Complicated Effects of Selective Serotonin Reuptake Inhibitors on Spontaneous Seizure-Induced Mortality in Dravet Mice
Abstract number :
1.119
Submission category :
2. Translational Research / 2E. Other
Year :
2023
Submission ID :
359
Source :
www.aesnet.org
Presentation date :
12/2/2023 12:00:00 AM
Published date :
Authors :
First Author: Daniel Min, BS – Massachusetts General Hospital
Presenting Author: Hua-Jun Feng, PhD – Massachusetts General Hospital and Harvard Medical School
Presenting Author: Hua-Jun Feng, PhD – Massachusetts General Hospital and Harvard Medical School
Presenting Author: Hua-Jun Feng, PhD – Massachusetts General Hospital and Harvard Medical School
Presenting Author: Hua-Jun Feng, PhD – Massachusetts General Hospital and Harvard Medical School
Yupeng Zhou, BS – Massachusetts General Hospital; Emory Farrell, BS – Massachusetts General Hospital; Hua-Jun Feng, PhD – Massachusetts General Hospital and Harvard Medical School
Rationale: Sudden unexpected death in epilepsy (SUDEP) is a lethal and underestimated complication of epilepsy. Previous studies showed that administering selective serotonin (5-HT) reuptake inhibitors (SSRIs) to enhance 5-HT function exerts differential effects on seizure-induced sudden death in provoked seizure models. While the SSRI citalopram has been shown to suppress provoked seizure-induced mortality, paroxetine produces no effect. However, it remains unknown how citalopram and paroxetine modify seizure-induced mortality in spontaneous seizure (epilepsy) models. This study aimed to examine the effects of systemic injection of citalopram and paroxetine on spontaneous seizure-induced mortality in the Dravet mouse, a rodent model mimicking human Dravet syndrome.
Methods: Dravet mice recapitulate the salient features of human Dravet syndrome, including hyperthermia-evoked seizures, spontaneous seizures and a high rate of SUDEP. Clinical studies observed that the first manifestations of Dravet syndrome are recurrent seizures provoked by fever. In order to simulate the clinical scenario, hyperthermia-priming was applied to Dravet mice of both sexes. An SSRI (citalopram or paroxetine) or vehicle (saline for citalopram or DI water for paroxetine) was intraperitoneally (i.p.) injected twice daily for seven days, and the effect of the drug or vehicle on spontaneous seizure-induced mortality was tested. Data were plotted using a Kaplan-Meier survival curve. Statistical comparison between the SSRI and control groups was performed using the log-rank (Mantel-Cox) test.
Results: Systematic administration (i.p.) of citalopram at 10 mg/kg (n = 10) significantly reduced spontaneous seizure-induced mortality as compared with vehicle control (n = 37) in Dravet mice (p < 0.05). However, compared with vehicle control, lowering citalopram dosage to 5 mg/kg (n = 12) or elevating citalopram dosage to 20 mg/kg (n = 8) or 40 mg/kg (n = 12) did not significantly alter spontaneous seizure-induced mortality. Injection of paroxetine at 10 mg/kg (n = 13) exerted no effect on spontaneous seizure-induced mortality compared with the vehicle control (n = 24). Interestingly, compared with vehicle control, paroxetine at 30 mg/kg (n = 9) (p < 0.01) or 40 mg/kg (n = 12) (p < 0.001) significantly increased spontaneous seizure-induced mortality.
Translational Research