Abstract
Endocannabinoids (eCBs) are lipid-based retrograde messengers with a relatively short half-life that are produced endogenously and, upon binding to the primary cannabinoid receptors CB1/2, mediate multiple mechanisms of intercellular communication within the body. Endocannabinoid signaling is implicated in brain development, memory formation, learning, mood, anxiety, depression, feeding behavior, analgesia, and drug addiction. It is now recognized that the endocannabinoid system mediates not only neuronal communications but also governs the crosstalk between neurons, glia, and immune cells, and thus represents an important player within the neuroimmune interface. Generation of primary endocannabinoids is accompanied by the production of their congeners, the N-acylethanolamines (NAEs), which together with N-acylneurotransmitters, lipoamino acids and primary fatty acid amides comprise expanded endocannabinoid/endovanilloid signaling systems. Most of these compounds do not bind CB1/2, but signal via several other pathways involving the transient receptor potential cation channel subfamily V member 1 (TRPV1), peroxisome proliferator-activated receptor (PPAR)-α and non-cannabinoid G-protein coupled receptors (GPRs) to mediate anti-inflammatory, immunomodulatory and neuroprotective activities. In vivo generation of the cannabinoid compounds is triggered by physiological and pathological stimuli and, specifically in the brain, mediates fine regulation of synaptic strength, neuroprotection, and resolution of neuroinflammation. Here, we review the role of the endocannabinoid system in intrinsic neuroprotective mechanisms and its therapeutic potential for the treatment of neuroinflammation and associated synaptopathy.
Highlights
Neuroinflammation is widely regarded as inflammation of the central nervous system (CNS) comprising the brain and spinal cord
N-acylethaolamines generated as AEA congeners together with lipoaminoacids and acyl conjugates of neurotransmitters exert their biological activities through different receptors such as peroxisome proliferator-activated receptor (PPAR)-α [4], transient receptor potential cation channel subfamily V member 1 (TRPV1) and non-cannabinoid G-protein coupled receptors (GPRs)
The interference of NAEs and other eCB congeners with enzymatic degradation or endocannabinoid signaling suggests their role in tuning the activity of primary eCBs
Summary
Retrograde endocannabinoid signaling provides a mechanism by which neurons can rapidly regulate the strength of their synaptic inputs. Stimulation of postsynaptic neurotransmitter receptors and sustained Ca2+ influx is a potent trigger for the production of endocannabinoids (eCBs) and their congeners. Neuroinflammation and alterations in endocannabinoid signaling is implicated in multiple neurological disorders. The activity-dependent flow of glutamate and eCBs from synapses controls microglial attraction, secretion of pro-inflammatory and pro-survival factors, and defines the synapse stability under inflammation and excitotoxicity. The pharmacological inhibition of eCB degradation exerts a primary effect in injured sites, where these mediators are actively produced de novo. The endocannabinoid system mediates communication within the tripartite synapse during the development and resolution of neuroinflammation
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