Brain uptake of diazepam and phenytoin in a genetic animal model of absence epilepsy.
Brain uptake of diazepam and phenytoin in a genetic animal model of absence epilepsy.
复制标题
失神性癫痫遗传动物模型中地西泮和苯妥英的大脑摄取。
DOI：
10.1111/j.1440-1681.2010.05362.x
复制
发表时间：
2010
影响因子：
2.9
通讯作者：
Petrou,Steven
中科院分区：
文献类型：
--
作者：
Nicolazzo,JosephA;Steuten,JessicaA;Charman,SusanA;Taylor,Nerida;Davies,PhilipJ;Petrou,Steven
1. 尽管许多研究评估了化学和电诱导癫痫模型中抗癫痫药物 (AED) 的大脑摄取变化，但关于自发性癫痫动物模型（例如遗传性失神癫痫）中 AED 的大脑摄取变化的数据有限。2。在本研究中，在携带人 GABAA 受体 γ2 亚基基因 GABRG2 突变（R43Q）的失神癫痫遗传小鼠模型中评估了地西泮和苯妥英的大脑摄取，并将结果与皮下注射戊四唑（PTZ；90mg/kg）诱导的急性癫痫发作期间获得的结果进行了比较。地西泮和苯妥英分别以 2 和 30 mg/kg 的剂量腹腔注射，给药后 60 分钟使用液相色谱-质谱法测定脑和血浆浓度。 3．尽管 PTZ 给药后大脑对苯妥英的摄取显着减少，但在遗传性失神癫痫模型中苯妥英的分布没有观察到变化。同样，PTZ给药后大脑对地西泮的摄取显着增强，但在失神性癫痫中则不受影响。4．与用PTZ处理的盐水处理的小鼠相比以及与突变型R43Q小鼠相比，用盐水处理的小鼠的脑血管血浆容量（通过施用不可吸收标记物[14C]-菊粉来评估）没有显着差异。5。这些结果表明，尽管 AED 的大脑摄取可能在急性癫痫模型中发生改变，但在非惊厥性遗传失神癫痫模型中可能不会观察到类似的大脑摄取变化。
1. Although many studies have assessed changes to brain uptake of anti‐epileptic drugs (AEDs) in chemically and electrically induced seizure models, there are limited data available on changes to brain uptake of AEDs in spontaneous seizure animal models, such as genetic absence epilepsy.2. In the present study, the brain uptake of diazepam and phenytoin was assessed in a genetic mouse model of absence seizures harbouring a human GABAAreceptor γ2‐subunit geneGABRG2mutation (R43Q) and results were compared with those obtained during acute seizures induced by subcutaneous administration of pentylenetetrazole (PTZ; 90 mg/kg). Diazepam and phenytoin were administered intraperitoneally at doses of 2 and 30 mg/kg, respectively, and brain and plasma concentrations were determined 60 min after administration using liquid chromatography–mass spectrometry.3. Although the brain uptake of phenytoin was significantly reduced following PTZ administration, no changes were observed in phenytoin disposition in the genetic absence epilepsy model. Similarly, the brain uptake of diazepam was significantly enhanced following PTZ administration, but it was not affected in absence epilepsy.4. The cerebrovascular plasma volume (assessed by administration of the non‐absorbable marker [14C]‐inulin) was not significantly different in saline‐treated compared with PTZ‐treated mice and in wild‐type compared with mutant R43Q mice.5. These results demonstrate that although the brain uptake of AEDs may be altered in acute seizure models, similar changes to brain uptake may not be observed in the non‐convulsive genetic absence epileptic model.