Alberto Lazarowski
Universidad de Buenos Aires – Buenos Aires, Argentina.
Departamento de Bioquímica Clínica.
LECTURE: Role of P-Glycoprotein in Pharmacoresistant Epilepsy and SUDEP.
Brain overexpression of P-glycoprotein (P-gp) is considered one of the most relevant factors related with refractory epilepsy (RE), the epileptic condition with higher risk of SUDEP. Neurons and cardiomyocytes, normally do not express P-gp, however, those cells can express it by a wide spectrum of damage signals including stress, inflammation, hypoxia or glutamate-dependent neuronal excitotoxicity (convulsive stress).
Dr. Alberto Lazarowski will show that because P-gp activity can modify the resting membrane potential producing depolarization with values from −70 to −10 mV, P-gp can also alter the normal physiological function of neurons and/or cardiomyocytes. Under repetitive severe seizures, as classically observed in RE, an increased neuronal P-gp expression could reduce the convulsive threshold, facilitating the recurrence of new and more severe seizures or Status Epilepticus.
Similarly, quite severe convulsive stress will induce a hypoxic-ischemic heart, with a HIF-1a-dependent P-gp ovexpression in cardiomyocytes, with a concomitant depolarization, evidenced by low heart retention of 99mTc-SESTAMIBI, malignant bradycardia,which ends in fatal acute heart deficiency.
All these mechanisms, could explain the potential role of P-gp overexpression in the development of SUDEP in RE.