دانلود رایگان مقاله آدیل مدرول یک آنالوگ پالمیتویل اتانولامید به عنوان درمان فارماکولوژیکی

Abstract

The aim of study was to examine the anti-inflammatory and analgesic effects of adelmidrol, an analogue of palmitoylethanolamide (PEA), in animal models of acute and chronic inflammation [carrageenan-induced paw edema (CAR) and collagen-induced arthritis (CIA)]. In order to elucidate whether the action of adelmidrol is related to activation of peroxisome proliferator-activated receptors (PPAR-α or PPAR-γ), we investigated the effects of PPAR-γ antagonist, GW9662 on adelmidrol mechanism. CAR induced paw edema, hyperalgesia and the activation of pro-inflammatory NF-κB pathway were markedly reduced by treatment with adelmidrol. GW9662, (administered prior to adelmidrol treatment), antagonized the effect of adelmidrol abolishing its positive action. On the contrary, the genetic absence of PPAR-α receptor did not modify the beneficial results of adelmidrol treatment in the acute model of inflammation. In addition, for the first time, we demonstrated that adelmidrol was able to ameliorate both the clinical signs and the histopathology of the joint and the hind paw during chronic inflammation. In particular, the degree of oxidative damage and proinflammatory cytokines and chemokines production were significantly reduced in adelmidrol-treated mice. Moreover, in CIA model, the effect of GW9662 pre-treatment on adelmidrol mechanism was also confirmed. Thus, in this study, we report that adelmidrol reduces the development of acute and chronic inflammation and could represent a novel therapeutic approach for inflammation and pain.

4. Discussion

The present study demonstrated the acute and chronic effects of adelmidrol and the mechanism underlying such an action, in a model of CAR induced paw inflammation as well as in an experimental model of autoimmune disease CIA. Adelmidrol belongs to the aliamide family [27] with similar anti-inflammatory and anti-nociceptive proprieties of PEA [28,29] and able to control MCs hyper-reactivity in several pathophysiological conditions [30,31]. Moreover, adelmidrol has been shown to negatively control canine skin MCs during pathological events [11]. Our previous work also demonstrated that PEA in combination with an antioxidant such as luteolin, was able to modulate MCs activation in paw tissues [7]. As PEA analogue, the pharmacological properties of adelmidrol can be related to the activation of a cell surface receptor cannabinoid CB2-like or the orphan GPR55 receptor, as well as a nuclear receptor of PPARs family [9,32]. Several studies have clearly demonstrated that PPAR-a and PPAR-c agonists exert positive effects in experimental models of CNS injury [9]. A previous work of ours also showed that the beneficial effects of PEA were in part dependent on PPAR-a pathway in an experimental model of kidney I/R [33]. We also confirmed that PPAR-a is involved in protecting effects of PEA in a model of spinal cord trauma. Specifically, the anti-inflammatory effect obtained by PEA was antagonized by the antagonists administration for PPAR-c (GW9662), and PPAR-d (GSK0660) [9]. With this aim in mind, in this work, we also investigated whether the protective effects of adelmidrol were associated with PPARs signaling pathway such as PPAR-a or PPAR-c. ROS/RNS production in addition to cyclooxygenase (COX)- derived prostaglandins play a crucial role during inflammatory events associated with the development of altered pain sensitivity [34,35].