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CysLT2R Antagonist HAMI 3379 Ameliorates Post-Stroke Depression through NLRP3 Inflammasome/Pyroptosis Pathway in
Li Zhou1, Jiajia Zhang2, Xue Han2
1School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
Insights
The cysteinyl leukotriene receptor 2 (CysLT2R) antagonist HAMI3379 (HM3379) effectively treats post-stroke depression (PSD) in gerbils. HM3379 alleviates neuroinflammation and pyroptosis by inhibiting the NLRP3 inflammasome pathway.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Post-stroke depression (PSD) is a common complication affecting stroke recovery and survival.
- Cysteinyl leukotriene receptor 2 (CysLT2R) antagonist HAMI3379 (HM3379) has shown promise in improving neurological injury.
- The role of HM3379 in PSD-related neuroinflammation and its underlying mechanisms require further investigation.
Purpose of the Study:
- To investigate the therapeutic effects of HM3379 on PSD-induced chronic neuroinflammation in a gerbil model.
- To elucidate the molecular mechanisms by which HM3379 exerts its anti-depressive effects in PSD.
- To determine the involvement of the NLRP3 inflammasome and pyroptosis pathways in HM3379's action.
Main Methods:
- A gerbil model of PSD was established using transient global cerebral ischemia (tGCI) and spatial restraint stress.
- Gerbils were treated with either vehicle or HM3379 (0.1 mg/kg) for 14 days.
- Neurological severity, depression-like behaviors, neuronal loss, microglial activation, and key proteins of the NLRP3 inflammasome/pyroptosis pathway were assessed.
Main Results:
- HM3379 significantly improved neurological deficit scores and reduced depression-like behaviors in PSD gerbils.
- HM3379 administration mitigated neuronal loss, decreased TUNEL-positive cells, and reduced microglial activation in the cerebral cortex.
- HM3379 downregulated the expression of NLRP3 inflammasome components (NLRP3, ASC, cleaved caspase-1) and pyroptosis markers (IL-1β, IL-18, cleaved GSDMD-N).
Conclusions:
- HM3379 demonstrates significant therapeutic benefits for post-stroke depression in a gerbil model.
- HM3379 exerts its anti-depressive effects, at least partially, by suppressing NLRP3 inflammasome activation and subsequent pyroptosis.
- Targeting CysLT2R with HM3379 represents a potential therapeutic strategy for managing PSD and associated neuroinflammation.
Abstract:
Post-stroke depression (PSD) is a kind of prevalent emotional disorder following stroke that usually results in slow functional recovery and even increased mortality. We had reported that the cysteinyl leukotriene receptor 2 (CysLT2R) antagonist HAMI3379 (HM3379) contributes to the improvement of neurological injury. The present study was designed to investigate the role of HM3379 in PSD-induced chronic neuroinflammation and related mechanisms in gerbils. The gerbils were subjected to transient global cerebral ischemia (tGCI) and spatial restraint stress to induce the PSD model. They were randomized to receive the vehicle or HM3379 (0.1 mg/kg, i.p.) for a consecutive 14 days. In the PSD-treated gerbils, HM3379 had noteworthy efficacy in improving the modified neurological severity score (mNSS) and depression-like behaviors, including the sucrose preference test and the forced swim test. HM3379 administration significantly mitigated neuron loss, lessened TUNEL-positive neurons, and reduced the activation of microglia in the cerebral cortex. Importantly, HM3379 downregulated protein expressions of the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome and pyroptosis including NLRP3, cleaved caspase-1, interleukin-1β (IL-1β), IL-18, cleaved gasdermin-N domain (GSDMD-N), and apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). Mechanistically, HM3379 could repress pyroptosis via inhibiting NLRP3 inflammasome activation under oxygen-glucose deprivation (OGD) stimulation. Knockdown of CysLT2R by short hairpin RNA (shRNA) or overexpression of CysLT2R by lentivirus (LV)-CysLT2R could abolish or restore the anti-depression effect of HM3379. Our results demonstrated that the selective CysLT2R antagonist HM3379 has beneficial effects on PSD, partially by suppressing the NLRP3 inflammasome/pyroptosis pathway.
