Sex and gonadectomy modify behavioral seizure susceptibility and mortality in a repeated low-dose kainic acid systemic injection paradigm in mice.
Sex and gonadectomy modify behavioral seizure susceptibility and mortality in a repeated low-dose kainic acid systemic injection paradigm in mice.
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在小鼠体内重复低剂量红藻氨酸全身注射范例中，性和性腺切除术改变了行为癫痫易感性和死亡率。
DOI：
10.1101/2023.05.22.541824
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Christian-Hinman,CatherineA
中科院分区：
文献类型：
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作者：
Lawande,NirajV;Conklin,ElisabethA;Christian-Hinman,CatherineA
癫痫的性别差异部分是由于性腺类固醇的影响，在不同种类、不同品系和不同致痫方法的实验模型中，其结果是不同的。此外，通过性腺切除术去除这些类固醇的主要来源可能会对男性和女性的癫痫发作特征产生不同的影响。重复小剂量红藻氨酸(RLDKA)全身注射可可靠地诱导C57BL/6J小鼠癫痫持续状态(SE)和海马区组织病理学改变。在这里，我们研究了RLDKA注射方案中的癫痫易感性是否表现出性别差异，以及性腺切除是否对这种癫痫诱导范式的反应产生了不同的影响。方法成年C57BL/6J小鼠作为对照，保留性腺完整或性腺切除(雌性：去卵巢，OVX；雄性：去，ORX)。至少2 周后，KA以7.5 mg/kg或更低的速度每隔30 分钟注射一次，直到动物达到SE，即至少5次全身性癫痫发作(GS，racine 3级或更高)。结果对照组男性和对照组女性在癫痫易感性和死亡率方面没有差异。与同性别的相应对照组相比，去性腺小鼠对GS和SE的敏感度增加，潜伏期缩短，但对雄性的影响更强。此外，OVX雄性，而不是OVX雌性，表现出强烈的癫痫诱导死亡率。意义RLDKA方案在C57BL/6J小鼠中诱导SE和癫痫诱导的组织病理学方面的有效性是显著的，这是目前许多转基因菌株用于癫痫研究的背景。目前的结果表明，这一方案可能有助于研究性腺激素替代对癫痫易感性、死亡率和癫痫诱导的组织病理学的影响，性腺切除揭示了性腺完整对照组中未观察到的癫痫易感性和死亡率的性别差异。
ObjectiveSex differences in epilepsy appear driven in part due to effects of gonadal steroids, with varying results in experimental models based on species, strain, and method of seizure induction. Furthermore, removing the main source of these steroids via gonadectomy may impact seizure characteristics differently in males and females. Repeated low‐dose kainic acid (RLDKA) systemic injection paradigms were recently shown to reliably induce status epilepticus (SE) and hippocampal histopathology in C57BL/6J mice. Here, we investigated whether seizure susceptibility in a RLDKA injection protocol exhibits a sex difference and whether gonadectomy differentially influences response to this seizure induction paradigm in males and females.MethodsAdult C57BL/6J mice were left gonad‐intact as controls or gonadectomized (females: ovariectomized, OVX; males: orchidectomized, ORX). At least 2 weeks later, KA was injected ip, every 30 minutes at 7.5 mg/kg or less until the animal reached SE, defined by at least 5 generalized seizures (GS, Racine stage 3 or higher). Parameters of susceptibility to GS induction, SE development, and mortality rates were quantified.ResultsNo differences in seizure susceptibility or mortality were observed between control males and control females. Gonadectomized mice exhibited increased susceptibility and reduced latency to both GS and SE in comparison to corresponding controls of the same sex, but the effects were stronger in males. In addition, ORX males, but not OVX females, exhibited strongly increased seizure‐induced mortality.SignificanceThe RLDKA protocol is notable for its efficacy in inducing SE and seizure‐induced histopathology in C57BL/6J mice, the background for many transgenic strains in current use in epilepsy research. The present results indicate that this protocol may be beneficial for investigating the effects of gonadal hormone replacement on seizure susceptibility, mortality, and seizure‐induced histopathology, and that gonadectomy unmasks sex differences in susceptibility to seizures and mortality not observed in gonad‐intact controls.