Mast Cells and Glia as Targets for the Anandamide Congener Palmitoylethanolamide: an Anti-inflammatory and Neuroprotective Lipid Signaling Molecule

Abstract

Glia and microglia in particular elaborate pro-inflammatory molecules which play key roles in central nervous system (CNS) disorders from neuropathic pain and epilepsy to neurodegenerative diseases. Microglia respond also to pro-inflammatory signals released from other nonneuronal cells, mainly those of immune origin such as mast cells. The latter can be found in most tissues, are CNS-resident, and traverse the blood–spinal cord and blood–brain barriers when barrier compromise results from CNS pathology. The existence of multiple lines of communication between mast cells and glia may provide new avenues for the development of therapies which target neuroinflammation by differentially modulating activation of those nonneuronal cell populations controlling neuronal sensitization—both peripherally and centrally. Mast cells and glia have “built in” homeostatic mechanisms/molecules that come into play as a result of tissue damage or stimulation of inflammatory responses. Such molecules include the N-acylethanolamine family. One such member, N-palmitoylethanolamine, is proposed to have a key role in the maintenance of cellular homeostasis in the face of external stressors provoking, for example, inflammation. N-Palmitoylethanolamine has been proven efficacious in mast cell-mediated experimental models of acute and neurogenic inflammation. This review will give an overview of current knowledge relating to the pathobiology of neuroinflammation, the role of microglia and mast cells, and the proposal that mast cell–microglia cross talk may exacerbate acute symptoms of chronic neurodegenerative disease and accelerate disease progression, as well as promote pain transmission pathways. We will conclude by considering the therapeutic potential of treating systemic inflammation or the blocking of signaling pathways from the periphery to the brain.