PMID- 29462915 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200930 IS - 1424-8247 (Print) IS - 1424-8247 (Electronic) IS - 1424-8247 (Linking) VI - 11 IP - 1 DP - 2018 Feb 16 TI - Pilocarpine-Induced Status Epilepticus Is Associated with P-Glycoprotein Induction in Cardiomyocytes, Electrocardiographic Changes, and Sudden Death. LID - 10.3390/ph11010021 [doi] LID - 21 AB - 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)-1alpha 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-1alpha, 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-1alpha 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. FAU - Auzmendi, Jeronimo AU - Auzmendi J AD - Laboratorio de Neuropatologia Molecular, Instituto de Biologia Celular y Neurociencia "Profesor E. De Robertis" IBCN UBA-CONICET, Buenos Aires CP1121, Argentina. jeronimo.auzmendi@gmail.com. FAU - Buchholz, Bruno AU - Buchholz B AD - Departamento de Patologia, Instituto de Fisiopatologia Cardiovascular (INFICA), Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires C1121ABG, Argentina. brunobuchholz@yahoo.com.ar. FAU - Salguero, Jimena AU - Salguero J AD - Departamento de Fisicomatematica, Laboratorio de Radioisotopos, Catedra de Fisica, Universidad de Buenos Aires, Facultad de Farmacia y Bioquimica, Junin 956, Buenos Aires C1113AAD, Argentina. jsalguei@yahoo.com. FAU - Canellas, Carlos AU - Canellas C AD - Laboratorio Tecnonuclear SA, Arias 4176, Buenos Aires C1430CRP, Argentina. ivanhoe_rowena@hotmail.com. FAU - Kelly, Jazmin AU - Kelly J AD - Departamento de Patologia, Instituto de Fisiopatologia Cardiovascular (INFICA), Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires C1121ABG, Argentina. jazminkelly@hotmail.com. FAU - Men, Paula AU - Men P AD - Departamento de Bioquimica Clinica, Instituto de Investigaciones en Fisiopatologia y Bioquimica Clinica (INFIBIOC), Universidad de Buenos Aires, Facultad de Farmacia y Bioquimica, Junin 956, Buenos Aires C1113AAD, Argentina. men.paula@hotmail.com. FAU - Zubillaga, Marcela AU - Zubillaga M AD - Departamento de Fisicomatematica, Laboratorio de Radioisotopos, Catedra de Fisica, Universidad de Buenos Aires, Facultad de Farmacia y Bioquimica, Junin 956, Buenos Aires C1113AAD, Argentina. marcelazubillaga@yahoo.com. FAU - Rossi, Alicia AU - Rossi A AD - Laboratorio de Neuropatologia Molecular, Instituto de Biologia Celular y Neurociencia "Profesor E. De Robertis" IBCN UBA-CONICET, Buenos Aires CP1121, Argentina. jramos@fmed.uba.ar. FAU - Merelli, Amalia AU - Merelli A AD - Departamento de Bioquimica Clinica, Instituto de Investigaciones en Fisiopatologia y Bioquimica Clinica (INFIBIOC), Universidad de Buenos Aires, Facultad de Farmacia y Bioquimica, Junin 956, Buenos Aires C1113AAD, Argentina. amerelli2002@yahoo.com.ar. FAU - Gelpi, Ricardo J AU - Gelpi RJ AD - Departamento de Patologia, Instituto de Fisiopatologia Cardiovascular (INFICA), Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires C1121ABG, Argentina. rjgelpi@gmail.com. FAU - Ramos, Alberto J AU - Ramos AJ AD - Laboratorio de Neuropatologia Molecular, Instituto de Biologia Celular y Neurociencia "Profesor E. De Robertis" IBCN UBA-CONICET, Buenos Aires CP1121, Argentina. canellas@tecnonuclear.com. FAU - Lazarowski, Alberto AU - Lazarowski A AD - Departamento de Bioquimica Clinica, Instituto de Investigaciones en Fisiopatologia y Bioquimica Clinica (INFIBIOC), Universidad de Buenos Aires, Facultad de Farmacia y Bioquimica, Junin 956, Buenos Aires C1113AAD, Argentina. nadiatom@ffyb.uba.ar. LA - eng PT - Journal Article DEP - 20180216 PL - Switzerland TA - Pharmaceuticals (Basel) JT - Pharmaceuticals (Basel, Switzerland) JID - 101238453 PMC - PMC5874717 OTO - NOTNLM OT - HIF-1alpha OT - P-glycoprotein OT - QT prolongation OT - SUDEP OT - Status Epilepticus OT - cardiomyocytes OT - hypoxia COIS- The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results. EDAT- 2018/02/22 06:00 MHDA- 2018/02/22 06:01 PMCR- 2018/03/01 CRDT- 2018/02/22 06:00 PHST- 2018/01/21 00:00 [received] PHST- 2018/02/07 00:00 [revised] PHST- 2018/02/13 00:00 [accepted] PHST- 2018/02/22 06:00 [entrez] PHST- 2018/02/22 06:00 [pubmed] PHST- 2018/02/22 06:01 [medline] PHST- 2018/03/01 00:00 [pmc-release] AID - ph11010021 [pii] AID - pharmaceuticals-11-00021 [pii] AID - 10.3390/ph11010021 [doi] PST - epublish SO - Pharmaceuticals (Basel). 2018 Feb 16;11(1):21. doi: 10.3390/ph11010021.