scholarly journals Enhancement of central norepinephrinergic neurotransmission contributes to inhibition of seizure-induced respiratory arrest by targeting the beta-1 adrenergic receptor (β1-AR) locating in the cardiomyocytes in the DBA/1 mouse SUDEP model

2022 ◽  
Author(s):  
XiTing Lian ◽  
Qian Yu ◽  
HaiXiang Ma ◽  
LeYuan Gu ◽  
Qing Xu ◽  
...  
Keyword(s):  
Cardiac Arrhythmia ◽  
Adrenergic Receptor ◽  
Respiratory Arrest ◽  
Acoustic Stimulation ◽  
Sudden Unexpected Death ◽  
Ventricular Premature Beat ◽  
Unexpected Death ◽  
Norepinephrine Reuptake Inhibitor ◽  
Patients With Epilepsy ◽  
Electrocardiogram Ecg

Sudden unexpected death of epilepsy (SUDEP) is the key cause of of death in patients with epilepsy. Due to the complicated pathogenesis of SUDEP, however, the exact mechanism of SUDEP remains elusive. Currently, although it is recognized that the seizure-induced respiratory arrest (S-IRA) may be a main cause for SUDEP, other factors resulting in SUDEP can not be excluded e.g arrhythmias. Our previous findings indicated that the incidence of seizure-induced respiratory arrest S-IRA and SUDEP evoked by acoustic stimulation or pentetrazol (PTZ) injection was significantly reduced by atomoxetine, a norepinephrine reuptake inhibitor (NRI), suggesting that noradrenergic neurotransmission modulates S-IRA and SUDEP. Given that norepinephrine acts on the central and peripheral target to modulate respiratory and circulation function by targeting adrenergic receptor α and beta (a-AR and β-AR) and the arrhythmias can be contributed to SUDEP. Meanwhile, to further test whether cardiac factors are implicated in S-IRA and SUDEP, we choose esmolol hydrochloride, a selective antagonist of beta-1 adrenergic receptor (β1-AR) to test it in our models. Our findings demonstrated that the lower incidence of S-IRA and SUDEP evoked by acoustic stimulation or PTZ in DBA/1 mice by administration with atomoxetine was significantly reversed by intraperitoneal (IP) of esmolol hydrochloride. Importantly, the data of electrocardiogram (ECG) showed that the cardiac arrhythmia evoked by acoustic stimulation including the ventricular tachycardia, ventricular premature beat and atrioventricular block and administration of atomoxetine significantly reduced theses arrhythmias and the incidence of S-IRA and SUDEP in our models. Thus, the dysfunction of respiratory and circulation may be implicated in the pathogenesis of S-IRA and SUDEP hand in hand and enhancing central norepinephrinergic neurotransmission contributes to inhibition of seizure-induced respiratory arrest by targeting β1-AR locating in the cardiomyocytes. Our findings will show a new light on decoding the pathogenesis of SUDEP. Keywords: sudden unexpected death in epilepsy (SUDEP); seizure-induced respiratory arrest S-IRA); esmolol hydrochloride (Esmolol); Electrocardiogram (ECG); locus coeruleus (LC); cardiac arrhythmia; pentetrazol (PTZ)

scholarly journals Myocardial Iron Overload in an Experimental Model of Sudden Unexpected Death in Epilepsy

2021 ◽  
Vol 12 ◽  
Author(s):  
Enes Akyuz ◽  
Zuleyha Doganyigit ◽  
Ece Eroglu ◽  
Franco Moscovicz ◽  
Amalia Merelli ◽  
...  
Keyword(s):  
Iron Overload ◽  
Cardiac Arrhythmia ◽  
Refractory Epilepsy ◽  
Experimental Models ◽  
Sudden Unexpected Death ◽  
Iron Accumulation ◽  
Hypoxic Stress ◽  
Unexpected Death ◽  
Transfusion Therapy ◽  
Iron Overload Cardiomyopathy

Uncontrolled repetitive generalized tonic-clonic seizures (GTCS) are the main risk factor for sudden unexpected death in epilepsy (SUDEP). GTCS can be observed in models such as Pentylenetetrazole kindling (PTZ-K) or pilocarpine-induced Status Epilepticus (SE-P), which share similar alterations in cardiac function, with a high risk of SUDEP. Terminal cardiac arrhythmia in SUDEP can develop as a result of a high rate of hypoxic stress-induced by convulsions with excessive sympathetic overstimulation that triggers a neurocardiogenic injury, recently defined as “Epileptic Heart” and characterized by heart rhythm disturbances, such as bradycardia and lengthening of the QT interval. Recently, an iron overload-dependent form of non-apoptotic cell death called ferroptosis was described at the brain level in both the PTZ-K and SE-P experimental models. However, seizure-related cardiac ferroptosis has not yet been reported. Iron overload cardiomyopathy (IOC) results from the accumulation of iron in the myocardium, with high production of reactive oxygen species (ROS), lipid peroxidation, and accumulation of hemosiderin as the final biomarker related to cardiomyocyte ferroptosis. Iron overload cardiomyopathy is the leading cause of death in patients with iron overload secondary to chronic blood transfusion therapy; it is also described in hereditary hemochromatosis. GTCS, through repeated hypoxic stress, can increase ROS production in the heart and cause cardiomyocyte ferroptosis. We hypothesized that iron accumulation in the “Epileptic Heart” could be associated with a terminal cardiac arrhythmia described in the IOC and the development of state-potentially in the development of SUDEP. Using the aforementioned PTZ-K and SE-P experimental models, after SUDEP-related repetitive GTCS, we observed an increase in the cardiac expression of hypoxic inducible factor 1α, indicating hypoxic-ischemic damage, and both necrotic cells and hemorrhagic areas were related to the possible hemosiderin production in the PTZ-K model. Furthermore, we demonstrated for the first time an accumulation of hemosiderin in the heart in the SE-P model. These results suggest that uncontrolled recurrent seizures, as described in refractory epilepsy, can give rise to high hypoxic stress in the heart, thus inducing hemosiderin accumulation as in IOC, and can act as an underlying hidden mechanism contributing to the development of a terminal cardiac arrhythmia in SUDEP. Because iron accumulation in tissues can be detected by non-invasive imaging methods, cardiac iron overload in refractory epilepsy patients could be treated with chelation therapy to reduce the risk of SUDEP.

scholarly journals Activation of central 5-HT2A receptor in brain inhibited the seizure-induced respiratory arrest in the DBA/1 mouse SUDEP model

2020 ◽  
Author(s):  
Yue Shen ◽  
HaiXiang Ma ◽  
XiTing Lian ◽  
LeYuan Gu ◽  
Qian Yu ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Drug Resistance ◽  
Nervous System ◽  
Underlying Mechanism ◽  
Respiratory Arrest ◽  
Acoustic Stimulation ◽  
Unexpected Death ◽  
Anti Epileptic Drug ◽  
The Brain

AbstractSudden unexpected death in epilepsy (SUDEP) is the fatal cause leading to the death of epilepsy patients with anti-epileptic drug resistance. However, the underlying mechanism of SUDEP remains to be elusive. Our previous study demonstrated that enhancement of serotonin (5-HT) synthesis by intraperitoneal (IP) injection of 5-hydroxytryptophan in brain significantly reduced the incidence of seizure-induced respiratory arrest (S-IRA) in DBA/1 mice SUDEP models. Given that 5-HT2A receptor (5-HT2AR) acts an important role in mediating respiration system in brain, we hypothesized that 5-HT2AR is of great significance to modulate S-IRA and SUDEP. To test this hypothesis, we examined whether the decreased incidence S-IRA evoked by either acoustic stimulation or PTZ by blocking 5-HT2AR by administration with ketanserin (KET), a selective antagonist of 5HT2AR, in DBA/1 mice SUDEP models to test the role of 5-HT2AR modulating S-IRA. Our results suggested that the decreased incidence of S-IRA by 5-Hydroxytryptophan (5-HTP), a precursor for central nervous system (CNS) serotonin (5-HT) synthesis, was significantly reversed by IP and intracerebroventricularly (ICV) injection of ketanserin in our models. Thus, our data suggested that 5-HT2AR in the brain may be a potential and specific target to prevent SUDEP.

scholarly journals Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy

2016 ◽  
Vol 79 (4) ◽  
pp. 522-534 ◽  
Author(s):  
Richard D. Bagnall ◽  
Douglas E. Crompton ◽  
Slavé Petrovski ◽  
Lien Lam ◽  
Carina Cutmore ◽  
...  
Keyword(s):  
Cardiac Arrhythmia ◽  
Respiratory Control ◽  
Sudden Unexpected Death ◽  
Unexpected Death

scholarly journals Central deficiency of norepinephrine synthesis and norepinephrinergic neurotransmission contributes to seizure-induced respiratory arrest

2019 ◽  
Author(s):  
Yue Shen ◽  
HaiXiang Ma ◽  
Han Lu ◽  
HaiTing Zhao ◽  
Jianliang Sun ◽  
...  
Keyword(s):  
Respiratory Function ◽  
Intractable Epilepsy ◽  
Respiratory Arrest ◽  
Acoustic Stimulation ◽  
Vital Role ◽  
Low Doses ◽  
Unexpected Death ◽  
Potential Therapeutic Target ◽  
Eeg Data ◽  
Rate Limiting

SummaryObjectiveSudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in patients in patients with intractable epilepsy. However, the pathogenesis of SUDEP seems to be poorly understood. Our previous findings showed that the incidence of seizure-induced respiratory arrest (S-IRA) was markedly reduced by atomoxetine in a murine SUDEP model. Because the central NE α-1 receptor (NEα-1R) plays a vital role in regulating respiratory function, we hypothesized that the suppression of S-IRA by atomoxetine was mediated by NE/NEα-1R interactions that can be reversed by NEα-1R antagonism.MethodsWe examined whether atomoxetine-mediated suppression of S-IRA evoked by either acoustic stimulation or pentylenetetrazole (PTZ) in DBA/1 mice can be reversed by intraperitoneal (IP) and intracerebroventricular (ICV) administration of prazosin, a selective antagonist of NEα-1R. The content and activity of tyrosine hydroxylase (TH), a rate-limiting enzyme for NE synthesis, in the lower brainstem was measured by ELISA. Electroencephalograms (EEG) were obtained by using the PTZ-evoked SUDEP model.ResultsAtomoxetine-mediated suppression of S-IRA evoked by either acoustic stimulation or PTZ was significantly reversed by low doses of IP and ICV prazosin. Neither repetitive acoustic stimulation nor S-IRA reduced TH levels in lower brainstem. However, the enzyme activity of TH levels in lower brainstem was significantly increased by mechanical ventilation with DBA/1 mice ,which makes dead DBA/1 mice suffered from S-IRA and SUDEP recover. EEG data showed that although the protective effect of atomoxetine was reversed by prazosin, neither drug affected EEG activity.SignificanceThese data suggest that deficient synthesis of NE and norepinephrinergic neurotransmission contributes to S-IRA and that the NEα-1R is a potential therapeutic target for the prevention of SUDEP.

scholarly journals Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors

Neurology ◽  
2017 ◽  
Vol 88 (17) ◽  
pp. 1674-1680 ◽  
Author(s):  
Cynthia Harden ◽  
Torbjörn Tomson ◽  
David Gloss ◽  
Jeffrey Buchhalter ◽  
J. Helen Cross ◽  
...  
Keyword(s):  
Risk Factors ◽  
Evaluation Process ◽  
Incidence Rates ◽  
Sudden Unexpected Death ◽  
Seizure Freedom ◽  
Unexpected Death ◽  
New Approach ◽  
Assessment Development ◽  
Clonic Seizures ◽  
Patients With Epilepsy

Objective:To determine the incidence rates of sudden unexpected death in epilepsy (SUDEP) in different epilepsy populations and address the question of whether risk factors for SUDEP have been identified.Methods:Systematic review of evidence; modified Grading Recommendations Assessment, Development, and Evaluation process for developing conclusions; recommendations developed by consensus.Results:Findings for incidence rates based on 12 Class I studies include the following: SUDEP risk in children with epilepsy (aged 0–17 years) is 0.22/1,000 patient-years (95% confidence interval [CI] 0.16–0.31) (moderate confidence in evidence). SUDEP risk increases in adults to 1.2/1,000 patient-years (95% CI 0.64–2.32) (low confidence in evidence). The major risk factor for SUDEP is the occurrence of generalized tonic-clonic seizures (GTCS); the SUDEP risk increases in association with increasing frequency of GTCS occurrence (high confidence in evidence).Recommendations:Level B: Clinicians caring for young children with epilepsy should inform parents/guardians that in 1 year, SUDEP typically affects 1 in 4,500 children; therefore, 4,499 of 4,500 children will not be affected. Clinicians should inform adult patients with epilepsy that SUDEP typically affects 1 in 1,000 adults with epilepsy per year; therefore, annually 999 of 1,000 adults will not be affected. For persons with epilepsy who continue to experience GTCS, clinicians should continue to actively manage epilepsy therapies to reduce seizures and SUDEP risk while incorporating patient preferences and weighing the risks and benefits of any new approach. Clinicians should inform persons with epilepsy that seizure freedom, particularly freedom from GTCS, is strongly associated with decreased SUDEP risk.

Sudden unexpected death in patients with epilepsy receiving renal replacement therapy with dialysis: A 17-year experience at a single institution

2010 ◽  
Vol 14 (4) ◽  
pp. 364-369 ◽  
Author(s):  
Fulvio A. SCORZA ◽  
Marcello SCATTOLINI ◽  
Roberta M. CYSNEIROS ◽  
Ricardo M. ARIDA ◽  
Marly DE ALBUQUERQUE ◽  
...  
Keyword(s):  
Renal Replacement Therapy ◽  
Replacement Therapy ◽  
Sudden Unexpected Death ◽  
Single Institution ◽  
Unexpected Death ◽  
Patients With Epilepsy

scholarly journals A High-Tryptophan Diet Reduces Seizure-Induced Respiratory Arrest and Alters the Gut Microbiota in DBA/1 Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Qiang Yue ◽  
Mingfei Cai ◽  
Bo Xiao ◽  
Qiong Zhan ◽  
Chang Zeng
Keyword(s):  
Gut Microbiota ◽  
Dietary Intervention ◽  
Intestinal Flora ◽  
Respiratory Arrest ◽  
Acoustic Stimulation ◽  
Normal Diet ◽  
Control Group ◽  
Unexpected Death ◽  
Significant Difference ◽  
Hydroxyindoleacetic Acid

Background and Aims: Central 5-hydroxytryptamine (5-HT) defects are responsible for the occurrence of sudden unexpected death in epilepsy (SUDEP). The DBA/1 mouse is an animal model of SUDEP since the mouse exhibits audiogenic seizure-induced respiratory arrest (S-IRA). The synthesis of central 5-HT is closely related to the gut microbiota. Moreover, emerging studies suggest a possible role for the microbiota in mitigating seizure likelihood. Based on this, we aimed to explore the effect of a high-tryptophan diet (HTD) on SUDEP as well as the synthesis and metabolism of central 5-HT. Furthermore, we investigated the involvement of the gut microbiota in this process.Methods: All DBA/1 mice were subjected to acoustic stimulation to induce seizures. Only those mice that exhibited S-IRA were randomly assigned to the normal diet (ND) group (n = 39) or HTD group (n = 53). After 1 month of dietary intervention, (1) S-IRA rates were evaluated, (2) the concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the plasma and brain were determined by ultra-high-pressure liquid chromatography, and (3) the fecal flora biodiversity and species composition were analyzed by 16S rDNA microbiota profiling.Results: The S-IRA rate in DBA/1 mice was significantly reduced in the HTD group compared with that in the control group. HTD increased the levels of 5-HT and 5-HIAA in both the telencephalon and midbrain. HTD significantly elevated the species richness and diversity of the gut microbiota. Moreover, there was a significant difference in the gut microbiota composition between the two groups, and the intestinal flora was dominated by Proteobacteria and Actinobacteria after HTD.Conclusions: HTD is efficient in lowering S-IRA rates and elevating the central 5-HT level in DBA/1 mice. The gut microbiota was altered after HTD intervention. The significant increase in Proteobacteria and Actinobacteria may be related to the SUDEP-protective effect of HTD. Our findings shed light on a candidate choice of dietary prevention for SUDEP.

scholarly journals Awareness f Sudden Unexpected Death in Epilepsy Among Neurologists in Latvia / Neirologu Informētība par Pēkšņas, Negaidītas Nāves Epilepsijas Laikā Sindromu Latvijā

2015 ◽  
Vol 69 (5) ◽  
pp. 265-268
Author(s):  
Normunds Sūna ◽  
Madara Lazdāne ◽  
Guntis Karelis ◽  
Egils Vītols
Keyword(s):  
Risk Factors ◽  
Sudden Unexpected Death ◽  
Unexpected Death ◽  
Partial Explanation ◽  
Common Cause ◽  
Counselling Practice ◽  
Depth Analysis ◽  
Improve Compliance ◽  
Patients With Epilepsy

Abstract Sudden unexpected death in epilepsy (SUDEP) is a common cause of mortality in patients with epilepsy, but it is unknown how neurologists disclose this risk when counselling patients. This study was aimed at examining SUDEP discussion practices of neurologists in Latvia, as well as the awareness of the syndrome. Two hundred questionnaires were distributed, and we received 84 responses. We found that the majority of Latvian neurologists (79.0%) do not inform their patients of SUDEP, which is opposite to the findings in other countries. Despite the existing practice, 93.1% of neurologists believed that patients should be informed about SUDEP. A partial explanation for not discussing the negative aspects of epilepsy is that 75.3% of caregivers believe that being informed about SUDEP would cause permanent anxiety in patients, whereas 69.4% believe that it would improve compliance. This study revealed average awareness of SUDEP risk factors and warrants further studies for in-depth analysis of existing counselling practice.

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