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Planta Med 2011; 77(15): 1669-1679
DOI: 10.1055/s-0030-1271019
Biological and Pharmacological Activity
Original Papers
© Georg Thieme Verlag KG Stuttgart · New York

Andrographolide Inhibits PI3K/AKT-Dependent NOX2 and iNOS Expression Protecting Mice against Hypoxia/Ischemia-Induced Oxidative Brain Injury

Chang-Ming Chern3 [*] , Kuo-Tong Liou6 [*] , Yea-Hwey Wang5 , 7 , Jyh-Fei Liao1 , Jiin-Cherng Yen1 , Yuh-Chiang Shen2 , 4
  • 1Department of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
  • 2National Research Institute of Chinese Medicine, Taipei, Taiwan
  • 3Division of Neurovascular Disease, Neurological Institute, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan
  • 4Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan
  • 5Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
  • 6Department of Chinese Martial Arts, Chinese Culture University, Taipei, Taiwan
  • 7Department of Nursing, College of Medicine and Nursing, Hungkuang University, Taichung, Taiwan
Further Information

Publication History

received January 5, 2011 revised March 8, 2011

accepted March 27, 2011

Publication Date:
21 April 2011 (online)

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Abstract

This study aimed to explore the mechanisms by which andrographolide protects against hypoxia-induced oxidative/nitrosative brain injury provoked by cerebral ischemic/reperfusion (CI/R) injury in mice. Hypoxia in vitro was modeled using oxygen-glucose deprivation (OGD) followed by reoxygenation of BV-2 microglial cells. Our results showed that treatment of mice that have undergone CI/R injury with andrographolide (10–100 µg/kg, i. v.) at 1 h after hypoxia ameliorated CI/R-induced oxidative/nitrosative stress, brain infarction, and neurological deficits in the mice, and enhanced their survival rate. CI/R induced a remarkable production in the mouse brains of reactive oxygen species (ROS) and a significant increase in protein nitrosylation; this primarily resulted from enhanced expression of NADPH oxidase 2 (NOX2), inducible nitric oxide synthase (iNOS), and the infiltration of CD11b cells due to activation of nuclear factor-kappa B (NF-κB) and hypoxia-inducible factor 1-alpha (HIF-1α). All these changes were significantly diminished by andrographolide. In BV-2 cells, OGD induced ROS and nitric oxide production by upregulating NOX2 and iNOS via the phosphatidylinositol-3-kinase (PI3K)/AKT-dependent NF-κB and HIF-1α pathways, and these changes were suppressed by andrographolide and LY294002. Our results indicate that andrographolide reduces NOX2 and iNOS expression possibly by impairing PI3K/AKT-dependent NF-κB and HIF-1α activation. This compromises microglial activation, which then, in turn, mediates andrographolide's protective effect in the CI/R mice.

Key words

andrographolide - HIF-1α - hypoxia - iNOS - gp91NADPH oxidase (NOX2) - phosphatidylinositol-3-kinase (PI3K)/AKT

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1 These authors contributed equally to this study.

Dr. Yuh-Chiang Shen

National Research Institute of Chinese Medicine

155-1 Li-Nung Street

Sec. 2, Shih-Pai

Taipei 112

Taiwan

Phone: +88 62 28 20 19 99 ext. 91 01

Fax: +88 62 28 26 42 66

Email: yuhcs@nricm.edu.tw

Dr. Jiin-Cherng Yen

Department of Pharmacology, School of Medicine
National Yang-Ming University

155 Li-Nung Street

Sec. 2, Shih-Pai

Taipei 112

Taiwan

Phone: +88 62 28 26 70 90

Fax: +88 62 28 23 15 21

Email: jcyen@ym.edu.tw

    www.thieme-connect.de/ejournals/toc/plantamedica