Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Hycanthone Inhibits Inflammasome Activation and Neuroinflammation-Induced Depression-Like Behaviors in Mice

  • Kyung-Jun, Boo (School of Medicine and Center for Neuroscience Research, Konkuk University) ;
  • Edson Luck, Gonzales (School of Medicine and Center for Neuroscience Research, Konkuk University) ;
  • Chilly Gay, Remonde (School of Medicine and Center for Neuroscience Research, Konkuk University) ;
  • Jae Young, Seong (Graduate School of Medicine, Korea University) ;
  • Se Jin, Jeon (School of Medicine and Center for Neuroscience Research, Konkuk University) ;
  • Yeong-Min, Park (Graduate School of Medicine, Konkuk University) ;
  • Byung-Joo, Ham (Department of Psychiatry, Korea University Anam Hospital, Korea University College of Medicine) ;
  • Chan Young, Shin (School of Medicine and Center for Neuroscience Research, Konkuk University)
  • Received : 2022.05.30
  • Accepted : 2022.09.20
  • Published : 2023.03.01
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Abstract

Despite the various medications used in clinics, the efforts to develop more effective treatments for depression continue to increase in the past decades mainly because of the treatment-resistant population, and the testing of several hypotheses- and target-based treatments. Undesirable side effects and unresponsiveness to current medications fuel the drive to solve this top global health problem. In this study, we focused on neuroinflammatory response-mediated depression which represents a cluster of depression etiology both in animal models and humans. Several meta-analyses reported that proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) were increased in major depressive disorder patients. Inflammatory mediators implicated in depression include type-I interferon and inflammasome pathways. To elucidate the molecular mechanisms of neuroinflammatory cascades underlying the pathophysiology of depression, we introduced hycanthone, an antischistosomal drug, to check whether it can counteract depressive-like behaviors in vivo and normalize the inflammation-induced changes in vitro. Lipopolysaccharide (LPS) treatment increased proinflammatory cytokine expression in the murine microglial cells as well as the stimulation of type I interferon-related pathways that are directly or indirectly regulated by Janus kinase-signal transducer and activator of transcription (JAK-STAT) activation. Hycanthone treatment attenuated those changes possibly by inhibiting the JAK-STAT pathway and inflammasome activation. Hycanthone also ameliorated depressive-like behaviors by LPS. Taken together, we suggest that the inhibitory action of hycanthone against the interferon pathway leading to attenuation of depressive-like behaviors can be a novel therapeutic mechanism for treating depression.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2016R1A5A2012284 and NRF-2020M3E5D9080165 to Dr. Shin) and by the Korea Drug Development Fund, funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (HN21C1076 to Dr. Jeon).

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