Delayed recanalization after MCAO ameliorates ischemic stroke by inhibiting apoptosis via HGF/c-Met/STAT3/Bcl-2 pathway in rats

• Published in: Experimental neurology 2020-08, Vol.330, p.113359-113359, Article 113359
• Main Authors: Tang, Hong, Gamdzyk, Marcin, Huang, Lei, Gao, Ling, Lenahan, Cameron, Kang, Ruiqing, Tang, Jiping, Xia, Ying, Zhang, John H.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - physiology; Delayed recanalization; Hepatocyte growth factor (HGF); Hepatocyte Growth Factor - metabolism; Infarction, Middle Cerebral Artery - metabolism; Infarction, Middle Cerebral Artery - pathology; Ischemic stroke; Ischemic Stroke - metabolism; Ischemic Stroke - pathology; Male; MCAO; Proto-Oncogene Proteins c-bcl-2 - metabolism; Proto-Oncogene Proteins c-met - metabolism; Rat; Rats; Rats, Sprague-Dawley; Signal Transduction - physiology; STAT3 Transcription Factor - metabolism
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2020.113359

The activation of tyrosine kinase receptor c-Met by hepatocyte growth factor (HGF) showed an anti-apoptotic effect in numerous disease models. This study aimed to investigate the neuroprotective mechanism of the HGF/c-Met axis-mediated anti-apoptosis underlying the delayed recanalization in a rat model of middle cerebral artery occlusion (MCAO). Permanent MCAO model (pMCAO) was induced by intravascular filament insertion. Recanalization was induced by withdrawing the filament at 3 days after MCAO (rMCAO). HGF levels in the blood serum and brain tissue expressions of HGF, c-Met, phosphorylated-STAT3 (p-STAT3), STAT3, Bcl-2, Bax, cleaved caspase-3(CC3) were assessed using ELISA and western blot, respectively. To study the mechanism, HGF small interfering ribonucleic acid (siRNA) and c-Met inhibitor, su11274, were administered intracerebroventricularly (i.c.v.) or intranasally, respectively. The concentration of HGF in the serum was increased significantly after MCAO. Brain expression of HGF was increased after MCAO and peaked at 3 days after recanalization. HGF and c-Met were both co-localized with neurons. Compared to rats received permanent MCAO, delayed recanalization after MCAO decreased the infarction volume, inhibited neuronal apoptosis, and improved neurobehavioral function, increased expressions of p-STAT3 and its downstream Bcl-2. Mechanistic studies indicated that HGF siRNA and su11274 reversed the neuroprotection including anti-apoptotic effects provided by delayed recanalization. In conclusion, the delayed recanalization after MCAO increased the expression of HGF in the brain, and reduced the infarction and neuronal apoptosis after MCAO, partly via the activation of the HGF/c-Met/STAT3/Bcl-2 signaling pathway. The delayed recanalization may serve as a therapeutic alternative for a subset of ischemic stroke patients. •Delayed recanalization at 3 days after MCAO decreases infarction and improves neurobehavioral score in rats.•Apoptosis can be detected at 6 days after permanent MCAO, and it is inhibited by delayed recanalization.•HGF/c-Met pathway plays an important role in anti-apoptotic effect observed after delayed recanalization.