Lafora disease (LD; OMIM#274780) is a fatal rare neurodegenerative disorder characterized by generalized epileptic seizures and the presence of polyglucosan inclusions (PGs), called Lafora bodies (LBs), typically in the brain. LD is caused by mutations in two genes EPM2A or EPM2B, which encode respectively laforin, a glucan phosphatase, and malin, an E3-ubiquitin ligase. Much remains unknown about the molecular bases of LD and, unfortunately, appropriate treatment is still missing; therefore patients die within 10 years from the onset of the disease. Recently, we have identified neuroinflammation as one of the initial determinants in LD. In this work, we have investigated anti-inflammatory treatments as potential therapies in LD. With this aim, we have performed a preclinical study in an Epm2b−/− mouse model with propranolol, a β-adrenergic antagonist, and epigallocatechin gallate (EGCG), an antioxidant from green tea extract, both of which displaying additional anti-inflammatory properties. In vivo motor and cognitive behavioral tests and ex vivo histopathological brain analyses were used as parameters to assess the therapeutic potential of propranolol and EGCG. After 2 months of treatment, we observed an improvement not only in attention defects but also in neuronal disorganization, astrogliosis, and microgliosis present in the hippocampus of Epm2b−/− mice. In general, propranolol intervention was more effective than EGCG in preventing the appearance of astrocyte and microglia reactivity. In summary, our results confirm the potential therapeutic effectiveness of the modulators of inflammation as novel treatments in Lafora disease.

拉福拉病 (LD; OMIM#274780) 是一种致命的罕见神经退行性疾病，其特征是全身性癫痫发作和存在称为拉福拉小体 (LB) 的聚葡萄糖包涵体 (PG)，通常存在于大脑中。 LD 是由EPM2A或EPM2B两个基因突变引起的，这两个基因分别编码 Laforin（一种葡聚糖磷酸酶）和 malin（一种 E3 泛素连接酶）。关于 LD 的分子基础仍有很多未知之处，不幸的是，仍然缺乏适当的治疗方法；因此，患者会在发病后 10 年内死亡。最近，我们发现神经炎症是 LD 的最初决定因素之一。在这项工作中，我们研究了抗炎治疗作为 LD 的潜在疗法。为此，我们在Epm2b−/−小鼠模型中进行了一项临床前研究，其中使用了普萘洛尔（一种 β-肾上腺素能拮抗剂）和表没食子儿茶素没食子酸酯 (EGCG)（一种来自绿茶提取物的抗氧化剂），这两种药物都具有额外的抗炎特性。使用体内运动和认知行为测试以及离体组织病理学脑分析作为参数来评估普萘洛尔和 EGCG 的治疗潜力。经过 2 个月的治疗，我们观察到Epm2b−/−小鼠海马区的神经元紊乱、星形胶质细胞增生和小胶质细胞增生不仅有改善，而且注意力缺陷也有改善。一般来说，普萘洛尔干预在预防星形胶质细胞和小胶质细胞反应性的出现方面比 EGCG 更有效。总之，我们的结果证实了炎症调节剂作为拉福拉病新疗法的潜在治疗效果。