PGE1 triggers Nrf2/HO-1 signal pathway to resist hemin-induced toxicity in mouse cortical neurons

Abstract

Background: Prostaglandin E1 (PGE1) exerts various pharmacological effects such as membrane stabilization, anti-inflammatory functions, vasodilation, and platelet aggregation inhibition. We have previously demonstrated that PGE1 has a beneficial impact on patients suffering from intracerebral hemorrhage (ICH). The related mechanism underlying PGE1's beneficial effect on ICH treatment needs further exploration.Methods: The present study elucidates the mechanism of PGE1 on ICH treatment using a neuronal apoptosis model in vitro. The mouse primary cortical neurons were pretreated with different concentrations of PGE1, followed by the treatment with hemin, the main catabolite in whole blood, to mimic the clinical ICH.Results: Comparing with the vehicle-treated group, PGE1 prevented cultured cortical neurons from the accumulation of inhibited intracellular levels of reactive oxygen species (ROS), amelioration of mitochondrial membrane potential, and hemin-induced apoptosis. The reduction of ROS and apoptosis were associated with the up-regulation of Heme oxygenase-1 (HO-1) expression. Knockdown of nuclear transcription factor erythroid 2-related factor (Nrf2) by siRNA attenuated the upregulation of HO-1 as well as the protective effect of PGE1.Conclusions: Our work suggests that the Nrf2/HO-1 molecular pathway may play a crucial role in treating ICH patients with PGE1 and may represent novel molecular targets, resulting in discovering new drugs for ICH treatment.

Neurometabolomic Impacts of Modeled Wildfire Smoke and Protective Benefits of Anti-Aging Therapeutics in Aged Female C57bl/6j Mice

“…G3P is used in the rapid replenishment of NAD + stores in the brain and is reduced in our model. Reductions to PGE1 could indicate a request for platelet aggregation (76). Homovanillic acid is a major terminal metabolite of dopamine, with downregulation being associated with neuroinflammation and depression (77).…”

Regulation of nuclear factor erythroid-2-related factor 2 as a potential therapeutic target in intracerebral hemorrhage

“…Nuclear factor erythroid-2-related factor 2 (Nrf2) has a critical role in regulating oxidative stress and in ameliorating brain damage, which may be a target of interest after ICH ( Bellezza et al, 2018 ). Nrf2 controls the expression of heme oxygenase-1 (HO-1) and multiple other proteins with antioxidant and anti-inflammatory effects, and plays an important role in reducing brain damage after ICH ( Deng et al, 2021 ; Shen et al, 2021 ). Studies show that Nrf2 nuclear accumulation can reduce brain injury in the early stage of ICH ( Wang et al, 2007 ).…”