Nobili Paola, Cattalini Alessandro, de Grazia Ugo, Cagnoli Cinzia, de Curtis Marco, Battaglia Giorgio Stefano, Colciaghi Francesca
Clinical and Experimental Epileptology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
Laboratory of Neurological Biochemistry and Neuropharmacology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
Front Pharmacol. 2020 Feb 28;11:181. doi: 10.3389/fphar.2020.00181. eCollection 2020.
Antiepileptic drug-resistance is a major health problem in patients with cortical dysplasia (CD). Whether drug-resistant epilepsy is associated with progressive brain damage is still debated. We previously generated a rat model of acquired CD, the methylazoxymethanol-pilocarpine (MP) rat, in which the occurrence of status epilepticus and subsequent spontaneous seizures induce progressive brain damage (Nobili et al., 2015). The present study tested the outcome of early-chronic carbamazepine (CBZ) administration on both seizure activity and brain damage in MP rats. We took advantage of the non-invasive CBZ-in-food administration protocol, established by Ali (2012), which proved effective in suppressing generalized convulsive seizures in kainic acid rat model of epilepsy. MP rats were treated immediately after the onset of the first spontaneous seizure with 300 mg/kg/day CBZ formulated in pellets for a two-months-trial. CBZ-treated rats were continuously video-monitored to detect seizure activity and were compared with untreated epileptic MP rats. Despite CBZ serum levels in treated rats were within the suggested therapeutic range for humans, CBZ affected spontaneous convulsive seizures in 2 out of 10 treated rats (responders), whereas the remaining animals (non-responders) did not show any difference when compared to untreated MP rats. Histological analysis revealed cortical thinning paralleled by robust staining of Fluoro-Jade (FJ) degenerating neurons and diffuse tissue necrosis in CBZ-non-responder CBZ-responder rats. Data reported here suggest that MP rat model represents suitable experimental setting where to investigate mechanisms of CD-related drug-resistant epilepsy and to verify if modulation of seizures, with appropriate treatment, may reduce seizure-induced brain damage.
抗癫痫药物耐药性是皮质发育异常（CD）患者的一个主要健康问题。耐药性癫痫是否与进行性脑损伤相关仍存在争议。我们之前建立了一种获得性CD的大鼠模型，即甲基偶氮甲醇-匹鲁卡品（MP）大鼠模型，其中癫痫持续状态的发生和随后的自发性癫痫发作会导致进行性脑损伤（Nobili等人，2015年）。本研究测试了早期长期给予卡马西平（CBZ）对MP大鼠癫痫活动和脑损伤的影响。我们利用了Ali（2012年）建立的非侵入性CBZ混入食物给药方案，该方案在抑制癫痫的红藻氨酸大鼠模型中的全身性惊厥发作方面被证明是有效的。在首次自发性癫痫发作开始后，立即用制成颗粒状的300mg/kg/天的CBZ对MP大鼠进行为期两个月的试验治疗。对接受CBZ治疗的大鼠进行连续视频监测以检测癫痫活动，并与未治疗的癫痫MP大鼠进行比较。尽管治疗大鼠的CBZ血清水平在人类建议的治疗范围内，但CBZ对10只接受治疗的大鼠中的2只（有反应者）的自发性惊厥发作有影响，而其余动物（无反应者）与未治疗的MP大鼠相比没有任何差异。组织学分析显示，在CBZ无反应者中，皮质变薄，同时氟玉髓（FJ）变性神经元有强烈染色，且有弥漫性组织坏死，而CBZ有反应者则不然。此处报告的数据表明，MP大鼠模型代表了一个合适的实验环境，可以在此研究与CD相关的耐药性癫痫的机制，并验证通过适当治疗调节癫痫发作是否可以减少癫痫发作引起的脑损伤。
