PKA signaling-mediated inhibition of the AIM2 inflammasome is involved in the radioprotective effect of Eleutheroside E

Objective: To investigate the protective effect and underlying mechanism of Eleutheroside E (EE), derived from Acanthopanax senticosus , against γ-ray radiation-induced splenic injury. Methods: The Cell Counting Kit-8 assay was used to determine the toxicity of the drug. Hematoxylin and eosin, terminal deoxynucleotidyl transferase dUTP nick end-labeling, and live/dead cell double staining assays were used to evaluate the protective effects of EE on the spleen. Immunofluorescence, immunohistochemical, and enzyme-linked immunosorbent assays (ELISA) were used to investigate the underlying mechanisms of EE. Cross-talk between the absent in melanoma 2 (AIM2) inflammasome and the protein kinase A (PKA) signaling pathway was clarified using selective inhibitors. Results: EE reduced IR-induced splenic injury—the increased apoptosis rates and the levels of γ-H2AX and inflammatory factors in splenic cells were significantly alleviated. ELISA showed that EE reduced the level of interferon-γ (IFN-γ), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-18 (IL-18), and tumor necrosis factor-α (TNF-α) in irradiated tissues. The radioprotective effects of EE were mediated by inhibition of the AIM2 inflammasome and stimulation of PKA signaling, in which EE inhibited the increased levels of AIM2, apoptosis-associated speck-like protein containing a CARD (ASC), and cleaved caspase-1 proteins upon ionizing radiation damage but rescued the decreased protein levels in PKA signaling. Suppression of AIM2 signaling was dependent on the activation of PKA signaling by EE treatment. Conclusions: EE exerts a significant radioprotective effect on the spleen in vitro and in vivo . Activation of the PKA signaling pathway leads to AIM2 inflammasome inhibition, thereby attenuating radiation-induced DNA damage. This was demonstrated to be the mechanism involved in the radioprotective effects of EE. Thus, EE can be used as a potential radioprotective drug in clinical practice.