Preliminary preclinical study on antischizophrenia efficacy of zicronapine in vitro and in vivo
10.3760/cma.j.cn113661-20220605-00144
- VernacularTitle:齐洛那平临床前体外及体内抗精神分裂症药效的初步研究
- Author:
Yaqin WEI
1
;
Xiangqing XU
;
Yinli QIU
;
Minquan YU
Author Information
1. 徐州医科大学药学院，徐州221004
- Publication Type:Journal Article
- Keywords:
Schizophrenia;
Antipsychotic agents;
Zicronapine;
Dopamine receptor
- From:
Chinese Journal of Psychiatry
2022;55(6):451-458
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate the efficacy of zicronapine on different animal models of schizophrenia and its affinity for dopamine D1 and D2 receptors in vitro.Methods:A total of 324 male SPF ICR mice, 72 male SPF Wistar rats, and 10 male and female each SPF SD rats were included in the study. (1) One hundred ICR mice were divided into 10 groups: Blank group (solvent+normal saline, Veh+NS), model group (Veh+APO 1 mg/kg), risperidone (0.03, 0.10, 0.30, 1.00 mg/kg, gavage)+APO group, and zicronapine (0.3, 1.0, 3.0, 10.0 mg/kg, gavage)+APO group; The effect of zicronapine on the climbing behavior of mice was observed. (2) Eighty-four ICR mice were divided into 10 groups: Blank group (Veh+NS), model group (Veh+MK-801 0.3 mg/kg), risperidone (0.01, 0.03, 0.10, 0.30 mg/kg, gavage)+MK-801 group, and zicronapine (0.3, 1.0, 3.0, 10.0 mg/kg, gavage)+MK-801 group; 8-10 rats were allocated in each group to observe the effect of zicronapine on MK-801-induced hyperactivity behavior in mice. (3) Seventy mice were divided into 7 groups: Blank group (Veh), risperidone 0.3, 1.0 and 3.0 mg/kg groups (gavage), and zicronapine15, 27 and 45 mg/kg groups (gavage), with 10 mice in each group. The maintaining immobilized time of rats was observed at 30 min, 60 min and 90 min after administration. (4) A total of 72 Wistar rats were selected for CAR training, and the successfully trained rats were divided into 7 groups: blank group, zicronapine20, 40 and 60 mg/kg groups, risperidone 0.2, 0.4 and 0.8 mg/kg groups, with 5 to 6 rats in each group. The effects of zicronapine on avoidance response times of rats were investigated. (5)Seventy ICR mice were divided into blank group (Veh+NS), model group (Veh+PCP) and risperidone 0.05 mg/kg+PCP group. The effects of zicronapine (0.5, 1.0, 2.0 mg/kg)+PCP groups on novel object recognition disorder in mice were investigated. (6) The affinity of zicronapine to D 1, D 2, 5-HT 2A, 5-HT 6 and 5-HT 2C was investigated by radiolig and receptor binding assay. One-way analysis of variance was used for measurement data, and non-parametric U test was used for count data. Results:(1) Compared with the model group, 3.0 and 10.0 mg/kg of zicronapine significantly inhibited APO-induced climbing behavior in mice ( Z=-3.43, -4.07; P<0.01), and its ED 50 was 4.31 mg/kg. Risperidone at doses of 0.10, 0.30 and 1.00 mg/kg significantly inhibited the climbing behavior of mice ( Z=-1.83, -2.48, -4.26; P<0.05 or P<0.01) and the ED 50 was 0.19 mg/kg. (2) Compared to the model group, zicronapine 3.0 and 10.0 mg/kg significantly inhibited MK-801-induced hyperactivity behavior in mice ( t=-7.18, 3.90; P<0.01), and the ED 50 was 2.63 mg/kg. Risperidone 0.01, 0.03, 0.10 and 0.30 mg/kg significantly inhibited hyperactivity behavior in mice ( t=-3.02, 4.98, -6.08, 7.10; all P<0.01), and the ED 50 was 0.011 mg/kg. (3) The ED 50 of zicronapine and risperidone were 35.36 mg/kg and 1.25 mg/kg, respectively. (4) Both zicronapine and risperidone could inhibit the number of avoidance responses in a dose-dependent manner. Zicronapine dose at 40 and 60 mg/kg significantly inhibited the number of conditioned avoidance responses in rats ( t=11.84, 13.07; P<0.01), and the ED 50 was 34.36 mg/kg. Risperidone of 0.8 mg/kg could significantly inhibit the number of conditioned avoidance responses in rats ( t=13.50, P<0.01), and the ED 50 was 0.60 mg/kg. (5) Compared to the model group, zicronapine 0.5 and 1.0 mg/kg could significantly improve the discrimination index of PCP-induced new object recognition disorder model mice ( t=-3.67, -2.12; P<0.05 and P<0.01) to improve cognitive ability. However, risperidone 0.05 mg/kg had no significant effect on the discrimination index of PCP-induced new object recognition disorder model mice. (6) Zilonapine had high affinity for D 1 (K i=3.21 nmol/L) and 5-HT 2A (K i=13.11 nmol/L) receptors, but weak affinity for D 2 (K i=563.20 nmol/L) receptors. In addition, chilonapine also had high affinity for 5-HT 6 (K i=21.49 nmol/L) and 5-HT 2C (K i=48.90 nmol/L). Risperidone had high affinity for 5-HT 2A , 5-HT 2C and D 2 receptors with K i of 2.37, 18.79 and 4.82 nmol/L, respectively. Risperidone had weak affinity for D 1 and 5-HT6 receptors. Conclusions:Zicronapine has good efficacy in multiple animal models with positive symptoms of schizophrenia and can improve the cognition of mice. Its in vivo efficacy may be related to dopamine D 1 and D 2 receptors and 5-HT 2A and 5-HT 6 receptors.
