Huperzine A Provides Robust and Sustained Protection against Induced Seizures in Scn1a Mutant Mice.
Huperzine A Provides Robust and Sustained Protection against Induced Seizures in Scn1a Mutant Mice.
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DOI：
10.3389/fphar.2016.00357
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发表时间：
2016
影响因子：
5.6
通讯作者：
Escayg A
中科院分区：
文献类型：
--
作者：
Wong JC;Dutton SB;Collins SD;Schachter S;Escayg A
电压门控钠通道（VGSC）SCN 1A（编码Nav1.1）的从头功能丧失突变是Dravet综合征（DS）的主要原因，这是一种灾难性的早期脑病，与长期和复发性早期热性惊厥（FS）、难治性无热性癫痫、认知和行为缺陷相关，死亡率为15-20%。SCN 1A突变还导致遗传性癫痫伴热性惊厥+（GEFS+），这是一种遗传性疾病，其特征是早期FS和一系列成人癫痫亚型的发展。目前的抗癫痫药物通常无法防止SCN 1A突变患者的严重癫痫发作以及行为和认知缺陷。为了解决更有效的治疗SCN 1A源性癫痫的需要，我们评估了石杉碱甲，一种天然可逆的乙酰胆碱酯酶抑制剂的治疗潜力。在CF 1小鼠中，发现石杉碱甲（0.56或1 mg/kg）对6 Hz、戊四唑（PTZ）和最大电休克（MES）诱导的癫痫发作具有保护作用。在DS（Scn 1a +/−）和GEFS+（Scn 1aRH/+）小鼠模型中，Hup A给药后也可对6 Hz-、MES-和高血压诱导的癫痫发作产生强有力的保护作用。此外，在Scn 1aRH/+突变体中，Hup A介导的癫痫发作保护作用在每天注射3周期间持续。最后，我们确定了毒蕈碱和GABAA受体在Hup A介导的癫痫发作保护中发挥作用。这些研究结果表明，石杉碱甲可能提供了一种新的治疗策略，增加癫痫发作抵抗DS和GEFS+，更广泛地说，在其他形式的难治性癫痫。
De novo loss-of-function mutations in the voltage-gated sodium channel (VGSC) SCN1A (encoding Nav1.1) are the main cause of Dravet syndrome (DS), a catastrophic early-life encephalopathy associated with prolonged and recurrent early-life febrile seizures (FSs), refractory afebrile epilepsy, cognitive and behavioral deficits, and a 15–20% mortality rate. SCN1A mutations also lead to genetic epilepsy with febrile seizures plus (GEFS+), which is an inherited disorder characterized by early-life FSs and the development of a range of adult epilepsy subtypes. Current antiepileptic drugs often fail to protect against the severe seizures and behavioral and cognitive deficits found in patients with SCN1A mutations. To address the need for more efficacious treatments for SCN1A-derived epilepsies, we evaluated the therapeutic potential of Huperzine A, a naturally occurring reversible acetylcholinesterase inhibitor. In CF1 mice, Hup A (0.56 or 1 mg/kg) was found to confer protection against 6 Hz-, pentylenetetrazole (PTZ)-, and maximal electroshock (MES)-induced seizures. Robust protection against 6 Hz-, MES-, and hyperthermia-induced seizures was also achieved following Hup A administration in mouse models of DS (Scn1a+/−) and GEFS+ (Scn1aRH/+). Furthermore, Hup A-mediated seizure protection was sustained during 3 weeks of daily injections in Scn1aRH/+ mutants. Finally, we determined that muscarinic and GABAA receptors play a role in Hup A-mediated seizure protection. These findings indicate that Hup A might provide a novel therapeutic strategy for increasing seizure resistance in DS and GEFS+, and more broadly, in other forms of refractory epilepsy.
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影响因子：
5.8
作者：
ELLMAN, GL;COURTNEY, KD;FEATHERSTONE, RM
通讯作者：
FEATHERSTONE, RM
影响因子：
2.2
作者：
Barton, ME;Klein, BD;White, HS
通讯作者：
White, HS
影响因子：
9.8
作者：
Escayg, A;Heils, A;Meisler, MH
通讯作者：
Meisler, MH
影响因子：
5.3
作者：
Brewster, A;Bender, RA;Baram, TZ
通讯作者：
Baram, TZ
影响因子：
5.1
作者：
Coleman, Brian R.;Ratcliffe, Ruthie H.;Nambiar, Madhusoodana P.
通讯作者：
Nambiar, Madhusoodana P.