New synthetic coumarinolignans as attenuators of pro-inflammatory cytokines in LPS-induced sepsis and carrageenan-induce
- PDF / 1,363,954 Bytes
- 9 Pages / 595.276 x 790.866 pts Page_size
- 40 Downloads / 161 Views
Inflammopharmacology
ORIGINAL ARTICLE
New synthetic coumarinolignans as attenuators of pro‑inflammatory cytokines in LPS‑induced sepsis and carrageenan‑induced paw oedema models Santhosh S. Kumar1 · Kirti Hira1 · Sajeli Begum Ahil1 · Onkar P. Kulkarni1 · Hiroshi Araya2 · Yoshinori Fujimoto2 Received: 26 December 2019 / Accepted: 13 April 2020 © Springer Nature Switzerland AG 2020
Abstract Objectives The aim of the study was to explore the inhibition efficacy of new synthetic coumarinolignans (SCLs) against the secretion of pro-inflammatory cytokines in two in vivo models of inflammation. Methods Four SCLs 1–4 were screened for their pro-inflammatory cytokine inhibitory potential through oral administration at a dose of 50 mg/kg body weight in lipopolysaccharide-induced mouse endotoxaemia and carrageenan-induced mouse paw oedema models. Levels of pro-inflammatory cytokines (IL-1β, TNFα and IL-6) in blood and paw tissue samples were estimated using ELISA. Paw oedema was measured using a plethysmometer. Results were compared with a natural coumarinolignan, cleomiscosin A (5), and the structure–activity relationship (SAR) was interpreted. Results and discussion Compound 2 had the greatest potential in the endotoxaemia model, exhibiting 66.41%, 62.56% and 43.15% inhibition of plasma IL-1β, TNFα and IL-6 secretions, respectively. Further dose-dependent study revealed its antiinflammatory potential even at dose of 10 mg/kg body weight with 24.42% decline in the level of IL-1β. Nevertheless, SCLs 1, 3 and 4 showed marked inhibitory activity with 57.54%, 51.48% and 62.46% reduction in the levels of IL-1β, respectively. Moreover, compound 2 decreased the plasma TNFα and IL-1β levels to 50.03% and 36.58% along with the reduction of paw oedema volume in the local inflammation induced by carrageenan. All compounds including cleomiscosin A (5) were more effective against IL-1β. By studying SAR, the presence of dihydroxyl groups in the phenyl ring of lignans was identified to be essential for the activity. Also, esterification of lignans and presence of a 4-methyl substituent in the coumarin nucleus were found to play some role in enhancing the activity. Conclusion All four SCLs, especially compound 2, have shown vast potential to emerge out as promising anti-inflammatory drugs. Keywords Synthetic coumarinolignans · Pro-inflammatory cytokines · Endotoxaemia · Paw oedema · ELISA
Introduction Santhosh S. Kumar and Kirti Hira contributed equally to this paper Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10787-020-00710-w) contains supplementary material, which is available to authorized users. * Sajeli Begum Ahil [email protected]‑pilani.ac.in 1
Department of Pharmacy, Birla Institute of Technology and Science, Pilani Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Hyderabad, Telangana 500 078, India
School of Agriculture, Meiji University, Kawasaki, Kanagawa 214‑8571, Japan
2
Perturbations between pro-inflammatory cytokines like tumour necrosis factor alpha
Data Loading...
