2. Academic Validation
  3. Pharmacological inhibition of PSPH reduces serine levels and epileptic seizures

Pharmacological inhibition of PSPH reduces serine levels and epileptic seizures

  • Nat Chem Biol. 2025 Jun 2. doi: 10.1038/s41589-025-01920-5.
Longze Sha # 1 2 3,  Yanbing Wang # 1,  Peixin Meng 1,  Yu Deng 1,  Ting Chen 4,  Xiuneng Zhang 1,  Yousong Ye 3 5,  Qi Xu 6 7
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, China.
  • 4 Institute of Child and Adolescent Health, School of Public Health, Peking University, Beijing, China.
  • 5 Institute of Medical Biology, Chinese Academy of Medical Sciences, Kunming, China.
  • 6 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. xuqi@pumc.edu.cn.
  • 7 Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, China. xuqi@pumc.edu.cn.
  • # Contributed equally.
PMID: 40456963 DOI: 10.1038/s41589-025-01920-5
Abstract

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.

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