Limbic Seizures Induce P-Glycoprotein in Rodent Brain: Functional Implications for Pharmacoresistance

Abstract

The causes and mechanisms underlying multidrug resistance (MDR) in epilepsy are still elusive and may depend on inadequate drug concentration in crucial brain areas. We studied whether limbic seizures or anticonvulsant drug treatments in rodents enhance the brain expression of the MDR gene (mdr) encoding a permeability glycoprotein (P-gp) involved in MDR to various cancer chemotherapeutic agents. We also investigated whether changes in P-gp levels affect anticonvulsant drug concentrations in the brain. Mdr mRNA measured by RT-PCR increased by 85% on average in the mouse hippocampus 3-24 hr after kainic acid-induced limbic seizures, returning to control levels by 72 hr. Treatment with therapeutic doses of phenytoin or carbamazepine for 7 d did not change mdr mRNA expression in the mouse hippocampus 1-72 hr after the last drug administration. Six hours after seizures, the brain/plasma ratio of phenytoin was reduced by 30% and its extracellular concentration estimated by microdialysis was increased by twofold compared with control mice. Knock-out mice (mdr1a/b -/-) lacking P-gp protein showed a 46% increase in phenytoin concentrations in the hippocampus 1 and 4 hr after injection compared with wild-type mice. A significant 23% increase was found in the cerebellum at 1 hr and in the cortex at 4 hr. Carbamazepine concentrations were measurable in the hippocampus at 3 hr in mdr1a/b -/- mice, whereas they were undetectable at the same time interval in wild-type mice. In rats having spontaneous seizures 3 months after electrically induced status epilepticus, mdr1 mRNA levels were enhanced by 1.8-fold and fivefold on average in the hippocampus and entorhinal cortex, respectively. Thus, changes in P-gp mRNA levels occur in limbic areas after both acute and chronic epileptic activity. P-gp alterations significantly affect antiepileptic drugs concentrations in the brain, suggesting that seizure-induced mdr mRNA expression contributes to MDR in epilepsy.

Widespread Upregulation of Drug‐resistance Proteins in Fatal Human Status Epilepticus

“…In mice, increased expression of ABCB1 mRNA was noted as early as 3 h after Ն90 min of recurrent seizures, and when tested at 6 h, increased ABCB1 levels were associated with significantly lower hippocampal PHT levels (9). In rats, increased ABCB1 levels in hippocampal astrocytes were noted by 24 h after kainate injection (15).…”

“…Thus members of the ABC superfamily ABCB1 (also known as MDR1 P-glycoprotein) and ABCC1 (also known as multidrug resistanceassociated protein 1) are upregulated in glia and neurons in resected and postmortem human brain tissue containing pathologies causing refractory epilepsy (1)(2)(3)(4)(5)(6). In animal studies, both ABCB1 and ABCC1 have been shown to transport a variety of AEDs, including phenytoin (PHT) (1,(7)(8)(9), phenobarbitone (PB) (10), carbamazepine (CBZ) (8,9), lamotrigine (LTG), topiramate (TPM), and felbamate (FBM) (8,11). Other AEDs are likely to be ABCB1 substrates, as most AEDs share a planar lipophilic chemical structure.…”

“…Recently Rizzi et al (9) showed that in rodent limbic epilepsy, seizures induce expression of ABCB1-encoding mRNA in hippocampus, and that such increased expression is associated with reduced hippocampal PHT levels. They also showed that repetitive treatment for 7 days with CBZ or PHT did not induce ABCB1 mRNA overexpression.…”

Evaluation of Carbamazepine Pharmacokinetic Profiles in Mice with Kainic Acid-Induced Acute Seizures

“…13) After intraloop administration, the brain CBZ and its active metabolite CBZ-epo concentrations in KA-treated mice were significantly retarded as compared to the control mice, and no significant decrease was found in plasma CBZ and CBZ-epo in the portal vein (Fig. 1).…”

“…1,13) However, there has been no clear answer to explain the mechanism in the relationship between invagination of epileptic fit and CBZ efficacy. On the other hand, P-gp, which locates on the inside cells of capillary vessel of blood-brain barrier (BBB), regulates the transfer of drug from blood circulation to the central nerve system to avoid neurotoxicity.…”