Laboratory of Nutrient Signaling, Institute of Biomedicine of Valencia (CSIC), Valencia, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 46010, Valencia, Spain.
Mol Neurobiol. 2022 Oct;59(10):6018-6032. doi: 10.1007/s12035-022-02956-7. Epub 2022 Jul 14.
Lafora disease (LD) is a fatal rare neurodegenerative disorder that affects young adolescents and has no treatment yet. The hallmark of LD is the presence of polyglucosan inclusions (PGs), called Lafora bodies (LBs), in the brain and peripheral tissues. LD is caused by mutations in either EPM2A or EPM2B genes, which, respectively, encode laforin, a glucan phosphatase, and malin, an E3-ubiquitin ligase, with identical clinical features. LD knockout mouse models (Epm2a - / - and Epm2b - / -) recapitulate PG body accumulation, as in the human pathology, and display alterations in glutamatergic transmission and neuroinflammatory pathways in the brain. In this work, we show the results of four pre-clinical trials based on the modulation of glutamatergic transmission (riluzole and memantine) and anti-neuroinflammatory interventions (resveratrol and minocycline) as therapeutical strategies in an Epm2b - / - mouse model. Drugs were administered in mice from 3 to 5 months of age, corresponding to early stage of the disease, and we evaluated the beneficial effect of the drugs by in vivo behavioral phenotyping and ex vivo histopathological brain analyses. The behavioral assessment was based on a battery of anxiety, cognitive, and neurodegenerative tests and the histopathological analyses included a panel of markers regarding PG accumulation, astrogliosis, and microgliosis. Overall, the outcome of ameliorating the excessive glutamatergic neurotransmission present in Epm2b - / - mice by memantine displayed therapeutic effectiveness at the behavioral levels. Modulation of neuroinflammation by resveratrol and minocycline also showed beneficial effects at the behavioral level. Therefore, our study suggests that both therapeutical strategies could be beneficial for the treatment of LD patients. A mouse model of Lafora disease (Epm2b-/-) was used to check the putative beneficial effect of different drugs aimed to ameliorate the alterations in glutamatergic transmission and/or neuroinflammation present in the model. Drugs in blue gave a more positive outcome than the rest.
拉福拉病 (LD) 是一种致命的罕见神经退行性疾病，影响青少年，目前尚无治疗方法。LD 的特征是脑和外周组织中存在多聚糖包涵体 (PGs)，称为拉福拉体 (LB)。LD 是由 EPM2A 或 EPM2B 基因突变引起的，分别编码葡聚糖磷酸酶 laforin 和 E3 泛素连接酶 malin，具有相同的临床特征。LD 基因敲除小鼠模型 (Epm2a−/−和 Epm2b−/−) 再现了 PG 体的积累，与人类病理学一致，并显示大脑中谷氨酸能传递和神经炎症途径的改变。在这项工作中，我们展示了基于谷氨酸能传递调节 (利鲁唑和美金刚) 和抗神经炎症干预 (白藜芦醇和米诺环素) 的四项临床前试验的结果，作为 Epm2b−/−小鼠模型的治疗策略。药物从 3 到 5 个月大的小鼠开始给药，对应于疾病的早期阶段，我们通过体内行为表型和体外组织学大脑分析评估药物的有益效果。行为评估基于一组焦虑、认知和神经退行性测试，组织病理学分析包括一组关于 PG 积累、星形胶质细胞增生和小胶质细胞增生的标志物。总的来说，通过美金刚缓解 Epm2b−/−小鼠中过度谷氨酸能神经传递的结果显示在行为水平上具有治疗效果。白藜芦醇和米诺环素对神经炎症的调节也显示出在行为水平上的有益效果。因此，我们的研究表明，这两种治疗策略都可能对 LD 患者的治疗有益。使用拉福拉病小鼠模型 (Epm2b−/−) 检查不同药物对改善模型中谷氨酸能传递和/或神经炎症改变的潜在有益作用。蓝色药物的结果比其他药物更积极。
