Bosentan, a mixed endothelin receptor antagonist, inhibits superoxide anion-induced pain and inflammation in mice

Abstract

Bosentan is a mixed endothelin receptor antagonist widely used to treat patients with pulmonary arterial hypertension, and the emerging literature suggests bosentan as a potent anti-inflammatory drug. Superoxide anion is produced in large amounts during inflammation, stimulates cytokine production, and thus contributes to inflammation and pain. However, it remains to be determined whether endothelin contributes to the inflammatory response triggered by the superoxide anion. The present study investigated the effects of bosentan in a mouse model of inflammation and pain induced by potassium superoxide, a superoxide anion donor. Male Swiss mice were treated with bosentan (10-100 mg/kg) by oral gavage, 1 h before potassium superoxide injection, and the inflammatory response was evaluated locally and at spinal cord (L4-L6) levels. Bosentan (100 mg/kg) inhibited superoxide anion-induced mechanical and thermal hyperalgesia, overt pain-like behavior (abdominal writhings, paw flinching, and licking), paw edema, myeloperoxidase activity (neutrophil marker) in the paw skin, and leukocyte recruitment in the peritoneal cavity. Bosentan also inhibited superoxide anion-induced interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) production, while it enhanced IL-10 production in the paw skin and spinal cord. Bosentan inhibited the reduction of antioxidant capacity (reduced glutathione, ferric reducing antioxidant power, and ABTS radical scavenging ability) induced by the superoxide anion. Finally, we demonstrated that intraplantar injection of potassium superoxide induces the mRNA expression of prepro-endothelin-1 in the paw skin and spinal cord. In conclusion, our results demonstrated that superoxide anion-induced inflammation, pain, cytokine production, and oxidative stress depend on endothelin; therefore, these responses are amenable to bosentan treatment.

Naringenin Inhibits Superoxide Anion-Induced Inflammatory Pain: Role of Oxidative Stress, Cytokines, Nrf-2 and the NO−cGMP−PKG−KATPChannel Signaling Pathway

“…Data indicates that O 2 − -induced pain depends on both direct superoxide anion effects, and indirect effects, partly via the production of peroxynitrite [ 37 ]. O 2 − injection triggers inflammatory pain by mechanisms involving cytokine, COX-2 and ET-1 synthesis [ 6 , 38 , 39 ]. Oxidative stress is involved in the pain of varied inflammatory diseases such as rheumatoid arthritis [ 40 , 41 ], gout [ 42 ], delayed onset muscle soreness [ 43 ] and diabetes [ 44 ].…”

“…Endothelin receptor antagonists inhibit cytokine-induced hyperalgesia and cytokines induce preproET-1 mRNA expression and ET-1 production [ 56 , 57 ]. Bosentan, an endothelin receptor antagonist, inhibits O 2 − -induced hyperalgesia, and O 2 − induces preproET-1 mRNA expression [ 39 ]. Naringenin inhibited O 2 − -induced prepro-ET-1 mRNA expression.…”

“…Therefore, it is likely that ET-1 also contributes to the regulation of oxidative stress. In fact, bosentan inhibited O 2 − -induced oxidative stress [ 39 ].…”

Oxidative Stress and Antioxidant Status in Immune Thrombocytopenia

“…Therefore, many experts hold the idea of using antioxidants to eliminate excessive oxidizing agent. Numerous therapies for oxidative stress related autoimmune disorders have been tried, including corticosteroids, biologics, antibiotics, immunosuppresive drugs, 5-aminosalicylates and vitamin D analogs [36]. As anti-oxidants serving to limit relevant damage, alpha lipoic acid (ALA) shows a clear metabolic influence, which could improve microcirculation, and has an anti-inflammatory effect, and it could contribute to the defense against oxidative stress by increasing the synthesis of anti-oxidants like glutathione, one of the most abundant intra-cellular anti-oxidants in the body.…”

Improvement of peripheral artery disease with Sildenafil and Bosentan combined therapy in a patient with limited cutaneous systemic sclerosis

“…[8] In one study, Bosentan inhibits superoxide anion-induced inflammation, pain, cytokine production, and oxidative stress that depend on ET1. [9] In SSc, ET1 is involved in the genesis of vasculopathy and fibrosis leading to vessel wall occlusion and vascular manifestations. [10] Recent studies have suggested that ET1 may play an important role in the alteration of endothelial function at the onset of PAD.…”