Neuronal MDR-1 Gene Expression and Persistent Low Levels of Anticonvulsants in a Child with Refractory Epilepsy

Abstract

It is estimated that 20-25% of epileptic patients fail to achieve good control with antiepileptic drug (AED) treatment; thus, refractory epilepsy (RE) has been described in patients who have adequate therapeutic levels of AEDs without control of seizures. Multidrug resistance genes have been reported to be highly expressed in brain of patients with RE. Persistent low plasma levels of AEDs and high brain expression of the multidrug resistance product P-glycoprotein (P-gp) have been previously communicated in a case report of RE secondary to tuberous sclerosis. Here, the authors report a case of an 8-year-old boy diagnosed with partial RE with focal seizures who was admitted to hospital for a severe episode of subintrant crisis. The patient received polytherapy with carbamazepine (CBZ), phenytoin (PHT), and valproic acid (VA); however, habitual doses of these AEDs failed to control the patient's symptoms. AED blood levels were monitored for 25 consecutive days and showed low values in 8/25 (33%) for CBZ, 10/25 (40%) for PHT, and 25/25 (100%) for VA of samples studied. Because the patient developed focal status epilepticus, surgical treatment by callosotomy was done, resulting in a significant improvement in epileptic symptoms. The immunostaining of brain specimens showed significantly increased expression of P-gp not only in vascular endothelial cells and related astrocytes but also in neurons. Overexpression of P-gp in the brain does not explain the low blood levels of AEDs described in these cases. Different mechanisms such as drug-drug interactions and drug transporters can be involved in the results observed. The P-gp overexpression and/or its pharmacologic induction should be considered as a potential mechanism responsible for drug resistance to epilepsy treatment and highly suspected in patients with persistent subtherapeutic AEDs plasma levels.

Neuronal mdr-1 gene expression after experimental focal hypoxia: A new obstacle for neuroprotection?

“…The brain protective role for the expression of P-gp and others drugs transporters in the BBB has been recently revised [36], and the over-expression of P-gp in the BBB has already been implicated in pharmacoresistance in epilepsy [37][38][39]. Moreover, as we also documented the neuronal expression of P-gp in brain specimens from both human and experimental refractory epilepsy [14,15], we suggest that the refractory phenotype commonly observed in stroke, additionally to BBB function, could be also related with the hypoxia-induced P-gp expression on neurons. The results showed here, are in agreement with our previously documented neuronal P-gp expression in experimental brain ischemia [13].…”

“…P-gp is a member of the ATP-binding cassette protein superfamily, characterized by the presence of one or two highly conserved domains that bind and hydrolyze ATP to produce an energydependent membrane efflux that transports a wide variety of structurally unrelated drugs, xenobiotics or potential dangerous endogenous compounds. The multidrug resistance phenotype is generally considered to be associated with the induction of the mdr-1 gene and P-gp expression [15]. The brain protective role for the expression of P-gp and others drugs transporters in the BBB has been recently revised [36], and the over-expression of P-gp in the BBB has already been implicated in pharmacoresistance in epilepsy [37][38][39].…”

“…In normal brain, P-glycoprotein is expressed in the endothelial cells of the BBB [12] supporting the concept of a protective role for MDR-1-type proteins in the removal of potentially toxic xeno-and endobiotics. We have previously demonstrated that, secondary to seizures or ischemic stress in rats, brain expression of P-gp is upregulated from normally non-expressive cells as astrocytes and neurons [13][14][15].…”

The complexity of roles of P-glycoprotein in refractory epilepsy: Pharmacoresistance, epileptogenesis, SUDEP and relapsing marker after surgical treatment

“…administration, 2 h are enough to reach steady state concentrations within the therapeutic range [32]. As previously described in two cases reports [23,33], patients can have persistent low plasmatic levels of at least one of the AEDs administered, despite their scrupulous compliance with the prescribed drugs regimen. Often, laboratory professionals and physicians have no rational explanations, and non-detectable errors in AED measurement procedures and methods are assumed.…”

“…This P-gp induced expression depends on the frequency and intensity of seizures and is related to a progressive increase of the pharmacoresistant phenotype [45]. Furthermore, the induced "de novo" expression of P-gp in previously non-expressive cells as observed particularly in neurons from epileptogenic brain areas, suggests a differential role of this transporter, perhaps related to the intrinsic convulsive mechanism [29,33,46].…”