Lumbrokinase regulates endoplasmic reticulum stress to improve neurological deficits in ischemic stroke

• Published in: Neuropharmacology 2022-12, Vol.221, p.109277-109277, Article 109277
• Main Authors: Wang, Yi-Hsin, Liao, Jiuan-Miaw, Chen, Ke-Min, Su, Hsing-Hui, Liu, Pei-Hsun, Chen, Yi-Hung, Tsuei, Yuang-Seng, Tsai, Chin-Feng, Huang, Shiang-Suo
• Format: Article
• Language: English
• Subjects: ER stress; IRE1; Ischemic stroke; Lumbrokinase; NLRP3
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2022.109277

Ischemic stroke is characterized by the loss of cerebral blood flow, which frequently leads to neurological deficits. Tissue plasminogen activator is the only therapeutic agent approved to treat ischemic stroke but increases the risk of intracranial hemorrhage and mortality. The fibrinogen-depleting agent lumbrokinase has been used to improve myocardial perfusion in symptomatic stable angina and to prevent secondary ischemic stroke. Lumbrokinase is highly fibrin-specific and only active in the presence of fibrin. Therefore, lumbrokinase has a low risk of hemorrhage due to excessive fibrinolysis. In this study, we aimed to clarify the neuroprotection of lumbrokinase in mice subjected to permanent middle cerebral artery occlusion. Lumbrokinase significantly attenuated infarct volume and improved neurological dysfunction. Lumbrokinase dramatically decreased the expressions of the endoplasmic reticulum (ER) transmembrane receptor protein inositol-requiring enzyme-1 (IRE1) and its downstream transcription factor, XBP-1, caspase-12, and NF-κB activity, thereby significantly inhibiting apoptosis and autophagy and decreasing the NLRP3 inflammasome. Our evidence indicates that post-stroke treatment with lumbrokinase protects against ischemic stroke, thereby regulating ER stress through the collective inhibitory effect of the IRE1 signaling pathways to decrease apoptosis, autophagy, and inflammatory responses. We suggest that lumbrokinase is potential as an adjuvant treatment for ischemic stroke. [Display omitted] •Lumbrokinase significantly attenuated the infarct volume and improved the neurological dysfunction in ischemic stroke mice.•The beneficial neuroprotective effects of lumbrokinase might be through the IRE1 signaling pathways to antagonize ischemic stroke injury.•Lumbrokinase has the potential as adjuvant therapy for ischemic stroke.