Lonchocarpine increases Nrf2/ARE-mediated antioxidant enzyme expression by modulating AMPK and MAPK signaling in brain astrocytes

Lonchocarpine is a phenylpropanoid compound isolated from Abrus precatorius that has anti-bacterial,anti-inflammatory,antiproliferative,and antiepileptic activities. In the present study,we investigated the antioxidant effects of lonchocarpine in brain glial cells and analyzed its molecular mechanisms. We found that lonchocarpine suppressed reactive oxygen species (ROS) production and cell death in hydrogen peroxide-treated primary astrocytes. In addition,lonchocarpine increased the expression of antioxidant enzymes,such as heme oxygenase-1 (HO-1),NAD(P)H:quinone oxidoreductase 1 (NQO1),and manganese superoxide dismutase (MnSOD),which are all under the control of Nrf2/antioxidant response element (ARE) signaling. Further,mechanistic studies showed that lonchocarpine increases the nuclear translocation and DNA binding of Nrf2 to ARE as well as ARE-mediated transcriptional activities. Moreover,lonchocarpine increased the phosphorylation of AMP-activated protein kinase (AMPK) and three types of mitogen-activated protein kinases (MAPKs). By treating astrocytes with each signaling pathway-specific inhibitor,AMPK,c-jun N-terminal protein kinase (JNK),and p38 MAPK were identified to be involved in lonchocarpine-induced HO-1 expression and ARE-mediated transcriptional activities. Therefore,lonchocarpine may be a potential therapeutic agent for neurodegenerative diseases that are associated with oxidative stress.