Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan 750004, China.
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China.
Life Sci. 2021 Nov 1;284:119912. doi: 10.1016/j.lfs.2021.119912. Epub 2021 Aug 28.
Sudden unexpected death in epilepsy (SUDEP) is a serious and underestimated public health burden. Both clinical and animal studies show that seizure-induced respiratory arrest (S-IRA) is the primary cause of death in SUDEP. Our previous studies demonstrated that atomoxetine, a norepinephrine reuptake inhibitor (NRI), suppresses S-IRA in DBA/1 mice, suggesting that noradrenergic neurotransmission modulates S-IRA. However, it remains unclear which adrenoceptors are implicated in S-IRA in DBA/1 mice.
Naïve DBA/1 mice exhibit a low incidence of S-IRA, but after primed by acoustic stimulation, they become consistently susceptible to S-IRA. Atomoxetine, adrenoceptor agonists, antagonists or vehicle was intraperitoneally (i.p.) administered alone or in combination, and the effects of drug treatments on S-IRA incidence and seizure behaviors were examined.
The incidence of S-IRA in primed DBA/1 mice was significantly reduced by clonidine, an α2 adrenoceptor agonist, as compared with that of the vehicle control. However, compared with the vehicle control, S-IRA was not altered by cirazoline, an α1 agonist. Consistent with previous reports, atomoxetine reduced S-IRA in primed DBA/1 mice. The suppressing effect of atomoxetine on S-IRA was prevented by injection of an α2 adrenoceptor antagonist, yohimbine or atipamezole, but not by prazosin, an α1 antagonist. Administration of α1 or α2 antagonists alone did not promote the incidence of S-IRA in nonprimed DBA/1 mice.
These data demonstrate that noradrenergic neurotransmission modulates S-IRA predominantly via α2 adrenoceptors in DBA/1 mice, indicating that selective activation of α2 adrenoceptors can potentially prevent SUDEP.
癫痫猝死（SUDEP）是一种严重且被低估的公共卫生负担。临床和动物研究均表明，癫痫发作引起的呼吸暂停（S-IRA）是 SUDEP 的主要致死原因。我们之前的研究表明，去甲肾上腺素再摄取抑制剂（NRI）托莫西汀可抑制 DBA/1 小鼠的 S-IRA，提示去甲肾上腺素能神经传递可调节 S-IRA。然而，DBA/1 小鼠的 S-IRA 涉及哪些肾上腺素能受体仍不清楚。
未处理的 DBA/1 小鼠 S-IRA 发生率较低，但经声刺激致敏后，其始终易发生 S-IRA。托莫西汀、肾上腺素能受体激动剂、拮抗剂或载体单独或联合腹腔内给药，观察药物处理对 S-IRA 发生率和癫痫发作行为的影响。
与载体对照组相比，α2 肾上腺素能受体激动剂可乐定可显著降低致敏 DBA/1 小鼠的 S-IRA 发生率。然而，与载体对照组相比，α1 激动剂赛洛唑啉并未改变 S-IRA。与之前的报道一致，托莫西汀可降低致敏 DBA/1 小鼠的 S-IRA。α2 肾上腺素能受体拮抗剂育亨宾或阿替美唑可阻止托莫西汀对 S-IRA 的抑制作用，但 α1 拮抗剂哌唑嗪则不能。单独给予 α1 或 α2 拮抗剂不会增加非致敏 DBA/1 小鼠的 S-IRA 发生率。
这些数据表明，去甲肾上腺素能神经传递主要通过 DBA/1 小鼠中的 α2 肾上腺素能受体调节 S-IRA，提示选择性激活 α2 肾上腺素能受体可能预防 SUDEP。
