Sudden unexpected death in epilepsy (
SUDEP) is the major cause of death that affects patients with
epilepsy. The risk of
SUDEP increases according to the frequency and severity of uncontrolled
seizures; therefore,
SUDEP risk is higher in patients with
refractory epilepsy (RE), in whom most
antiepileptic drugs (AEDs) are ineffective for both seizure control and
SUDEP prevention. Consequently, RE and
SUDEP share a multidrug resistance (MDR) phenotype, which is mainly associated with brain overexpression of
ABC-transporters such as
P-glycoprotein (P-gp). The activity of P-gp can also contribute to membrane depolarization and affect the normal function of neurons and cardiomyocytes. Other molecular regulators of membrane potential are the
inwardly rectifying potassium channels (Kir), whose genetic variants have been related to both
epilepsy and heart dysfunctions. Although it has been suggested that dysfunctions of the cardiac, respiratory, and brainstem arousal systems are the causes of
SUDEP, the molecular basis for explaining its dysfunctions remain unknown. In rats, repetitive
seizures or
status epilepticus induced high expression of P-gp and loss Kir expression in the brain and heart, and promoted membrane depolarization, malignant
bradycardia, and the high rate of mortality. Here we reviewed clinical and experimental evidences suggesting that abnormal expression of depolarizing/repolarizing factors as P-gp and Kir could favor persistent depolarization of membranes without any rapid functional recovery capacity. This condition induced by convulsive stress could be the molecular mechanism leading to acquired severe
bradycardia, as an ineffective heart response generating the appropriate scenario for
SUDEP development. This article is part of the Special Issue "NEWroscience 2018".