Authors :
Presenting Author: YuLing Wang, BS – Department of Anesthesiology, the Fourth Clinical School of Medicine, Zhejiang Chinese Medical University, Hangzhou, 310006, China
Qing Xu, BS – YuLing Wang, Qing Xu , Yue Shen and Le Yuan Gucontributed equally to this work, Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China; Yue Shen, BS – Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China; LeYuan Gu, PHD – Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China; HongHai Zhang, PHD – Corresponding author: HongHai Zhang Email address: zhanghonghai_0902@163.com, Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
Rationale:
Sudden Unexpected Death of Epilepsy (SUDEP) is a severe complication of patients with this disease. However, the exact mechanism of SUDEP has not been established yet. Our previous studies showed seizure-induced respiratory arrest (S-IRA) is a main factor in SUDEP. Furthermore, we present finding showed that 5-hydroxytryptophan (5-HTP)-mediated suppression of PTZ-induced S-IRA was significantly reversed by the basolateral amygdala (BLA) delivery of ketanserin (KET), a selective antagonist for 5-HT2A/C receptor (5-HT2A/CR) in the DBA/1 mice. Our findings showed that 5-HT2RA/CR in the BLA plays a key role in modulating S-IRA and SUDEP.
Methods:
All experimental procedures were consistent with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and approved by the Animal Advisory Committee of Zhejiang University. DBA/1 mice were housed and bred in the Animal Center of Zhejiang University School of Medicine and given rodent food and water ad libitum. For the PTZ-evoked seizure model, S-IRA was evoked in non-primed DBA/1 mice by IP administration of a single dose of PTZ (Cat #P6500; Sigma-Aldrich, St. Louis, MO) at a dose of 75 mg/kg. Mice with S-IRA were resuscitated within 5 s after the final respiratory gasp using a rodent respirator (YuYan Instruments, Shanghai, China). 5-HTP (Cat #107751; Sigma-Aldrich)(200 mg/kg) or vehicle (saline) was administered IP once daily for 2 days and induction of S-IRA was performed 75 min after the second administration. KET (Cat #8006; Sigma-Aldrich) at different doses or vehicle (25% dimethyl sulfoxide [DMSO]) by microinjection of KET into the bilateral BLA was administered IP 15 min before PTZ injection. The incidence of S-IRA, latency to AGSz, duration of wild running and clonic seizures, duration of tonic-clonic seizures, and seizure scores were determined via offline analysis of video recordings (n=8/group).
Results:
Compared with that in the vehicle control group that received BLA injection of 25% DMSO post pre-treatment with 5-HTP, the incidence of PTZ-induced S-IRA was significantly increased in the group that received BLA injection of KET (18.3 nmol) post pre-treatment with 5-HTP (P< 0.01).