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

Acta Pharmacologica Sinica (2025)Cite this article

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.

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Fig. 1: Esflurbiprofen could block SERT-nNOS interaction.
Fig. 2: Esflurbiprofen exerts fast-onset antidepressant effects.
Fig. 3: Esflurbiprofen improves depression-like behaviors in depressed mice.
Fig. 4: Esflurbiprofen improved the functional connectivity of CSDS mice.
Fig. 5: Esflurbiprofen increased the firing activity of serotonin neuron.
Fig. 6: Esflurbiprofen exerts a fast-onset antidepressant effect by disrupting SERT-nNOS interaction in DRN.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82130109, U2202214, U21A20410), and CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-020). The figures were created with BioRender.com.

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  1. These authors contributed equally: Yu-qi Chen, Jun-rui Ye

Authors and Affiliations

  1. College of Medicine and Health Sciences, China Three Gorges University, Yichang, 443002, China

    Yu-qi Chen & Nai-hong Chen

  2. 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

    Jun-rui Ye, Sha-sha Wang, Ye Peng, Run Zhou, Ruo-lan Yuan, Shi-feng Chu, Zhao Zhang & Nai-hong Chen

  3. Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China

    Sha-sha Wang, Ye Peng, Wen-fei Wang & Nai-hong Chen

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Contributions

SFC, ZZ, and NHC designed research. YQC, JRY, SSW, YP, and RZ performed research and wrote the paper. RLY and WFW participated in data analysis. SFC, ZZ, and NHC revised the paper. All the authors have read and approved the final version of the manuscript.

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Correspondence to Shi-feng Chu, Zhao Zhang or Nai-hong Chen.

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Chen, Yq., Ye, Jr., Wang, Ss. et al. Esflurbiprofen exerts a fast-onset antidepressant effect by blocking SERT-nNOS interaction. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01666-9

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