea and experimental basis for the treatment of CP.Methods: This study is divided into the following three parts:(1)Animal models were established by hypoxia-ischemia combined with infection,randomly grouping: HIL group(intraperitoneal injection of the sovent),low-dose group(administered 5 mg/kg),middle-dose group(administered 10 mg/kg),high-dose group(administered 20 mg/kg),and positive drug group(GM1 20 mg/kg)and control group(intraperitoneal injection of the sovent).(2)After the end of drug treatment,the spatial learning and memory abilities of each group of rats was observed by Morris water maze test.The gait balance ability of each group was evaluated by foot fault test.The pathological changes of brain tissue and cells in rats of each group were compared by Nissl staining and HE staining.And the submicroscopic structure of neurons in each group was observed by transmission electron microscopy.(3)Immunohistochemistry was used to detect the expression of cleaved caspase 3,and TUNEL staining with it was used to evaluate the occurrence of apoptosis.Western blot was used to detect the expressions of Akt,p-Akt,GSK-3?,p-GSK-3?,Bcl-2,Bax and cleaved caspase 3,which initially explore the possible mechanism of drug action.Results:(1)Compared with the control group,the abilities of gait balance and spatial memory were decreased in the model group,and the drug-administered groups improved them(P<0.05).(2)By HE staining and Nissl staining,in the HIL group,the neuronal loss and morphological changes in the CA1 region were observed,compared with the control group.The mitochondrial swelling lesions in the HIL group were observed by transmission electron microscopy.The immunohistochemistry showed that the protein expression of cleaved caspase 3 increased in the HIL group,compared with the control group;TUNEL staining showed that the positive rate of apoptotic cells in HIL group increased;western blot results showed that compared with control group,HIL group down-regulated the ratio of p-Akt/Akt,p-GSK-3?/GSK-3? and Bcl-2/Bax protein expression(P<0.05),and up-regulated the expression of cleaved caspase 3 protein(P<0.05).Compared with the HIL group,the drug-administered groups improved the cell loss in the hippocampus,and the mitochondrial morphology was greatly restored.What's more,the apoptotic cell ratio was significantly decreased,and the ratio of p-Akt/Akt,p-GSK-3?/GSK-3? and Bcl-2/Bax were improved(P<0.05),with decreasing the expression of cleaved caspase 3 protein(P<0.05).Conclusion:(1)?-Mangostin derivatives can effectively improve spatial cognitive impairment and gait balance disorder in cerebral palsy model rats.(2)?-mangostin derivatives can regulate neuronal apoptosis in the acute phase of hypoxia-ischemia combined with infection through the Akt/GSK-3? signaling pathway,and alleviate the damage and loss of developing brain neurons. |
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