Hydrogen sulfide donors alleviate itch secondary to the activation of type-2 protease activated receptors (PAR-2) in mice

Abstract

Hydrogen sulfide (HS) has been highlighted as an endogenous signaling molecule and we have previously found that it can inhibit histamine-mediated itching. Pruritus is the most common symptom of cutaneous diseases and anti-histamines are the usual treatment; however, anti-histamine-resistant pruritus is common in some clinical settings. In this way, the involvement of mediators other than histamine in the context of pruritus requires new therapeutic targets. Considering that the activation of proteinase-activated receptor 2 (PAR-2) is involved in pruritus both in rodents and humans, in this study we investigated the effect of HS donors on the acute scratching behavior mediated by PAR-2 activation in mice, as well as some of the possible pharmacological mechanisms involved. The intradermal injection of the PAR-2 peptide agonist SLIGRL-NH (8-80nmol) caused a dose-dependent scratching that was unaffected by intraperitoneal pre-treatment with the histamine H1 antagonist pyrilamine (30mg/kg). Co-injection of SLIGRL-NH (40nmol) with either the slow-release HS donor GYY4137 (1 and 3nmol) or the spontaneous donor NaHS (1 and 0.3nmol) significantly reduced pruritus. Co-treatment with the K channel blocker glibenclamide (200nmol) or the nitric oxide (NO) donor sodium nitroprusside (10nmol) abolished the antipruritic effects of NaHS; however, the specific soluble guanylyl cyclase inhibitor ODQ (30μg) had no significant effects. The transient receptor potential ankyrin type 1 (TRPA1) antagonist HC-030031 (20μg) significantly reduced SLIGRL-NH-induced pruritus; however pruritus induced by the TRPA1 agonist AITC (1000nmol) was unaffected by NaHS. Based on these data, we conclude that pruritus secondary to PAR-2 activation can be reduced by HS, which acts through K channel opening and involves NO in a cyclic guanosine monophosphate (cGMP)-independent manner. Furthermore, TRPA1 receptors mediate the pruritus induced by activation of PAR-2, but HS does not interfere with this pathway. These results provide additional support for the development of new therapeutical alternatives, mainly intended for treatment of pruritus in patients unresponsive to anti-histamines.

Hydrogen sulfide and dermatological diseases

“…When histamine‐independent pruritus was induced by the activation of PAR2 with the peptide agonist SLIGRL‐NH 2 , the response was effectively reduced by NaHS, via ATP‐sensitive potassium channel opening and involving the participation of NO (in a cGMP‐independent manner). Furthermore, in this model, TRPA1 cation channels mediate the PAR2‐induced pruritus, but H 2 S does not interfere with this pathway (Coavoy‐Sánchez et al, 2016).…”

“…We have previously shown that inhibition of endogenous H 2 S synthesis with β‐cyano‐ l ‐alanine (a CSE/CBS inhibitor) results in significant potentiation of the scratching behavior induced by compound 48/80 in mice, along with increased neutrophil recruitment, as measured by myeloperoxidase activity (Rodrigues et al, 2017). Moreover, H 2 S donors can have important therapeutic applications for treatment of both histaminergic and non‐histaminergic pruritus in mice (Coavoy‐Sánchez et al, 2016; Rodrigues et al, 2017). Regarding the histaminergic pathway, the H 2 S donors sodium sulfide (Na 2 S) and Lawesson's reagent (Figure 1) significantly reduced the pruritus induced in mice by the intradermal injection of either histamine or the mast cell degranulator compound 48/80, and these effects were, at least in part, mediated by stabilization of mast cells (Rodrigues et al, 2017).…”

Vasorelaxant Activity of AP39, a Mitochondria-Targeted H2S Donor, on Mouse Mesenteric Artery Rings In Vitro

“…Protein expression of the H 2 S producing enzymes (CSE, CBS, and MPST) in mouse mesenteric artery homogenates was analyzed by Western blotting as previously described [ 32 ]. Briefly, 10 µg of total proteins from homogenates were separated by 10% SDS-PAGE electrophoresis.…”

Recent advances on endogenous gasotransmitters in inflammatory dermatological disorders

“… Inflammatory cutaneous disease Protective role of H 2 S Psoriasis H 2 S level in psoriasis patients are significantly lower than those of healthy controls [155] ; H 2 S inhibits keratinocytes growth, adhesion and IL-8 expression through inhibiting mitogen-activated protein kinase(MAPK) signaling [156] , [157] ; H 2 S donors NaHS and GYY4137 significantly enhance iNOS, resulting in the increase of NO, which down-regulates ERK1/2 activation [158] . Itching-related inflammatory diseases H 2 S donors GYY4137and NaHS significantly reduce pruritus secondary to type-2 protease activated receptors (PAR-2) activation in mice [161] . Chronic skin ulcers or wounds H 2 S accelerates wound healing via inhibiting ROS production, ERK1/2 and p38 activation and enhancing VEGF expression [163] , [164] .…”

“…In addition, Coavoy-Sánchez SA et al indicate that both H 2 S donors GYY4137 and NaHS significantly reduce pruritus secondary to type-2 protease activated receptors (PAR-2) activation in mice [161] . Since pruritus or itching is an unpleasant sensation relevant to disorders of the skin and other organs [162] , H 2 S donors may be promising candidates to treat itching-related inflammatory diseases.…”