Effect of glycine transporter 1 inhibitor on epileptic seizures and cognitive dysfunction in epilepsy mice / 中华行为医学与脑科学杂志

ABSTRACT

Objective To study the effect of glycine transporter 1 inhibitor M22 on epileptic sei-zures and cognitive dysfunction in epilepsy mice. Methods A total of 110 C57BL/6 mice were randomly divided into Normal control group (CON group,n=10),Model group (Mod group n=20),M22-1 group (n=20),M22-2 group (n=20),M22-3 group (n=20),M22-4 group ( n=20) according to weight. The chronic epileptic model was established by intraperitoneal injection of PTZ(30 mg/kg). The mice in CON group was injected with normal saline(10 mg/kg). The mice in Mod group were intraperitoneally injected with normal saline (10 ml/kg) and were injected with PT2 30 min later. The mice in M22-1 group,M22-2 group,M22-3 group,M22-4 group were intraperitoneally injected with M22 of corresponding dose(10 mg/kg,20 mg/kg,40 mg/kg,80 mg/kg)respectively,lasting for 2 weeks. Epilepsy seizures of mice in each group were recorded. The learning and memory function of epilepsy mice were evaluated by Morris water maze test . Then the mice were sacrificed and the apoptosis related proteins Bcl-2,Bax,Cyt-c in the cerebral cortex of mice were meas-ured by Western blot. Results (1)The mortality kindling rate,epileptic seizure grade and rate of tonic clo-nus in M22-2 and M22-3 group were significantly lower than those in Mod,M22-1 and M22-4 group( all P<0. 05). (2) In the directional navigation experiment,the escape latency of mice in each group decreased with time. On the 4th day,the escape latency of mice in M22-3 group was significantly shorter than that in Mod group,and the difference was statistically significant ((30. 24±9. 46),(16. 05±5. 72),t=20. 36,P<0. 05). In space exploration experiment,compared with Mod group,M22-3 group had more times of crossing platform ((6. 45±3. 62),(3. 23±2. 47),t=38. 63,P=0. 004) and longer time of target quadrant activity((21. 53± 6. 38) s,(11. 52±3. 15) s,t=37. 53,P<0. 05). (3)It was showed by Western blotting that the relative ex-pression levels of Bcl-2 in M22-3 group were significantly higher than those in Mod group(P<0. 05),while the Bax and Cyt-c in M22-3 group were significantly lower than those in Mod group(P<0. 05). There was no significant difference in Bcl-2, Bax and Cyt-c between M22-1 group, M22-4 group and model group ( P>0. 05). Conclusion M22 (40 mg/kg) has significant anti-epileptic effect and can effectively improve the cognitive dysfunction of epileptic mice,which may be related to the inhibition of neuronal apoptosis in mice.[Key words] Epilepsy; Glycine transporter 1 inhibitor; M22; Cognitive function; Pentyle-netetrazole