Inhibition of PDE4 protects neurons against oxygen-glucose deprivation-induced endoplasmic reticulum stress through activation of the Nrf-2/HO-1 pathway.

摘要: Abstract Inhibition of phosphodiesterase 4 (PDE4) produces neuroprotective effects against cerebral ischemia. However, the involved mechanism remains unclear. Augmentation endoplasmic reticulum (ER) stress promotes neuronal apoptosis, and excessive oxidative is an inducer ER stress. The present study aimed to determine whether suppression in protective PDE4 inhibition We found that exposing HT-22 cells oxygen-glucose deprivation (OGD) significantly activated stress, as evidenced by increased expression 78-kDa glucose-regulated protein (GRP78), phosphorylated eukaryotic translation-initiation factor 2α (eIF2α), C/EBP-homologous (CHOP). Overexpression PDE4B while knocking down or treatment with inhibitor, FCPR03, prevented OGD-induced HT-22 cells. Furthermore, FCPR03 promoted translocation nuclear erythroid 2-related 2 (Nrf-2) from cytoplasm nucleus. Importantly, Nrf-2 ML385, blocked inhibitory role on ML385 also abolished subjected OGD. Knocking heme oxygenase-1 (HO-1), which a target Nrf-2, enhanced level reactive oxygen species (ROS), cell death. then antioxidant, N-Acetyl- l -cysteine, reduced cells exposed This effect was accompanied viability decreased In primary cultured neurons, we production ROS phosphorylation eIF2α. OGD neurons ML385. These results demonstrate activates Nrf-2/HO-1, attenuates ROS, thereby Additionally, conclude may represent promising therapeutic agent for stress-related disorders.