Esflurbiprofen exerts a fast-onset antidepressant effect by blocking SERT-nNOS interaction.

Journal: Acta pharmacologica Sinica
Published Date: Oct 9, 2025

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are characterized by delayed therapeutic onset largely due to their reliance on the desensitization of 5-HT1A autoreceptors (5-HT1ARautos) within the dorsal raphe nucleus (DRN). It has been shown that dissociation of serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS) interaction selectively modulates 5-HT1ARautos, thereby facilitating fast-onset antidepressant responses. Targeting the atypical disk large/ZO-1 (PDZ) domain has been implicated in the SERT-nNOS interaction. In this study, we established a drug screening system based on mBRET combined with biological tests to find SERT-nNOS interaction blockers (SNIBs). During screening the compound libraries, 9 top candidates were found to be capable of binding to the PDZ domain of nNOS. We then identified esflurbiprofen as a promising fast-onset antidepressant candidate. Pharmacodynamic studies revealed that esflurbiprofen effectively penetrated the DRN following systemic administration. Esflurbiprofen (10, 20, 40 mg/kg, i.p., once every 4 days) dose-dependently ameliorated depressive-like behaviors in mice subjected to chronic social defeat stress (CSDS) and chronic restraint stress (CRS). In rs-fMRI analysis, we found that esflurbiprofen enhanced the functional connectivity of emotion-related neural networks in CSDS mice. We further demonstrated that esflurbiprofen disrupted the SERT-nNOS complex in the DRN, augmented membrane-associated SERT, and reduced the concentration of 5-HT in the extracellular space of the DRN. This cascade subsequently enhanced serotonergic neuronal firing through the inhibition of negative feedback mediated by 5-HT1ARautos, culminating in an augmented release of 5-HT from serotonergic neurons projecting to the prefrontal cortex and hippocampus. These results highlight the potential of esflurbiprofen to induce rapid antidepressant effects by targeting the SERT-nNOS interaction within the DRN.

Authors

  • Yu-Qi Chen
    Department of Preventive Medicine, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, China.
  • Jun-Rui Ye
    State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • Sha-Sha Wang
    State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • Ye Peng
    Key Laboratory of Environmentally Friendly Chemistry and Applications of Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan 410005, P. R. China.
  • Run Zhou
    State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • Ruo-Lan Yuan
    State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • Wen-Fei Wang
    Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China.
  • Shi-Feng Chu
    State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. [email protected].
  • Zhao Zhang
  • Nai-Hong Chen
    College of Medicine and Health Sciences, China Three Gorges University, Yichang, 443002, China. [email protected].

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