Abstract
Cadherin epidermal growth factor (EGF) laminin G (LAG) seven-pass G-type receptor 1 (CELSR1) is a member of a special subgroup of adhesion G protein-coupled receptors. Although Celsr1 has been reported to be a sensitive gene for stroke, the effect of CELSR1 in ischemic stroke is still not known. Here, we investigated the effect of CELSR1 on neuroprotection, neurogenesis and angiogenesis in middle cerebral artery occlusion (MCAO) rats. The mRNA expression of Celsr1 was upregulated in the subventricular zone (SVZ), hippocampus and ischemic penumbra after cerebral ischemic injury. Knocking down the expression of Celsr1 in the SVZ with a lentivirus significantly reduced the proliferation of neuroblasts, the number of CD31-positive cells, motor function and rat survival and increased cell apoptosis and the infarct volume in MCAO rats. In addition, the expression of p-PKC in the SVZ and peri-infarct tissue was downregulated after ischemia/ reperfusion. Meanwhile, in the dentate gyrus of the hippocampus, knocking down the expression of Celsr1 significantly reduced the proliferation of neuroblasts; however, it had no influence on motor function, cell apoptosis or angiogenesis. These data indicate that CELSR1 has a neuroprotective effect on cerebral ischemia injury by reducing cell apoptosis in the peri-infarct cerebral cortex and promoting neurogenesis and angiogenesis, mainly through the Wnt/PKC pathway.
Highlights
Stroke is the second-most fatal disease worldwide [1], and approximately 87% of stroke cases are ischemic stroke triggered by blood flow blockage within major cerebral arteries
To test whether CELSR1 participates in the process of cerebral ischemia, we investigated the mRNA expression of Celsr1 by quantitative RT-PCR after 2 h of ischemia/22 h of reperfusion
Compared to that in the sham group (100%), the mRNA expression of Celsr1 in the middle cerebral artery occlusion (MCAO) group was significantly increased in the subventricular zone (SVZ) and dentate gyrus (DG) (SVZ: 271.4% ± 48.69%, p = 0.0180; DG: 175.9% ± 26.26%, p = 0.0446, Figure 1A), decreased in the ischemic penumbra (83.74% ± 3.635%, p = 0.0110, Figure 1A), and showed no obvious change in the ischemic core (58.81% ± 28.14%, p = 0.2809, Figure 1A) and striatum (71.53% ± 15.89%, p = 0.1477, Figure 1A)
Summary
Stroke is the second-most fatal disease worldwide [1], and approximately 87% of stroke cases are ischemic stroke triggered by blood flow blockage within major cerebral arteries. Cerebral ischemic can induce spontaneous neurological repair processes, including neurogenesis and angiogenesis [5,6]. In the middle cerebral artery occlusion (MCAO) model, neural stem cells (NSCs) in the SVZ can generate many neuroblasts and migrate to the ischemic penumbra, improving neurological functional recovery [9]. Cerebral ischemia injury can stimulate the expression of endogenous vascular-related factors, thereby promoting the rapid proliferation of vascular endothelial cells, and migrate to the damaged areas to form new blood vessels, providing nutrients and oxygen for the neurons in the ischemic penumbra [5,10]
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