N-Palmitoylethanolamine and Neuroinflammation: a Novel Therapeutic Strategy of Resolution

Abstract

Inflammation is fundamentally a protective cellular response aimed at removing injurious stimuli and initiating the healing process. However, when prolonged, it can override the bounds of physiological control and becomes destructive. Inflammation is a key element in the pathobiology of chronic pain, neurodegenerative diseases, stroke, spinal cord injury, and neuropsychiatric disorders. Glia, key players in such nervous system disorders, are not only capable of expressing a pro-inflammatory phenotype but respond also to inflammatory signals released from cells of immune origin such as mast cells. Chronic inflammatory processes may be counteracted by a program of resolution that includes the production of lipid mediators endowed with the capacity to switch off inflammation. These naturally occurring lipid signaling molecules include the N-acylethanolamines, N-arachidonoylethanolamine (an endocannabinoid), and its congener N-palmitoylethanolamine (palmitoylethanolamide or PEA). PEA may play a role in maintaining cellular homeostasis when faced with external stressors provoking, for example, inflammation. PEA is efficacious in mast cell-mediated models of neurogenic inflammation and neuropathic pain and is neuroprotective in models of stroke, spinal cord injury, traumatic brain injury, and Parkinson disease. PEA in micronized/ultramicronized form shows superior oral efficacy in inflammatory pain models when compared to naïve PEA. Intriguingly, while PEA has no antioxidant effects per se, its co-ultramicronization with the flavonoid luteolin is more efficacious than either molecule alone. Inhibiting or modulating the enzymatic breakdown of PEA represents a complementary therapeutic approach to treat neuroinflammation. This review is intended to discuss the role of mast cells and glia in neuroinflammation and strategies to modulate their activation based on leveraging natural mechanisms with the capacity for self-defense against inflammation.

Involvement of the endocannabinoid system in the physiological response to transient common carotid artery occlusion and reperfusion

“…This last observation is in line with studies showing that brain focal ischemia and reperfusion activate the eCB system by driving a combination of biochemical adaptations of the NAE degrading and synthesizing enzymes that, collectively, lead to the accumulation of eCBs [12, 33]. The eCB congener PEA is an important player in the endogenous defense against neuroinflammation [33] and has beneficial pharmacological effects in several animal models of inflammation [11, 33–35]. In particular, PEA may exert neuroprotective effects by modulating the immune cells [36], activating PPAR-alpha [23, 37] and blunting COX-2 activity [11].…”

“…Moreover, in human stroke eCBs and congeners have been shown to become detectable during the acute phase of an ischemic stroke where they may play a role through multiple potential mechanisms [17]. Research into this suggested that the inhibition or modulation of the enzymatic breakdown of PEA may represent a complementary therapeutic approach to counteract neuroinflammation [33]. …”

Mast Cells Release Chemokine CCL2 in Response to Parkinsonian Toxin 1-Methyl-4-Phenyl-Pyridinium (MPP+)

“…However, even smaller number of activated mast cells can impact vascular, microvascular and perivascular structures as well as neurons, astrocytes and microglial activation [39]. Normally mast cells can move through blood-brain-barrier (BBB) and also traverse the blood-spinal cord and BBB in disease conditions [41]. Recent reports have suggested that mast cells induce neuroinflammation by releasing proinflammatory cytokines, chemokines and other inflammatory mediators including TNF-α, IL-1β, IL-6, CCL2, histamine, reactive oxygen species (ROS), reactive nitrogen species (RNS) and nitric oxide (NO) [32,38,42–44].…”

“…However, significant increase of CCL2 could result in over-infiltration of inflammatory cells thereby inducing neuroinflammatory pathways and neuronal death. Astrocytes can be activated by mast cells through CD40-CD40 ligand interactions in the in vitro co-culture system [1,28,41]. It is known that activated astrocytes release GMF.…”

Ultramicronized palmitoylethanolamide in spinal cord injury neuropathic pain: a randomized, double-blind, placebo-controlled trial

“…Therefore, efforts concentrate about the development of cannabinoids with a better therapeutic index [22,23,42]. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide that is suggested to potentiate endocannabinoids and to have effect on neuropathic pain and spasticity [1,15,16,19,21,25,31,35,36]. PEA prolongs and potentiates the action of endocannabinoids through an inhibition of fatty acid amide hydrolase [40].…”