Open AccessReversal of P‐glycoprotein overexpression by Ginkgo biloba extract in the brains of pentylenetetrazole‐kindled and phenytoin‐treated mice
Author(s) -
Zhang Ce,
Fan Qing,
Chen ShuLiang,
Ma Hui
Publication year - 2015
Publication title -
the kaohsiung journal of medical sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.439
H-Index - 36
eISSN - 2410-8650
pISSN - 1607-551X
DOI - 10.1016/j.kjms.2015.05.007
Subject(s) - ginkgo biloba , medicine , phenytoin , pharmacology , glycoprotein , epilepsy , traditional medicine , microbiology and biotechnology , psychiatry , biology
The purpose of this study was to investigate the combined effects of Ginkgo biloba extract and phenytoin (PHT) sodium as a dose regimen simulating the clinical treatment of patients with epilepsy, on P‐glycoprotein (P‐GP) overexpression in a pentylenetetrazole‐kindled mouse model of epilepsy. Epilepsy was induced by intraperitoneal administration of pentylenetetrazole (40 mg/kg) for 7 days followed by intragastric administration of PHT (40 mg/kg) for 14 days. Thirty mice that developed seizures were randomly divided into three groups and administered PHT as well as the following treatments: saline (negative control); verapamil (20 mg/kg, positive control); and G. biloba (30 mg/kg). Seizure severity was recorded 30 minutes after treatment on Day 4 of drug administration, after which the mice were euthanized, and their brains isolated. Western blots and immunohistochemistry were performed to analyze the expression of P‐GP and caspase‐3, respectively, in the brain tissue. High‐performance liquid chromatography was used to measure the concentrations of PHT in the brains of the treated mice. After 4 consecutive days of treatment, the seizure severity in the mice in the G. biloba extract group was more significantly reduced than the seizure severity in the saline control group, and a significant difference was observed between the G. biloba extract and verapamil control groups ( p < 0.05). P‐GP expression in the brain more significantly decreased in the mice treated with G. biloba extract and verapamil than it did in the saline‐treated control group ( p < 0.05). Compared with the saline‐treated control group, the mice treated with G. biloba extract and verapamil showed significantly increased brain PHT concentrations ( p < 0.05). Furthermore, caspase‐3 expression in the brain tissue of the G. biloba extract group was significantly lower than that in the vehicle control group ( p < 0.05); this finding demonstrated the neuroprotective effects of G. biloba . Therefore, this study showed that treatment with G. biloba extract in combination with PHT prevented the upregulation of P‐GP expression in mice. Moreover, G. biloba extract decreased seizure severity in pentylenetetrazole‐kindled/PHT‐treated mice through a mechanism that might be related to the reduction of P‐GP expression in the brain.