anandamide and Neurodegenerative-Diseases

Recent years have yielded significant advances in our understanding of microglia, the immune cells of the central nervous system (CNS). Microglia are key players in CNS development, immune surveillance, and the maintenance of proper neuronal function throughout life. In the healthy brain, homeostatic microglia have a unique molecular signature. In neurological diseases, microglia become activated and adopt distinct transcriptomic signatures, including disease-associated microglia (DAM) implicated in neurodegenerative disorders. Homeostatic microglia synthesise the endogenous cannabinoids 2-arachidonoylglycerol and anandamide and express the cannabinoid receptors CB1 and CB2 at constitutively low levels. Upon activation, microglia significantly increase their synthesis of endocannabinoids and upregulate their expression of CB2 receptors, which promote a protective microglial phenotype by enhancing their production of neuroprotective factors and reducing their production of pro-inflammatory factors. Here, we summarise the effects of the microglial cannabinoid system in the CNS demyelinating disease multiple sclerosis, the neurodegenerative diseases Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, chronic inflammatory and neuropathic pain, and psychiatric disorders including depression, anxiety and schizophrenia. We discuss the therapeutic potential of cannabinoids in regulating microglial activity and highlight the need to further investigate their specific microglia-dependent immunomodulatory effects.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Anxiety Disorders; Arachidonic Acids; Chronic Pain; Depressive Disorder; Endocannabinoids; Glycerides; Humans; Mental Disorders; Microglia; Multiple Sclerosis; Neuralgia; Neurodegenerative Diseases; Parkinson Disease; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Schizophrenia

The endocannabinoid (eCB) system is an important part of both the human central nervous system (CNS) and peripheral tissues. It is involved in the regulation of various physiological and neuronal processes and has been associated with various diseases. The eCB system is a complex network composed of receptor molecules, their cannabinoid ligands, and enzymes regulating the synthesis, release, uptake, and degradation of the signalling molecules. Although the eCB system and the molecular processes of eCB signalling have been studied extensively over the past decades, the involved molecules and underlying signalling mechanisms have not been described in full detail. An example pose the two poorly characterised eCB-degrading enzymes α/β-hydrolase domain protein six (ABHD6) and ABHD12, which have been shown to hydrolyse 2-arachidonoyl glycerol-the main eCB in the CNS. We review the current knowledge about the eCB system and the role of ABHD6 and ABHD12 within this important signalling system and associated diseases. Homology modelling and multiple sequence alignments highlight the structural features of the studied enzymes and their similarities, as well as the structural basis of disease-related ABHD12 mutations. However, homologies within the ABHD family are very low, and even the closest homologues have widely varying substrate preferences. Detailed experimental analyses at the molecular level will be necessary to understand these important enzymes in full detail.

Topics: Animals; Arachidonic Acids; Ataxia; Cataract; Computational Biology; Endocannabinoids; Glycerides; Humans; Lipid Metabolism; Monoacylglycerol Lipases; Mutation; Neurodegenerative Diseases; Polyneuropathies; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Retinitis Pigmentosa; Signal Transduction

2-Arachidonoyl-glycerol (2-AG) and arachidonyl-ethanolamide (AEA) are endocannabinoids that have been implicated in many physiologic disorders, including obesity, metabolic syndromes, hepatic diseases, pain, neurologic disorders, and inflammation. Their immunomodulatory effects are numerous and are not always mediated by cannabinoid receptors, reflecting the presence of an arachidonic acid (AA) molecule in their structure, the latter being the precursor of numerous bioactive lipids that are pro- or anti-inflammatory. 2-AG and AEA can thus serve as a source of AA but can also be metabolized by most eicosanoid biosynthetic enzymes, yielding additional lipids. In this regard, enhancing endocannabinoid levels by using endocannabinoid hydrolysis inhibitors is likely to augment the levels of these lipids that could regulate inflammatory cell functions. This review summarizes the metabolic pathways involved in the biosynthesis and metabolism of AEA and 2-AG, as well as the biologic effects of the 2-AG and AEA lipidomes in the regulation of inflammation.

Topics: Animals; Arachidonic Acids; Dendritic Cells; Endocannabinoids; Glycerides; Humans; Inflammation; Lipid Metabolism; Liver Diseases; Lymphocytes; Metabolic Syndrome; Neurodegenerative Diseases; Obesity; Pain; Phosphatidic Acids; Polyunsaturated Alkamides; Receptors, Cannabinoid

Endocannabinoids are a new class of lipids, which include amides, esters and ethers of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol are the main endogenous agonists of cannabinoid receptors, able to mimic several pharmacological effects of Delta(9)-tetrahydrocannabinol, the active principle of Cannabis sativa preparations like hashish and marijuana. It is known that the activity of AEA is limited by cellular uptake through a specific membrane transporter, followed by intracellular degradation by a fatty acid amide hydrolase. Together with AEA and congeners these proteins form the "endocannabinoid system". The endogenous cannabinoids were identified in brain, and also in neuronal and endothelial cells, suggesting a potential role as modulators in the central nervous system and in the periphery. This review summarises the metabolic routes for the synthesis and degradation of AEA, and the latest advances in the involvement of this lipid in neurovascular biology. In addition, the therapeutic potential of the modulation of endocannabinoid metabolism for neuronal and vascular system will be also reviewed.

Topics: Animals; Arachidonic Acids; Blood Vessels; Cannabinoid Receptor Modulators; Cardiovascular System; Central Nervous System; Endocannabinoids; Humans; Multiple Sclerosis; Nervous System; Neurodegenerative Diseases; Polyunsaturated Alkamides

N-Acyl-ethanolamines (NAEs) and their precursors, N-acyl-ethanolamine phospholipids (NAPEs), are present in the mammalian brain at levels of a few hundred picomoles/gram tissue and a few nanomoles/gram tissue, respectively. NAE-containing arachidonic acid is called anandamide, and it has attracted particular attention since it is a partial agonist for the cannabinoid receptors, for which 2-arachidonoylglycerol is the full agonist. In addition, anandamide may also activate the vanilloid receptor. Anandamide usually amounts to 1-10% of NAEs, as the vast majority of N-acyl groups are saturated and monounsaturated fatty acids. Formation of NAPE and NAE is catalyzed by an N-acyltransferase and an NAPE-hydrolyzing phospholipase D, respectively, two enzymes that have been characterized only preliminary. Interestingly, NAPEs and NAEs accumulate in the brain in response to neurodegenerative insults at a time when other phospholipids are subjected to rapid degradation. This is an important biosynthetic aspect of NAPE and NAE, as NAEs may be neuroprotective by a number of different mechanisms involving both receptor activation and non-receptor-mediated effects, e.g. by binding to cannabinoid receptors and interfering with ceramide turnover, respectively.

Topics: Animals; Arachidonic Acids; Brain; Brain Ischemia; Ceramides; Endocannabinoids; Ethanolamines; Humans; Neurodegenerative Diseases; Neuroprotective Agents; Phospholipids; Polyunsaturated Alkamides; Receptors, Cannabinoid; Receptors, Drug

Topics: Amyloid beta-Peptides; Animals; Arachidonic Acids; Brain; Cyclooxygenase 2; Dementia; Endocannabinoids; Fluorodeoxyglucose F18; Glucose; Hippocampus; Humans; Insulin; Ligands; Mice; Mice, Transgenic; Neurodegenerative Diseases; Neurons; Polyunsaturated Alkamides; Positron-Emission Tomography; Protein Folding; Receptor, Cannabinoid, CB2; Signal Transduction

The psychoactive component of the cannabis resin and flowers, delta9-tetrahydrocannabinol (THC), was first isolated in 1964, and at least 70 other structurally related 'phytocannabinoid' compounds have since been identified. The serendipitous identification of a G-protein-coupled cannabinoid receptor at which THC is active in the brain heralded an explosion in cannabinoid research. Elements of the endocannabinoid system (ECS) comprise the cannabinoid receptors, a family of nascent lipid ligands, the 'endocannabinoids' and the machinery for their biosynthesis and metabolism. The function of the ECS is thus defined by modulation of these receptors, in particular, by two of the best-described ligands, 2-arachidonoyl glycerol and anandamide (arachidonylethanolamide). Research on the ECS has recently aroused enormous interest not only for the physiological functions, but also for the promising therapeutic potentials of drugs interfering with the activity of cannabinoid receptors. Many of the former relate to stress-recovery systems and to the maintenance of homeostatic balance. Among other functions, the ECS is involved in neuroprotection, modulation of nociception, regulation of motor activity, neurogenesis, synaptic plasticity and the control of certain phases of memory processing. In addition, the ECS acts to modulate the immune and inflammatory responses and to maintain a positive energy balance. This theme issue aims to provide the reader with an overview of ECS pharmacology, followed by discussions on the pivotal role of this system in the modulation of neurogenesis in the developing and adult organism, memory processes and synaptic plasticity, as well as in pathological pain and brain ageing. The volume will conclude with discussions that address the proposed therapeutic applications of targeting the ECS for the treatment of neurodegeneration, pain and mental illness.

Topics: Arachidonic Acids; Brain; Cannabidiol; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Dronabinol; Electrical Synapses; Endocannabinoids; Glycerides; Humans; Inflammation; Neurodegenerative Diseases; Neurogenesis; Neuroprotective Agents; Nociceptors; Polyunsaturated Alkamides; Receptors, Cannabinoid; Synaptic Transmission

Topics: Arachidonic Acids; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cannabinoids; Dronabinol; Endocannabinoids; Glycerides; Humans; Neurodegenerative Diseases; Polyunsaturated Alkamides; Receptors, Cannabinoid; Signal Transduction

It has been demonstrated that the endogenous cannabinoid receptor ligand, anandamide, and other N-acylethanolamines (NAEs), accumulate during neuronal injury in vitro, a process that may be linked to the neuroprotective effects of NAEs. The crucial step for generation of NAEs is the synthesis of the corresponding precursors, N-acylethanolamine phospholipids (NAPEs). However, it is unknown whether this key event for NAE formation is regulated differently in the context of insults causing necrotic or apoptotic neuronal death. To address this question, we monitored a range of cortical NAPE species in three infant rat models of in vivo neurodegeneration: (i) necrosis caused by intrastriatal injection of NMDA (25 nmol); (ii) apoptosis induced by systemic administration of the NMDA-receptor antagonist (+)MK-801 (3 x 0.5 mg/kg, i.p.); and (iii) apoptosis following focal necrosis triggered by concussive head trauma. A marked increase of all NAPE species was observed in both hemispheres 4 and 24 h after NMDA-induced injury, with a relatively larger increase in N-stearoyl-containing NAPE species. Thus, the percentage of the anandamide precursor fell from 1.1 to 0.5 mol %. In contrast, administration of (+)MK-801 did not alter cortical NAPE levels. Concussion head trauma resulted in a similar but less pronounced upregulation of NAPE levels at both 4 and 24 h as compared to NMDA injections. Increased levels of NAPE 24 h post-trauma possibly reflect that necrosis is still ongoing at this time point. Consequently, our data suggest that excitotoxic necrotic mechanisms of neurodegeneration, as opposed to apoptotic neurodegeneration, have a profound effect on in vivo NAE precursor homeostasis.

Topics: Animals; Apoptosis; Arachidonic Acids; Brain Injuries; Cerebral Cortex; Corpus Striatum; Disease Models, Animal; Dizocilpine Maleate; Endocannabinoids; Ethanolamines; Male; N-Methylaspartate; Necrosis; Neurodegenerative Diseases; Neurons; Phospholipids; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Species Specificity; Wounds, Nonpenetrating