Comparative effects of the ω3 polyunsaturated fatty acid derivatives resolvins E1 and D1 and protectin DX in models of inflammation and pain

Abstract

PurposeSpecialized pro-resolving lipid mediators (SPMs), also known as lipoxins, resolvins (Rvs), protectins and maresins, have been implicated in the resolution of the inflammatory process. However, a systematic comparison of their activity in the relief of inflammation and pain models is still lacking.Materials and methodsThe effects of Rvs E1 and D1 and protectin DX (PDX) were assessed in rat paws inflamed by the standard proinflammatory stimulus carrageenan or by histamine, 5-hydroxytryptamine, substance P or prostaglandin E2. The experimental outcomes were the mechanical nociceptive threshold and increase in paw volume as a measure of pain and edema formation, respectively. The analgesic and anti-inflammatory activities of the indicated SPMs were also compared with nonsteroidal (indomethacin and celecoxib) and steroidal (dexamethasone) anti-inflammatory drugs.ResultsOnly RvE1 and RvD1 presented analgesic and anti-inflammatory activities in the carrageenan model, and RvE1 was twice as potent as RvD1. Both substances tended to be better analgesics than anti-inflammatory agents, with a modeling profile similar to steroidal anti-inflammatory drugs. However, proinflammatory effects (edema formation) were also detected when the mediators histamine, 5-hydroxytryptamine or substance P replaced carrageenan as the proinflammatory stimuli. The analgesic and anti-inflammatory effects of resolvins were specifically prevented by an antagonist of the leukotriene B4 receptor 1 (BLT1).ConclusionRvs, as analgesic agents, may be better therapeutic agents than nonsteroidal anti-inflammatory drugs, the current choice in the relief of pain of an inflammatory origin. However, the possibility of developing adverse effects cannot be overlooked.

Identification and structure elucidation of the pro‐resolving mediators provides novel leads for resolution pharmacology

“…RvE1 was also found to carry potent antinociceptive actions reducing inflammatory pain by regulating both central and peripheral responses with activities of 10 ng per mouse when administered intrathecally and 285–570 pmol when administered peripherally in vivo . These actions were also displayed in vitro at concentrations as low as 3 nM (Xu et al ., ; Jo et al ., ; Fonseca et al ., ). Of note, the antinociceptive properties of RvE1 are more potent than those exerted by the COX‐2 inhibitor NS398 and morphine (Xu et al ., ).…”

Novel mediators and mechanisms in the resolution of infectious inflammation: evidence for vagus regulation

“…The double lipoxygenase product 10,17-diHDHA denoted PDX is obtained via sequential steps of lipoxygenation to yield 10S,17S-diHDHA [33]. This PDX is an isomer of PD1 and has several actions on its own [60][61][62][63][64]. When PD1 is produced in neural systems, it is coined neuroprotectin D1 (NPD1), with protective actions demonstrated in retina, brain and pain [65][66][67].…”

Resolvin E1 Inhibits Osteoclastogenesis and Bone Resorption by Suppressing IL-17-induced RANKL Expression in Osteoblasts and RANKL-induced Osteoclast Differentiation

“…Moreover, a recent study indicated that RvE1 influenced pain, a major symptom of RA, showing simultaneous anti-inflammatory and analgesic properties in experimental models closely related to translational sites in humans. 30 These studies have demonstrated the good therapeutic potential of RvE1 in many chronic inflammatory diseases. Indeed, RvE1 (Rx-10001) and its synthetic analog (Rx-10045) are currently under clinical trials for the relief of chronic dry eyes.…”