CysLT<sub>2</sub>R Antagonist HAMI 3379 Ameliorates Post-Stroke Depression through NLRP3 Inflammasome/Pyroptosis Pathway in Gerbils
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 (CysLT<sub>2</sub>R) antagonist HAMI3379 (HM3379) contributes t...
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MDPI AG
2022-07-01
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| Online Access: | https://www.mdpi.com/2076-3425/12/8/976 |
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| author | Li Zhou Jiajia Zhang Xue Han Jie Fang Shasang Zhou Lingqun Lu Qiaojuan Shi Huazhong Ying |
| author_facet | Li Zhou Jiajia Zhang Xue Han Jie Fang Shasang Zhou Lingqun Lu Qiaojuan Shi Huazhong Ying |
| author_sort | Li Zhou |
| collection | DOAJ |
| description | 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 (CysLT<sub>2</sub>R) 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>i.p.</i>) 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 CysLT<sub>2</sub>R by short hairpin RNA (shRNA) or overexpression of CysLT<sub>2</sub>R by lentivirus (LV)-CysLT<sub>2</sub>R could abolish or restore the anti-depression effect of HM3379. Our results demonstrated that the selective CysLT<sub>2</sub>R antagonist HM3379 has beneficial effects on PSD, partially by suppressing the NLRP3 inflammasome/pyroptosis pathway. |
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| spelling | doaj.art-99499f08e9ed48e584cdb28c273847682023-12-03T13:23:29ZengMDPI AGBrain Sciences2076-34252022-07-0112897610.3390/brainsci12080976CysLT<sub>2</sub>R Antagonist HAMI 3379 Ameliorates Post-Stroke Depression through NLRP3 Inflammasome/Pyroptosis Pathway in GerbilsLi Zhou0Jiajia Zhang1Xue Han2Jie Fang3Shasang Zhou4Lingqun Lu5Qiaojuan Shi6Huazhong Ying7School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, ChinaZhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, ChinaZhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, ChinaZhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, ChinaZhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, ChinaZhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, ChinaZhejiang Provincial Key Laboratory of Laboratory Animals and Safety Research, Hangzhou Medical College, Hangzhou 310013, ChinaSchool of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, ChinaPost-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 (CysLT<sub>2</sub>R) 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>i.p.</i>) 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 CysLT<sub>2</sub>R by short hairpin RNA (shRNA) or overexpression of CysLT<sub>2</sub>R by lentivirus (LV)-CysLT<sub>2</sub>R could abolish or restore the anti-depression effect of HM3379. Our results demonstrated that the selective CysLT<sub>2</sub>R antagonist HM3379 has beneficial effects on PSD, partially by suppressing the NLRP3 inflammasome/pyroptosis pathway.https://www.mdpi.com/2076-3425/12/8/976cysteinyl leukotriene receptor 2HAMI 3379post-stroke depressionneuroinflammationNLRP3 inflammasomepyroptosis |
| spellingShingle | Li Zhou Jiajia Zhang Xue Han Jie Fang Shasang Zhou Lingqun Lu Qiaojuan Shi Huazhong Ying CysLT<sub>2</sub>R Antagonist HAMI 3379 Ameliorates Post-Stroke Depression through NLRP3 Inflammasome/Pyroptosis Pathway in Gerbils Brain Sciences cysteinyl leukotriene receptor 2 HAMI 3379 post-stroke depression neuroinflammation NLRP3 inflammasome pyroptosis |
| title | CysLT<sub>2</sub>R Antagonist HAMI 3379 Ameliorates Post-Stroke Depression through NLRP3 Inflammasome/Pyroptosis Pathway in Gerbils |
| title_full | CysLT<sub>2</sub>R Antagonist HAMI 3379 Ameliorates Post-Stroke Depression through NLRP3 Inflammasome/Pyroptosis Pathway in Gerbils |
| title_fullStr | CysLT<sub>2</sub>R Antagonist HAMI 3379 Ameliorates Post-Stroke Depression through NLRP3 Inflammasome/Pyroptosis Pathway in Gerbils |
| title_full_unstemmed | CysLT<sub>2</sub>R Antagonist HAMI 3379 Ameliorates Post-Stroke Depression through NLRP3 Inflammasome/Pyroptosis Pathway in Gerbils |
| title_short | CysLT<sub>2</sub>R Antagonist HAMI 3379 Ameliorates Post-Stroke Depression through NLRP3 Inflammasome/Pyroptosis Pathway in Gerbils |
| title_sort | cyslt sub 2 sub r antagonist hami 3379 ameliorates post stroke depression through nlrp3 inflammasome pyroptosis pathway in gerbils |
| topic | cysteinyl leukotriene receptor 2 HAMI 3379 post-stroke depression neuroinflammation NLRP3 inflammasome pyroptosis |
| url | https://www.mdpi.com/2076-3425/12/8/976 |
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