Delayed recanalization at 3 days after permanent MCAO attenuates neuronal apoptosis through FGF21/FGFR1/PI3K/Caspase-3 pathway in rats

• Published in: Experimental neurology Vol. 320; p. 113007
• Main Authors: Zheng, Wen, Matei, Nathanael, Pang, Jinwei, Luo, Xu, Song, Zhi, Tang, Jiping, Zhang, John H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2019
• Subjects: Animals; Apoptosis - physiology; Caspase 3 - metabolism; Delayed recanalization; FGF21; Fibroblast Growth Factors - metabolism; Infarction, Middle Cerebral Artery - pathology; Ischemia/reperfusion injury; Male; Neuronal apoptosis; Neurons - metabolism; Neurons - pathology; Permanent MCAO; Phosphatidylinositol 3-Kinases - metabolism; Rats; Rats, Sprague-Dawley; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Signal Transduction - physiology; Delayed recanalization; Neuronal apoptosis; Permanent MCAO; Ischemia/reperfusion injury; FGF21
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2019.113007

Reperfusion exceeded time window may induce ischemia/reperfusion injury, increase hemorrhagic transformation, and deteriorate neurological outcomes in ischemic stroke models. However, the increasing clinical evidences supported that reperfusion even within 6–24 h may salvage ischemic tissue and improve neurological outcomes in selected large vessel occlusion patients, without inducing serious ischemia/reperfusion injury and hemorrhagic transformation. The underlying molecular mechanisms are less clear. In present study, we demonstrated that delayed recanalization at 3 days after permanent middle cerebral artery occlusion (MCAO) decreased infarct volumes and improved neurobehavioral deficits in rats, with no increasing animal mortality and intracerebral hemorrhage. Meanwhile, we observed that endogenous neuroprotective agent fibroblast growth factor 21 (FGF21) significantly increased in serum after MCAO, but which did not synchronously increase in penumbra due to permanent MCAO. Recanalization dramatically increased the endogenous FGF21 expression on neurons in penumbra after MCAO. We confirmed that FGF21 activated the FGFR1/PI3K/Caspase-3 signaling pathway, which attenuated neuronal apoptosis in penumbra. Conversely, knockdown of FGFR1 via FGFR1 siRNA abolished the anti-apoptotic effects of FGF21, and in part abrogated beneficial effects of recanalization on neurological outcomes. These findings suggested that delayed recanalization at 3 days after MCAO improved neurological outcomes in rats via increasing endogenous FGF21 expression and activating FGFR1/PI3K/Caspase-3 pathway to attenuate neuronal apoptosis in penumbra. Delayed recanalization at 3 days after ischemic stroke onset may be a promising treatment strategy in selected patients.