Vitexin reduces hypoxia-ischemia neonatal brain injury by the inhibition of HIF-1alpha in a rat pup model.

Abstract

Previous studies have demonstrated that the early suppression of HIF-1α after hypoxia-ischemia (HI) injury provides neuroprotection. Vitexin (5, 7, 4-trihydroxyflavone-8-glucoside), an HIF-1α inhibitor, is a c-glycosylated flavone that has been identified in medicinal plants. Therefore, we hypothesized that treatment with vitexin would protect against HI brain injury. Newborn rat pups were subjected to unilateral carotid artery ligation followed by 2.5 h of hypoxia (8% O2 at 37 °C). Vitexin (30, 45 or 60 mg/kg) was administered intraperitoneally at 5 min or 3 h after HI. Vitexin, administered 5 min after HI, was neuroprotective as seen by decreased infarct volume evaluated at 48 h post-HI. This neuroprotection was removed when vitexin was administered 3 h after HI. Neuronal cell death, blood-brain barrier (BBB) integrity, brain edema, HIF-1α and VEGF protein levels were evaluated using a combination of Nissl staining, IgG staining, brain water content, immunohistochemistry and Western blot at 24 and 48 h after HI. The long-term effects of vitexin were evaluated by brain atrophy measurement, Nissl staining and neurobehavioral tests. Vitexin (45 mg/kg) ameliorated brain edema, BBB disruption and neuronal cell death; Upregulation of HIF-1α by dimethyloxalylglycine (DMOG) increased the BBB permeability and brain edema compared to HI alone. Vitexin attenuated the increase in HIF-1α and VEGF. Vitexin also had long-term effects of protecting against the loss of ipsilateral brain and improveing neurobehavioral outcomes. In conclusion, our data indicate early HIF-1α inhibition with vitexin provides both acute and long-term neuroprotection in the developing brain after neonatal HI injury.

• Authors: Jia-Wei Min, Jiang-Jian Hu, Miao He, Russell M Sanchez, Wen-Xian Huang, Yu-Qiang Liu, Najeeb Bassam Bsoul, Song Han, Jun Yin, Wan-Hong Liu, Xiao-Hua He, Bi-Wen Peng
• Journal: Neuropharmacology (Neuropharmacology) Vol. 99 Pg. 38-50 (Dec 2015) ISSN: 1873-7064 [Electronic] England
• PMID: 26187393 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Hif1a protein, rat
• Hypoxia-Inducible Factor 1, alpha Subunit
• Neuroprotective Agents
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, rat
• Apigenin
• vitexin

Topics

• Animals
• Animals, Newborn
• Apigenin (chemistry, pharmacology)
• Atrophy (drug therapy, physiopathology)
• Blood-Brain Barrier (drug effects, pathology, physiopathology)
• Brain (drug effects, pathology, physiopathology)
• Brain Edema (drug therapy, pathology, physiopathology)
• Capillary Permeability (drug effects, physiology)
• Cell Death (drug effects, physiology)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, metabolism)
• Hypoxia-Ischemia, Brain (drug therapy, pathology, physiopathology)
• Maze Learning (drug effects, physiology)
• Neurons (drug effects, pathology, physiology)
• Neuroprotective Agents (chemistry, pharmacology)
• Random Allocation
• Rats, Sprague-Dawley
• Treatment Outcome
• Vascular Endothelial Growth Factor A (metabolism)