甘氨酸转运体1抑制剂M22对癫痫小鼠认知障碍的改善作用研究
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摘要
目的研究甘氨酸转运体1(GlyT 1)抑制剂M22对戊四氮(PTZ)诱导的癫痫小鼠认知功能障碍的改善作用。方法按照体质量随机将筛选的50只C57BL/6小鼠分为3组:空白对照组(Control,n=10),模型组(Model,n=20),M22组(M22,n=20)。空白对照组腹腔注射等量的生理盐水,模型组和M22组小鼠腹腔注射PTZ (30 mg/kg)制备慢性点燃癫痫模型,连续腹腔注射PTZ 2周时间,并同时通过灌胃给予M22组小鼠40 mg/(kg·d)的M22。2周后采用Morris水迷宫实验对其学习记忆功能进行评价,然后将小鼠处死,对其海马进行HE染色,并测定小鼠大脑皮层的凋亡相关蛋白,对其神经元细胞的凋亡情况进行评价。结果Morris水迷宫实验结果显示癫痫发作导致了小鼠认知功能障碍,而M22对其认知障碍具有改善作用;HE染色结果显示模型组小鼠神经元明显发生凋亡,而M22具有保护作用。凋亡相关蛋白测定显示M22对于癫痫导致的神经元凋亡具有显著的保护作用。结论甘氨酸转运体1抑制剂M22能够显著提高癫痫小鼠的学习、记忆能力,抑制神经元细胞凋亡,为癫痫或者难治性癫痫患者提供新的选择。
Objective To study the effects of glycine transporter 1( GlyT1) inhibitor M22 on cognitive impairment in epileptic mice induced by amyl four nitrogen. Methods According to the weight,50 C57 BL/6 mice were randomly divided into three groups: blank control group( Control,n = 10),model group( Model,n = 20),M22 group( M22,n = 20). Chronic ignited epilepsy model were prepared by intraperitoneal injection of PTZ(30 mg/kg) in model group and M22 mice,while the control group was injected saline,continuous intraperitoneal injection of four nitrogen for 2 weeks and at the same time by intragastric administration of M22 mice 40 mg/( kg·d) M22.After two weeks,the learning and memory function was evaluated by Morris water maze test. Then the mice were sacrificed and their hippocampus were stained with HE stainning,and the apoptosis related proteins in the cerebral cortex of mice were measured,and the apoptosis of neurons was evaluated. Results The results of Morris water maze test showed that epileptic seizures induced cognitive impairment in mice,while M22 could improve their cognitive impairment. HE staining showed that neurons in the model group were obviously apoptosis,while M22 exerted protective effect. Apoptosis related protein assay showed that M22 had a significant protective effect on the neuronal apoptosis induced by epilepsy. Conclusion Glycine transporter 1 inhibitor M22 can significantly improve the learning and memory ability of epileptic mice,inhibit neuronal apoptosis,and provide new options for patients with epilepsy or intractable epilepsy.
Objective To study the effects of glycine transporter 1( GlyT1) inhibitor M22 on cognitive impairment in epileptic mice induced by amyl four nitrogen. Methods According to the weight,50 C57 BL/6 mice were randomly divided into three groups: blank control group( Control,n = 10),model group( Model,n = 20),M22 group( M22,n = 20). Chronic ignited epilepsy model were prepared by intraperitoneal injection of PTZ(30 mg/kg) in model group and M22 mice,while the control group was injected saline,continuous intraperitoneal injection of four nitrogen for 2 weeks and at the same time by intragastric administration of M22 mice 40 mg/( kg·d) M22.After two weeks,the learning and memory function was evaluated by Morris water maze test. Then the mice were sacrificed and their hippocampus were stained with HE stainning,and the apoptosis related proteins in the cerebral cortex of mice were measured,and the apoptosis of neurons was evaluated. Results The results of Morris water maze test showed that epileptic seizures induced cognitive impairment in mice,while M22 could improve their cognitive impairment. HE staining showed that neurons in the model group were obviously apoptosis,while M22 exerted protective effect. Apoptosis related protein assay showed that M22 had a significant protective effect on the neuronal apoptosis induced by epilepsy. Conclusion Glycine transporter 1 inhibitor M22 can significantly improve the learning and memory ability of epileptic mice,inhibit neuronal apoptosis,and provide new options for patients with epilepsy or intractable epilepsy.
引文
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[8] Liu D S,Pan X D,Zhang J,et al. APOE4 enhances age-dependent decline in cognitive function by down-regulating an NMDA receptor pathway in EFAD-Tg mice[J]. Mol Neurodegener,2015,10:7.
[9] Xu M H,Wang X T. NMDA-type glutamate receptor and cognitive disorder in epilepsy[J]. Med Recapitulate,2007,37(4):52-7.
[10] Chaki S,Shimazaki T,Karasawa J,et al. Efficacy of a glycine transporter 1 inhibitor TASP0315003 in animal models of cognitive dysfunction and negative symptoms of schizophrenia[J]. Psychopharmacology,2015,232(15):2849-61.
[11] Shen H Y,Vliet E V,Bright K A,et al. Glycine transporter 1 is a target for the treatment of epilepsy[J]. Neuropharmacology,2015,99:554-65.
[12] Barry J M,Tian C,Spinella A,et al. Spatial cognition following early-life seizures in rats:performance deficits are dependent on task demands[J]. Epilepsy Behav,2016,60:1-6.
[13] Aliparasti M R,Alipour M R,Almasi S,et al. Ghrelin administration increases the Bax/Bcl-2 gene expression ratio in the heart of chronic hypoxic rats[J]. Adv Pharm Bull,2015,5(2):195-9.
[14] Bercum F M,Rodgers K M,Benison A M,et al. Maternal stress combined with terbutaline leads to comorbid autistic-like behavior and epilepsy in a rat model[J]. J Neurosci,2015,35(48):15894-902.
[14] Paradiso B,Zucchini S,Su T,et al. Localized overexpression of FGF-2 and BDNF in hippocampus reduces mossy fiber sprouting and spontaneous seizures up to 4 weeks after pilocarpine-induced status epilepticus[J]. Epilepsia,2011,52(3):572-8.
[2] Fares R P,Belmeguenai A,Sanchez P E,et al. Standardized environmental enrichment supports enhanced brain plasticity in healthy rats and prevents cognitive impairment in epileptic rats[J]. PLo S One,2013,8(1):e53888.
[3] Xiao Y W,Wang R,Ma X T,et al. Cognitive impairment and spontaneous epilepsy in rats with malformations of cortical development[J]. Seizure,2015,33:29-34.
[4] Zhen J L,Chang Y N,Qu Z Z,et al. Luteolin rescues pentylenetetrazole-induced cognitive impairment in epileptic rats by reducing oxidative stress and activating PKA/CREB/BDNF signaling[J]. Epilepsy Behavior,2016,57(Pt A):177-84.
[5] Zhao J,Tao H,Xian W,et al. A highly selective inhibitor of glycine transporter-1 elevates the threshold for maximal electroshockinduced tonic seizure in mice[J]. Biol Pharm Bull,2016,39(2):174.
[6] Alabri M,Alasmi A,Alshukairi A,et al. Frequency of obstructive sleep apnea syndrome among patients with epilepsy attending a tertiary neurology clinic[J]. Oman Med J,2015,30(1):31-5.
[7] Peng W,Hong S,Min Z,et al. Effect of sodium valproate on cognitive function and hippocampus of rats after convulsive status epilepticus[J]. Med Sci Monit,2016,22:5197-205.
[8] Liu D S,Pan X D,Zhang J,et al. APOE4 enhances age-dependent decline in cognitive function by down-regulating an NMDA receptor pathway in EFAD-Tg mice[J]. Mol Neurodegener,2015,10:7.
[9] Xu M H,Wang X T. NMDA-type glutamate receptor and cognitive disorder in epilepsy[J]. Med Recapitulate,2007,37(4):52-7.
[10] Chaki S,Shimazaki T,Karasawa J,et al. Efficacy of a glycine transporter 1 inhibitor TASP0315003 in animal models of cognitive dysfunction and negative symptoms of schizophrenia[J]. Psychopharmacology,2015,232(15):2849-61.
[11] Shen H Y,Vliet E V,Bright K A,et al. Glycine transporter 1 is a target for the treatment of epilepsy[J]. Neuropharmacology,2015,99:554-65.
[12] Barry J M,Tian C,Spinella A,et al. Spatial cognition following early-life seizures in rats:performance deficits are dependent on task demands[J]. Epilepsy Behav,2016,60:1-6.
[13] Aliparasti M R,Alipour M R,Almasi S,et al. Ghrelin administration increases the Bax/Bcl-2 gene expression ratio in the heart of chronic hypoxic rats[J]. Adv Pharm Bull,2015,5(2):195-9.
[14] Bercum F M,Rodgers K M,Benison A M,et al. Maternal stress combined with terbutaline leads to comorbid autistic-like behavior and epilepsy in a rat model[J]. J Neurosci,2015,35(48):15894-902.
[14] Paradiso B,Zucchini S,Su T,et al. Localized overexpression of FGF-2 and BDNF in hippocampus reduces mossy fiber sprouting and spontaneous seizures up to 4 weeks after pilocarpine-induced status epilepticus[J]. Epilepsia,2011,52(3):572-8.