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

Abstract

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

Rolipram Prevents the Formation of Abdominal Aortic Aneurysm (AAA) in Mice: PDE4B as a Target in AAA

“…The attenuation of the AngII-mediated increase of the aortic diameter observed in mice treated with rolipram results from combined anti-inflamatory and anti-oxidant effects, which provide an overall vasoprotection and th eimprovement of vascular remodelling. Rolipram significantly attenuated the oxidative stress induced by AngII, in agreement with previous studies showing antioxidant effects derived from PDE4 inhibition [ 21 , 22 , 23 ]. Remarkably, the rolipram-mediated inhibition of AngII-induced AAA was also associated with a potent anti-inflammatory effect, as it strongly reduced the local inflammatory infiltrate and the expression of inflammatory markers.…”

“…Targeting PDE4 has been validated as an effective therapeutic strategy for inflammatory conditions, including chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases (IBD), rheumatic arthritis (RA), atopic dermatitis (AD), asthma, psoriasis, and lupus [ 14 , 15 ]. PDE4 enzymes seem to play non-redundant functions, but both PDE4D and PDE4B have been involved in inflammation and oxidative stress [ 19 , 20 , 21 ], and PDE4 inhibitors have been shown to be able to reduce inflammation and oxidative stress both in vitro and in animal models of tissue damage [ 21 , 22 , 23 ]. Although inflammation and oxidative stress are key hallmarks of AAA, it is uncertain whether PDE4 isoforms could contribute to this human disease, thereby constituting potential targets for pharmacological interventions.…”

Upregulation of Extracellular Vesicles-Encapsulated miR-132 Released From Mesenchymal Stem Cells Attenuates Ischemic Neuronal Injury by Inhibiting Smad2/c-jun Pathway via Acvr2b Suppression

“…After the neurons had been infected with corresponding lentivirus for 6 h, medium was replaced with a new medium. After 18–24 h of culture, neurons were exposed to OGD conditions ( Xu et al, 2020 ). In order to simulate neuronal hypoxia-ischemia in vitro , neurons were treated with OGD.…”

EPO and TMBIM3/GRINA Promote the Activation of the Adaptive Arm and Counteract the Terminal Arm of the Unfolded Protein Response after Murine Transient Cerebral Ischemia

“…To improve stroke outcome, new pharmacological approaches must be considered, such as boosting endogenous pro-survival pathways. Among them, the unfolded protein response (UPR) is a promising cellular mechanism, since the UPR maintains and restores endoplasmic reticulum (ER) function, which is critical for the survival of stressed cells in general and of hypoxic cells in particular [5,6,7,8].…”