Oxidation-sensitive nociception involved in endometriosis-associated pain

Abstract

Endometriosis is a disease characterized by the growth of endometrial tissue outside the uterus and is associated with chronic pelvic pain. Peritoneal fluid (PF) of women with endometriosis is a dynamic milieu, rich in inflammatory markers and pain-inducing prostaglandins PGE2/PGF2α and lipid peroxides, and the endometriotic tissue is innervated with nociceptors. Our clinical study showed the abundance of oxidatively-modified lipoproteins in the PF of women with endometriosis and the ability of antioxidant supplementation to alleviate endometriosis-associated pain. We hypothesized that oxidatively-modified lipoproteins present in the PF are the major source of nociceptive molecules that play a key role in endometriosis-associated pain. In this study, PF obtained from women with endometriosis or control women were used for (i) the detection of lipoprotein derived oxidation-sensitive pain molecules, (ii) the ability of such molecules to induce nociception, and (iii) the ability of antioxidants to suppress this nociception. LC-MS/MS showed the generation of eicosanoids by oxidized-lipoproteins similar to that seen in the PF. The oxidatively-modified lipoproteins induced hypothermia (intra-cerebroventricular) in CD-1 mice and nociception in the Hargreaves paw-withdrawal latency assay in Sprague-Dawley rats. Antioxidants, vitamin-E and N-acetylcysteine and the NSAID, indomethacin suppressed the pain inducing ability of oxidatively-modified lipoproteins. Treatment of human endometrial cells with oxidatively-modified lipoproteins or PF from women with endometriosis showed up-regulation of similar genes belonging to the opioid and inflammatory pathways. Our finding that oxidatively-modified lipoproteins can induce nociception has a broader impact not only in the treatment of endometriosis-associated pain but also in other diseases associated with chronic pain.

Targeting oxidative stress to treat endometriosis

“…Onalan G et al [138] Animal study Significant decreases in the mean implant areas and significant decreases in serum and peritoneal TNF-a levels NAC elevates GSH levels and improves the toxic effects of ROS, a protection that is related to scavenging of free radicals Ray K et al [139] In vitro + Animal study (samples obtained from endometriosis patients)…”

“…The authors reported that treatment with NAC as well as other anti-inflammatory and antioxidant drugs suppressed the pain-inducing capability of the lipoproteins. The proposed mechanism was that of an inhibition of oxidation of LDL by the treatment agents [139].…”

Redox regulation of microRNAs in endometriosis-associated pain

“…Since we recently identified that ox-LDLs parallel nociceptive responses similar to PF from women with endometriosis-associated pain [28], we hypothesized that these lipoprotein components function through modulating miRNAs that regulate inflammatory and nociceptive genes in endometriosis. We compared the miRNA profile of PF treated endometriotic cells to Ox-LDL treated cells.…”

Effects of cooking techniques on fatty acid and oxylipin content of farmed rainbow trout (Oncorhynchus mykiss)

“…Oxylipins are oxidized products of PUFA (Gabbs et al., ). Omega‐6 ( n ‐6)‐derived oxylipins tend to have increased inflammatory and vasoconstrictive effects, while n ‐3‐derived oxylipins tend to be anti‐inflammatory (Calder, ; Gabbs et al., ; Ray et al., ). It is unknown how the method of preparation affects the oxylipin content of fish fillets and the potential health impact of those oxylipins.…”