The role of P-glycoprotein (P-gp) and inwardly rectifying potassium (Kir) channels in sudden unexpected death in epilepsy (SUDEP)

Auzmendi, Jerónimo; Akyüz, Enes; Lazarowski, Alberto

doi:10.1016/j.yebeh.2019.106590

Cited by 22 publications

(22 citation statements)

References 94 publications

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“…The notion that seizure activity represents a condition that induces brain hypoxia (a discrepancy between an adequate supply of oxygen through blood vessels cells and consumption) and ischemia is well established [285,286]. Experimental evidence demonstrates that both processes enhance glutamate release [221,287,288] and facilitate neuronal cell death [289,290], membrane depolarization [291,292], subsequent epileptic seizures and overexpression of the MDR-1 gene that encodes the multidrug efflux transporter P-glycoprotein (condition associated with drug-resistance) [293,294]. In addition, this augmented expression of P-glycoprotein can also facilitate cell membrane depolarization as a consequence of increased amounts of intracellular free radicals and Ca 2+ [295,296].…”

Section: Erythropoietin and Epilepsymentioning

confidence: 99%

Insights into Potential Targets for Therapeutic Intervention in Epilepsy

Zavala-Tecuapetla

Cuéllar-Herrera

Luna-Munguía

2020

IJMS

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Epilepsy is a chronic brain disease that affects approximately 65 million people worldwide. However, despite the continuous development of antiepileptic drugs, over 30% patients with epilepsy progress to drug-resistant epilepsy. For this reason, it is a high priority objective in preclinical research to find novel therapeutic targets and to develop effective drugs that prevent or reverse the molecular mechanisms underlying epilepsy progression. Among these potential therapeutic targets, we highlight currently available information involving signaling pathways (Wnt/β-catenin, Mammalian Target of Rapamycin (mTOR) signaling and zinc signaling), enzymes (carbonic anhydrase), proteins (erythropoietin, copine 6 and complement system), channels (Transient Receptor Potential Vanilloid Type 1 (TRPV1) channel) and receptors (galanin and melatonin receptors). All of them have demonstrated a certain degree of efficacy not only in controlling seizures but also in displaying neuroprotective activity and in modifying the progression of epilepsy. Although some research with these specific targets has been done in relation with epilepsy, they have not been fully explored as potential therapeutic targets that could help address the unsolved issue of drug-resistant epilepsy and develop new antiseizure therapies for the treatment of epilepsy.

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Section: Erythropoietin and Epilepsymentioning

confidence: 99%

Insights into Potential Targets for Therapeutic Intervention in Epilepsy

Zavala-Tecuapetla

Cuéllar-Herrera

Luna-Munguía

2020

IJMS

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“…An impairment of the autonomic nervous system in the regulation of CV functions during seizures has been recently reported by our previous study performed in a PTZ-kindled rat model, showing aberrant blood pressure and electrocardiographic (ECG) recordings [16]. We suggested that this data may be related to an altered expression of inwardly rectifying potassium (Kir) channels in the heart [17]. In this regard, Kir channels play a key role in cardiac excitability and they have been proposed to explain autonomic CV dysfunctions, observed also in multiple sclerosis [18].…”

Section: Discussionmentioning

confidence: 79%

Investigating Cardiac Morphological Alterations in a Pentylenetetrazol-Kindling Model of Epilepsy

et al. 2020

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Epilepsy is a group of neurological disorders characterized by abnormal electrical activity in the central nervous system (CNS) and recurrent seizures representing the principal clinical manifestation. Sudden unexpected death in epilepsy (SUDEP) is the predominant cause of death in young epileptic patients. SUDEP patients displayed an increased cardiovascular (CV) risk, probably due to an impaired autonomic control of CV functions, but the underlying mechanisms need to be explored yet. Therefore, we aimed to examine the cardiac morphological alterations in a pentylenetetrazol (PTZ)-kindled rat model, a well-established tool for studying chronic epilepsy. To complete this, the distance between the atria, between the atrium and ventricle were measured, the heart was weighed, and the pathological morphology of dissected hearts was analyzed by histological assessment with hematoxylin and eosin staining. A significantly decreased distance between atria and a significant increase in heart weight were observed in PTZ-kindled rats which interestingly also displayed increased hemorrhagic content when compared with controls. Our findings provided evidence that changes in cardiac morphology may be related to autonomic CV dysfunctions occurring during SUDEP while also opening up more avenues to better develop novel drugs for the treatment of this disorder.

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“…Several other clinical aspects have been observed, including frequent changes in dosage and persistently low plasma levels of AEDs, in addition to low medication adherence. Such factors are commonly identified as primary risk factors not only for SUDEP, but also seen in patients with ER 2,5 .…”

Section: Introductionmentioning

confidence: 99%

“…The risk of SUDEP is known to increase with the severity and frequency of uncontrolled epileptic seizures, which is also common in patients with ER, so the risk is greater in this population. More than one mechanism appears to play a role in the development of SUDEP, but its specific mechanical cause has not yet been identified 5 .…”

Section: Introductionmentioning

confidence: 99%

“…Despite the close relationship between the severity of ER and the risk of SUDEP and the biomolecular information available that elucidate the diversity of mechanisms in ER, there are no adequate biomarkers to predict the risk of SUDEP to the point of avoiding the fatal outcome. For now, electrocardiograms, electroencephalograms and imaging studies are used as the only clinically relevant biomarkers available, however, they do not clarify the molecular cause that produces them and, therefore, it is not possible to use them for an effectively preventive approach 5 .…”

Section: Introductionmentioning

confidence: 99%

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Hemosiderin, a possible biomarker for sudep?

Pereira¹,

Brandão²,

Auzmend³

et al. 2021

Rev Neurocienc

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Epilepsy is one of the neurological diseases of complex etiology that affects around 50 million people worldwide and is characterized by abnormal electrical activity and recurrent seizures. Uncontrolled generalized repetitive tonic-clonic seizures (GTCS) are the main causes of unexpected sudden death in epilepsy (SUDEP). Hypoxic stress induced by seizure results in neurocardiogenic dysfunctions, including iron overload and cardiomyopathy (IOC) which is related to severe lipid peroxidation caused by the production of reactive oxygen species (ROS). ROS induces recurrent seizure activity, favoring the overexpression of P glycoprotein (P-gp) in the heart. P-gp plays a depolarizing role in cardiomyocyte membranes and potassium (Kir) channels control cellular excitability regarding the repolarization of the cardiac action potential. All these events result in a possible appearance of severe bradycardia and fatal arrhythmia. Several studies have sought evidence for different possible biomarkers for potential prediction of the risk of SUDEP avoiding its fatal outcome.

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The role of P-glycoprotein (P-gp) and inwardly rectifying potassium (Kir) channels in sudden unexpected death in epilepsy (SUDEP)

Cited by 22 publications

References 94 publications

Insights into Potential Targets for Therapeutic Intervention in Epilepsy

Insights into Potential Targets for Therapeutic Intervention in Epilepsy

Investigating Cardiac Morphological Alterations in a Pentylenetetrazol-Kindling Model of Epilepsy

Hemosiderin, a possible biomarker for sudep?

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