Loss of normal Alzheimer's disease-associated Presenilin 2 function alters antiseizure medicine potency and tolerability in the 6-Hz focal seizure model.
Loss of normal Alzheimer's disease-associated Presenilin 2 function alters antiseizure medicine potency and tolerability in the 6-Hz focal seizure model.
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正常阿尔茨海默病相关早老素2功能的丧失改变了6 Hz局灶性癫痫发作模型中抗癫痫药物的效力和耐受性
DOI：
10.3389/fneur.2023.1223472
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发表时间：
2023
影响因子：
3.4
通讯作者：
中科院分区：
文献类型：
--
作者：
早发性阿尔茨海默病（EOAD）患者会出现癫痫发作和亚临床癫痫样活动，这可能会加速认知和功能衰退。抗癫痫药物（ASMs）可能是一种易于处理的疾病改善策略;许多ASMs已上市，具有良好的安全性。然而，很少有信息可用于指导ASM的选择，因为很少有研究在具有EOAD相关风险因素的啮齿动物的传统癫痫发作模型中严格量化ASM的效力和耐受性。早老素2（PSEN 2）变体诱发EOAD，这些患者会出现癫痫发作。因此，本研究在PSEN 2敲除（KO）小鼠中诱发的一线6-Hz边缘癫痫发作试验中建立了机制上不同的ASM的抗惊厥谱，以更好地为EOAD中的癫痫发作管理提供信息。在雄性和雌性PSEN 2-KO和野生型（WT）C57 BL/6 J小鼠（3-4月龄）中，在6-Hz测试中定量原型ASM的中值有效剂量（ED 50）。评估最小运动损伤（MMI）以估计保护指数（PI）。cFos的免疫组织学检测确定了6 Hz刺激激活KO与WT小鼠中离散脑区域的程度。几种ASM的效力和耐受性存在显著的基因型相关差异。丙戊酸和左乙拉西坦在雄性KO小鼠中的效力显著高于WT小鼠。此外，高剂量丙戊酸显著加重KO小鼠的MMI。相反，卡马西平在雌性KO小鼠中的效力显著低于WT小鼠。在雄性和雌性KO小鼠与WT中，perampanel和拉莫三嗪的效力相同。然而，卡马西平和perampanel的PI均存在明显的基因型相关变化，KO小鼠在最高试验剂量下表现出更低的MMI。加巴喷丁对KO小鼠与无MMI变化的WT相比的6 Hz癫痫发作无效。6 Hz刺激后90分钟，WT小鼠CA 1上的后顶叶联合皮质和梨状皮质的神经元激活显着增加，而KO小鼠中不存在刺激诱导的cFos免疫反应性增加。高通量6 Hz测试中的急性ASM效力和耐受性可能会随着正常PSEN 2功能的丧失而显著改变。离散EOAD人群的癫痫发作可能受益于针对主要ASM药理学机制优化的精确选择的药物。
Patients with early-onset Alzheimer's disease (EOAD) experience seizures and subclinical epileptiform activity, which may accelerate cognitive and functional decline. Antiseizure medicines (ASMs) may be a tractable disease-modifying strategy; numerous ASMs are marketed with well-established safety. However, little information is available to guide ASM selection as few studies have rigorously quantified ASM potency and tolerability in traditional seizure models in rodents with EOAD-associated risk factors. Presenilin 2 (PSEN2) variants evoke EOAD, and these patients experience seizures. This study thus established the anticonvulsant profile of mechanistically distinct ASMs in the frontline 6-Hz limbic seizure test evoked in PSEN2-knockout (KO) mice to better inform seizure management in EOAD. The median effective dose (ED50) of prototype ASMs was quantified in the 6-Hz test in male and female PSEN2-KO and wild-type (WT) C57BL/6J mice (3–4 months old). Minimal motor impairment (MMI) was assessed to estimate a protective index (PI). Immunohistological detection of cFos established the extent to which 6-Hz stimulation activates discrete brain regions in KO vs. WT mice. There were significant genotype-related differences in the potency and tolerability of several ASMs. Valproic acid and levetiracetam were significantly more potent in male KO than in WT mice. Additionally, high doses of valproic acid significantly worsened MMI in KO mice. Conversely, carbamazepine was significantly less potent in female KO vs. WT mice. In both male and female KO mice vs. WTs, perampanel and lamotrigine were equally potent. However, there were marked genotype-related shifts in PI of both carbamazepine and perampanel, with KO mice exhibiting less MMI at the highest doses tested. Gabapentin was ineffective against 6-Hz seizures in KO mice vs. WTs without MMI changes. Neuronal activation 90 min following 6-Hz stimulation was significantly increased in the posterior parietal association cortex overlying CA1 and in the piriform cortex of WT mice, while stimulation-induced increases in cFos immunoreactivity were absent in KO mice. Acute ASM potency and tolerability in the high-throughput 6-Hz test may be significantly altered with loss of normal PSEN2 function. Seizures in discrete EOAD populations may benefit from precisely selected medicines optimized for primary ASM pharmacological mechanisms.
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影响因子：
5.7
作者：
Anggono V;Huganir RL
通讯作者：
Huganir RL
影响因子：
7.4
作者：
Farr, Susan A.;Ripley, Jessica L.;Sultana, Rukhsana;Zhang, Zhaoshu;Niehoff, Michael L.;Platt, Thomas L.;Murphy, M. Paul;Morley, John E.;Kumar, Vijaya;Butterfield, D. Allan
通讯作者：
Butterfield, D. Allan
影响因子：
5.4
作者：
De Strooper, Bart;Iwatsubo, Takeshi;Wolfe, Michael S.
通讯作者：
Wolfe, Michael S.
影响因子：
2.2
作者：
Barton, ME;Klein, BD;White, HS
通讯作者：
White, HS
影响因子：
6.1
作者：
Beckman, Megan;Knox, Kevin;Barker-Haliski, Melissa
通讯作者：
Barker-Haliski, Melissa