Astragaloside IV Protects Primary Cerebral Cortical Neurons from Oxygen and Glucose Deprivation/Reoxygenation by Activating the PKA/CREB Pathway

Stroke is one of the major leading causes of death and disability worldwide, and post-stroke cognitive impairment is a major contributor to this disability. Astragaloside IV (AST-IV) is a primary bioactive compound of Radix Astragali, which is widely used in traditional Chinese medicine to treat stroke. AST-IV was found to possess cognition-enhancing properties against ischemic stroke; however, the mechanisms underlying this effect remain largely elusive. Mitochondrial health is critical to cell viability after ischemic injury. Cyclic AMP response element-binding protein (CREB) is a transcription factor that can be activated by protein kinase A (PKA) to preserve mitochondria, regulate memory and cognitive functions. We used an in vitro model of ischemic injury via oxygen and glucose deprivation (OGD) of cultured neurons, which led to PKA inactivation and decreased CREB phosphorylation, reduced cell viability, and increased neuronal apoptosis. We hypothesized that AST-IV could protect OGD-exposed cerebral cortical neurons by modulating the PKA/CREB signaling pathway and preserving mitochondrial function. We found that the mitochondrial and cellular injuries induced by OGD were reversed following treatment with AST-IV. The activity of neuronal mitochondria was evaluated by measuring the mitochondrial potential and the levels of reactive oxygen species (ROS) and adenosine triphosphate (ATP). AST-IV significantly enhanced PKA and CREB phosphorylation and prevented OGD-induced mitochondrial dysfunction, thereby protecting neurons exposed to OGD from injury and death. Furthermore, the effects of AST-IV were partially blocked by a PKA inhibitor. Collectively, these data elucidated the molecular mechanisms underlying the protective effects of AST-IV against ischemic injury in cortical neurons. (C) 2019 The Authors. Published by Elsevier Ltd on behalf of IBRO.