A new synthetic protectin D1 analog 3-oxa-PD1n-3 DPA reduces neuropathic pain and chronic itch in mice

The resolution of inflammation is a biosynthetically active process controlled by the interplay between oxygenated polyunsaturated mediators and G-protein coupled receptor-signaling pathways. These enzymatically oxygenated polyunsaturated fatty acids belong to distinct families of specialized pro-resolving autacoids. The protectin family of mediators has attracted an interest because of their potent pro-resolving and anti-inflammatory actions verified in several in vivo disease models. Herein, we present the stereoselective synthesis and biological evaluations of 3-oxa-PD1(n-3 DPA), a protectin D1 analog. Results from mouse models indicate that the mediators protectin D1, PD1(n-3 DPA) and the new analog 3-oxa-PD1(n-3 DPA) all relieved streptozotocin-induced diabetic neuropathic pain at doses of 90 and 300 pmol, equivalent to 30 and 100 ng, respectively, following intrathecal (I.T.) injection. Of interest, at a low dose of only 30 pmol (10 ng; I.T.) only 3-oxa PD1(n-3 DPA) was able to alleviate neuropathic pain, directly compared to vehicle controls. Moreover, using a chronic itch model of cutaneous T-cell lymphoma (CTCL), all three compounds at 300 pmol (100 ng) showed a significant reduction in itching for several hours. The biomolecular information on the structure-functions of the protectins and the new synthetic analog 3-oxa-PD1(n-3 DPA) is of interest towards developing new immunoresolvents.

Automated summary

This study focuses on a new analog of protectin D1, 3-oxa-PD1(n-3 DPA), which demonstrated significant alleviation of streptozotocin-induced diabetic neuropathic pain in mouse models as well as itching symptoms in a chronic itch model of cutaneous T-cell lymphoma. These findings highlight the potential of developing new immunoresolvents based on the structure-functions of protectins and their synthetic analogs.