Imidazole alkaloids inhibit the pro-inflammatory mechanisms of human neutrophil and exhibit anti-inflammatory properties in vivo

Abstract

Objectives Epiisopiloturine (EPI) and epiisopilosine (EPIIS) are side products in the pharmaceutical industry. The present study aimed to investigate the anti‐inflammatory potential of the alkaloids EPI and EPIIS in human neutrophils and mechanical hyperalgesia in mice. Methods Neutrophils (5 × 106 cells/ml) incubated with EPI and EPIIS and stimulated by the addition of N‐formyl‐methionyl‐leucyl‐phenylalanine or phorbol 12‐myristate‐13‐acetate. The release of myeloperoxidase (MPO), reactive oxygen species (ROS) production, calcium influx, gene expression of NF‐κB and pro‐inflammatory cytokines production were evaluated. It was also investigated the effect these alkaloids on carrageenan‐induced mechanical hyperalgesia model in mice. Key findings We demonstrated that both EPI and EPIIS inhibited the degranulation of activated neutrophils. This effect was accompanied by the reduction in ROS, the prevention of the increase in intracellular Ca2+ and decrease in the density of cytosolic NF‐κB, and inhibition of TNF‐α and IL‐6 production. Evaluating hypernociception in mice, EPI and EPIIS inhibited carrageenan‐induced inflammatory hypernociception and reduced MPO levels. Conclusions The results obtained suggest EPI and EPIIS not only inhibit neutrophils functions in vitro, but also exhibits anti‐inflammatory properties in vivo, acting through the modulation of the activation and/or accumulation of neutrophils in the inflammatory focus. Thus, EPI and EPIIS possess promising anti‐inflammatory therapeutic potential.

Imidazole as a Promising Medicinal Scaffold: Current Status and Future Direction

“…These results were confirmed using in vivo model that decreased inflammatory hypernociception and myeloperoxidase (MPO) release in mice. 48 …”

“…According to the bioactivity scores, the most promising compounds were found to be I30, I31, I33, and I34 with scores of 0.24, 0.32, 0.21, and 0.72, respectively, as an enzyme inhibitor suggesting COX enzyme may be involved in mediating this anti-inflammatory effect that correlated well with Shankar et al, Bukhari et al, Nascimento et al and Rocha et al studies. 45 , 48–50 On the contrary, Katikireddy et al believed that compound I32 works by inhibiting the COX-2 enzyme, however, the target prediction did not show a promising bioactivity score at this target suggesting computational studies should not be used solely for target predictions. 47 …”

“… 45 , 48–50 On the contrary, Katikireddy et al believed that compound I32 works by inhibiting the COX-2 enzyme, however, the target prediction did not show a promising bioactivity score at this target suggesting computational studies should not be used solely for target predictions. 47 …”

“…These results were confirmed using in vivo model that decreased inflammatory hypernociception and myeloperoxidase (MPO) release in mice. 48 Moreover, some authors reported SAR studies based on applying a medicinal chemistry approach from available anti-inflammatory drugs. For example, Husain et al believed that safe and effective NSAIDs would still be needed.…”

“…36 The findings shown in Table 9, demonstrated that some anti-inflammatory mechanisms of imidazole derivatives could be due to the interactions with GPCRs, nuclear receptors, ion channels, proteases, kinases, and enzymes. According to the bioactivity scores, the most promising compounds were found to be I30, I31, I33, and I34 with scores of 0.24, 0.32, 0.21, and 0.72, respectively, as an enzyme inhibitor suggesting COX enzyme may be involved in mediating this anti-inflammatory effect that 45,[48][49][50] On the contrary, Katikireddy et al believed that compound I32 works by inhibiting the COX-2 enzyme, however, the target prediction did not show a promising bioactivity score at this target suggesting computational studies should not be used solely for target predictions. 47…”