2. Academic Validation
  3. The neuroprotective mechanisms of naringenin: Inhibition of apoptosis through the PI3K/AKT pathway after hypoxic-ischemic brain damage

The neuroprotective mechanisms of naringenin: Inhibition of apoptosis through the PI3K/AKT pathway after hypoxic-ischemic brain damage

  • J Ethnopharmacol. 2023 Jul 20;116941. doi: 10.1016/j.jep.2023.116941.
Luyao Li 1,  Zhen Lin 2,  Junhui Yuan 3,  Pingping Li 4,  Qi Wang 4,  Namki Cho 5,  Yi Wang 6,  Zhenlang Lin 7
Affiliations

Affiliations

  • 1 Wenzhou Key Laboratory of Perinatal Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang Province, China; College of Pharmacy, Chonnam National University, Gwangju, South Korea; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
  • 2 Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, China.
  • 3 Wenling Maternal and Child Health Care Hospital, Xiabao Road, Chengdong Street of Wenling City, Zhejiang Province, 317500, China.
  • 4 Wenzhou Key Laboratory of Perinatal Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang Province, China.
  • 5 College of Pharmacy, Chonnam National University, Gwangju, South Korea. Electronic address: cnamki@jnu.ac.kr.
  • 6 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China. Electronic address: yi.wang1122@wmu.edu.cn.
  • 7 Wenzhou Key Laboratory of Perinatal Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang Province, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, 325000, Zhejiang Province, China. Electronic address: linzhenlang@hotmail.com.
PMID: 37480970 DOI: 10.1016/j.jep.2023.116941
Abstract

Ethnopharmacological relevance: Naringenin (NGN) is a widely distributed flavonoid with potent antioxidant and neuroprotective properties. Neuroprotective agents play a crucial role in the treatment of hypoxic-ischemic encephalopathy (HIE). It has shown potential therapeutic effects for neurological disorders. However, its efficacy on HIE is yet to be investigated.

Aim of the study: This study aims to investigate the potential neuroprotective effect of naringenin and its underlying molecular mechanisms in reducing oxidative stress, Apoptosis, and improving brain outcomes following HIE. Additionally, the study aims to identify the potential targets, mechanisms, and functions of naringenin using network pharmacology analysis.

Materials and methods: Neonatal mice were exposed to the hypoxic-ischemic brain damage (HIBD) model to determine brain water content, and brain tissue was subjected to hematoxylin and eosin (HE), immunohistochemistry (IHC), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and Nissl staining to investigate its neuroprotective effects. Furthermore, the neonatal mouse primary neuron oxygen-glucose deprivation (OGD) model to measure Reactive Oxygen Species (ROS) production in vitro. The protein levels were characterized by Western Blot, and mRNA levels were evaluated by a real-time quantitative PCR detecting system (qPCR). Transmission electron microscopy (TEM) and mitochondrial fluorescent staining were used to observe mitochondrial morphology. Neuronal nuclei (NeuN) and microtubule-associated protein 2 (MAP2) were detected by Immunofluorescence (IF). Finally, network pharmacology was employed to determine the common target of naringenin and HIE. The core genes were obtained via protein-protein interaction networks (PPI) analysis and molecular docking was examined, and the mechanism of action was explored through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Additionally, small interfering RNA (siRNA) was constructed for verification.

Results: Naringenin has a neuroprotective effect in HIBD by modulating Vegfa expression and activating the PI3K/Akt pathway to inhibit Apoptosis. Furthermore, molecular docking results suggest that Vegfa is a potential binding target of naringenin, and silencing Vegfa partially reverses the pharmacological effects of NGN.

Conclusion: Our findings suggest that naringenin demonstrates potential clinical application for treating HIE as a novel neuroprotective agent.

Keywords

Apoptosis; Hypoxic-ischemic encephalopathy (HIE); Naringenin; Neuroprotective; PI3K/AKT pathway.

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