Risperidone Induced Metabolic Disorders And Its Intervention With Berberine Co-Treatment In Juvenile Rats

Background:The global incidence of schizophrenia in children and adolescents is increasing with years,and the demand for medicines is increasing with it.The clinical utilization rate of risperidone is about 70%,but during the treatment,patients have adverse reactions such as abnormal weight gain and elevated blood glucose and lipids,which are life-threatening.Metabolic disorder is caused by the imbalance of energy intake and consumption,in the way of energy consumption,the production of heat energy is indispensable.Brown adipose tissue(BAT)as an important adaptive heat-producing organ,it is far more distributed among children and adolescents than adults,after administration of risperidone in adult patients,it was found that the thermogenic function of BAT was significantly impaired,and the heat dissipation was reduced,leading to metabolic abnormalities.It has rarely been reported in the adolescent patient population.Berberine has been widely concerned because of its good hypoglycemic and hypolipidemic effects.Clinical studies have confirmed that berberine can reduce obesity.Can the combination of berberine and risperidone enhance the thermogenic activity of BAT and regulate metabolic abnormalities? This matter is worth exploring in depth.Objective:Through Meta-analysis,this study systematically summarized the effects of risperidone on body weight,blood glucose,blood lipids and appetite in children and adolescents with mental disorders,and fully assessed the potential risk factors of metabolic diseases caused by risperidone.Based on the above clinical statistical analysis,through in vitro and in vivo studies,the causes of risperidone-mediated imbalance in energy metabolism were further elucidated.Combined with berberine for effective intervention,so as to provide guidance for the safety of medication for children and adolescents with mental disorders.Methods:1.Meta-analysis: Pub Med,Web of Science,Science Direct,CNKI,VIP,and US clinical trials registries were searched until December 2022,and randomized controlled trials of risperidone for the treatment of mental disorders in children and adolescents were included.Selected studies were screened,data were collected and collated,the Cochrane bias risk assessment tool was selected for qualitative quality assessment,and Rev Man 5.4 was selected for the analysis software.2.Risperidone mediates metabolic disorders in juvenile rats: 4-week-old rats were divided into control group and risperidone group(Risperidone,1 mg/kg,i.g),with 24 rats in each group.The rats were treated with the drug for 10 days,and then the drug was withdrawn for observation.Body weight,water and food intake,body temperature and spontaneous activity were recorded,blood glucose and blood lipid were measured.Immunohistochemistry was used to detect the expression of proteins related to differentiation and thermogenesis.Section staining is done to observe tissue morphology.The model of brown fat cell was established,the changes of differentiation function and thermogenic activity of brown far cells after risperidone treatment were explored by Oil red O staining,Western Blot and q PCR experiments.3.Effects of berberine co-treatment on risperidone-induced metabolic disorder in juvenile rats: the previous control group was randomly divided into the control group,berberine group(Berberine,150 mg/kg,i.g).The previous risperidone group was randomly divided into risperidone group,berberine and risperidone co-treatment group.Body weight,water and food intake,body temperature and spontaneous activity were recorded,blood glucose and blood lipid were measured,organs weight were measured.Western Blot and immunohistochemistry were used to detect the expression of protein related to BAT differentiation and thermogenesis,and section staining was used to observe lipid and tissue morphology.Oil red O staining and mitochondrial green fluorescence staining were used to detect the effect of berberine co-treatment on the differentiation of brown fat cells.Results:1.Meta-analysis of risperidone on glucose and lipid metabolism in children and adolescents with mental disorderThe patients of weight and Total Cholesterol(TC)in children and adolescents with mental disorders were significantly increased after risperidone treatment(P <0.05),the risk of eating and thirst were also significantly increased(P < 0.05).Compared with the control group,outpatient risperidone patients had a higher risk of weight gain,a significant upward regulation of triglyceride(P = 0.02),an upward trend of blood glucose and low-density lipoprotein cholesterol,and a significant increase in the risk of thirst(P < 0.05).Hospitalized patients had a relatively high risk of increased appetite in hospitalized patients.2.Risperidone mediated metabolic disorders and energy expenditure in juvenile SD ratsCompared with the control group,the cumulative weight gain and food intake of juvenile SD rats in the risperidone group were significantly increased(P < 0.05),high density lipoprotein cholesterol(HDL-C)was significantly decreased in risperidone group(P < 0.01),while Glu,TG and LDL-C were significantly increased(P < 0.05),liver lipid accumulation and BAT tended to be white.After administration of risperidone,the activity of rats was significantly reduced(P < 0.0001),the body temperature of scapula was significantly decreased(P < 0.05),and the expression of proteins related to differentiation and thermogenesis was significantly down-regulated(P < 0.05).Pearson correlation analysis showed that there was a significant negative correlation between thermogenic ability and body weight gain in rats(r =-0.471,P <0.05).Risperidone(1.0 μmol/L)significantly inhibited the differentiation and thermogenic activity of brown fat cells during the whole differentiation process(P <0.05),and down-regulated the transcription of Ucp1 and Pparγ(P < 0.05).3.Berberine intervenes the effect of risperidone on metabolic disorder and energy expenditure in juvenile SD rats.Compared with the risperidone group,the cumulative weight gain,TG and TC in the berberine and risperidone combination group were significantly decreased(P <0.05),and HDL-C was significantly increased(P < 0.01),fat accumulation in liver was reduced,fat droplets existed in mature BAT and weight was significantly increased(P< 0.05).The total amount of exercise and low temperature state of rats were significantly improved(P < 0.05),the expression of BAT-mediated differentiation and thermogenic proteins were significantly up-regulated(P < 0.05).Berberine(5 μmol/L)significantly promoted the differentiation and thermogenesis of brown fat cells.The expression of PPARγ and PGC1α protein was significantly up-regulated(P < 0.05),and the mitochondrial activity was significantly increased(P < 0.05).Conclusion:Clinical Meta-analysis showed that risperidone increased body weight,glucose and lipid metabolism,and increased appetite in children and adolescents with mental disorders,which led to increased energy intake.Risperidone on juvenile SD rats caused significant weight and food intake,and the thermogenic capacity was negatively correlated with weight gain.Furthermore,risperidone inhibits the differentiated capacity of brown fat cells and the thermogenic activity of BAT,reducing heat energy consumption.Intervention with berberine co-treatment significantly unregulated differentiation and thermogenic protein expression,enhanced mitochondrial activity,promoted non-fibrillating thermogenesis of BAT,increased energy expenditure,decreased weight gain rate.These results suggest that berberine can be used as a combination drug for adolescents with metabolic side effects caused by risperidone,and it has a broad clinical application prospect.