TRPA1 Ion Channel Determines Beneficial and Detrimental Effects of GYY4137 in Murine Serum-Transfer Arthritis

Abstract

Modulation of nociception and inflammation by sulfide in rheumatoid arthritis and activation of transient receptor potential ankyrin 1 (TRPA1) ion channels by sulfide compounds are well documented. The present study aims to investigate TRPA1-mediated effects of sulfide donor GYY4137 in K/BxN serum-transfer arthritis, a rodent model of rheumatoid arthritis. TRPA1 and somatostatin sst4 receptor wild-type (WT) and knockout mice underwent K/BxN serum transfer and were treated daily with GYY4137. Functional and biochemical signs of inflammation were recorded, together with histological characterization. These included detection of hind paw mechanical hyperalgesia by dynamic plantar esthesiometry, hind paw volume by plethysmometry, and upside-down hanging time to failure. Hind paw erythema, edema, and passive movement range of tibiotarsal joints were scored. Somatostatin release from sensory nerve endings of TRPA1 wild-type and knockout mice in response to polysulfide was detected by radioimmunoassay. Polysulfide formation from GYY4137 was uncovered by cold cyanolysis. GYY4137 aggravated mechanical hyperalgesia in TRPA1 knockout mice but ameliorated it in wild-type ones. Arthritis score was lowered by GYY4137 in TRPA1 wild-type animals. Increased myeloperoxidase activity, plasma extravasation, and subcutaneous MIP-2 levels of hind paws were detected in TRPA1 knockout mice upon GYY4137 treatment. Genetic lack of sst4 receptors did not alter mechanical hyperalgesia, edema formation, hanging performance, arthritis score, plasma extravasation, or myeloperoxidase activity. TRPA1 WT animals exhibited smaller cartilage destruction upon GYY4137 administration. Sodium polysulfide caused TRPA1-dependent somatostatin release from murine nerve endings. Sulfide released from GYY4137 is readily converted into polysulfide by hypochlorite. Polysulfide potently activates human TRPA1 receptors expressed in Chinese hamster ovary (CHO) cells. According to our data, the protective effect of GYY4137 is mediated by TRPA1, while detrimental actions are independent of the ion channel in the K/BxN serum-transfer arthritis model in mice. At acidic pH in inflamed tissue sulfide is released from GYY4137 and reacts with neutrophil-derived hypochlorite. Resulting polysulfide might be responsible for TRPA1-mediated antinociceptive and anti-inflammatory as well as TRPA1-independent pro-inflammatory effects.

Dimethyl Trisulfide Diminishes Traumatic Neuropathic Pain Acting on TRPA1 Receptors in Mice

“…DMTS molecules have much better chance to reach and activate peripheral or central TRPA1 channels. These findings seem to conflict with our earlier data demonstrating efficacy of POLY in carrageenan-induced paw inflammation, as well as that of polysulfide originating from slow-release sulfide donor GYY4137 [ 16 , 20 ]. In these cases, the inflammation driving nociception was still ongoing when POLY was applied.…”

“…TRPA1 activation was detected by calcium-sensitive fluorescent markers (either in a ratiometric way or not) and by automated patch clamp. Ion channel activation could be inhibited by selective TRPA1 antagonist HC030031 and lack of TRPA1 [ 16 , 22 ]. However, polysulfides react potentially with any thiol groups of proteins and change the protein function.…”

“…Both sodium polysulfide (POLY) and DMTS induce calcium signals in primary cultures of sensory neurons expressing TRPA1, as well as in cell lines transfected with the ion channel. Similar data could be produced by a patch clamp [ 16 , 21 , 22 ]. While POLY is unstable and short-lived, DMTS is a stable chemical.…”

“…TRPA1 ion channels can be activated by polysulfides. Inorganic polysulfides might arise in cells from reactions of sulfide with nitric oxide, reaction of sulfide with hypochlorous acid or produced by the enzyme 3-mercaptopyruvate sulfurtransferase [ 15 , 16 , 17 ]. Dimethyl trisulfide (DMTS) is an organic dialkyl polysulfide.…”

Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-κB and STAT3

“…It has been demonstrated that polysulfides are potential regulators in mammalian physiology, such as regulating the activity of ion channels, serving as tumor suppressor, and modulating the activities of protein kinases [ 10 , 15 , 16 , 25 , 26 ]. Koike and colleagues have found that Na 2 S 4 , a polysulfide donor, protects neuroblastoma SH-SY5Y cells from t -buthylhydroperoxide-induced cytotoxicity, this effect may be ascribed to the suppression of oxidative damage [ 27 ].…”