| Schizophrenia is a severe brain disorder, which can generally be divided into positive symptoms(delusions, hallucinations and auditory hallucinations) and negative symptoms(social withdrawal function, etc.), as well as cognitive impairment including the deficits of attention, executive ability and short-term memory based on the clinical symptoms. The current clinical antipsychotic drugs can antagonize dopamine D2 receptors. The classical antipsychotic drug haloperidol is effective on positive symptoms, while ineffective on the negative symptoms and cognitive impairment even exacerbation. Negative symptoms and cognitive impairments of schizophrenia are too difficult to treat, even if some patients taking long-term medication. Therefore, improving patients with negative symptoms and cognitive impairment is the core problem of the treatment of schizophrenia. In order to develop a new kind of effective medicine for negative symptoms and cognitive impairments of schizophrenia, our study is designed as follow: Objective:The current study aims to evaluate the effects of compound l-Scoulerine(l-SLR) on positive symptoms, negative symptoms and cognitive impairment of schizophrenia. Competitive antagonism of radioactive ligand is applied to explore its mechanism, and a new type of antipsychotic drugs, which is effective on positive symptoms, negative symptoms and cognitive impairment of schizophrenia with little extrapyramidal side effects, can be developed according to this mechanism. Methods:Using spontaneous locomotor activity to determine whether compound l-SLR has a sedative effect and the duration. A variety of clinical symptoms of schizophrenia can be caused by NMDA receptor antagonist MK-801. Using prepulse inhibition and climbing test, the pharmacodynamics of compound l-SLR on positive symptoms of schizophrenia is evaluated. In prepulse inhibition experiment, the model is established based on prepulse inhibition deficit in rats which is caused by injecting MK-801(0.3 mg / kg, i.p.). After the injection of compound l-SLR(5,10,15 mg / kg), the rats are observed to determine whether the prepulse inhibition deficits can be reversed, and then the effects of l-SLR are compared with of typical antipsychotic haloperidol(0.2 mg / kg). In climbing test, modeling is on the basis of the mice’s climbing behaviors which are resulted from the injection of apomorphine(2 mg / kg, s.c.), and the changes of mice’s climbing time and climbing behaviors’ inhibition after the injection of l-SLR(10, 30 mg / kg) are observed and then are compared with the effects of typical antipsychotic haloperidol. Social withdrawal test is conducted in mice to evaluate the effects of compound l-SLR on negative symptoms of schizophrenia. In this experiment, social withdrawal modeling in two strange mice intraperitoneally injected by MK-801(0.2 mg / kg, i.p.) is established to determine whether the injection of l-SLR can increase the interaction time between strange mice and compare the effect of compound l-SLR and typical antipsychotic haloperidol on the negative symptoms of schizophrenia. In the cognitive impairment of schizophrenia, Y-maze test is used in mice to evaluate the antipsychotic effects of compound l-SLR. The model is established in accordance with the decreased spatial resolution capability, i.e., the appearance of cognitive impairment of schizophrenia, resulted from injecting MK-801(0.2 mg / kg, i.p.) to observe whether the injection of l-SLR can improve spatial cognitive ability in mice and compare the effects of compound l-SLR and typical antipsychotic drug haloperidol. The extrapyramidal side effects are evaluated by comparing compound l-SLR with typical antipsychotic drug haloperidol, l-SPD and the analogues of l-SLR. The catalepsy times in 45 or 90 min after the injection of haloperidol(0.8 mg / kg), l-SLR(10, 30, 60 and 80 mg / kg) and l-SPD(30, 60, 80 mg / kg) are recorded and extrapyramidal side effects of different compounds are compared. In the mechanism study, PET is used to measure the affinity of compound l-SLR with dopamine receptor. Results:In locomotor activity experiment, the activity of mice was reduced in the first 30 minutes after the injection of l-SLR, but after a period of time the activity of mice was resumed, indicating that the compound l-SLR has a sedative effect and the duration of this effect is 30 minutes. So in experimental design it is necessary to avoid pharmacodynamic studies during this time. In prepulse inhibition experiment, compared with the VEH group(F5, 44 = 6.696, P < 0.0001), MK-801(0.3 mg / kg) can significantly reduce the prepulse inhibition in rats, and the prepulse inhibition injury caused by MK-801(P < 0.01) can significantly be improved by injecting l-SLR(10 mg of / kg, 15 mg / kg) and haloperidol(0.2 mg / kg), indicating that both the compound l-SLR and haloperidol have effects on prepulse inhibition injury induced by MK-801. In the climbing test, the hypodermic injection of apomorphine(2 mg / kg) can significantly increase the climbing time in mice compared with the VEH group(F4, 45 = 19.13, P < 0.0001) while haloperidol(0.2 mg / kg) and l-SLR(30mg / kg) significantly inhibit the climbing behavior induced by apomorphine, indicating that compounds l-SLR and haloperidol are effective on apomorphine-induced climbing behavior in mice. In the social interaction test in mice, compared with VEH group, MK-801 can significantly inhibit the social contact behavior and lower the social contact time of the mice(F3, 36 = 7.566, P = 0.0084), and typical antipsychotic drug haloperidol cannot make the social contact time of the mice extended. Correspondingly, the compound l-SLR at the dose of 30 mg / kg can significantly increase social contact time of mice(F5,54 = 6.285, P = 0.0001), showing that compound l-SLR at such dose is effective to the negative symptoms of schizophrenia whereas haloperidol is invalid. In the Y-maze test of cognitive impairment of schizophrenia, compared with VEH group, MK-801 can significantly inhibit the spatial cognitive ability of mice(F3,36 = 10.60, P < 0.0001), and the injection of haloperidol cannot improve the spatial cognitive impairment in mice; whereas the compound l-SLR at the dose of 30 mg / kg can significantly improve the spatial cognitive impairment in mice(F5,54 = 11.58, P < 0.0001), suggesting that compound l-SLR at the dose of 30 mg / kg can improve cognitive impairment in schizophrenia. In terms of extrapyramidal side effects, compared with VEH group, the catalepsy time in mice is significantly increased in 45 minutes after the administration of haloperidol(0.8 mg / kg) and l-SPD(60 mg / kg, 80 mg / kg)(F8,64 = 13.63, P < 0.001) and the catalepsy behavior still exists in 90 minutes after the administration of haloperidol and l-SPD(30 mg / kg, 60 mg / kg, 80 mg / kg)(F8,64 = 14.54, P < 0.001), whereas compound l-SLR at the dose of 30 mg / kg, 60 mg / kg does not cause catalepsy, pointing out that compound l-SLR at an effective dose of anti-schizophrenia does not produce extrapyramidal side effects. In the study of the mechanism of compound l-SLR, 18F-Fallypride rapidly spreads into the various parts of the mouse brain after the injection, and in the mice which are injecting l-SLR quickly after 18F-Fallypride, the distribution of 18F-Fallypride in various parts of the brain in 15 minutes after the drug administration are significantly lower than the FP group(P < 0.05), indicating that the compound l-SLR can be combined with the D2 and D3 receptors in the brain, thereby antagonizing the combination of 18F-Fallypride with the D2 and D3 receptor. Conclusion:From the spontaneous activity test it is concluded that the compound l-SLR has a sedative effect, and this effect disappeared 30 minutes after the injection, So this period should be avoided in the pharmacodynamical study of the compound. From the test of prepulse inhibition and climbing test, we can see that the compound l-SLR is able to resist the positive symptoms of schizophrenia. In the experiment of social withdrawal, the injection of l-SLR can increase the contact time between the strange mice and improve the negative symptoms of schizophrenia. In the Y-maze test, compound l-SLR is much more superior to haloperidol. From the aspect of extrapyramidal adverse reactions, the compound l-SLR cannot cause catalepsy at an effective dose, indicating that compared with haloperidol and l-SPD, compound l-SLR causes less extrapyramidal side effects in mice at the effective dose on the positive and negative symptoms as well as cognitive impairment and has evident advantages. In receptor binding studies, the reduced radioactivity of each brain region caused by antagonistic 18F-Fallypride suggests that the compound l-SLR can be combined with dopamine D3 and D2 receptors. |
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