Pilocarpine-Induced Status Epilepticus Is Associated with P-Glycoprotein Induction in Cardiomyocytes, Electrocardiographic Changes, and Sudden Death

AUZMENDI J; CARLOS CAÑELLAS ; MARCELA ZUBILLAGA ; RICARDO J. GELPI; AUZMENDI J; BRUNO BUCHHOLZ ; CARLOS CAÑELLAS ; JAZMÍN KELLY; MARCELA ZUBILLAGA ; ALICIA ROSSI ; RICARDO J. GELPI; ALBERTO J. RAMOS; BRUNO BUCHHOLZ ; JIMENA SALGUERO ; JAZMÍN KELLY; PAULA MEN; ALICIA ROSSI ; AMALIA MERELLI ; ALBERTO J. RAMOS; ALBERTO LAZAROWSKI; JIMENA SALGUERO ; PAULA MEN; AMALIA MERELLI ; ALBERTO LAZAROWSKI

Pharmaceuticals

Molecular Diversity Preservation International, MDPI

Lugar: Basel; Año: 2018 vol. 11 p. 1 - 12

1424-8247

Sudden unexpected death in epilepsy (SUDEP) is the major cause of death in thosepatients suffering from refractory epilepsy (RE), with a 24-fold higher risk relative to the normal population. SUDEP risk increases with seizure frequency and/or seizure-duration as in RE and Status Epilepticus (SE). P-glycoprotein (P-gp), the product of the multidrug resistant ABCB1-MDR-1 gene, is a detoxifying pump that extrudes drugs out of the cells and can confer pharmacoresistanceto the expressing cells. Neurons and cardiomyocytes normally do not express P-gp, however, it is overexpressed in the brain of patients or in experimental models of RE and SE. P-gp was also detected after brain or cardiac hypoxia. We have previously demonstrated that repetitive pentylenetetrazole (PTZ)-induced seizures increase P-gp expression in the brain, which is associatedwith membrane depolarization in the hippocampus, and in the heart, which is associated with fatal SE. SE can produce hypoxic-ischemic altered cardiac rhythm (HIACR) and severe arrhythmias, and both are related with SUDEP. Here, we investigate whether SE induces the expression of hypoxiainducibletranscription factor (HIF)-1α and P-gp in cardiomyocytes, which is associated with altered heart rhythm, and if these changes are related with the spontaneous death rate. SE was induced in Wistar rats once a week for 3 weeks, by lithium-pilocarpine-paradigm. Electrocardiograms, HIF-1α, and P-gp expression in cardiomyocytes, were evaluated in basal conditions and 72 h after SE. Allspontaneous deaths occurred 48 h after each SE was registered. We observed that repeated SE induced HIF-1α and P-gp expression in cardiomyocytes, electrocardiographic (ECG) changes, and a high rate of spontaneous death. Our results suggest that the highly accumulated burden of convulsive stress results in a hypoxic heart insult, where P-gp expression may play a depolarizingrole in cardiomyocyte membranes and in the development of the ECG changes, such as QT interval prolongation, that could be related with SUDEP. We postulate that this mechanism could explain, in part, the higher SUDEP risk in patients with RE or SE.