Here are several Free Full Text PMC articles from PubMed about anandamide, which was mentioned in the previous post: The Feel-Good Gene. The articles start with the most recent one annotated:
Neural Plast. 2015; 2015: 130639.
Microglial activation is a polarized process divided into potentially neuroprotective phenotype M2 and neurotoxic phenotype M1, predominant during chronic neuroinflammation.
Endocannabinoid system provides an attractive target to control the balance between microglial phenotypes.
Anandamide as an immune modulator in the central nervous system acts via not only cannabinoid receptors (CB1 and CB2) but also other targets (e.g., GPR18/GPR55).
We studied the effect of anandamide on lipopolysaccharide-induced changes in rat primary microglial cultures. Microglial activation was assessed based on nitric oxide (NO) production. Analysis of mRNA was conducted for M1 and M2 phenotype markers possibly affected by the treatment.
Our results showed that lipopolysaccharide-induced NO release in microglia was significantly attenuated, with concomitant downregulation of M1 phenotypic markers, after pretreatment with anandamide. This effect was not sensitive to CB1 or GPR18/GPR55 antagonism. Administration of CB2 antagonist partially abolished the effects of anandamide on microglia.
Interestingly, administration of a GPR18/GPR55 antagonist by itself suppressed NO release. In summary, we showed that the endocannabinoid system plays a crucial role in the management of neuroinflammation by dampening the activation of an M1 phenotype. This effect was primarily controlled by the CB2 receptor, although functional cross talk with GPR18/GPR55 may occur.
Neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, stroke, and chronic pain, are associated with ongoing inflammation in the central nervous system (CNS) [1–6]. One of the striking hallmarks of these neurodegenerative disorders is chronic microglial activation.
Recent studies have shown that activated microglia can be divided into two phenotypic profiles. The classical M1 state, characterized by proinflammatory factors for example, interleukins (IL-1Β, IL-18, and IL-6) and inducible nitric oxide synthase (NOS2) [11–14], is neurotoxic and therefore contributes to secondary neuronal damage, cell death, and demyelination, which lead to neurodegeneration [15, 16]. The neuroprotective M2 state, known as “alternative activation,” is associated with the release of anti-inflammatory factors, such as IL-10, IL-4, and NGF
Several studies indicate that the endocannabinoid system provides an attractive target for managing microglial-derived neuroinflammation and may regulate many aspects of the brain’s inflammatory response, including the release of M1 phenotype specific cytokines . The endocannabinoid system modulates both neuronal and immune functions through two protein-coupled cannabinoid receptors (CB1 and CB2), although endocannabinoids, especially anandamide (AEA), can activate numerous other receptors like PPARS, TRPV1, and GPR18/GPR55 . The latter, involved in immunological responses, represents an interesting molecular target for the control of neuroinflammation
Both cannabinoid receptors are expressed in microglia and may act as immune modulators in the CNS
Moreover, it has been proposed that microglia are the main population of cells responsible for the production of AEA in the CNS, as primary microglial cultures produce approximately 20-fold more of this compound than neuronal or astrocyte cultures . Therefore, it is important to investigate the effect of AEA on microglia,
Many of the neurodegenerative conditions of the CNS result in increased levels of endogenous AEA [28–30]; therefore, the endocannabinoid system may provide an attractive target to influence microglial phenotype during chronic inflammation. Therefore, to increase our understanding of the role of the endocannabinoid system in the modulation of microglial polarization, we explored the possible therapeutic action of AEA and AM-251, AM-630, and CID-16020046 at cannabinoid and GPR18/GPR55 receptors in the in vitro model of LPS-induced microglial activation.
3.1. The Concentrations of Compounds Used in the Biochemical and Molecular Analyses Did Not Show Signs of Toxicity
3.2. Involvement of Cannabinoid and GPR Receptors in the AEA-Mediated Alleviation of NO Production
3.3. Alteration of Cb1, Cb2, Gpr18, and Gpr55 Expression in LPS-Stimulated Primary Microglial Cells after Treatment with the Tested Compounds
3.5. Changes in M2 Phenotype-Related Molecules in LPS-Stimulated Rat Primary Microglia after Treatment with the Tested Compounds
Expression of anti-inflammatory IL-10 mRNA was significantly elevated after AEA treatment in LPS-stimulated cells (Figure 5(a)). Moreover, administration of AM-251 also showed similar results.
In the present study, we have demonstrated that the alleviating effect of AEA on NO production in primary microglial cultures is mediated mainly through CB2 receptors. Activated upon CNS damage, microglia initiate and play a critical role in the development of CNS inflammation. Various stimuli can activate microglia, causing proinflammatory or anti-inflammatory functions depending on the duration, nature, and scale of the stimulus
It has been shown that the inflammatory response of LPS-stimulated microglia, which leads to increased secretion of NO, contributes to events underlying brain inflammation and neuronal degeneration
Some studies have indicated that short-term cannabinoid exposure can have a neuroprotective effect at the time of the sudden failure of CNS tissues . Bursts of AEA, which is synthesized “on demand” in areas of cellular stress (e.g., in damaged tissue or at the site of inflammation), have been suggested as the mechanism that inhibits the immune response in both normal and injured tissues, where it is involved in the migration of immune cells to the site of inflammation
Our study demonstrated a reduction in NO release after pretreatment with AEA in LPS-stimulated primary microglial cultures, which suggests it has a neuroprotective action during CNS tissue damage
studies have shown that CB2 receptor activation reduces the immune response during CNS inflammation, brain edema, and the death of neurons, alleviating the symptoms of neurodegenerative diseases in animal models . CB2 receptor stimulation inhibits the activation of microglia, slowing down the development of Alzheimer’s disease
Similarly, CB2 receptor activation in microglial cells in the spinal cord can reduce inflammatory reactions and pain after peripheral nerve injury
Microglial activation is a polarized process that can be divided into M1 and M2 phenotypes [11, 48]. During the short-term activation of microglia, the presence of both the M1 and M2 phenotypes is balanced, allowing the restoration of CNS homeostasis; however, chronic inflammation causes a shift toward the proinflammatory M1 phenotype. One of the actions of activated microglia is the promotion of inflammation, which causes an influx of immune cells to the site of injury. To this end, the M1 phenotype of microglial cells initiates neuroinflammation by producing cytotoxic factors such as cytokines
and enzymes (NOS2 and COX2), which, in addition to acting as chemoattractants, may lead to neuronal damage upon chronic activation
Moreover, cannabinoids can modulate cytokine production , which in turn contributes to a reduction of the immune response and can be beneficial in autoimmune diseases.
Our studies showed that AEA causes a reduction in microglial cell activation, especially by dampening activation of the M1 phenotype. We demonstrated the involvement of the CB2 receptor in the cytoprotective effect of AEA.
Summing up, the use of pharmacological tools to control the phenotype of microglia through the endocannabinoid system may be useful in the treatment of neurodegenerative conditions.
The “classic” endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. An emerging literature documents the “eCB deficiency syndrome” as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system—ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation.
A long-standing literature linking endocannabinoids (ECBs) to stress, fear, and anxiety has led to growing interest in developing novel anxiolytics targeting the ECB system. Following rapid on-demand biosynthesis and degradation upon neuronal activation, the ECB N-arachidonoylethanolamide (anandamide, AEA) is actively degraded by the serine hydrolase enzyme, fatty acid amide hydrolase (FAAH). Exposure to stress rapidly mobilizes FAAH to deplete the signaling pool of AEA and increase neuronal excitability in a key anxiety-mediating region – the basolateral amygdala (BLA). Gene deletion or pharmacological inhibition of FAAH prevents stress-induced reductions in AEA and associated increases in BLA dendritic hypertrophy and anxiety-like behavior. Additionally, inhibition of FAAH facilitates long-term fear extinction and rescues deficient fear extinction in rodent models by enhancing AEA–CB1 (cannabinoid type 1) receptor signaling and synaptic plasticity in the BLA. These preclinical findings propose restoring deficient BLA AEA levels by pharmacologically inhibiting FAAH as a mechanism to therapeutically mitigate the effects of traumatic stress.
The objective of this review is to point out some important facts that we don’t know about endogenous cannabinoids — lipid-derived signaling molecules that activate CB1 cannabinoid receptors and play key roles in motivation, emotion and energy balance. The first endocannabinoid substance to be discovered, anandamide, was isolated from brain tissue in 1992. Research has shown that this molecule is a bona fide brain neurotransmitter involved in the regulation of stress responses and pain, but the molecular mechanisms that govern its formation and the neural pathways in which it is employed are still unknown. There is a general consensus that enzyme-mediated cleavage, catalyzed by fatty acid amide hydrolase (FAAH), terminates the biological actions of anandamide, but there are many reasons to believe that other as-yet-unidentified proteins are also involved in this process. We have made significant headway in understanding the second arrived in the endocannabinoid family, 2-arachidonoyl-sn-glycerol (2-AG), which was discovered three years after anandamide. Researchers have established some of the key molecular players involved in 2-AG formation and deactivation, localized them to specific synaptic components, and showed that their assembly into a multi-molecular protein complex (termed the ‘2-AG signalosome’) allows 2-AG to act as a retrograde messenger at excitatory synapses of the brain. Basic questions that remain to be answered pertain to the exact molecular composition of the 2-AG signalosome, its regulation by neural activity and its potential role in the actions of drugs of abuse such as Δ9-THC and cocaine.
The analgesic effects of cannabinoid ligands, mediated by CB1 receptors are well established. However, the side-effect profile of CB1 receptor ligands has necessitated the search for alternative cannabinoid-based approaches to analgesia. Herein, we review the current literature describing the impact of chronic pain states on the key components of the endocannabinoid receptor system, in terms of regionally restricted changes in receptor expression and levels of key metabolic enzymes that influence the local levels of the endocannabinoids. The evidence that spinal CB2 receptors have a novel role in the modulation of nociceptive processing in models of neuropathic pain, as well as in models of cancer pain and arthritis is discussed. Recent advances in our understanding of the spinal location of the key enzymes that regulate the levels of the endocannabinoid 2-AG are discussed alongside the outcomes of recent studies of the effects of inhibiting the catabolism of 2-AG in models of pain. The complexities of the enzymes capable of metabolizing both anandamide (AEA) and 2-AG have become increasingly apparent. More recently, it has come to light that some of the metabolites of AEA and 2-AG generated by cyclooxygenase-2, lipoxygenases and cytochrome P450 are biologically active and can either exacerbate or inhibit nociceptive signalling
FEBS J. 2013 May
The discovery of the endocannabinoid system (ECS; comprising of G-protein coupled cannabinoid 1 and 2 receptors, their endogenous lipid ligands or endocannabinoids, and synthetic and metabolizing enzymes, triggered an avalanche of experimental studies that have implicated the ECS in a growing number of physiological/pathological functions. They also suggested that modulating ECS activity holds therapeutic promise for a broad range of diseases, including neurodegenerative, cardiovascular and inflammatory disorders, obesity/metabolic syndrome, cachexia, chemotherapy-induced nausea and vomiting, tissue injury and pain, among others. However, clinical trials with globally acting CB1 antagonists in obesity/metabolic syndrome, and other studies with peripherally restricted CB1/2 agonists and inhibitors of the endocannabinoid metabolizing enzyme in pain introduced unexpected complexities, and suggested that better understanding of the pathophysiological role of the ECS is required in order to devise clinically successful treatment strategies, which will be critically reviewed in this brief synopsis.
Nat Rev Neurosci. 2015 Jan;16(1):30-42. doi: 10.1038/nrn3876.
Ageing is characterized by the progressive impairment of physiological functions and increased risk of developing debilitating disorders, including chronic inflammation and neurodegenerative diseases. These disorders have common molecular mechanisms that can be targeted therapeutically. In the wake of the approval of the first cannabinoid-based drug for the symptomatic treatment of multiple sclerosis, we examine how endocannabinoid (eCB) signalling controls–and is affected by–normal ageing and neuroinflammatory and neurodegenerative disorders. We propose a conceptual framework linking eCB signalling to the control of the cellular and molecular hallmarks of these processes, and categorize the key components of endocannabinoid signalling that may serve as targets for novel therapeutics.