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<p>Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy. Lowering the levels of <i>N</i>-methyl-<span>d</span>-aspartate receptor (NMDAR) ligands has been suggested as a promising therapeutic strategy for TLE. <span>d</span>-Serine gates synaptic NMDARs in the hippocampus but the effect of <span>d</span>-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 <span>d</span>-serine or blocking its binding with NMDARs suppressed seizures in mouse models. Astrocyte-derived <span>l</span>-serine was found to regulate interstitial <span>d</span>-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.</p><p></p>

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Pharmacological inhibition of PSPH reduces serine levels and epileptic seizures

  • 期刊论文

  • 发表日期：

    2025年6月2日

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  • Longze Sha,
  • Yanbing Wang,
  • Peixin Meng,
  • Yu Deng,
  • Ting Chen,
  • Xiuneng Zhang,
  • Yousong Ye,
  • Qi Xu

摘要

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.