CysLTR Antagonist HAMI 3379 Ameliorates Post-Stroke Depression Through NLRP3 Inflammasome/Pyroptosis Pathway in Gerbils

Overview

Journal Brain Sci

Publisher MDPI

Date 2022 Jul 27

PMID 35892417

Authors

Li Zhou

Jiajia Zhang

Xue Han

Jie Fang

Shasang Zhou

Lingqun Lu

Qiaojuan Shi

Huazhong Ying

Affiliations

Soon will be listed here.

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 (CysLTR) 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, ) 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 CysLTR by short hairpin RNA (shRNA) or overexpression of CysLTR by lentivirus (LV)-CysLTR could abolish or restore the anti-depression effect of HM3379. Our results demonstrated that the selective CysLTR antagonist HM3379 has beneficial effects on PSD, partially by suppressing the NLRP3 inflammasome/pyroptosis pathway.

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References

Kim J, Kim S, Kim D, Lee C, Park S, Jung J . Neuroprotective effect of forsythiaside against transient cerebral global ischemia in gerbil. Eur J Pharmacol. 2011; 660(2-3):326-33. DOI: 10.1016/j.ejphar.2011.03.051. View

Rachfalska N, Putowski Z, Krzych L . Distant Organ Damage in Acute Brain Injury. Brain Sci. 2020; 10(12). PMC: 7767338. DOI: 10.3390/brainsci10121019. View

Rubin E, Pippione A, Boyko M, Einaudi G, Sainas S, Collino M . A New NF-κB Inhibitor, MEDS-23, Reduces the Severity of Adverse Post-Ischemic Stroke Outcomes in Rats. Brain Sci. 2022; 12(1). PMC: 8773493. DOI: 10.3390/brainsci12010035. View

Zhang X, Wang X, Xu D, Yu S, Shi Q, Zhang L . HAMI 3379, a CysLT2 receptor antagonist, attenuates ischemia-like neuronal injury by inhibiting microglial activation. J Pharmacol Exp Ther. 2013; 346(2):328-41. DOI: 10.1124/jpet.113.203604. View

Du Y, Liang H, Zhang L, Fu F . Administration of Huperzine A exerts antidepressant-like activity in a rat model of post-stroke depression. Pharmacol Biochem Behav. 2017; 158:32-38. DOI: 10.1016/j.pbb.2017.06.002. View

Siotto M, Germanotta M, Santoro M, Cipollini V, Guardati G, Papadopoulou D . Serotonin Levels and Cognitive Recovery in Patients with Subacute Stroke after Rehabilitation Treatment. Brain Sci. 2021; 11(5). PMC: 8156601. DOI: 10.3390/brainsci11050642. View

Yang Y, Wang H, Kouadir M, Song H, Shi F . Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death Dis. 2019; 10(2):128. PMC: 6372664. DOI: 10.1038/s41419-019-1413-8. View

Shi Q, Xiao L, Zhao B, Zhang X, Wang X, Xu D . Intracerebroventricular injection of HAMI 3379, a selective cysteinyl leukotriene receptor 2 antagonist, protects against acute brain injury after focal cerebral ischemia in rats. Brain Res. 2012; 1484:57-67. DOI: 10.1016/j.brainres.2012.09.020. View

Koo Y, Kim H, Park J, Kim M, Shin Y, Choi B . Indoleamine 2,3-Dioxygenase-Dependent Neurotoxic Kynurenine Metabolism Contributes to Poststroke Depression Induced in Mice by Ischemic Stroke along with Spatial Restraint Stress. Oxid Med Cell Longev. 2019; 2018:2413841. PMC: 6332926. DOI: 10.1155/2018/2413841. View

10.

Chen L, Yang Y, Li C, Zhang S, Zheng W, Wei E . CysLT2 receptor mediates lipopolysaccharide-induced microglial inflammation and consequent neurotoxicity in vitro. Brain Res. 2015; 1624:433-445. DOI: 10.1016/j.brainres.2015.08.007. View

11.

Medeiros G, Roy D, Kontos N, Beach S . Post-stroke depression: A 2020 updated review. Gen Hosp Psychiatry. 2020; 66:70-80. DOI: 10.1016/j.genhosppsych.2020.06.011. View

12.

Li Y, Long W, Gao M, Jiao F, Chen Z, Liu M . TREM2 Regulates High Glucose-Induced Microglial Inflammation via the NLRP3 Signaling Pathway. Brain Sci. 2021; 11(7). PMC: 8306970. DOI: 10.3390/brainsci11070896. View

13.

Guo J, Wang J, Sun W, Liu X . The advances of post-stroke depression: 2021 update. J Neurol. 2021; 269(3):1236-1249. DOI: 10.1007/s00415-021-10597-4. View

14.

Man S, Karki R, Kanneganti T . Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev. 2017; 277(1):61-75. PMC: 5416822. DOI: 10.1111/imr.12534. View

15.

Ayuso M, Martinez-Alonso E, Chioua M, Escobar-Peso A, Gonzalo-Gobernado R, Montaner J . Quinolinyl Nitrone RP19 Induces Neuroprotection after Transient Brain Ischemia. ACS Chem Neurosci. 2017; 8(10):2202-2213. DOI: 10.1021/acschemneuro.7b00126. View

16.

Rahman S, Singh R, Hussain S, Akhtar M, Najmi A . A novel therapeutic potential of cysteinyl leukotrienes and their receptors modulation in the neurological complications associated with Alzheimer's disease. Eur J Pharmacol. 2018; 842:208-220. DOI: 10.1016/j.ejphar.2018.10.040. View

17.

Yu H, Tang M, Zeng Z, Huang S, Zheng X, Liu Z . Suppressive Effects of Gelsemine on Anxiety-like Behaviors Induced by Chronic Unpredictable Mild Stress in Mice. Brain Sci. 2022; 12(2). PMC: 8870043. DOI: 10.3390/brainsci12020191. View

18.

Yu P, Zhang M, Nan X, Zhao H, Gong D . Differences in the number of oxytocin, vasopressin, and tyrosine hydroxylase cells in brain regions associated with mating among great, midday, and Mongolian gerbils. Brain Res. 2020; 1733:146677. DOI: 10.1016/j.brainres.2020.146677. View

19.

Cao G, Jiang N, Hu Y, Zhang Y, Wang G, Yin M . Ruscogenin Attenuates Cerebral Ischemia-Induced Blood-Brain Barrier Dysfunction by Suppressing TXNIP/NLRP3 Inflammasome Activation and the MAPK Pathway. Int J Mol Sci. 2016; 17(9). PMC: 5037697. DOI: 10.3390/ijms17091418. View

20.

Ma D, Zhang N, Zhang Y, Chen H . Salvianolic Acids for Injection alleviates cerebral ischemia/reperfusion injury by switching M1/M2 phenotypes and inhibiting NLRP3 inflammasome/pyroptosis axis in microglia in vivo and in vitro. J Ethnopharmacol. 2021; 270:113776. DOI: 10.1016/j.jep.2021.113776. View