Research Progress on the Role of ABC Transporters in the Drug Resistance Mechanism of Intractable Epilepsy

Abstract

The pathogenesis of intractable epilepsy is not fully clear. In recent years, both animal and clinical trials have shown that the expression of ATP-binding cassette (ABC) transporters is increased in patients with intractable epilepsy; additionally, epileptic seizures can lead to an increase in the number of sites that express ABC transporters. These findings suggest that ABC transporters play an important role in the drug resistance mechanism of epilepsy. ABC transporters can perform the funcions of a drug efflux pump, which can reduce the effective drug concentration at epilepsy lesions by reducing the permeability of the blood brain barrier to antiepileptic drugs, thus causing resistance to antiepileptic drugs. Given the important role of ABC transporters in refractory epilepsy drug resistance, antiepileptic drugs that are not substrates of ABC transporters were used to obtain ABC transporter inhibitors with strong specificity, high safety, and few side effects, making them suitable for long-term use; therefore, these drugs can be used for future clinical treatment of intractable epilepsy.

Figure 1

mdr1 mRNA levels in the hippocampus and entorhinal cortex of rats with spontaneous seizures. Data are the means ± SE (n = 5-6) of the optical density values of gel bands representing the PCR amplification products of mdr1 mRNA normalized to the corresponding β-actin band used in each sample as an internal standard. Values in spontaneously epileptic rats (SE) are expressed as a percentage of the control levels (sham-stimulated rats (Sham)). HP, stimulated hippocampus (1.8-fold increase); EC, contralateral entorhinal cortex (5.5-fold increase). ^∗∗ P < 0.01 versus sham according to a Mann-Whitney test.

Figure 2

Extracellular concentrations of glutamate increase during epileptic seizures. Glutamate signaling can occur via endothelial NMDA receptors to activate an intracellular cascade that upregulates P-glycoprotein [60]. Ca²⁺ influx via the NMDA receptor is known to activate phospholipase A2, which can release arachidonic acid from the cell membrane. Therefore, Ca²⁺ might represent the link that drives the activation of arachidonic acid signaling. The inflammatory enzyme cyclooxygenase-2 was clearly demonstrated to be a key downstream effector that processes arachidonic acid [60, 61]. Prostaglandin E2, as the main end product of cyclooxygenase-2, was shown to act via the endothelial EP1 receptor [62]. The events downstream of EP1 receptors must still be identified; these events then drive the transcriptional activation of the P-glycoprotein-encoding gene.