Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China; Department of Anesthesiology, Neurosurgery and Neurology, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA.
Department of Anesthesiology, Neurosurgery and Neurology, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA.
Exp Neurol. 2019 Oct;320:113007. doi: 10.1016/j.expneurol.2019.113007. Epub 2019 Jul 8.
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.
再灌注超过时间窗可能会导致缺血/再灌注损伤，增加出血性转化，并恶化缺血性中风模型中的神经功能结局。然而，越来越多的临床证据支持，即使在 6-24 小时内再灌注也可能挽救缺血组织，并改善选定的大血管闭塞患者的神经功能结局，而不会引起严重的缺血/再灌注损伤和出血性转化。其潜在的分子机制尚不清楚。在本研究中，我们表明，永久性大脑中动脉闭塞（MCAO）后 3 天延迟再通可减少大鼠的梗死体积并改善神经行为缺陷，而不会增加动物死亡率和颅内出血。同时，我们观察到，内源性神经保护剂成纤维细胞生长因子 21（FGF21）在 MCAO 后血清中显著增加，但由于永久性 MCAO，其在半影区并未同步增加。再通后 MCAO 可显著增加半影区神经元中的内源性 FGF21 表达。我们证实，FGF21 激活 FGFR1/PI3K/Caspase-3 信号通路，减轻了半影区神经元的凋亡。相反，通过 FGFR1 siRNA 敲低 FGFR1 可消除 FGF21 的抗凋亡作用，并部分消除再通对神经功能结局的有益作用。这些发现表明，MCAO 后 3 天延迟再通通过增加内源性 FGF21 表达和激活 FGFR1/PI3K/Caspase-3 通路来减轻半影区神经元凋亡，从而改善大鼠的神经功能结局。缺血性中风发作后 3 天延迟再通可能是一种有前途的治疗策略，适用于特定患者。
