BIO alleviates inflammation through inhibition of GSK-3β in a rat model of intracerebral hemorrhage

Abstract

<jats:sec><jats:title>OBJECTIVE</jats:title><jats:p>Inflammation plays a key role in secondary brain damage following intracerebral hemorrhage (ICH). Glycogen synthase kinase–3β (GSK-3β) plays a strong proinflammatory role in many CNS diseases, including stroke. The present study was undertaken to examine the effects of 6-bromoindirubin-3ʹ-oxime (BIO), a specific inhibitor of GSK-3β, on inflammation in ICH rats.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>An ICH rat model was induced by autologous whole-blood injection into the striatum. First, 10, 20, 40, 60, 80, or 100 μg/kg BIO was applied to ICH animals to determine an optimal dosage for producing sufficient GSK-3β inhibition in rat ipsilateral hippocampus by Western blotting. Second, 40 μg/kg BIO was applied to ICH rats for 1, 3, 7, or 14 days, respectively, to determine a suitable intervention time course of BIO by Western blotting analysis on GSK-3β. Third, Western blotting and enzyme-linked immunosorbent assay were used for quantification of inflammation-related factors upstream or downstream of GSK-3β in rat ipsilateral hippocampus. Then, immunohistochemical staining was applied to detect activated microglia and apoptotic cells in rat ipsilateral hippocampus. Last, neurobehavioral tests were performed to assess the sensorimotor impairments in the ICH rats.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>The results show that BIO 1) blocked GSK-3β<jats:sup>Tyr216</jats:sup> phosphorylation/activation, thus stabilizing β-catenin, increasing upstream brain-derived neurotrophic factor and downstream heat shock protein 70 levels, and decreasing the levels of nuclear factor–κB p65 and cyclooxygenase 2; 2) decreased the levels of the proinflammatory cytokines tumor necrosis factor–α and interleukin (IL)–1β and IL-6 and elevated the level of antiinflammatory cytokine IL-10; 3) inhibited microglia activation and cell apoptosis; and 4) improved the sensorimotor deficits of ICH rats.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>BIO posttreatment inhibited microglia activation, prevented inflammation and hippocampal cell death, and ameliorated functional and morphological outcomes in a rat ICH model through inactivation of GSK-3β.</jats:p></jats:sec>

Neurogenesis After Stroke: A Therapeutic Perspective

“…Factors like Sirtuin 7, Glucagon-Like Peptide-1, and Nei like DNA Glycosylase 1 enhance neurogenesis by suppressing neuroinflammation [43][44][45]. Inhibition of Glycogen Synthase Kinase-3 (GSK-3) has also been shown to increase neurogenesis, while reducing neuroinflammation, implicating Wnt signaling in the process [46][47][48]. However, depending on the timing, duration, and the profile of cytokines and chemokines released, neurogenesis could be positively impacted [17,18,[49][50][51].…”

“…One GSK inhibitor called Tideglusib has been investigated in clinical trials as well, where it was deemed clinically safe but was not effective [122,123]. Other GSK inhibitors that may be worth exploring include 6-bromoindirubin-30-oxime (BIO) [46,48] and lithium chloride [47,124].…”

Metal ion-responsive nanocarrier derived from phosphonated calix[4]arenes for delivering dauricine specifically to sites of brain injury in a mouse model of intracerebral hemorrhage

“…Toxins released from an intracerebral hematoma may contribute to brain damage after ICH [37]. Two putative neurotoxins are hemoglobin, the most abundant protein in blood, and its heme group, which are released from lysed erythrocytes after ICH [38][39][40] Hemoglobin and its heme group play an essential role in ROS production after ICH [41][42][43].…”

Microglia: A Double-Edged Sword in Intracerebral Hemorrhage From Basic Mechanisms to Clinical Research

“…Consistently, the GSK-3β inhibitor 6-bromoindirubin-3′-oxime (BIO) has been shown to relieve inflammation by blocking GSK-3β Tyr216 phosphorylation/activation following ICH. BIO may exert a protective effect against ICH by increasing the number of anti-inflammatory microglia through inactivating GSK-3β ( 78 ).…”