Scutellarin protects cortical neurons against neonatal hypoxic‐ischemic encephalopathy injury via upregulation of vascular endothelial growth factor

• Published in: Ibrain Vol. 8; no. 3; pp. 353 - 364
• Main Authors: Zou, Yu, Fang, Chang‐Le, Wang, Ya‐Ting, Li, Hua, Guo, Xi‐Liang
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.09.2022; John Wiley and Sons Inc; Wiley-VCH
• Subjects: Angiogenesis; Antibodies; Brain damage; Hypoxia; hypoxic‐ischemic encephalopathy; Ischemia; Laboratory animals; Neurons; neuroprotective effects; Original; Proteins; Scutellarin; siRNA; Stroke; Temperature; Traumatic brain injury; Vascular endothelial growth factor; VEGF (vascular endothelial growth factor); China; Scutellarin; neuroprotective effects; siRNA; VEGF (vascular endothelial growth factor); hypoxic‐ischemic encephalopathy
• ISSN: 2769-2795; 2313-1934; 2769-2795
• DOI: 10.1002/ibra.12052

Neonatal hypoxic‐ischemic encephalopathy (NHIE) causes devastating cerebral damage and neurological deficits that seldom have effective therapies. This study aimed to explore the mechanisms underlying the therapeutic efficacy of Scutellarin in NHIE. NHIE models were successfully established. Zea‐longa score and triphenyte‐trazoliumchloride (TTC) staining demonstrated that hypoxia and ischemia (HI) insult induced prominent neurological dysfunctions and brain infarction. Protein microarray was applied to detect the differentially expressed genes in the cortex, hippocampus, and lung tissues of HI rats, which revealed the downregulation of vascular endothelial growth factor (VEGF) in these tissues. Additionally, double immunostaining uncovered VEGF expression was localized in the neurons. Besides, VEGF was decreasingly expressed in oxygen‐glucose deprivation (OGD) neurons, which was intriguingly reversed by Scutellarin treatment. Moreover, VEGF silencing increased OGD‐induced neuronal apoptosis and attenuated neurite outgrowth, which was enhanced by Scutellarin administration. GeneMANIA predicted a close correlation of VEGF with caspase 3, caspase 7, and interleukin (IL)‐1β, and qRT‐PCR revealed that Scutellarin treatment depressed the expression levels of them elevated in OGD neurons, but the Scutellarin‐depressed levels of these factors were prominently increased after VEGF silencing. Our findings suggested that Scutellarin exerted neuroprotective effects in NHIE potentially through mediating VEGF‐targeted inactivation of caspase 3, caspase 7, and IL‐1β. In this study, it was revealed that severe neurologic impairment and cerebral infarction were induced after hypoxia and ischemia insult, and microarray data unveiled differential expression of vascular endothelial growth factor (VEGF) in the cortex, hippocampus, and lung tissues, along with its colocalization with neurons. Though the expression of VEGF was decreased in oxygen‐glucose deprivation (OGD) neurons, it was obviously elevated after Scutellarin administration. Moreover, VEGF silencing depressed the effects of Scutellarin, which promoted neurite regrowth and attenuated cell apoptosis of OGD neurons. Thus, the efficacy of Scutellarin was partly abolished by interfering VEGF‐triggered upregulation of caspase 3,  caspase 7, and interleukin (IL)‐1β, which provided a new idea for the clinical therapeutics of hypoxic‐ischemic encephalopathy.