Kumar Sandeep, Goel Rajesh K
Department of Pharmaceutical Sciences & Drug Research Punjabi University Patiala Punjab India.
Animal Model Exp Med. 2020 Aug 3;3(3):245-255. doi: 10.1002/ame2.12131. eCollection 2020 Sep.
Pentylenetetrazole kindling has long been used for the screening of investigational antiseizure drugs. The presence of lamotrigine, at a very low dose, does not hamper kindling in mice; rather it modifies this epileptogenesis process into drug-resistant epilepsy. The lamotrigine-pentylenetetrazole kindled mice show resistance to lamotrigine, phenytoin, and carbamazepine. It may also be possible that other licensed antiseizure drugs, like the mentioned drugs, remain ineffective in this model; therefore, this was the subject of this study.
Swiss albino mice were kindled with pentylenetetrazole for 35 days in the presence of either methylcellulose vehicle or lamotrigine (subtherapeutic dose, ie, 5 mg/kg). Vehicle vs lamotrigine-kindled mice were compared in terms of (a) resistance/response toward nine antiseizure drugs applied as monotherapies and two drug combinations; (b) lamotrigine bioavailability in blood and brain; (c) blood-brain barrier integrity; and (d) amino acids and monoamines in the cerebral cortex and hippocampus.
Lamotrigine vs vehicle-kindled mice are similar (or not significantly different > .05 from each other) in terms of (a) response toward drug combinations; (b) lamotrigine bioavailability; and (c) blood-brain barrier integrity except for, significantly ( < .05) reduced taurine and increased glutamate in the cerebral cortex and hippocampus. Aside from these, lamotrigine-kindled mice show significant ( < .05) resistant to lamotrigine (15 mg/kg), levetiracetam (40 mg/kg); carbamazepine (40 mg/kg), zonisamide (100 mg/kg), gabapentin (224 mg/kg), pregabalin (30 mg/kg), phenytoin (35 mg/kg), and topiramate (300 mg/kg).
Lamotrigine-pentylenetetrazole kindling takes longer to develop (5 weeks) in comparison to lamotrigine-amygdale (4 weeks) and lamotrigine-corneal (~2 weeks) kindling models. However, drug screening through this model may yield superior drugs with novel antiseizure mechanisms.
戊四氮点燃模型长期以来一直用于筛选抗癫痫研究药物。低剂量拉莫三嗪的存在并不妨碍小鼠的点燃；相反，它会将这种癫痫发生过程转变为耐药性癫痫。拉莫三嗪 - 戊四氮点燃的小鼠对拉莫三嗪、苯妥英和卡马西平表现出耐药性。其他已获许可的抗癫痫药物，如上述药物，在该模型中可能也无效；因此，这是本研究的主题。
将瑞士白化小鼠在甲基纤维素载体或拉莫三嗪（亚治疗剂量，即5mg/kg）存在的情况下用戊四氮点燃35天。比较载体组和拉莫三嗪点燃组小鼠在以下方面的情况：（a）对作为单一疗法应用的9种抗癫痫药物和两种药物组合的耐药性/反应；（b）血液和脑中拉莫三嗪的生物利用度；（c）血脑屏障完整性；以及（d）大脑皮层和海马中的氨基酸和单胺。
拉莫三嗪组和载体点燃组小鼠在以下方面相似（或彼此之间差异不显著，P>.05）：（a）对药物组合的反应；（b）拉莫三嗪的生物利用度；以及（c）血脑屏障完整性，除了大脑皮层和海马中牛磺酸显著减少（P<.05）和谷氨酸增加。除此之外，拉莫三嗪点燃组小鼠对拉莫三嗪（15mg/kg）、左乙拉西坦（40mg/kg）、卡马西平（40mg/kg）、唑尼沙胺（100mg/kg）、加巴喷丁（224mg/kg）、普瑞巴林（30mg/kg）、苯妥英（35mg/kg）和托吡酯（300mg/kg）表现出显著的（P<.05）耐药性。
与拉莫三嗪 - 杏仁核点燃模型（约4周）和拉莫三嗪 - 角膜点燃模型（约2周）相比，拉莫三嗪 - 戊四氮点燃模型的建立需要更长时间（约5周）。然而，通过该模型进行药物筛选可能会产生具有新型抗癫痫机制的优质药物。
