The Inhibitory Effects of Slow-Releasing Hydrogen Sulfide Donors in the Mechanical Allodynia, Grip Strength Deficits, and Depressive-Like Behaviors Associated with Chronic Osteoarthritis Pain

Abstract

Osteoarthritis and its associated comorbidities are important clinical problems that have a negative impact on the quality of life, and its treatment remains unresolved. We investigated whether the systemic administration of slow-releasing hydrogen sulfide (H2S) donors, allyl isothiocyanate (A-ITC) and phenyl isothiocyanate (P-ITC), alleviates chronic osteoarthritis pain and the associated emotional disorders. In C57BL/6 female mice with osteoarthritis pain induced by the intra-articular injection of monosodium iodoacetate, we evaluated the effects of repeated administration of A-ITC and P-ITC on the (i) mechanical allodynia and grip strength deficits; (ii) emotional conducts; and (iii) glial activity and expression of inducible nitric oxide synthase (NOS2), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), and antioxidant enzymes (heme oxygenase 1, NAD(P)H:quinone oxidoreductase-1, glutathione S-transferase mu 1 and alpha 1) in the hippocampus. The administration of A-ITC and P-ITC inhibited the mechanical allodynia, the grip strength deficits, and the depressive-like behaviors accompanying osteoarthritis. Both treatments inhibited microglial activation, normalized the upregulation of NOS2 and PI3K/p-Akt, and maintained high levels of antioxidant/detoxificant enzymes in the hippocampus. Data suggest that treatment with low doses of slow-releasing H2S donors might be an interesting strategy for the treatment of nociception, functional disability, and emotional disorders associated with osteoarthritis pain.

Intraarticular Administration Effect of Hydrogen Sulfide on an In Vivo Rat Model of Osteoarthritis

“…In agreement, we have previously described that GYY-4137 decreased the expression of pro-inflammatory markers in chondrocytes by an in vitro experimental approach [ 19 ]. Besides this, other authors have also detected the capacity of H 2 S to reduce the levels of inflammatory mediators in the joint in in vivo studies [ 27 ] [ 44 , 46 ]. iNOS and COX-2 are enzymes responsible for the synthesis of NO and PGE 2 , respectively, which are widely known to be key mediators that contribute to the pain and pathogenesis of OA [ 6 , 51 ].…”

“…This is despite the fact that the intraarticular injection of saline has also shown some beneficial effects, as it is now considered to be effective at alleviating nociceptive pain and in turn is not a true placebo in OA [ 40 ]. Accordingly, Batalle et al (2019) observed that the systemic administration of slow-releasing H 2 S donors reduces mechanical allodynia and the grip strength deficits induced by the intraarticular injection of monosodium iodoacetate (MIA) in mice [ 27 ]. Lucarini et al (2018) also demonstrated the antinociceptive effects of different compounds exhibiting slow H 2 S-release properties in an osteoarthritic pain model [ 41 ].…”

“…Interestingly, ATB-346, a novel H 2 S-releasing naproxen, more efficiently reduces TNF-α release in a rat model of arthritis [ 55 ], and GYY-4137 inhibits the expression of effectors of the TNF pathway [ 56 ]. Thus, the inhibition of the production of these mediators has been associated with the chondroprotective effect of H 2 S [ 27 , 55 , 56 ], and subsequently it could be responsible for the lesser OA severity and pain observed in our model under GYY-4137 treatment.…”

“…Nonetheless, we and other authors observed an upregulation of Nrf-2 levels in OA joint, likely as an insufficient response against the oxidative stress generated during this articular disorder [ 61 , 62 ]. Additionally, a recent study described that the expression of Nrf-2-regulated detoxicant enzymes, such as HO-1 and NQO1, is significantly increased in MIA-injected mice and that treatment with slow H 2 S-release donors maintains these high levels [ 27 ]. Wu et al (2016) observed that S-propargyl-cysteine, an endogenous inductor of H 2 S synthesis, activates Nrf-2 signaling in adjuvant-induced arthritis rats and inhibits inflammatory response, ameliorating the severity of the arthritis model [ 46 ].…”

“…Additionally, other authors observed in vitro similar actions of the gas in the chondrocyte, such as attenuating inflammatory signaling and exerting chondroprotective effects [ 21 , 22 , 25 ]. By in vivo experimental approaches, different studies have also detected the beneficial effect of the administration of H 2 S donors on rheumatic disease progression and pain [ 26 , 27 ]. Interestingly, we have recently shown that balneotherapy in sulfur-rich water attenuates the destruction of cartilage and pain levels in an OA model in rats by the surgical destabilization of the joint [ 28 ].…”