Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia.
Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia.
Epilepsy Res. 2022 Oct;186:106994. doi: 10.1016/j.eplepsyres.2022.106994. Epub 2022 Aug 2.
To assess the effects of synaptic vesicle protein 2A (SV2A) modulators brivaracetam and levetiracetam on amygdala kindling epileptogenesis in Tg2576 mice, a model of Alzheimer's disease which exhibits sensitivity to seizures.
First, aged Tg2576 mice (13-25 months; n = 17) were treated subcutaneously with either brivaracetam (10 mg/kg/day), levetiracetam (150 mg/kg/day) or vehicle via osmotic pumps for 28 days prior to, and during electrical amygdala kindling epileptogenesis. Next, we treated young (4-6 months; n = 24) Tg2576 mice with brivaracetam (10 mg/kg/day) or vehicle for 28 days and allowed one week's 'washout' before commencing kindling. Progression of seizure severity and duration were compared between treatment groups and wildtype mice (WT).
In older Tg2576 mice, treatment with brivaracetam (p < 0.001) and levetiracetam (p < 0.05) before and during kindling significantly delayed the progression of seizure severity, compared to vehicle. Animals treated with brivaracetam required significantly more stimulations to reach the first class V (convulsive) seizure and had a lower mortality rate (p < 0.05) compared to those treated with vehicle. Young Tg2576 mice also exhibited increased susceptibility to kindling epileptogenesis compared to WT. Treatment with brivaracetam in younger animals only prior to kindling also delayed kindling acquisition compared to vehicle treatment, increasing the number of stimulations required to experience class V seizures (p < 0.05).
Brivaracetam treatment displayed marked anti-epileptogenic effects in both aged and young Tg2576 mice, including when treatment is ceased prior to initiating kindling. Targeting SV2A might represent a strategy for prevention of epilepsy in patients with Alzheimer's disease.
评估突触囊泡蛋白 2A（SV2A）调节剂布里瓦卡坦和左乙拉西坦对 Tg2576 小鼠杏仁核点燃癫痫发生的影响，Tg2576 小鼠是一种对癫痫发作敏感的阿尔茨海默病模型。
首先，将年龄较大的 Tg2576 小鼠（13-25 个月；n=17）通过皮下植入渗透泵给予布里瓦卡坦（10mg/kg/天）、左乙拉西坦（150mg/kg/天）或载体，在电刺激杏仁核点燃癫痫发生之前和期间进行 28 天治疗。接下来，我们用布里瓦卡坦（10mg/kg/天）或载体处理年轻（4-6 个月；n=24）Tg2576 小鼠 28 天，并在开始点燃之前进行一周的“洗脱”。然后比较治疗组和野生型小鼠（WT）之间的癫痫发作严重程度和持续时间的进展。
在年龄较大的 Tg2576 小鼠中，在点燃之前和期间用布里瓦卡坦（p<0.001）和左乙拉西坦（p<0.05）治疗与用载体治疗相比，显著延迟了癫痫发作严重程度的进展。与用载体治疗的动物相比，用布里瓦卡坦治疗的动物达到第一次 V 级（惊厥性）发作所需的刺激次数明显更多，死亡率更低（p<0.05）。年轻的 Tg2576 小鼠也比 WT 小鼠更容易发生点燃癫痫发生。在点燃之前仅用布里瓦卡坦治疗年轻动物也延迟了点燃获得，增加了经历 V 级发作所需的刺激次数（p<0.05）。
布里瓦卡坦治疗在年龄较大和年轻的 Tg2576 小鼠中均显示出明显的抗癫痫发生作用，包括在开始点燃之前停止治疗。靶向 SV2A 可能是预防阿尔茨海默病患者癫痫的一种策略。
