Gallic Acid Improves Comorbid Chronic Pain and Depression Behaviors by Inhibiting P2X7 Receptor-Mediated Ferroptosis in the Spinal Cord of Rats

Abstract

Ferroptosis is an inflammatory programmed cell death process that is dependent on iron deposition and lipid peroxidation. The P2X7 receptor not only is involved in the pain process but also is closely related to the onset of depression. Gallic acid (3,4,5-trihydroxybenzoic acid), which is naturally found in a variety of plants, exhibits anti-inflammatory, antioxidant, and analgesic effects. This study established a rat model with the comorbidity of chronic constrictive injury (CCI) plus chronic unpredictable mild stress (CUMS) to explore the role and mechanism of gallic acid in the treatment of pain and depression comorbidity. Our experimental results showed that pain and depression-like behaviors were more obvious in the chronic constriction injury (CCI) plus chronic unpredictable mild stimulation (CUMS) group than they were in the sham operation group, and the P2X7-reactive oxygen species (ROS) signaling pathway was activated. The tissue iron concentration was increased, and mitochondrial damage was observed in the CCI plus CUMS group. These results were alleviated with gallic acid treatment. Therefore, we speculate that gallic acid inhibits the ferroptosis of the spinal microglia by regulating the P2X7-ROS signaling pathway and relieves the behavioral changes in rats with comorbid pain and depression.

Effect of Shenqi Jieyu formula on inflammatory response pathway in hippocampus of postpartum depression rats

“…Various studies have been conducted on the anti-depressive effects of the active chemical constituents in SJF. Gallic acid [ 25 ] and 3,4,5-trimethoxycinnamic acid [ 26 ] in SJF can ameliorate depression. Alpha-asarone acts in SJF on the hippocampal neurons to attenuate depression-like behavior in rats [ 27 ].…”

Induction of ferroptosis by natural phenols: A promising strategy for cancer therapy

“…GA exhibits a range of pharmacological effects, including antioxidant and anti‐inflammatory properties. GA had a protective effect in a rat model with comorbid pain and depression by inhibiting ferroptosis in spinal microglia, possibly through modulation of the P2X7‐ROS signaling pathway (Yang, Shi, et al, 2023). Notably, GA shows considerable potential in impeding tumor progression by inducing programmed cell death mechanisms such as apoptosis, ferroptosis, and necroptosis in cancer cells.…”

Ferroptosis: a new antidepressant pharmacological mechanism

“…Inhibition of P2X7 expression leads to downregulation of TNF-α, NF-κB expression levels, and STAT3 phosphorylation. Consequently, the expression of GSH and GPX4 increases, which suppresses ROS accumulation and the generation of MDA, ultimately alleviating the pain and depressive symptoms in CCI and CUMS rats through the inhibition of ferroptosis ( YANG R. et al, 2023 ). Silybin, another primary active ingredient derived from Chinese herbal medicine Silybin, has been shown to possess neuroprotective effects as well as antidepressant effects ( SONG et al, 2018 ; LIU et al, 2021 ).…”