| Tourette Syndrome is a chronic,neuropsychiatric disorders of unknown etiology that afflicts approximately 0.05-3 percent of the population. Recented surveys show that the incidence of Tourette syndrome has increased, so more and more people pay attention to this disorder . Symptoms of Tourette syndrome can be divided into sport disorder (such as blinking,stretching out tongue,shaking his head, shrug, etc.), vocal disorder (such as cough, hum, clearing voice sound, offensive language, etc.) and often accompanied by behavior problems ( Forced behavior, learning difficulties, sleep disorders, self-injurious behaviors, etc.) and cognitive dysfunction (memory deficit, attention deficit, sensation and perception defects, etc.). Many studies indicated that the central nervous system dysfunction may be related with Tourette syndrome, and researchers put forward many hypotheses, the most important hypothesis is the dopamine system dysfunction. The best treatment of Tourette syndrome should be physical - mental - social medical model. Today it is't breakthrough in the treatment of Tourette syndrome. The treatment of principle is still psychological behavioral treatment and drugs . Drugs used in the hospital is mostly dopamine receptor blockers, such as haloperidol, Tiapride, etc. Effective rate of haloperidol was 70-80 percent of patients, but it has no use in behavior disorders and often results in serious extrapyramidal side effect(EPS). (such as acute dystonia, akathisia, Parkinson's disease-like tremors), lethargy, fatigue, etc. About 20 to 30 percent of the patients have to stop using it because of its side effects. Side effects of Tiapride isn't obvious, but its curative effect isn't as good as haloperidol.Recent researches shows that movement is activated by a dopamine D3 receptor , it can control the animal instinct of movement. Dopamine D3 receptor is the highest affinity receptor , mainly localed in the mesolimbic area which has nothing to do with motor function.The dopamine D3 receptor is more concentrated than other receptors, if drugs work through these receptors in the treatment of Tourette syndrome , they may have less side effects. In this study,we used Tourette syndrome model mice to test the toxicological effects of a dopamine D3 receptor agonist BP897 which has 68 times affinity to D3 receptor rather than D2 receptors and very poor affinity to D1, D4 receptor,and find new drugs for Tourette syndrome with least side effects. Objective: To study the effects of dopamine D3 receptor agonist BP897 on liver, kidney, brain, intestine and stomach,blood and extrapyramidal of Tourette syndrome mice,we can get a guide for clinical. Methods 1 Grouping: Dividing 72 male ICR mice into 6 groups: normal control group, model group, BP897 high dose group (BP897 3mg/kg), middle dose group (BP897 1mg/kg), low dose group (BP897 0.3mg/kg), haloperidol (0.5mg/kg)group randomly and averagely. 2 Establishing animal models: Mice model of Tourette syndrome was established by crotoxin systemic administration method which was set up by Diamond BI. After the animal models are built, we start to grade stereotyped behavior of mice in double blind way. 3 Route and method: Administering different doses of BP897, haloperidol and saline , once a day for 28 days. Then ,we give normal food to the 6 mice in the high dose group(recovery group) for 14 days to observe their changes in convalescence, and dissect other mice.4 Detecting indexes: mice general conditions, weekly food intake, weekly weight, urine , tonic stupor time, hematology, organ index, pathology of heart,liver, kidney, brain, intestine and stomach. Results: 1 Establishing model : After injected iminodipropionitrile for 7 days, mice Tourette syndrome models were successfully built. 2 The effect of BP897 on mice weight: compared with the model group, weight of mice in different doses of BP897 groups were significantly increased, Among all groups, weight of middle and high dose groups is the most significant growth, it suggested that BP897 had no effect on weight of mice. 3 The effect of BP897 on mice food intake: After administrated with BP897 for 28 days, compared with high dose of BP897 group ,mice intake in middle dose of BP897 group, low dose of BP897 group and model group has increased significantly, especially in middle dose group. it suggested that high dose (3mg/kg) of BP897 may be affect the digestive system of mice. 4 The effect of BP897 on the urine biochemical: After administrated with BP897 for 28 days, indexes of urine Cr, Urea, AST, ALT in BP897 high ,middle and low dose groups were close to the model group . And there was no significant difference among different doses of BP897 groups.It suggested that BP897 may be no effect on liver and kidney function. 5 The effect of BP897 on the indexes of blood: After administrated with BP897 for 28 days, the indexes of blood in BP897 high, middle and low dose group were close to the model group. And there was no significant difference among different doses of BP897 groups.It suggested that BP897 may be no effect on blood. 6 The effect of BP897 on the organ indexes (organ indexes equal to body weight divide by weight organ): weighed the liver, kidney, brain, heart of mice, the organ indexes of high, middle and low dose groups were close to the model group. And there was no significant difference among different doses of BP897 groups. It suggested that BP897 may be no effect on vital organs. 7 The effect of BP897 on the extrapyramidal system of Tourette syndrome model mice: Compared with the haloperidol (0.5mg/kg) group, the catalepsy time of high, middle and low dose BP897 groups were significantly shorter. And there was no significant difference among different doses of BP897 groups. It suggested that BP897 may be have small effect on extrapyramidal system than haloperidol. 8 Pathological section of liver, kidney, brain, intestine and stomach: After administrated with BP897 for 28 days, killed the mice, dyed these organs with HE fluid, and observed them with light microscope. There was no significant difference in rate of pathological lesions in the liver, kidney,brain, intestine between BP897 groups and model group. Among different doses of BP897 groups, the rate of pathologic lesions in the liver, kidney, brain, intestinal mucosa was close. Gastric mucosa of some mice in the high dose group was mild edema. Compared with the low, middle dose group and model group, the rate of pathologic lesions in high dose BP897 group was statistically difference. There were no pathological lesions in the gastric mucosa of recovery group mice. It suggested that high doses of BP897 may be mild irritate toward the gastric mucosa, but the damage is reversible. Conclusion: BP897 has less side effects on the liver, kidney, brain, blood and extrapyramidal system. Safe dose range is wide (0.1mg-3.0mg/kg). Although high doses had slight affect on gastric mucosa , but it is reversible. So BP897 is a new better D3 receptor agonist, and has a good prospect of in the treatment with Tourette syndrome. |
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