New model of pharmacoresistant seizures induced by 3-mercaptopropionic acid in mice

Enrique, Andrea; Goicoechea, Sofía; Castaño, Rocío; Taborda, Facundo D.; Rocha, Luisa; Orozco, Sandra; Girardi, Elena; Blanch, Luis Bruno

doi:10.1016/j.eplepsyres.2016.10.012

Cited by 19 publications

(12 citation statements)

References 53 publications

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“…Resistance was strongly associated with overexpression of P-gp in the cerebral cortex, hippocampus, and striatum. Importantly, resistance to drugs that are not P-gp substrates such as carbamazepine, diazepam, or levetiracetam was not observed (136). Therefore, this new model could be useful for screening novel ASDs that are P-gp substrates and have the potential to control seizures in pharmacoresistant epilepsy.…”

Section: Potential Mechanisms Of Asd Resistancementioning

confidence: 99%

Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers

2017

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Epilepsy is a common neurological disorder that affects over 70 million people worldwide. Despite the recent introduction of new antiseizure drugs (ASDs), about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Early identification of patients who will become refractory to ASDs could help direct such patients to appropriate non-pharmacological treatment, but the complexity in the temporal patterns of epilepsy could make such identification difficult. The target hypothesis and transporter hypothesis are the most cited theories trying to explain refractory epilepsy, but neither theory alone fully explains the neurobiological basis of pharmacoresistance. This review summarizes evidence for and against several major theories, including the pharmacokinetic hypothesis, neural network hypothesis, intrinsic severity hypothesis, gene variant hypothesis, target hypothesis, and transporter hypothesis. The discussion is mainly focused on the transporter hypothesis, where clinical and experimental data are discussed on multidrug transporter overexpression, substrate profiles of ASDs, mechanism of transporter upregulation, polymorphisms of transporters, and the use of transporter inhibitors. Finally, future perspectives are presented for the improvement of current hypotheses and the development of treatment strategies as guided by the current understanding of refractory epilepsy.

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Section: Potential Mechanisms Of Asd Resistancementioning

confidence: 99%

Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers

2017

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“…Several conditions were described as risk factors for SUDEP, among which we can mention the high frequency of generalized seizures without control, mainly in patients aged between 20 and 40 years, or non-compliance with the specific medications that leads to a lack of seizure control. Interestingly, these situations can be observed in patients with RE receiving polytherapy where one of the pharmacoresistant mechanisms is likely related to high P-glycoprotein (P-gp) brain expression [ 6 , 7 , 8 ]. In this regard, higher risk factors of SUDEP, such as the high frequency of generalized tonic-clonic seizures (GTCS) and nocturnal seizures or a long history (more than 15 years) of seizures, have been observed mainly in patients with a pharmacoresistant phenotype.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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“…According to the WHO, the number of affected individuals is around 50 million worldwide and its impacts bring neurological, cognitive, psychological, and social damage and sequelae. It is estimated that approximately 30% of these individuals are resistant to antiepileptic drugs (AEDs), which is called refractory epilepsy (ER) 2 .…”

Section: Introductionmentioning

confidence: 99%

“…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%

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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New model of pharmacoresistant seizures induced by 3-mercaptopropionic acid in mice

Cited by 19 publications

References 53 publications

Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers

Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers

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

Hemosiderin, a possible biomarker for sudep?

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