Protective effect of furofuranone against cerebral ischemic stroke via activation of PI3k/Akt/GSK 3β signaling pathway

Purpose: To study the protective effects of furofuranone on oxygen and glucose-deprived damage to brain microvascular endothelial cells (BMECs) in vitro, and in vivo in cerebral ischemic stroke rat model. Methods: BMECs were isolated from the Sprague Dawley rats and deprived of oxygen and glucose. The effect of 10, 20, 30, 40, 50 and 100 μM furofuranone on the oxygen/glucose-deprived BMECs was studied using Transwell chamber method. A rat cerebral ischemic stroke model was established using middle cerebral arterial occlusion method. Caspase-3 and other proteins, inflammatory cytokines, and other parameters of the brain tissue were evaluated by enzyme-linked assay (ELISA), polymerase chain reaction (PCR) and Western blot as appropriate. Further studies on the brain tissues was carried out by immunochemical analysis and hematoxylin and eosin staining. Results: Furofuranone decreased caspase 3 levels in a dose-based manner in rat BMECs, and significantly reduced the release of lactate dehydrogenase (LDH) in ischemic stroke rat model (p < 0.05). It also led to marked increases in the levels of p PI3k, p Akt and p GSK3β in cerebral ischemic stroke rats. Growth-associated protein-43 (GAP-43) and microtubule-associated protein 2 (MAP-2) levels increased in the cerebral ischemic stroke rat brain tissues, in addition to marked increase in ionized calcium-binding adaptor protein (IBA-1) and glial fibrillary acidic protein (GFAP) (p < 0.05). Furofuranone treatment reduced the population of microtubule-associated protein light chain 3 (MAP1LC3A) and Beclin 1-positive cells, and significantly downregulated L selectin, leptin, monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor (TNF)-α (p < 0.05). The release of tissue inhibitor of metalloproteinases 1 (TIMP-1) was enhanced in the cerebral ischemic stroke rats by furofuranone treatment. Conclusion: Furofuranone treatment prevents cerebral ischemic stroke-induced damage in rats via phosphorylation of PI3k, Akt and GSK3β proteins, and reduction of inflammatory cytokine levels. Therefore, furofuranone may be useful as chemotherapeutic agent for cerebral ischemic stroke.

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