anandamide and Nervous-System-Diseases

It has been established that the endogenous cannabinoid (endocannabinoid) system plays key modulatory roles in a wide variety of pathological conditions. The endocannabinoid system comprises both cannabinoid receptors, their endogenous ligands including 2-arachidonoylglycerol (2-AG), N-arachidonylethanolamine (anandamide, AEA), and enzymes that regulate the synthesis and degradation of endogenous ligands which include diacylglycerol lipase alpha (DAGL-α), diacylglycerol lipase beta (DAGL-β), fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), α/β hydrolase domain 6 (ABHD6). As the endocannabinoid system exerts considerable involvement in the regulation of homeostasis and disease, much effort has been made towards understanding endocannabinoid-related mechanisms of action at cellular, physiological, and pathological levels as well as harnessing the various components of the endocannabinoid system to produce novel therapeutics. However, drug discovery efforts within the cannabinoid field have been slower than anticipated to reach satisfactory clinical endpoints and raises an important question into the validity of developing novel ligands that therapeutically target the endocannabinoid system. To answer this, we will first examine evidence that supports the existence of an endocannabinoid system role within inflammatory diseases, neurodegeneration, pain, substance use disorders, mood disorders, as well as metabolic diseases. Next, this review will discuss recent clinical studies, within the last 5 years, of cannabinoid compounds in context to these diseases. We will also address some of the challenges and considerations within the cannabinoid field that may be important in the advancement of therapeutics into the clinic.

Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Agonists; Cannabinoids; Drug Discovery; Endocannabinoids; Glycerides; Humans; Inflammation; Metabolic Diseases; Mood Disorders; Nervous System Diseases; Pain; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Substance-Related Disorders

Endocannabinoids are amides, esters and ethers of long chain polyunsaturated fatty acids, which act as new lipidic mediators. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol (2-AG) are the main endogenous agonists of cannabinoid receptors, able to mimic several pharmacological effects of (-)-Delta9-tetrahydrocannabinol (THC), the active principle of Cannabis sativa preparations like hashish and marijuana. The activity of AEA and 2-AG at their receptors is limited by cellular uptake through an anandamide membrane transporter (AMT), followed by intracellular degradation. A fatty acid amide hydrolase (FAAH) is the main AEA hydrolase, whereas a monoacylglycerol lipase (MAGL) is critical in degrading 2-AG. Here, we will review growing evidence that demonstrates that these hydrolases are pivotal regulators of the endogenous levels of AEA and 2-AG in vivo, overall suggesting that specific inhibitors of AMT, FAAH or MAGL may serve as attractive therapeutic targets for the treatment of human disorders. Recently, the N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD), which synthesizes AEA from N-arachidonoylphosphatidylethanolamine (NArPE), and the diacylglycerol lipase (DAGL), which generates 2-AG from diacylglycerol (DAG) substrates, have been characterized. The role of these synthetic routes in maintaining the endocannabinoid tone in vivo will be discussed. Finally, the effects of inhibitors of endocannabinoid degradation in animal models of human disease will be reviewed, with an emphasis on their ongoing applications in anxiety, cancer and neurodegenerative disorders.

Topics: Arachidonic Acid; Arachidonic Acids; Cannabinoid Receptor Agonists; Cannabinoid Receptor Modulators; Cannabis; Cell Membrane; Chemistry, Pharmaceutical; Dronabinol; Endocannabinoids; Glycerides; Humans; Lipoprotein Lipase; Monoacylglycerol Lipases; Neoplasms; Nervous System Diseases; Phosphatidylethanolamines; Phospholipase D; Polyunsaturated Alkamides

Topics: Animals; Arachidonic Acids; Brain; Cannabinoids; Endocannabinoids; Humans; Nervous System Diseases; Polyunsaturated Alkamides; Receptors, Cannabinoid; Receptors, Drug; Signal Transduction; Synaptic Transmission

Endocannabinoids (eCBs) are ubiquitous lipid mediators that act on specific (CB1, CB2) and non-specific (TRPV1, PPAR) receptors. Despite many experimental animal studies proved eCB involvement in the pathogenesis of stroke, such evidence is still lacking in human patients. Our aim was to determine eCB peripheral levels in acute stroke patients and evaluate their relationship with clinical disability and stroke volume.. A cohort of ten patients with a first acute (within six hours since symptoms onset) ischemic stroke and a group of eight age- and sex-matched normal subjects were included. Groups were also matched for metabolic profile. All subjects underwent a blood sample collection for anandamide (AEA), 2-arachidonoylglycerol (2-AG) and palmitoylethanolamide (PEA) measurement; blood sampling was repeated in patients on admission (T0), at 6 (T1) and 18 hours (T2) thereafter. Patients neurological impairment was assessed using NIHSS and Fugl-Meyer Scale arm subitem (FMSa); stroke volume was determined on 48 h follow-up brain CT scans. Blood samples were analyzed by liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry.. 1)T0 AEA levels were significantly higher in stroke patients compared to controls. 2)A significant inverse correlation between T0 AEA levels and FMSa score was found. Moreover a positive correlation between T0 AEA levels and stroke volume were found in stroke patients. T0 PEA levels in stroke patients were not significantly different from the control group, but showed a significant correlation with the NIHSS scores. T0 2-AG levels were lower in stroke patients compared to controls, but such difference did not reach the significance threshold.. This is the first demonstration of elevated peripheral AEA levels in acute stroke patients. In agreement with previous murine studies, we found a significant relationship between AEA or PEA levels and neurological involvement, such that the greater the neurological impairment, the higher were these levels.

Topics: Aged; Aged, 80 and over; Amides; Arachidonic Acids; Cannabinoid Receptor Modulators; Chromatography, Liquid; Endocannabinoids; Ethanolamines; Glycerides; Humans; Male; Mass Spectrometry; Metabolomics; Middle Aged; Nervous System Diseases; Palmitic Acids; Polyunsaturated Alkamides; Stroke

Cannabinoid receptor agonists including anandamide and noladin either have recently been suggested to exhibit neuroprotective properties. The amyloid-beta (Abeta) peptide is thought to be responsible for the neurodegenerative changes associated with Alzheimer's disease pathology. This study characterizes the effects of anandamide and noladin ether on the neurotoxicity of Abeta in differentiated human teratocarcinoma cell line, Ntera 2/cl-D1 neurons. Anandamide and noladin ether, at nanomolar concentrations, showed concentration dependent inhibition of Abeta toxicity. A CB(1) cannabinoid receptor antagonist, AM251, prevented the protective effects of anandamide and noladin ether. The mitogen activated protein kinase (MAPK) pathway inhibitor PD98059 also prevented the protective effects of cannabinoids and corticotrophin-releasing hormone. These results suggest that activation of the MAPK pathway by either cannabinoids or corticotrophin-releasing hormone could be used to prevent Abeta peptide induced neurodegeneration.

Topics: Amyloid beta-Peptides; Arachidonic Acids; Cannabinoids; Corticotropin-Releasing Hormone; Endocannabinoids; Enzyme Inhibitors; Flavonoids; Glycerides; Humans; Mitogen-Activated Protein Kinases; Nervous System Diseases; Neurons; Neuroprotective Agents; Neurotoxins; Oxidation-Reduction; Peptide Fragments; Polyunsaturated Alkamides; Receptors, Cannabinoid; Receptors, Drug