Reversal of P‐glycoprotein overexpression by Ginkgo biloba extract in the brains of pentylenetetrazole‐kindled and phenytoin‐treated mice

Abstract

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.

Effects of aged garlic and ginkgo biloba extracts on the pharmacokinetics of sofosbuvir in rats

“…In the present study, repeated administration of verapamil, aged garlic, and ginkgo biloba extracts for 14 days showed a significant impact on P-gp expression, either upregulation (for aged garlic) or downregulation (for verapamil and ginkgo biloba). These findings are in line with previous studies that examined the intestinal P-gp expression following repeated dose administration of aged garlic extract (Hajda et al, 2010) and ginkgo biloba extract (Zhang et al, 2015).…”

Effect of gabapentin on fetal rat brain and its amelioration by ginger

“…(2015) who found that administration of different dosages of phenobarbital resulted in decreased number of Bcl-2 positive cells and increased number of cells positive for Bax in the brain of rats compared with those of the control group. Intragastric administration of phenytoin in epileptic mice resulted in increased expression of Caspase-3 in both the hippocampal and cortical region (Zhang et al., 2015).…”

A sensitive LC‐MS/MS method for quantification of phenytoin and its major metabolite with application to in vivo investigations of intravenous and intranasal phenytoin delivery

“…As stated earlier, the LLOQ for phenytoin and 4-HPPH in this study was 7.81 ng/mL for plasma and 23.4 ng/g for brain tissue showing that the assay has ample range to detect lower concentrations in future studies of other phenytoin intranasal delivery systems, if necessary. For comparison, the sensitivity of previously reported methods for phenytoin (and occasionally 4-HPPH) measurement in rat plasma or brain have been restricted to lower limits of quantification between 50 and 500 ng/mL, as these studies have generally dealt with typical systemic doses of phenytoin which produce high plasma and brain concentrations [5,9,[23][24][25]46].…”