法国索邦大学Stéphanie Baulac小组发现，抗衰老药物靶向病理细胞可减少与神经发育mTOR相关的癫痫发作。这一研究成果于2024年5月6日在线发表在国际学术期刊《自然—神经科学》上。

据介绍，FCDII等皮质畸形与需要进行神经外科手术的小儿耐药性癫痫有关。FCDII是由于PI3K-AKT-mTOR通路基因的杂合子后突变导致的体细胞镶嵌，在健康的脑组织中产生一个畸形细胞亚群。

附：英文原文

Title: Targeting pathological cells with senolytic drugs reduces seizures in neurodevelopmental mTOR-related epilepsy

Author: Ribierre, Tho, Bacq, Alexandre, Donneger, Florian, Doladilhe, Marion, Maletic, Marina, Roussel, Delphine, Le Roux, Isabelle, Chassoux, Francine, Devaux, Bertrand, Adle-Biassette, Homa, Ferrand-Sorbets, Sarah, Dorfmller, Georg, Chipaux, Mathilde, Baldassari, Sara, Poncer, Jean-Christophe, Baulac, Stphanie

Issue&Volume: 2024-05-06

Abstract: Cortical malformations such as focal cortical dysplasia type II (FCDII) are associated with pediatric drug-resistant epilepsy that necessitates neurosurgery. FCDII results from somatic mosaicism due to post-zygotic mutations in genes of the PI3K-AKT-mTOR pathway, which produce a subset of dysmorphic cells clustered within healthy brain tissue. Here we show a correlation between epileptiform activity in acute cortical slices obtained from human surgical FCDII brain tissues and the density of dysmorphic neurons. We uncovered multiple signatures of cellular senescence in these pathological cells, including p53/p16 expression, SASP expression and senescence-associated β-galactosidase activity. We also show that administration of senolytic drugs (dasatinib/quercetin) decreases the load of senescent cells and reduces seizure frequency in an MtorS2215F FCDII preclinical mouse model, providing proof of concept that senotherapy may be a useful approach to control seizures. These findings pave the way for therapeutic strategies selectively targeting mutated senescent cells in FCDII brain tissue.

DOI: 10.1038/s41593-024-01634-2

Source: https://www.nature.com/articles/s41593-024-01634-2