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 98195.
Department of Neurology, School of Medicine, University of Washington, Seattle, WA 98195.
bioRxiv. 2024 Oct 7:2024.10.06.616921. doi: 10.1101/2024.10.06.616921.
Alzheimer's disease (AD) patients are at greater risk of focal seizures than similarly aged adults; these seizures, left untreated, may worsen functional 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 mouse model of acquired chronic secondarily generalized focal seizures allows for precisely timed drug administration studies to quantify the efficacy and tolerability of ASMs in an AD-associated genetic model. Wh+e hypothesized that mechanistically distinct ASMs would exert differential anticonvulsant activity and tolerability in aged AD mice (8-15 months) to define whether rational ASM selection may benefit specific AD genotypes.
Aged male and female PSEN2-N141I versus age-matched non-transgenic control (PSEN2 control) C57Bl/6J mice, and APP/PS1 versus transgene negative (APP control) littermates underwent corneal kindling to quantify latency to fully kindled criterion. Dose-related ASM efficacy was then compared in each AD model versus matched control over 1-2 months using ASMs commonly prescribed in older adults with epilepsy: valproic acid, levetiracetam, lamotrigine, phenobarbital, and gabapentin.
Sex and AD genotype differentially impacted seizure susceptibility. Male PSEN2-N141I mice required more stimulations to attain kindling criterion (X=5.521; p<0.05). Male APP/PS1 mice did not differ in kindling rate versus APP control mice, but they 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 than APP controls to valproic acid, levetiracetam, and gabapentin. PSEN2-N141I mice were more sensitive than PSEN2 controls to valproic acid and lamotrigine.
AD genotypes may differentially impact ASMs activity and tolerability 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, thus reducing functional decline.
与年龄相仿的成年人相比，阿尔茨海默病（AD）患者发生局灶性癫痫发作的风险更高；这些癫痫发作若不治疗，可能会使功能衰退恶化。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能否在AD中差异控制癫痫发作尚不清楚。获得性慢性继发性全身性局灶性癫痫发作的角膜点燃小鼠模型允许进行精确计时的药物给药研究，以量化ASMs在AD相关遗传模型中的疗效和耐受性。我们假设，机制不同的ASMs在老年AD小鼠（8 - 15个月）中会发挥不同的抗惊厥活性和耐受性，以确定合理选择ASMs是否可能使特定的AD基因型受益。
对老年雄性和雌性PSEN2 - N141I小鼠与年龄匹配的非转基因对照（PSEN2对照）C57Bl/6J小鼠，以及APP/PS1小鼠与转基因阴性（APP对照）同窝小鼠进行角膜点燃，以量化达到完全点燃标准的潜伏期。然后，在1 - 2个月的时间里，使用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），比较每个AD模型与匹配对照的剂量相关的ASM疗效。
性别和AD基因型对癫痫易感性有不同影响。雄性PSEN2 - N141I小鼠达到点燃标准需要更多刺激（X = 5.521；p < 0.05）。雄性APP/PS1小鼠与APP对照小鼠的点燃率没有差异，但它们的癫痫发作更严重。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小鼠比APP对照小鼠对丙戊酸、左乙拉西坦和加巴喷丁更敏感。PSEN2 - N141I小鼠比PSEN2对照小鼠对丙戊酸和拉莫三嗪更敏感。
随着生物学年龄的增长，AD基因型可能在体内对ASMs的活性和耐受性产生不同影响。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，从而减少功能衰退。
