Serotonin and sudden death: Differential effects of serotonergic drugs on seizure-induced respiratory arrest in DBA/1 mice

Faingold, Carl L.; Kommajosyula, Srinivasa P.; Long, Xiaoyan; Plath, Kristin; Randall, Marcus E.

doi:10.1016/j.yebeh.2014.06.028

Cited by 47 publications

(70 citation statements)

References 42 publications

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“…In DBA/2 mice, similar findings are observed as oxygenation prevents death after seizure 64. Fluoxetine, which is a selective serotonin reuptake inhibitor, has been shown to reduce the incidence of respiratory arrest in DBA/166 and DBA/2 mice65 67 after audiogenic seizures, suggesting serotonin (5-HT) may play a role in the molecular mechanisms underlying seizure-induced hypoventilation. Additionally, 5-HT receptor expression in DBA mice exhibits abnormal levels, including reductions of 5-HT2C levels 68…”

Section: Pathophysiologymentioning

confidence: 57%

Sudden unexpected death in epilepsy: basic mechanisms and clinical implications for prevention

Dlouhy

Gehlbach

Richerson

2015

J Neurol Neurosurg Psychiatry

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Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with intractable epilepsy. The substantial lifetime risk of SUDEP and the lack of a clear pathophysiological connection between epilepsy itself and sudden death have fuelled increased attention to this phenomenon. Understanding the mechanisms underlying SUDEP is paramount to developing preventative strategies. In this review, we discuss SUDEP population studies, case-control studies, witnessed and monitored cases, as well as human seizure cardiorespiratory findings related to SUDEP, and SUDEP animal models. We integrate these data to suggest the most probable mechanisms underlying SUDEP. Understanding the modifiable risk factors and pathophysiology allows us to discuss potential preventative strategies.

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Section: Pathophysiologymentioning

confidence: 57%

Sudden unexpected death in epilepsy: basic mechanisms and clinical implications for prevention

Dlouhy

Gehlbach

Richerson

2015

J Neurol Neurosurg Psychiatry

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“…Another SSRI fluvoxamine (55–80 mg/kg, i.p.) reduces S-IRA in a dose-dependent manner without blocking AGS in DBA/1 mice [18]. The involvement of 5-HT neurotransmission in the pathogenesis of S-IRA is confirmed in another study that the SSRI, citalopram (20 mg/kg, i.p.…”

Section: Evidence Of 5-ht Neurotransmission Defects In Dba Micementioning

confidence: 79%

“…DBA mice (both DBA/1 and DBA/2) are genetically susceptible to audiogenic seizures (AGS) evoked by acoustic stimulation (95–122 dB SPL) [16, 17]. The AGS in DBA mice are characterized by wild running, generalized clonic and/or tonic seizures, ending in tonic hind-limb extension [17, 18]. Thus, DBA/2 mice have been used as a genetic epilepsy model for many years [19].…”

Section: Dba Mice As Relevant Sudep Modelsmentioning

confidence: 99%

“…DBA/1 and DBA/2 mice have different patterns of S-IRA susceptibility (Table 1). Like human SUDEP, the occurrence of S-IRA is unpredictable in DBA/1 mice that have not been subjected to high intensity of acoustic stimulation, as the incidence of S-IRA (~10–30%) when tested at ~30 days of age is relatively low on initial testing [18, 22]. However, the incidence of S-IRA can reach up to ~100% after three or four consecutive days of testing (“priming”) [16].…”

Section: Dba Mice As Relevant Sudep Modelsmentioning

confidence: 99%

“…It was reported that paroxetine administered up to 100 mg/kg is ineffective in suppressing S-IRA in DBA/1 mice. Although paroxetine at 120 mg/kg significantly reduces the incidence of S-IRA, it results in substantial toxicity to DBA/1 mice at this dose [18]. The reasons why some SSRIs, such as fluoxetine, are more effective in suppressing S-IRA than others such as paroxetine remain elusive.…”

Section: Evidence Of 5-ht Neurotransmission Defects In Dba Micementioning

confidence: 99%

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Abnormalities of serotonergic neurotransmission in animal models of SUDEP

Feng

Faingold

2017

Epilepsy & Behavior

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Sudden unexpected death in epilepsy (SUDEP) is a devastating event, and both DBA/1 and DBA/2 mice have been shown to be relevant animal models for studying SUDEP. DBA mice exhibit seizure-induced respiratory arrest (S-IRA), leading to cardiac arrest and subsequent sudden death after generalized audiogenic seizures (AGS). This sequence of terminal events is also observed in the majority of witnessed human SUDEP cases. Several pathophysiological mechanisms, including respiratory/cardiac dysfunction, have been proposed to contribute to human SUDEP. Several (but not all) selective serotonin (5-HT) reuptake inhibitors (SSRIs), including fluoxetine, can reversibly block S-IRA, and abnormal expression of 5-HT receptors is found in the brainstem of DBA mice. DBA mice, which do not initially show S-IRA, exhibit S-IRA after treatment with a non-selective 5-HT antagonist. These studies suggest that abnormalities of 5-HT neurotransmission are involved in the pathogenesis of S-IRA in DBA mice. 5-HT transmission plays an important role in normal respiration, and DBA mice exhibiting S-IRA can be resuscitated using a rodent ventilator. It is important and interesting to know if fluoxetine blocks S-IRA in DBA mice by enhancing respiratory ventilation. To test this, the effects of breathing stimulants, doxapram and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (PK-THPP) were compared to fluoxetine on S-IRA in DBA/1 mice. Although fluoxetine reduces the incidence of S-IRA in DBA/1 mice, as reported previously, the same dose of fluoxetine fails to enhance baseline respiratory ventilation in the absence of AGS. Doxapram and PK-THPP augment the baseline ventilation in DBA/1 mice. However, these breathing stimulants are ineffective in preventing S-IRA in DBA/1 mice. These data suggest that fluoxetine blocks S-IRA in DBA/1 mice by cellular/molecular mechanisms other than enhancement of basal ventilation. Future research directions are also discussed.

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Intraperitoneal injection of lipopolysaccharide prevents seizure‐induced respiratory arrest in a DBA/1 mouse model of SUDEP

Adhikari

Jin

2020

Epilepsia Open

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Objective Sudden unexpected death in epilepsy (SUDEP) is the cause of premature death of 50% patients with chronic refractory epilepsy. Respiratory failure during seizures is regarded as an important mechanism of SUDEP. Previous studies have shown that abnormal serotonergic neurotransmission is involved in the pathogenesis of seizure‐induced respiratory failure, while enhancing serotonergic neurotransmission in the brainstem suppresses it. Because peripheral inflammation is known to enhance serotonergic neuron activation and 5‐HT synthesis and release, we investigated the effect of intraperitoneal lipopolysaccharide (LPS)‐induced inflammation on the S‐IRA susceptibility during audiogenic seizures in DBA/1 mice. Methods After DBA/1 mice were primed by exposing to sound stimulation for three consecutive days, they were tested for seizure severity and seizure‐induced respiratory arrest (S‐IRA) induced by sound stimulation under different conditions. We determined the dose and time course of the effects of intraperitoneal administration of LPS on audiogenic seizures and S‐IRA. The effects of blocking TLR4 or RAGE receptors and blocking 5‐HT receptors on the LPS‐induced effect on S‐IRA were investigated. Statistical significance was evaluated using the Kruskal‐Wallis test. Results Intraperitoneal injection of LPS significantly had dose‐dependent effects in reducing the incidence of S‐IRA as well as seizure severity in DBA/1 mice. The protective effect of LPS on S‐IRA peaked at 8‐12 hours after LPS injection and was related to both reducing seizure severity and enhancing autoresuscitation. Blocking TLR4 or RAGE receptor with TAK‐242 or FPS‐ZM1, respectively, prior to LPS injection attenuated its effects on S‐IRA and seizure severity. Injection of a nonselective 5‐HT receptor antagonist, cyproheptadine, or a 5‐HT3 receptor antagonist, ondansetron, was effective in blocking LPS‐induced effect on S‐IRA. Immunostaining results showed a significant increase in c‐Fos‐positive serotonergic neurons in the dorsal raphe. Significance This is the first study that demonstrates the effect of intraperitoneal LPS injection‐induced inflammation on reducing S‐IRA susceptibility and provides additional evidence supporting the serotonin hypothesis on SUDEP. Our study suggests that inflammation may enhance brainstem 5‐HT neurotransmission to promote autoresuscitation during seizure and prevent SUDEP.

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Serotonin and sudden death: Differential effects of serotonergic drugs on seizure-induced respiratory arrest in DBA/1 mice

Cited by 47 publications

References 42 publications

Sudden unexpected death in epilepsy: basic mechanisms and clinical implications for prevention

Sudden unexpected death in epilepsy: basic mechanisms and clinical implications for prevention

Abnormalities of serotonergic neurotransmission in animal models of SUDEP

Intraperitoneal injection of lipopolysaccharide prevents seizure‐induced respiratory arrest in a DBA/1 mouse model of SUDEP

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