Biomolecules & Therapeutics
Hycanthone Inhibits Inflammasome Activation and Neuroinflammation-Induced Depression-Like Behaviors in Mice
Kyung-Jun Boo1, Edson Luck Gonzales1, Chilly Gay Remonde1, Jae Young Seong2, Se Jin Jeon1,3, Yeong-Min Park4, Byung-Joo Ham5 and Chan Young Shin1,4,*
1School of Medicine and Center for Neuroscience Research, Konkuk University, Seoul 05029,
2Graduate School of Medicine, Korea University, Seoul 02841,
3Department of Integrative Biotechnology, College of Science and Technology, Sahmyook University, Seoul 01795,
4Graduate School of Medicine, Konkuk University, Seoul 05029,
5Department of Psychiatry, Korea University Anam Hospital, Korea University College of Medicine, Seoul 02841, Republic of Korea
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Received: May 30, 2022; Revised: August 19, 2022; Accepted: September 20, 2022; Published online: October 7, 2022.
© The Korean Society of Applied Pharmacology. All rights reserved.

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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: Neuroinflammation, Depression, Hycanthone, Animal model, Interferon signaling

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