Journal of Food and Drug Analysis (JFDA)
【Update Date:2021-12-17】unit:
Medicarpin isolated from Radix Hedysari ameliorates brain injury in a murine model of cerebral ischemia
Chang-Ming Chern c,d,e,1, Chung-Kuang Lu a, Kuo-Tong Liou a,g,h, Yea-Hwey Wang b, Keng-Chang Tsai a, Chia-Lin Chang i, Chia-Che Chang j,k,l,m,1, Yuh-Chiang Shen a,b,f,*
a National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei City, Taiwan
b National Taipei University of Nursing and Health Sciences, Taipei City, Taiwan
c Taipei Municipal Gan-Dau Hospital, Taipei City, Taiwan
d Division of Neurovascular Disease, Neurological Institute, Taipei Veterans General Hospital, Taipei City, Taiwan
e Institute of Brain Science, School of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
f Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei City, Taiwan
g Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
h Department of Chinese Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan
i Research Institute of Biotechnology, Hung Kuang University, Taichung City, Taiwan
j Institute of Biomedical Sciences, Department of Life Sciences, Ph.D. Program in Translational Medicine, Rong Hsing Research Center for Translational Medicine, The iEGG and Animal Biotechnology Research Center, National Chung Hsing University, Taichung City, Taiwan
k Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung City, Taiwan
l Department of Medical Research, China Medical University Hospital, Taichung City, Taiwan
m Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei City, Taiwan
The development of effective post-stroke therapy is highly demanded. Medicarpin is a key active component of a famous Chinese herbal prescription used for post-stroke treatment in Taiwan; however, little is known about its biological effects and mechanisms of action. Herein, we implemented a murine model of cerebral ischemic/reperfusional injury-related stroke to elucidate medicarpin’s neuroprotective effect. In male ICR mice 24 h after stroke induction, treatment with medicarpin (0.5 and 1.0 mg/kg, i.v.) markedly enhanced the survival rates, improved moving distance and walking area coverage, reduced brain infarction, and preserved the blood-brain barrier, supporting medicarpin’s protective effect on stroke-induced injury. Immunohistochemistry analysis further revealed that medicarpin treatment decreased the expression/activation of p65NF-kB and caspase 3, especially near the infarct cortex, while promoting the expression of neurogenesis-associated proteins, including doublecortin (DCX), brain-derived neurotrophic factor (BDNF), and tyrosine receptor kinase B (TrkB). These changes of expression levels were accompanied by GSK-3 inactivation and β-catenin upregulation. Notably, pretreatment with LY294002, a PI3K inhibitor, abolished the aforementioned beneficial effects of medicarpin, illustrating an essential role of PI3K/Akt activation in medicarpin’s neuroprotective and reparative activities. In vitro studies revealed that medicarpin displayed strong anti-inflammatory activity by reducing nitric oxide (NO) production in lipopolysaccharide-stimulated microglial cells (BV2) with an IC50 around 5±1 (μM) and anti-apoptotic activity in neuronal cells (N2A) subjected to oxygen-glucose deprivation with an IC50 around 13±2 (μM). Collectively, this is the first report to demonstrate that medicarpin, isolated from Radix Hedysari, ameliorates ischemic brain injury through its anti-inflammatory microglia/NO), anti-apoptotic (neuronal cells/OGD) and neuroprotective effects by activating the PI3K/Akt-dependent GSK-3 inactivation for upregulating β-catenin, which in turn decreases the expression/activation of p65NF-kB and caspase 3 and promotes the expression of neurogenic (DCX, BDNF, TrkB) and neuroprotective (Bcl2) factors in the brain.
Keywords: BDNF/TrkB, GSK-3/β-catenin, Ischemic stroke, Medicarpin, PI3K/Akt
https://doi.org/10.38212/2224-6614.3377