Adrenergic α2 receptors are implicated in seizure-induced respiratory arrest in DBA/1 mice

Zhang, Rui; Tan, Zheren; Niu, Junfeng; Feng, Huajun

doi:10.1016/j.lfs.2021.119912

Cited by 8 publications

(12 citation statements)

References 39 publications

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“…It was well known that norepinephrine transmission is closely related to the activity of sympathetic neurons and modulates the respiratory and circulation function by targeting the adrenergic α1, α2, β1, and β2 receptors. The findings from our and other laboratories showed α1 and α2 receptors were implicated in the S-IRA and SUDEP medicated by atomoxetine in the DBA/1 mice models 11, 12 . As for β1 and β2 receptors, especially β1 receptor, the postganglionic nerve endings of cardiac sympathetic neurons mainly release NE and act on β1receptors which locate in the myocardial cell and play a key role in modulating the cardiac function 13, 14 .…”

Section: Introductionsupporting

confidence: 53%

“…In recent years, more and more researches have shown that the apnea and cardiac dysfunction are important potential mechanisms in SUDEP. Studies in animal models and SUDEP patients have shown that S-IRA is one of the main induced factors that lead to death in many cases 12, 27, 28 . Our previous findings showed that administration of atomoxetine inhibited S-IRA and SUDEP in DBA/1 mice independently of seizure induction methods, and its inhibition of S-IRA induced by acoustic stimulation was dose-dependent and the suppression of S-IRA by atomoxetine could be mediated by NE/NEα-1R interactions that can be reversed by prazosin, a NEα-1R antagonism.…”

Section: Discussionmentioning

confidence: 99%

“…S-IRA was established by acoustic stimulation as we previously described [5][6][7][8][9][10][11][12] . For the acoustic stimulation model, each mouse was placed in a cylindrical plexiglass chamber in a sound-isolated room, and audiogenic seizures (AGSZs) were evoked by 4 using an electric bell (96 dB SPL, Zhejiang People's Electronics, China).…”

Section: Seizure Induction and Resuscitationmentioning

confidence: 99%

“…It was well known that norepinephrine transmission modulates the respiratory and circulation function by targeting the adrenergic α1, α2, β1, and β2 receptors. The findings from our and other laboratories showed α1 and α2 receptors were implicated in the S-IRA and SUDEP medicated by atomoxetine in the DBA/1 mice models [7][8] . However, whether both of β1 and β2 receptors, especially β1 receptor located in the cardiomyocytes that play a key role in modulating the cardiac function seems to essentially be explored based on our and other findings.…”

Section: Introductionmentioning

confidence: 99%

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The Interaction Between The Noradrenergic Neurons In The Locus Coeruleus And Beta-1 Adrenergic Receptor (β1-AR) In The Cardiomyocytes Was Implicated In Modulating SUDEP

Lian

et al. 2022

Preprint

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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)

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Section: Introductionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Seizure Induction and Resuscitationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Interaction Between The Noradrenergic Neurons In The Locus Coeruleus And Beta-1 Adrenergic Receptor (β1-AR) In The Cardiomyocytes Was Implicated In Modulating SUDEP

Lian

et al. 2022

Preprint

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“…Consistent with this, it was reported that genistein inhibits the reuptake of norepinephrine by reducing the activity of norepinephrine transporters in human neuroblastoma cells ( 26 ), indicating that genistein is an NRI. Interestingly, our recent data show that the traditional NRI atomoxetine reduces S-IRA via activation of α2 adrenoceptors ( 50 ). α2 adrenoceptors are found both pre-synaptically and post-synaptically in the CNS ( 51 ).…”

Section: Discussionmentioning

confidence: 99%

Genistein, a Natural Isoflavone, Alleviates Seizure-Induced Respiratory Arrest in DBA/1 Mice

2021

Self Cite

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Objective: Sudden unexpected death in epilepsy (SUDEP) is a fatal event that ranks second in years of potential life lost among neurological disorders. Seizure-induced respiratory arrest (S-IRA) is the primary instigator leading to death in many SUDEP cases. However, there are currently no effective preventive strategies against S-IRA other than the seizure control. Therefore, it is critical to develop new avenues to prevent SUDEP by investigating the pharmacological interventions of S-IRA. In the present study, we examined the effect of genistein, an isoflavone found in various dietary vegetables, on the incidence of S-IRA in DBA/1 mice.Methods: DBA/1 mice exhibited generalized seizures and S-IRA when subjected to acoustic stimulation. Genistein was intraperitoneally administered alone or in combination with an adrenoceptor antagonist and a serotonin (5-HT) receptor antagonist, respectively. The effects of drug treatments on S-IRA incidence and seizure behaviors were examined.Results: The incidence of S-IRA in DBA/1 mice was significantly reduced 2 h after injection of genistein at 1–90 mg/kg as compared with that in the vehicle control. Genistein could block S-IRA without interfering with any component of seizures, especially at relatively lower dosages. The S-IRA-suppressing effect of genistein was reversed by an α2 adrenoceptor antagonist but was not altered by an α1 antagonist. The inhibitory effect of genistein on S-IRA was not affected by a 5-HT3 or 5-HT2A receptor antagonist.Significance: Our data show that genistein reduces S-IRA incidence and can specifically block S-IRA in DBA/1 mice. Its suppressing effect on S-IRA is dependent on activating α2 adrenoceptors. Our study suggests that genistein, a dietary supplement, is potentially useful to prevent SUDEP in at-risk patients.

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Noradrenergic pathway from the locus coeruleus to heart is implicated in modulating SUDEP

Lian¹,

Xu²,

Wang³

et al. 2023

iScience

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Adrenergic α2 receptors are implicated in seizure-induced respiratory arrest in DBA/1 mice

Cited by 8 publications

References 39 publications

The Interaction Between The Noradrenergic Neurons In The Locus Coeruleus And Beta-1 Adrenergic Receptor (β1-AR) In The Cardiomyocytes Was Implicated In Modulating SUDEP

The Interaction Between The Noradrenergic Neurons In The Locus Coeruleus And Beta-1 Adrenergic Receptor (β1-AR) In The Cardiomyocytes Was Implicated In Modulating SUDEP

Genistein, a Natural Isoflavone, Alleviates Seizure-Induced Respiratory Arrest in DBA/1 Mice

Noradrenergic pathway from the locus coeruleus to heart is implicated in modulating SUDEP

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