Abstract
Poststroke hyperglycemia and inflammation have been implicated in the pathogenesis of stroke. Janus Kinase 2 (Jak2), a catalytic signaling component for cytokine receptors such as Interleukin-6 (IL-6), has inflammatory and metabolic properties. This study aimed to investigate the roles of Jak2 in poststroke inflammation and metabolic abnormality in a rat model of permanent cerebral ischemia. Pretreatment with Jak2 inhibitor AG490 ameliorated neurological deficit, brain infarction, edema, oxidative stress, inflammation, caspase-3 activation, and Zonula Occludens-1 (ZO-1) reduction. Moreover, in injured cortical tissues, Tumor Necrosis Factor-α, IL-1β, and IL-6 levels were reduced with concurrent decreased NF-κB p65 phosphorylation, Signal Transducers and Activators of Transcription 3 phosphorylation, Ubiquitin Protein Ligase E3 Component N-Recognin 1 expression, and Matrix Metalloproteinase activity. In the in vitro study on bEnd.3 endothelial cells, AG490 diminished IL-6-induced endothelial barrier disruption by decreasing ZO-1 decline. Metabolically, administration of AG490 lowered fasting glucose, with improvements in glucose intolerance, plasma-free fatty acids, and plasma C Reactive Proteins. In conclusion, AG490 improved the inflammation and oxidative stress of neuronal, hepatic, and muscle tissues of stroke rats as well as impairing insulin signaling in the liver and skeletal muscles. Therefore, Jak2 blockades may have benefits for combating poststroke central and peripheral inflammation, and metabolic abnormalities.
Highlights
The Janus Kinase 2 (Jak2) inhibitor AG490 has been used in investigations of cerebral ischemia to explore the role of IL-6 [34,36,45]
The blockade of potential IL-6/Jak2 signaling was produced through the intraperitoneal introduction of AG490 30 min prior to cerebral ischemia
Our findings revealed that poststroke hyperglycemia, glucose intolerance, and brain injury were linked to high IL-6 content, and the Jak2 inhibitor AG490 reversed these alterations
Summary
Occlusion, or rupture can cause insufficient blood flow and perfusion in the brain, potentially leading to hypoxia, neurological deficits, physical creativecommons.org/licenses/by/ 4.0/). Antioxidants 2021, 10, 1958 disability, and even death [1]. In a recently published review, it is reported that in patients with acute ischemic stroke, early intravenous thrombolysis improves the likelihood of minimal or no disability by around one third within 3–4.5 h of presentation [2]. Acute stroke patients due to large-vessel occlusions are more likely to be functionally independent when treated with mechanical thrombectomy within 6 h of presentation. 10% of ischemic stroke patients receive these therapies due to constraints such as narrow therapeutic windows, and many patients progress into persistent disability [3,4,5,6].
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