Delayed recanalization reduced neuronal apoptosis and neurological deficits by enhancing liver-derived trefoil factor 3-mediated neuroprotection via LINGO2/EGFR/Src signaling pathway after middle cerebral artery occlusion in rats

被引：2

作者：

Li, Dujuan ^{[1
,2
]}

Lian, Lifei ^{[3
]}

Huang, Lei ^{[2
,4
]}

Gamdzyk, Marcin ^{[2
]}

Huang, Yi ^{[2
]}

Doycheva, Desislava ^{[2
]}

Li, Gaigai ^{[2
,3
]}

Yu, Shufeng ^{[2
]}

Guo, Yong ^{[2
,5
]}

Kang, Ruiqing ^{[2
]}

Tang, Hong ^{[2
]}

Tang, Jiping ^{[2
]}

Kong, Lingfei ^{[1
,6
]}

Zhang, John H. ^{[2
,4
]}

机构：

[1] Zhengzhou Univ, Peoples Hosp, Henan Prov Peoples Hosp, Dept Pathol,Peoples Hosp, Zhengzhou 450003, Peoples R China

[2] Loma Linda Univ, Dept Physiol & Pharmacol, 11041 Campus St, Loma Linda, CA 92354 USA

[3] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Neurol, Wuhan 430030, Peoples R China

[4] Loma Linda Univ, Dept Neurosurg, Loma Linda, CA 92354 USA

[5] Henan Prov Peoples Hosp, Dept Neurosurg, Zhengzhou 450003, Peoples R China

[6] Henan Prov Peoples Hosp, Dept Pathol, 7 Weiwu Rd, Zhengzhou 450003, Peoples R China

来源：

EXPERIMENTAL NEUROLOGY | 2024年 / 371卷

基金：

美国国家卫生研究院;

关键词：

Ischemic stroke; Middle cerebral artery occlusion; Apoptosis; Delayed recanalization; TFF3; LINGO2; ACUTE ISCHEMIC-STROKE; TFF3; PEPTIDE; BRAIN; INJURY; THROMBECTOMY; ACTIVATION; EXPRESSION; INDUCTION; EVOLUTION; PARADIGM;

D O I：

10.1016/j.expneurol.2023.114607

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Delayed recanalization at days or weeks beyond the therapeutic window was shown to improve functional outcomes in acute ischemic stroke (AIS) patients. However, the underlying mechanisms remain unclear. Previous preclinical study reported that trefoil factor 3 (TFF3) was secreted by liver after cerebral ischemia and acted a distant neuroprotective factor. Here, we investigated the liver-derived TFF3-mediated neuroprotective mechanism enhanced by delayed recanalization after AIS. A total of 327 male Sprague-Dawley rats and the model of middle cerebral artery occlusion (MCAO) with permanent occlusion (pMCAO) or with delayed recanalization at 3 d post-occlusion (rMCAO) were used. Partial hepatectomy was performed within 5 min after MCAO. Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 2 (LINGO2) siRNA was administered intracerebroventricularly at 48 h after MCAO. Recombinant rat TFF3 (rr-TFF3, 30 mu g/Kg) or recombinant rat epidermal growth factor (rr-EGF, 100 mu g/Kg) was administered intranasally at 1 h after recanalization, and EGFR inhibitor Gefitinib (75 mg/Kg) was administered intranasally at 30 min before recanalization. The evaluation of outcomes included neurobehavior, ELISA, western blot and immunofluorescence staining. TFF3 in hepatocytes and serum were upregulated in a similar time-dependent manner after MCAO. Compared to pMCAO, delayed recanalization increased brain TFF3 levels and attenuated brain damage with the reduction in neuronal apoptosis, infarct volume and neurological deficits. Partial hepatectomy reduced TFF3 levels in serum and ipsilateral brain hemisphere, and abolished the benefits of delayed recanalization on neuronal apoptosis and neurobehavioral deficits in rMCAO rats. Intranasal rrTFF3 treatment reversed the changes associated with partial hepatectomy. Delayed recanalization after MCAO increased the co-immunoprecipitation of TFF3 and LINGO2, as well as expressions of p-EGFR, p-Src and Bcl-2 in the brain. LINGO2 siRNA knockdown or EGFR inhibitor reversed the effects of delayed recanalization on apoptosis and brain expressions of LINGO2, p-EGFR, p-Src and Bcl-2 in rMCAO rats. EGFR activator abolished the deleterious effects of LINGO2 siRNA. In conclusion, our investigation demonstrated for the first time that delayed recanalization may enhance the entry of liver-derived TFF3 into ischemic brain upon restoring blood flow after MCAO, which attenuated neuronal apoptosis and neurological deficits at least in part via activating LINGO2/EGFR/Src pathway.

引用

页数：16