The Curative Effect And Possible Mechanisms Of BP897 In Treatment Of Mice With Tourette Syndrome

Objective This study was designed to observe the effect and suitable treatment dose of dopamine D3 receptor agonist BP897 on the ICR mice models with Tourette syndrome(TS) evoked by iminodipropionitrile through comparing the differences of therapeutic effect in groups of different doses of BP897, and its effect on dopamine D3 receptor, dopamine transmitter and dopamine in brain tissue,in order to find its possible mechanisms in treatment of mice with TS.Methods 1.Dividing into groups.Divid 72 male ICR mice into blank control group,model group,positive control group(haloperidol 0.5mg/kg), BP897â… group(low dose group,0.3mg/kg),BP897â…¡group(middle dose group, 1.0 mg/kg), BP897â…¢group (high dose group,3.0mg/kg) averagely and randomly,12 mice for each group.2.Building models.TS model is builded by crotoxin systemic administration method which is set up by Diamond BI. Firstly,dissolve IDPN in normal saline,according to the dose of 200mg/kg,density of 0.1ml/100g,route of administration is peritoneal injection, use 7 days,once a day.At the same time, give equal normal saline to blank control group by peritoneal injection.3.Grading stereotyped behavior:Daily feed with normal saline,haloperidol and BP897 from the eighth day of the experiment,once a day,28 days in total.Score stereotyped behavior in double blind way during three periods:After the modeling,7 days dosage,28 days dosage,three times a day,focus on the night,due to nocturnal habits of mice,5 minutes each time,scores averaged.Grading standard:zero:without stereotyped movement;one point:circling behavior; two points:vertical motor disorders for head and neck(too much up-down movements);three points:vertical motor disorders of head and neck plus circling behavior;four points:head sideway accompanying with too much up-down movements of head and neck.4.Detecting indexes:DAD3R, DAT and DA content in mice brain tissue.5.Pathological section of tissue:1)Cerebrums of ICR mice in blank control group and model group. 2)Method:10% formalin fix tissues, imbed with paraffin,6 micrometer slices,HE dyeing,light microscope inspection.Results 1.The effects of BP897 on stereotyped behavior of TS mice.Score stereotyped behavior after 7 days and 28 days dosage,the result is as follows:Middle and high dose of BP897 can suppress the stereotyped behavior,but the latter gains lower score(P<0.05),which is quite close to the haloperidol group(P>0.05).Low dose of BP897 can not obviously suppress the stereotyped behavior,the score of which group is close to the model group(P>0.05).2.The effects of BP897 on DAD3R content in mice brain tissue.After 28 days dosage,use enzyme linked immunosorbent assay to detect DAD3R content in mice brain tissue,the result is as follows:Brain tissue DAD3R content in high dose of BP897 is more than that of model group(P<0.05),but lower than haloperidol group (P<0.05), whose brain tissue DAD3R content is close to blank control group (P>0.05),brain tissue DAD3R content in model group is much lower than blank control group,but is close to low and middle dose of group.3.The effects of BP897 on DAT content in mice brain tissue.After 28 days dosage,use enzyme linked immunosorbent assay to detect DAT content in mice brain tissue,the result is as follows:Brain tissue DAT content in high dose of BP897 is more than that of model group(P<0.05),but lower than haloperidol group(P<0.05),whose brain tissue DAT content is close to blank control group (P>0.05),brain tissue DAT content in model group is much lower than blank control group,but is close to low and middle dose of group.4.The effects of BP897 on DA content in mice brain tissue.After 28 days dosage,use enzyme linked immunosorbent assay to detect DA content in mice brain tissue,the result is as follows:Brain tissue DA content in high dose of BP897 is more than that of model group(P<0.05),but lower than haloperidol group(P<0.05),whose brain tissue DA content is close to blank control group (P>0.05),brain tissue DA content in model group is much lower than blank control group,but is close to low and middle dose of group.Conclusions This study suggests that 1.0-3.Omg/kg dose of BP897 can treat TS effectively,and 3.0mg/kg dose of BP897 can much better control the stereotyped behavior,which can reach the same curative effect with haloperidol,0.3mg/kg dose of BP897 can not make obvious effect.The reason for this phenomenon may be that low dose of BP897 can only activate dopamine D3 receptors, middle dose of BP897 can antagonize a few dopamine D2 receptors in the basis of activating dopamine D3 receptors,and high dose of BP897 can antagonize a lot of dopamine D2 receptors in the basis of activating dopamine D3 receptors.But the exact curative mechanism needs further research.