Anti-Inflammatory Effect of Homo- and Heterodimers of Natural Enkephalinase Inhibitors in Experimental Colitis in Mice

Abstract

Background: the pharmacological treatment and/or maintenance of remission in inflammatory bowel diseases (IBDs) is currently one of the biggest challenges in the field of gastroenterology. Method: our aim was the synthesis of homo- and heterodimers of natural enkephalinase inhibitors (opiorphin; sialorphin; spinorphin) and the in vitro characterization of their effect on the degradation of enkephalin by neutral endopeptidase (NEP) and stability in human plasma. We investigated the in vivo heterodimer of Cys containing analogs of sialorphin and spinorphin (peptide X) in a mouse model of colitis. The extent of inflammation was evaluated based on the microscopic score; macroscopic score; ulcer score, colonic wall thickness, colon length and quantification of myeloperoxidase activity. Results: we showed that the homo- and heterodimerization of analogs of sialorphin, spinorphin and opiorphin containing Cys residue at the N-terminal position resulted in dimeric forms which in vitro exhibited higher inhibitory activity against NEP than their parent and monomeric forms. We showed that peptide X was more stable in human plasma than sialorphin and spinorphin. Peptide X exerts potent anti-inflammatory effect in the mouse model of colitis. Conclusion: we suggest that peptide X has the potential to become a valuable template for anti-inflammatory therapeutics for the treatment of gastrointestinal (GI) tract inflammation.

Assessment of salivary opiorphin in oral lichen planus

“…Sobocińska et al 7 (2020) studied the effects of sialorphin and spinorphin on a mouse model of colitis and suggested these peptides as anti-inflammatory elements.…”

Central administration of human opiorphin alleviates dextran sodium sulfate-induced colitis in mice through activation of the endogenous opioid system

“…NEP inhibitors, thiorphan and acetorphan, are identified to exert anti-diarrheal activity in rodents via the protection of endogenous enkephalins ( Marҫais-Collado et al, 1987 ; Sałaga et al, 2013 ). Recent studies show that a natural inhibitor of NEP/APN, sialorphin, attenuates TNBS-induced colitis in mice ( Sałaga et al, 2017 ; Sobocińska et al, 2020 ). Similarly, our results revealed that i.c.v.…”

“…Overall, our data demonstrated that HO attenuates DSS-induced colitis by blocking NEP and APN through activation of the endogenous enkephalin-dependent opioid pathway. However, a recent study reports that systemic administration of human opiorphin has no effect on TNBS-induced colitis in mice ( Sobocińska et al, 2020 ). Although inflammatory pathways induced by DSS and TNBS in experimental models of colitis in mice are similar, DSS-induced ulcerative colitis is more severe than TNBS-induced colitis.…”

“…Systemic administration of sialorphin attenuates TNBS-induced colitis in mice by activating MOR and KOR (Sałaga et al, 2017). However, more recent study on natural enkephalinase inhibitors suggests that sialorhin has no effect on DSS-induced colitis, and human opiorphin does not alleviate colitis induced by TNBS in mice (Sałaga et al, 2017;Sobocińska Frontiers in Pharmacology frontiersin.org et al, 2020), the cause of which still remains unclear and needs further investigations. In the present study, our results establish that central administration of HO effectively prevents DSSinduced colitis in mice.…”

New Advances in Short Peptides: Looking Forward

“…This was reflected in the first edition of the Special Issue Advances in Research of Short Peptides . The issue received a large number of truly impressive and gratifying contributions, each of which reveals still open problems or challenges [ 1 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]; therefore, it seems advisable to the Editors to extend a follow-up collection of articles providing the newest results of research on short peptides with a more flexible approach worth being further developed toward applications in bio-medicine. As we move forward to new advances and look back on the studies on short peptides, the aim remains the same—reaching their full potential.…”