P-糖蛋白(P-gp)的过度表达有助于癫痫患者的耐药,位于血脑屏障的P-gp表达的变化疏远了P-gp底物的抗癫痫作用。因此,本研究探讨了芬戈莫德(FTY720)通过内皮素-鞘脂途径对P-gp诱导的戊四氮(PTZ)点燃的苯巴比妥(PB)抵抗大鼠的作用。
使用PTZ点燃(30mg/kg;i.p.)和PB(40mg/kg;口服)来建立难治性癫痫的动物模型。芬戈莫德对癫痫发作评分(拉辛量表)的影响,血浆和大脑中的PB水平(高效液相色谱法),并测定血脑屏障通透性(伊文思蓝染料)。Further,芬戈莫德的神经保护作用是通过测量各种炎症细胞因子的水平,氧化应激参数,和大鼠脑匀浆中的神经营养因子。通过逆转录-聚合酶链反应和免疫组织化学评估了芬戈莫德对大鼠脑P-gp表达的影响。进行H和E染色以确定神经元损伤。
芬戈莫以剂量依赖性方式显着降低癫痫发作评分(P<0.001),并减轻血脑屏障通透性。它降低了P-gp的表达,这进一步增加了大脑PB浓度。芬戈莫德显着(P<0.01)降低了氧化应激和炎症。此外,在抗性癫痫模型中,它减弱了神经元损伤评分的升高。
芬戈莫德对P-gp表达的调节改善了难治性癫痫动物模型中药物向大脑的递送。因此,S1P信号传导可以作为克服难治性的额外治疗靶标。
The overexpression of P-glycoprotein (P-gp) contributes to drug resistance in patients with epilepsy, and the change of P-gp expression located at the blood-brain barrier alienates the anti-seizure effects of P-gp substrates. Thus, the present
study explored the effect of fingolimod (FTY720) acting through an endothelin-sphingolipid pathway on P-gp-induced pentylenetetrazol (PTZ)-kindled phenobarbital (PB)-resistant rats.
PTZ kindling (30 mg/kg; i.p.) and PB (40 mg/kg; orally) were used to develop an animal model of refractory epilepsy. The effect of Fingolimod on seizure score (Racine scale), plasma and brain levels of PB (high-performance liquid chromatography), and blood-brain barrier permeability (Evans blue dye) was determined. Further, Fingolimod\'s neuroprotective effect was determined by measuring the levels of various inflammatory cytokines, oxidative stress parameters, and neurotrophic factors in rat brain homogenate. The Fingolimod\'s effect on P-gp expression was estimated by reverse transcriptase-polymerase chain reaction and immunohistochemistry in rat brain. The H and E staining was done to determine the neuronal injury.
Fingolimod significantly (P < 0.001) reduced the seizure score in a dose-dependent manner and alleviated the blood-brain barrier permeability. It decreased the P-gp expression, which further increased the brain PB concentration. Fingolimod significantly (P < 0.01) reduced oxidative stress as well as inflammation. Moreover, it attenuated the raised neuronal injury score in a resistant model of epilepsy.
The modulation of the P-gp expression by Fingolimod improved drug delivery to the brain in an animal model of refractory epilepsy. Therefore, S1P signaling could serve as an additional therapeutic target to overcome refractoriness.