Brominated indoles from a marine mollusc inhibit inflammation in a murine model of acute lung injury

Abstract

New drug leads for the treatment of inflammation are urgently needed. Marine molluscs are widely used as traditional medicines for the treatment of inflammation. Here we report the positive effects of a hypobranchial gland (HBG) extract and the dominant bioactive compound 6-bromoisatin from the Muricidae mollusc Dicathais orbita, for reducing lipopolysaccharide (LPS) induced acute lung inflammation in a mouse model. Both 6-bromoisatin and the HBG extract suppressed the inflammatory response in mice that were pre-treated by oral gavage at 48, 24 and 1 h prior to LPS infusion. The inflammatory antagonists were tested at concentrations of 0.5 mg/g and 0.1 mg/g HBG extract and 0.1 mg/g and 0.05 mg/g 6-bromoisatin in carrier oil and all treatments reduced inflammation as indicated by a significant suppression of inflammatory markers present in bronchoalveolar lavage fluid (BALF), in comparison to LPS induced positive control mice administered the carrier oil alone (p < 0.0001). Tumour necrosis factor-alpha (TNFα) and interleukin-1 beta (IL-1β) levels, in addition to total protein concentration were all significantly reduced in BALF from mice treated with the extract or 6-bromoisatin. Furthermore, all treatment groups showed significant reductions in neutrophil sequestration and preservation of the lung tissue architecture compared to the positive control (p < 0.0001). The combined results from this study and our previous in vitro studies indicate that 6-bromoisatin in the HGB extracts inhibit the activation of inflammatory signalling pathway. The results from this study further confirm that the HBG extract from Muricidae molluscs and 6-bromoisatin are bioavailable and effective in vivo, thus have potential for development as natural therapeutic agents for inflammation.

Marine natural products

“…636 An extract derived from the hypobranchial gland of Dicathais orbita, and 6bromoisatin and analogues found in this gland, exhibit anti-inammatory activity in in vitro and in vivo models. 637,638 A series of halogenated N-methylpyrroles were synthesised and used as standards to quantify their presence in European Atlantic, North Sea and Baltic Sea specimens of Mytilus sp. 639 Exposure to okadaic acid has been found to reduce the antioxidant and non-specic immune responses of bay scallops Argopecten irradians.…”

High-value compounds from the molluscs of marine and estuarine ecosystems as prospective functional food ingredients: An overview

“…A diacylguanidine actinofide 191 with moderately antiproliferative activity was reported from Actinocyclus papillatus ( Carbone et al, 2017 ), and three ulapualides, C-E 192 – 194 were isolated from the Hawaiian H. sanguineus ( Parrish, Yoshida, Yang, & Williams, 2017 ). Goniobranchus collingwoodi was reported to yield spongian-16-one analogs 195 – 200 ( Forster et al, 2017 ), and 6-bromoisatin, and its analogs with anti-inflammatory activities were reported from Dicathais orbita ( Ahmad et al, 2017 ). Chemical investigation of the organic extract of muricid gastropod mollusc, C. ramosus reported the presence of cembrane-type diterpenoid 201 with anti-inflammatory and antioxidative properties ( Chakraborty, Salas, & Joy, 2020 ).…”

Bioactive Compounds Isolated from Neglected Predatory Marine Gastropods

“…In pre-clinical trials on mouse models of colorectal cancer, 6-bromoisatin induced apoptosis and prevented proliferation in cancer cells [ 93 , 94 , 95 ]. Other applications of these compounds and their relatives include use as anti-inflammatory agents [ 50 , 96 , 97 , 98 ]. In mouse model of acute lung inflammation, the hypobranchial gland extract from Dicathais orbita preserved lung tissue significantly better than the controls [ 98 ].…”

“…Other applications of these compounds and their relatives include use as anti-inflammatory agents [ 50 , 96 , 97 , 98 ]. In mouse model of acute lung inflammation, the hypobranchial gland extract from Dicathais orbita preserved lung tissue significantly better than the controls [ 98 ]. In fact, isatins and indole derivatives have been patented for treatment of inflammation and allergies [ 50 , 99 ].…”