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Pharmaceuticals 2018, 11(1), 21; https://doi.org/10.3390/ph11010021

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

1
Laboratorio de Neuropatología Molecular, Instituto de Biología Celular y Neurociencia “Profesor E. De Robertis” IBCN UBA-CONICET, Buenos Aires CP1121, Argentina
2
Departamento de Patología, Instituto de Fisiopatología Cardiovascular (INFICA), Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires C1121ABG, Argentina
3
Departamento de Fisicomatemática, Laboratorio de Radioisótopos, Cátedra de Física, Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Junín 956, Buenos Aires C1113AAD, Argentina
4
Laboratorio Tecnonuclear SA, Arias 4176, Buenos Aires C1430CRP, Argentina
5
Departamento de Bioquímica Clínica, Instituto de Investigaciones en Fisiopatología y Bioquímica Clínica (INFIBIOC), Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Junín 956, Buenos Aires C1113AAD, Argentina
*
Author to whom correspondence should be addressed.
Received: 21 January 2018 / Revised: 7 February 2018 / Accepted: 13 February 2018 / Published: 16 February 2018
(This article belongs to the Special Issue Epilepsy and Neurodegeneration: Current Therapeutic Implications)
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Abstract

Sudden unexpected death in epilepsy (SUDEP) is the major cause of death in those patients 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 pharmacoresistance to 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 associated with 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 hypoxia-inducible transcription 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. All spontaneous 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 depolarizing role 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. View Full-Text
Keywords: Status Epilepticus; SUDEP; HIF-1α; hypoxia; P-glycoprotein; cardiomyocytes; QT prolongation Status Epilepticus; SUDEP; HIF-1α; hypoxia; P-glycoprotein; cardiomyocytes; QT prolongation
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Auzmendi, J.; Buchholz, B.; Salguero, J.; Cañellas, C.; Kelly, J.; Men, P.; Zubillaga, M.; Rossi, A.; Merelli, A.; Gelpi, R.J.; Ramos, A.J.; Lazarowski, A. Pilocarpine-Induced Status Epilepticus Is Associated with P-Glycoprotein Induction in Cardiomyocytes, Electrocardiographic Changes, and Sudden Death. Pharmaceuticals 2018, 11, 21.

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