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Published on: August 11, 2015
Tomentosin selectively targets microglial pyroptosis to overcome fluoxetine-resistant depression: a network-based
Jin-Seok Lee1,2, Ji-Yun Kang3, Won-Yung Lee4
1Institute of Bioscience & Integrative Medicine, Daejeon University, Daejeon, Republic of Korea. neptune@dju.ac.kr.
Abstract:
Treatment-resistant depression (TRD), a clinically challenging issue of major depressive disorder (MDD), affects up to one-third of patients and is associated with elevated suicide risk and limited treatment options. Cumulative evidence highlights pathological microglial state and inflammasome-derived pyroptosis as key contributors to TRD pathophysiology. This study aimed to validate tomentosin as a network-based identified antidepressants and anti-microglial candidate and to define its mechanisms in suppressing microglial pyroptosis. Through a network-based multiscale interactome screening of a large terpenoid library exceeding 170,000 compounds, we identified tomentosin, a brain-penetrant sesquiterpene lactone with favorable drug-likeness and network relevance. In mice unresponsive to fluoxetine (called as FRD, fluoxetine-resistant depression), tomentosin (20 mg/kg) significantly alleviated depressive behaviors and normalized reactive microglial states in the anterior cingulate cortex (ACC). These pharmacological effects were observed in systemic and intracerebral inflammation-induced depressive mice models. We found that tomentosin mechanistically targeted the suppression of microglial NOD-like receptor protein-3 (NLRP3)/caspase-1/gasdermin D (GSDMD) signaling pathway. This inflammasome-specific suppressive effect was confirmed by the absence of pharmacological effects in caspase-1 knockout (Casp1 KO) mice. Underlying mechanisms were further validated through molecular interaction analyses, comparative studies with inhibitors, and overexpression vector transfections. Our findings suggest that tomentosin is a novel agent that selectively modulates inflammasome-associated microglia in FRD, primarily by suppressing pyroptosis in the ACC.
Insights
Tomentosin, a novel compound, effectively treats depression resistant to fluoxetine by reducing harmful microglial pyroptosis. This discovery offers new hope for treatment-resistant depression (TRD) patients.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Treatment-resistant depression (TRD) affects up to one-third of major depressive disorder (MDD) patients, presenting significant clinical challenges.
- Pathological microglial activation and inflammasome-mediated pyroptosis are increasingly recognized as key contributors to TRD.
- Current treatment options for TRD are limited, highlighting the need for novel therapeutic strategies.
Purpose of the Study:
- To validate tomentosin, identified via network-based screening, as a potential antidepressant and anti-microglial agent.
- To elucidate the precise mechanisms by which tomentosin suppresses microglial pyroptosis in the context of depression.
Main Methods:
- Network-based multiscale interactome screening of over 170,000 terpenoids identified tomentosin.
- Pharmacological evaluation of tomentosin in fluoxetine-resistant depression (FRD) and inflammation-induced depression mouse models.
- Mechanistic studies involving molecular interaction analyses, caspase-1 knockout mice, and overexpression vectors to confirm pathway targeting.
Main Results:
- Tomentosin (20 mg/kg) significantly alleviated depressive behaviors and normalized reactive microglial states in the anterior cingulate cortex (ACC) of FRD mice.
- These antidepressant effects were observed in both systemic and intracerebral inflammation-induced depression models.
- Tomentosin was confirmed to mechanistically suppress the NOD-like receptor protein-3 (NLRP3)/caspase-1/gasdermin D (GSDMD) signaling pathway, inhibiting pyroptosis.
Conclusions:
- Tomentosin is a novel, brain-penetrant sesquiterpene lactone with antidepressant properties.
- It selectively targets inflammasome-associated microglia in FRD by suppressing pyroptosis, particularly in the ACC.
- Tomentosin represents a promising therapeutic candidate for treating TRD by modulating microglial inflammatory pathways.
