TY - JOUR
T1 - Delayed recanalization at 3 days after permanent MCAO attenuates neuronal apoptosis through FGF21/FGFR1/PI3K/Caspase-3 pathway in rats
AU - Zheng, Wen
AU - Matei, Nathanael
AU - Pang, Jinwei
AU - Luo, Xu
AU - Song, Zhi
AU - Tang, Jiping
AU - Zhang, John H.
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/10
Y1 - 2019/10
N2 - 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.
AB - 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.
KW - Delayed recanalization
KW - FGF21
KW - Ischemia/reperfusion injury
KW - Neuronal apoptosis
KW - Permanent MCAO
KW - Caspase 3/metabolism
KW - Phosphatidylinositol 3-Kinases/metabolism
KW - Rats
KW - Male
KW - Rats, Sprague-Dawley
KW - Signal Transduction/physiology
KW - Animals
KW - Infarction, Middle Cerebral Artery/pathology
KW - Apoptosis/physiology
KW - Neurons/metabolism
KW - Receptor, Fibroblast Growth Factor, Type 1/metabolism
KW - Fibroblast Growth Factors/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85069455014&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85069455014&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/75184d87-c04d-3961-b8e7-39cd06f542d9/
U2 - 10.1016/j.expneurol.2019.113007
DO - 10.1016/j.expneurol.2019.113007
M3 - Article
C2 - 31295445
SN - 0014-4886
VL - 320
JO - Experimental Neurology
JF - Experimental Neurology
M1 - 113007
ER -