Medicarpin isolated from Radix Hedysari ameliorates brain injury in a murine model of cerebral ischemia   全文下載

Medicarpin isolated from Radix Hedysari ameliorates brain injury in a murine model of cerebral ischemia

"The development of effective post-stroke therapy is highly demanded. Medicarpin is a key active component of a famousChinese herbal prescription usedfor post-stroke treatment in Taiwan; however, little is known about its biological effects andmechanisms of action. Herein, we implemented a murine model of cerebral ischemic/reperfusional injury-related stroke toelucidate medicarpin's neuroprotective effect. In male ICR mice 24 h after stroke induction, treatment with medicarpin (0.5and 1.0 mg/kg, i.v.) markedly enhanced the survival rates, improved moving distance and walking area coverage, reducedbrain infarction, and preserved the bloodebrain barrier, supportingmedicarpin's protective effect on stroke-induced injury.Immunohistochemistry analysis further revealed thatmedicarpin treatment decreased the expression/activation of p65NF-kBand 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). Thesechanges of expression levels were accompanied by GSK-3 inactivation and b-catenin upregulation. Notably, pretreatmentwith LY294002, a PI3K inhibitor, abolished the aforementioned beneficial effects ofmedicarpin, illustrating an essential roleof PI3K/Akt activation in medicarpin's neuroprotective and reparative activities. In vitro studies revealed that medicarpindisplayed strong anti-inflammatory activity by reducing nitric oxide (NO) production in lipopolysaccharide-stimulatedmicroglial cells (BV2) with an IC50 around 5±1 (mM) and anti-apoptotic activity in neuronal cells (N2A) subjected to oxygenglucosedeprivation with an IC50 around 13±2 (mM). Collectively, this is the first report to demonstrate that medicarpin,isolated fromRadixHedysari, ameliorates ischemic brain injury through its anti-inflammatory microglia/NO), anti-apoptotic(neuronal cells/OGD) and neuroprotective effects by activating the PI3K/Akt-dependentGSK-3 inactivation for upregulatingb-catenin, which in turn decreases the expression/activation of p65NF-kB and caspase 3 and promotes the expression ofneurogenic (DCX, BDNF, TrkB) and neuroprotective (Bcl2) factors in the brain."