Sha Longze, Wang Yanbing, Meng Peixin, Deng Yu, Chen Ting, Zhang Xiuneng, Ye Yousong, Xu Qi
State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
State Key Laboratory of Complex, Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Nat Chem Biol. 2025 Jun 2. doi: 10.1038/s41589-025-01920-5.
Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy. Lowering the levels of N-methyl-D-aspartate receptor (NMDAR) ligands has been suggested as a promising therapeutic strategy for TLE. D-Serine gates synaptic NMDARs in the hippocampus but the effect of D-serine on seizure activity remains poorly understood. Here, we show that serine levels in the hippocampus were increased in persons with TLE and in a mouse model of TLE. Eliminating D-serine or blocking its binding with NMDARs suppressed seizures in mouse models. Astrocyte-derived L-serine was found to regulate interstitial D-serine levels and seizure activity through a process controlled by phosphoserine phosphatase (PSPH). We identified a potent PSPH inhibitor, Z218484536, and found that its systemic administration reduced spontaneous epileptic discharges in mouse and cynomolgus monkey models of TLE. Overall, these results indicate that PSPH is a promising therapeutic target for TLE and support further preclinical studies of Z218484536.
颞叶癫痫（TLE）是最常见的耐药性癫痫类型。降低N-甲基-D-天冬氨酸受体（NMDAR）配体水平已被认为是治疗TLE的一种有前景的策略。D-丝氨酸控制海马体中的突触NMDAR，但D-丝氨酸对癫痫发作活动的影响仍知之甚少。在此，我们表明TLE患者和TLE小鼠模型中海马体中的丝氨酸水平升高。消除D-丝氨酸或阻断其与NMDAR的结合可抑制小鼠模型中的癫痫发作。发现星形胶质细胞衍生的L-丝氨酸通过磷酸丝氨酸磷酸酶（PSPH）控制的过程调节间质D-丝氨酸水平和癫痫发作活动。我们鉴定出一种有效的PSPH抑制剂Z218484536，并发现全身给予该抑制剂可减少TLE小鼠和食蟹猴模型中的自发性癫痫放电。总体而言，这些结果表明PSPH是TLE的一个有前景的治疗靶点，并支持对Z218484536进行进一步的临床前研究。
