Knox Kevin M, Davidson Stephanie, Lehmann Leanne M, Skinner Erica, Lo Alexandria, Jayadev Suman, Barker-Haliski Melissa
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA.
Department of Neurology, School of Medicine, University of Washington, Seattle, WA, USA.
J Alzheimers Dis. 2025 Jun 3:13872877251343321. doi: 10.1177/13872877251343321.
BackgroundAlzheimer's disease (AD) patients are at greater risk of focal seizures than similarly aged adults, which may accelerate cognitive decline. Older people with epilepsy generally respond well to antiseizure medications (ASMs). However, whether specific ASMs can differentially control seizures in AD is unknown. The corneal kindled model of chronic seizures allows for precisely timed drug administration studies to expediently evaluate efficacy and tolerability of investigational treatments in AD-associated mouse models.ObjectiveWe hypothesized that mechanistically distinct ASMs would differentially control seizures of aged AD mice (9-14 months), thereby informing rational ASM selection for AD.MethodsPSEN2-N141I and APP/PS1 mice underwent corneal kindling at 9-14 months old to quantify latency to kindled criterion versus matched wild-type mice. Dose-related response to commonly prescribed ASMs for older adults with epilepsy (valproic acid, levetiracetam, lamotrigine, phenobarbital, and gabapentin) was then assessed.ResultsSex and AD genotype differentially impacted seizure susceptibility. Male PSEN2-N141I mice required more kindling stimulations to reach criterion (χ = 5.521; p < 0.05). Male APP/PS1 mice were no different in kindling rate versus controls, but did have more severe seizures. There were significant ASM class-specific differences in acute seizure control and dose-related tolerability. APP/PS1 mice were more sensitive to valproic acid, levetiracetam, and gabapentin. PSEN2-N141I mice were more sensitive to valproic acid and lamotrigine.ConclusionsAD genotypes may differentially impact ASMs activity in vivo with advanced biological age. These findings highlight the heterogeneity of seizure risk in AD and suggest that precisely selected ASMs may beneficially control seizures in AD to slow cognitive decline.
背景
阿尔茨海默病（AD）患者比同龄成年人更容易发生局灶性癫痫发作，这可能会加速认知衰退。老年癫痫患者通常对抗癫痫药物（ASMs）反应良好。然而，特定的ASMs是否能在AD中差异控制癫痫发作尚不清楚。慢性癫痫发作的角膜点燃模型允许进行精确计时的药物给药研究，以便快速评估AD相关小鼠模型中研究性治疗的疗效和耐受性。
目的
我们假设机制不同的ASMs会差异控制老年AD小鼠（9 - 14个月）的癫痫发作，从而为AD患者合理选择ASM提供依据。
方法
PSEN2 - N141I和APP/PS1小鼠在9 - 14个月大时进行角膜点燃，以量化达到点燃标准的潜伏期，并与匹配的野生型小鼠进行比较。然后评估老年癫痫患者常用的ASMs（丙戊酸、左乙拉西坦、拉莫三嗪、苯巴比妥和加巴喷丁）的剂量相关反应。
结果
性别和AD基因型对癫痫易感性有差异影响。雄性PSEN2 - N141I小鼠达到标准需要更多的点燃刺激（χ = 5.521；p < 0.05）。雄性APP/PS1小鼠的点燃率与对照组无差异，但癫痫发作更严重。在急性癫痫控制和剂量相关耐受性方面存在显著的ASM类别特异性差异。APP/PS1小鼠对丙戊酸、左乙拉西坦和加巴喷丁更敏感。PSEN2 - N141I小鼠对丙戊酸和拉莫三嗪更敏感。
结论
随着生物学年龄的增长，AD基因型可能在体内差异影响ASMs的活性。这些发现突出了AD中癫痫发作风险的异质性，并表明精确选择的ASMs可能有益地控制AD中的癫痫发作以减缓认知衰退。
