The Experts below are selected from a list of 31923 Experts worldwide ranked by ideXlab platform
Vincenzo Di Marzo - One of the best experts on this subject based on the ideXlab platform.
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Cannabinoids and the expanded Endocannabinoid system in neurological disorders
Nature Reviews Neurology, 2020Co-Authors: Luigia Cristino, Tiziana Bisogno, Vincenzo Di MarzoAbstract:Anecdotal evidence that cannabis preparations have medical benefits together with the discovery of the psychotropic plant cannabinoid Δ^9-tetrahydrocannabinol (THC) initiated efforts to develop cannabinoid-based therapeutics. These efforts have been marked by disappointment, especially in relation to the unwanted central effects that result from activation of cannabinoid receptor 1 (CB1), which have limited the therapeutic use of drugs that activate or inactivate this receptor. The discovery of CB2 and of endogenous cannabinoid receptor ligands (Endocannabinoids) raised new possibilities for safe targeting of this Endocannabinoid system. However, clinical success has been limited, complicated by the discovery of an expanded Endocannabinoid system — known as the Endocannabinoidome — that includes several mediators that are biochemically related to the Endocannabinoids, and their receptors and metabolic enzymes. The approvals of nabiximols, a mixture of THC and the non-psychotropic cannabinoid cannabidiol, for the treatment of spasticity and neuropathic pain in multiple sclerosis, and of purified botanical cannabidiol for the treatment of otherwise untreatable forms of paediatric epilepsy, have brought the therapeutic use of cannabinoids and Endocannabinoids in neurological diseases into the limelight. In this Review, we provide an overview of the Endocannabinoid system and the Endocannabinoidome before discussing their involvement in and clinical relevance to a variety of neurological disorders, including Parkinson disease, Alzheimer disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy and glioblastoma. In this Review, Cristino, Bisogno and Di Marzo outline the biology of cannabinoids, the Endocannabinoid system and the expanded Endocannabinoid system and discuss the involvement of these systems and the therapeutic potential of cannabinoids across the spectrum of neurological disease. Cannabinoid receptors 1 and 2 (CB1 and CB2), the two Endocannabinoids anandamide and 2-arachidonoylglycerol, and Endocannabinoid anabolic and catabolic enzymes form the Endocannabinoid system. Endocannabinoid signalling is involved in regulation of cell, tissue, organ and organism homeostasis, brain development, neurotransmitter release and synaptic plasticity, and cytokine release from microglia, and hence is implicated in multiple neurological disorders. Endocannabinoid signalling is altered in most neurological disorders; enhancers or inhibitors of Endocannabinoid signalling can have therapeutic effects in preclinical models, depending on disease characteristics and the roles of CB1 and CB2. Endocannabinoids can activate different receptors and their biosynthetic and catabolic pathways are often shared with other mediators. Consequently, the system is considered to be part of an expanded signalling system, the Endocannabinoidome. The Endocannabinoidome hinders therapeutic targeting of Endocannabinoid anabolic or catabolic enzymes but inhibitors of Endocannabinoid inactivation and allosteric modulators of CB1 and CB2 are being actively investigated in neurological disorders. The existence of the Endocannabinoidome explains in part why some non-euphoric cannabinoids, which affect several Endocannabinoidome proteins, are useful for the treatment of neurological disorders, such as multiple sclerosis and epilepsy.
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cannabinoids and the expanded Endocannabinoid system in neurological disorders
Nature Reviews Neurology, 2020Co-Authors: Luigia Cristino, Tiziana Bisogno, Vincenzo Di MarzoAbstract:Anecdotal evidence that cannabis preparations have medical benefits together with the discovery of the psychotropic plant cannabinoid Δ9-tetrahydrocannabinol (THC) initiated efforts to develop cannabinoid-based therapeutics. These efforts have been marked by disappointment, especially in relation to the unwanted central effects that result from activation of cannabinoid receptor 1 (CB1), which have limited the therapeutic use of drugs that activate or inactivate this receptor. The discovery of CB2 and of endogenous cannabinoid receptor ligands (Endocannabinoids) raised new possibilities for safe targeting of this Endocannabinoid system. However, clinical success has been limited, complicated by the discovery of an expanded Endocannabinoid system — known as the Endocannabinoidome — that includes several mediators that are biochemically related to the Endocannabinoids, and their receptors and metabolic enzymes. The approvals of nabiximols, a mixture of THC and the non-psychotropic cannabinoid cannabidiol, for the treatment of spasticity and neuropathic pain in multiple sclerosis, and of purified botanical cannabidiol for the treatment of otherwise untreatable forms of paediatric epilepsy, have brought the therapeutic use of cannabinoids and Endocannabinoids in neurological diseases into the limelight. In this Review, we provide an overview of the Endocannabinoid system and the Endocannabinoidome before discussing their involvement in and clinical relevance to a variety of neurological disorders, including Parkinson disease, Alzheimer disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy and glioblastoma. In this Review, Cristino, Bisogno and Di Marzo outline the biology of cannabinoids, the Endocannabinoid system and the expanded Endocannabinoid system and discuss the involvement of these systems and the therapeutic potential of cannabinoids across the spectrum of neurological disease.
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New approaches and challenges to targeting the Endocannabinoid system
Nature Reviews Drug Discovery, 2018Co-Authors: Vincenzo Di MarzoAbstract:The Endocannabinoid signalling system was discovered because receptors in this system are the targets of compounds present in psychotropic preparations of Cannabis sativa . The search for new therapeutics that target Endocannabinoid signalling is both challenging and potentially rewarding, as Endocannabinoids are implicated in numerous physiological and pathological processes. Hundreds of mediators chemically related to the Endocannabinoids, often with similar metabolic pathways but different targets, have complicated the development of inhibitors of Endocannabinoid metabolic enzymes but have also stimulated the rational design of multi-target drugs. Meanwhile, drugs based on botanical cannabinoids have come to the clinical forefront, synthetic agonists designed to bind cannabinoid receptor 1 with very high affinity have become a societal threat and the gut microbiome has been found to signal in part through the Endocannabinoid network. The current development of drugs that alter Endocannabinoid signalling and how this complex system could be pharmacologically manipulated in the future are described in this Opinion article. Dysregulation of the Endocannabinoid system has been implicated in numerous diseases, particularly pain, psychiatric and neurological disorders, but therapeutic intervention in this complex system has proved challenging. In this Perspective article, Di Marzo discusses the lessons learned from the development of drugs that alter Endocannabinoid signalling and highlights novel opportunities for pharmacologically manipulating the Endocannabinoid system, such as the use of multi-target drugs.
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new approaches and challenges to targeting the Endocannabinoid system
Nature Reviews Drug Discovery, 2018Co-Authors: Vincenzo Di MarzoAbstract:The Endocannabinoid signalling system was discovered because receptors in this system are the targets of compounds present in psychotropic preparations of Cannabis sativa. The search for new therapeutics that target Endocannabinoid signalling is both challenging and potentially rewarding, as Endocannabinoids are implicated in numerous physiological and pathological processes. Hundreds of mediators chemically related to the Endocannabinoids, often with similar metabolic pathways but different targets, have complicated the development of inhibitors of Endocannabinoid metabolic enzymes but have also stimulated the rational design of multi-target drugs. Meanwhile, drugs based on botanical cannabinoids have come to the clinical forefront, synthetic agonists designed to bind cannabinoid receptor 1 with very high affinity have become a societal threat and the gut microbiome has been found to signal in part through the Endocannabinoid network. The current development of drugs that alter Endocannabinoid signalling and how this complex system could be pharmacologically manipulated in the future are described in this Opinion article.
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Endocannabinoids and Endocannabinoid related mediators targets metabolism and role in neurological disorders
Progress in Lipid Research, 2016Co-Authors: Fabio Arturo Iannotti, Vincenzo Di Marzo, Stefania PetrosinoAbstract:Abstract The Endocannabinoid system (ECS) is composed of two G protein-coupled receptors (GPCRs), the cannabinoid CB1 and CB2 receptors, and the two main endogenous lipid ligands of such receptors (also known as the “Endocannabinoids”), anandamide and 2-arachidonoyl-glycerol. The ECS is a pleiotropic signalling system involved in all aspects of mammalian physiology and pathology, and for this reason it represents a potential target for the design and development of new therapeutic drugs. However, the Endocannabinoids as well as some of their congeners also interact with a much wider range of receptors, including members of the Transient Receptor Potential (TRP) channels, Peroxisome Proliferator-Activated Receptors (PPARs), and other GPCRs. Indeed, following the discovery of the Endocannabinoids, Endocannabinoid-related lipid mediators, which often share the same metabolic pathways of the Endocannabinoids, have also been identified or rediscovered. In this review article, we discuss the role of Endocannabinoids and related lipids during physiological functions, as well as their involvement in some of the most common neurological disorders.
Yuki Hashimotodani - One of the best experts on this subject based on the ideXlab platform.
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Endocannabinoid Signaling and Synaptic Function
Neuron, 2012Co-Authors: Pablo E Castillo, Thomas J. Younts, Andrés E. Chávez, Yuki HashimotodaniAbstract:Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors expressed in the central nervous system, these lipid messengers can regulate several neural functions and behaviors. As experimental tools advance, the repertoire of known Endocannabinoid-mediated effects at the synapse, and their underlying mechanism, continues to expand. Retrograde signaling is the principal mode by which Endocannabinoids mediate short- and long-term forms of plasticity at both excitatory and inhibitory synapses. However, growing evidence suggests that Endocannabinoids can also signal in a nonretrograde manner. In addition to mediating synaptic plasticity, the Endocannabinoid system is itself subject to plastic changes. Multiple points of interaction with other neuromodulatory and signaling systems have now been identified. In this Review, we focus on new advances in synaptic Endocannabinoid signaling in the mammalian brain. The emerging picture not only reinforces Endocannabinoids as potent regulators of synaptic function but also reveals that Endocannabinoid signaling is mechanistically more complex and diverse than originally thought.
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Endocannabinoid Signaling and Synaptic Function
Neuron, 2012Co-Authors: Pablo E Castillo, Thomas J. Younts, Andrés E. Chávez, Yuki HashimotodaniAbstract:Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors expressed in the central nervous system, these lipid messengers can regulate several neural functions and behaviors. As experimental tools advance, the repertoire of known Endocannabinoid-mediated effects at the synapse, and their underlying mechanism, continues to expand. Retrograde signaling is the principal mode by which Endocannabinoids mediate short- and long-term forms of plasticity at both excitatory and inhibitory synapses. However, growing evidence suggests that Endocannabinoids can also signal in a nonretrograde manner. In addition to mediating synaptic plasticity, the Endocannabinoid system is itself subject to plastic changes. Multiple points of interaction with other neuromodulatory and signaling systems have now been identified. In this Review, we focus on new advances in synaptic Endocannabinoid signaling in the mammalian brain. The emerging picture not only reinforces Endocannabinoids as potent regulators of synaptic function but also reveals that Endocannabinoid signaling is mechanistically more complex and diverse than originally thought.
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Endocannabinoids and Retrograde Modulation of Synaptic Transmission
The Neuroscientist : a review journal bringing neurobiology neurology and psychiatry, 2011Co-Authors: Takako Ohno-shosaku, Yuki Hashimotodani, Asami Tanimura, Masanobu KanoAbstract:Since the first reports of Endocannabinoid-mediated retrograde signaling in 2001, great advances have been made toward understanding the molecular basis and functions of the Endocannabinoid system. Electrophysiological studies have revealed that the Endocannabinoid system is functional at various types of synapses throughout the brain. Basic mechanisms have been clarified as to how Endocannabinoids are produced and released from postsynaptic neurons and regulate neurotransmitter release through activating presynaptic cannabinoid CB1 receptors, although there remain unsolved questions and some discrepancies. In addition to this major function, recent studies suggest diverse functions of Endocannabinoids, including control of other Endocannabinoid-independent forms of synaptic plasticity, regulation of neuronal excitability, stimulation of glia-neuron interaction, and induction of CB1R-independent plasticity. Using recently developed pharmacological and genetic tools, behavioral studies have elucidated the ...
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Presynaptic Monoacylglycerol Lipase Activity Determines Basal Endocannabinoid Tone and Terminates Retrograde Endocannabinoid Signaling in the Hippocampus
The Journal of Neuroscience, 2007Co-Authors: Yuki Hashimotodani, Takako Ohno-shosaku, Masanobu KanoAbstract:Endocannabinoids function as retrograde messengers and modulate synaptic transmission through presynaptic cannabinoid CB1 receptors. The magnitude and time course of Endocannabinoid signaling are thought to depend on the balance between the production and degradation of Endocannabinoids. The major Endocannabinoid 2-arachidonoylglycerol (2-AG) is hydrolyzed by monoacylglycerol lipase (MGL), which is shown to be localized at axon terminals. In the present study, we investigated how MGL regulates Endocannabinoid signaling and influences synaptic transmission in the hippocampus. We found that MGL inhibitors, methyl arachidonoyl fluorophosphonate and arachidonoyl trifluoromethylketone, caused a gradual suppression of cannabinoid-sensitive IPSCs in cultured hippocampal neurons. This suppression was reversed by blocking CB1 receptors and was attenuated by inhibiting 2-AG synthesis, indicating that MGL scavenges constitutively released 2-AG. We also found that the MGL inhibitors significantly prolonged the suppression of both IPSCs and EPSCs induced by exogenous 2-AG and depolarization-induced suppression of inhibition/excitation, a phenomenon known to be mediated by retrograde Endocannabinoid signaling. In contrast, inhibitors of other Endocannabinoid hydrolyzing enzymes, fatty acid amide hydrolase and cyclooxygenase-2, had no effect on the 2-AG-induced IPSC suppression. These results strongly suggest that presynaptic MGL not only hydrolyzes 2-AG released from activated postsynaptic neurons but also contributes to degradation of constitutively produced 2-AG and prevention of its accumulation around presynaptic terminals. Thus, the MGL activity determines basal Endocannabinoid tone and terminates retrograde Endocannabinoid signaling in the hippocampus.
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Endocannabinoids and Synaptic Function in the CNS
The Neuroscientist : a review journal bringing neurobiology neurology and psychiatry, 2007Co-Authors: Yuki Hashimotodani, Takako Ohno-shosaku, Masanobu KanoAbstract:Marijuana affects neural functions through the binding of its active component (Delta(9)-THC) to cannabinoid receptors in the CNS. Recent studies have elucidated that endogenous ligands for cannabinoid receptors, Endocannabinoids, serve as retrograde messengers at central synapses. Endocannabinoids are produced on demand in activity-dependent manners and released from postsynaptic neurons. The released Endocannabinoids travel backward across the synapse, activate presynaptic CB1 cannabinoid receptors, and modulate presynaptic functions. Retrograde Endocannabinoid signaling is crucial for certain forms of short-term and long-term synaptic plasticity at excitatory or inhibitory synapses in many brain regions, and thereby contributes to various aspects of brain function including learning and memory. Molecular identities of the CB1 receptor and enzymes involved in production and degradation of Endocannabinoids have been elucidated. Anatomical studies have demonstrated unique distributions of these molecules around synapses, which provide morphological bases for the roles of Endocannabinoids as retrograde messengers. CB1-knockout mice exhibit various behavioral abnormalities and multiple defects in synaptic plasticity, supporting the notion that Endocannabinoid signaling is involved in various aspects of neural function. In this review article, the authors describe molecular mechanisms of the Endocannabinoid-mediated synaptic modulation and its possible physiological significance.
Jürg Gertsch - One of the best experts on this subject based on the ideXlab platform.
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Endocannabinoid transport revisited.
Vitamins and Hormones Series, 2015Co-Authors: Simon Nicolussi, Jürg GertschAbstract:Endocannabinoids are arachidonic acid-derived endogenous lipids that activate the Endocannabinoid system which plays a major role in health and disease. The primary Endocannabinoids are anandamide (AEA, N-arachidonoylethanolamine) and 2-arachidonoyl glycerol. While their biosynthesis and metabolism have been studied in detail, it remains unclear how Endocannabinoids are transported across the cell membrane. In this review, we critically discuss the different models of Endocannabinoid trafficking, focusing on AEA cellular uptake which is best studied. The evolution of the current knowledge obtained with different AEA transport inhibitors is reviewed and the confusions caused by the lack of their specificity discussed. A comparative summary of the most important AEA uptake inhibitors and the studies involving their use is provided. Based on a comprehensive literature analysis, we propose a model of facilitated AEA membrane transport followed by intracellular shuttling and sequestration. We conclude that novel and more specific probes will be essential to identify the missing targets involved in Endocannabinoid membrane transport.
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immunomodulatory lipids in plants plant fatty acid amides and the human Endocannabinoid system
Planta Medica, 2008Co-Authors: Jürg GertschAbstract:Since the discovery that endogenous lipid mediators show similar cannabimimetic effects as phytocannabinoids from CANNABIS SATIVA, our knowledge about the Endocannabinoid system has rapidly expanded. Today, Endocannabinoid action is known to be involved in various diseases, including inflammation and pain. As a consequence, the G-protein coupled cannabinoid receptors, Endocannabinoid transport, as well as Endocannabinoid metabolizing enzymes represent targets to block or enhance cannabinoid receptor-mediated signalling for therapeutic intervention. Based on the finding that certain Endocannabinoid-like fatty acid N-alkylamides from purple coneflower ( ECHINACEA spp.) potently activate CB2 cannabinoid receptors we have focused our interest on plant fatty acid amides (FAAs) and their overall cannabinomodulatory effects. Certain FAAs are also able to partially inhibit the action of fatty acid amide hydrolase (FAAH), which controls the breakdown of Endocannabinoids. Intriguingly, plants lack CB receptors and do not synthesize Endocannabinoids, but express FAAH homologues capable of metabolizing plant endogenous N-acylethanolamines (NAEs). While the site of action of these NAEs in plants is unknown, endogenous NAEs and arachidonic acid glycerols in animals interact with distinct physiological lipid receptors, including cannabinoid receptors. There is increasing evidence that also plant FAAs other than NAEs can pharmacologically modulate the action of these endogenous lipid signals. The interference of plant FAAs with the animal Endocannabinoid system could thus be a fortunate evolutionary cross point with yet unexplored therapeutic potential.
Tiziana Bisogno - One of the best experts on this subject based on the ideXlab platform.
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Cannabinoids and the expanded Endocannabinoid system in neurological disorders
Nature Reviews Neurology, 2020Co-Authors: Luigia Cristino, Tiziana Bisogno, Vincenzo Di MarzoAbstract:Anecdotal evidence that cannabis preparations have medical benefits together with the discovery of the psychotropic plant cannabinoid Δ^9-tetrahydrocannabinol (THC) initiated efforts to develop cannabinoid-based therapeutics. These efforts have been marked by disappointment, especially in relation to the unwanted central effects that result from activation of cannabinoid receptor 1 (CB1), which have limited the therapeutic use of drugs that activate or inactivate this receptor. The discovery of CB2 and of endogenous cannabinoid receptor ligands (Endocannabinoids) raised new possibilities for safe targeting of this Endocannabinoid system. However, clinical success has been limited, complicated by the discovery of an expanded Endocannabinoid system — known as the Endocannabinoidome — that includes several mediators that are biochemically related to the Endocannabinoids, and their receptors and metabolic enzymes. The approvals of nabiximols, a mixture of THC and the non-psychotropic cannabinoid cannabidiol, for the treatment of spasticity and neuropathic pain in multiple sclerosis, and of purified botanical cannabidiol for the treatment of otherwise untreatable forms of paediatric epilepsy, have brought the therapeutic use of cannabinoids and Endocannabinoids in neurological diseases into the limelight. In this Review, we provide an overview of the Endocannabinoid system and the Endocannabinoidome before discussing their involvement in and clinical relevance to a variety of neurological disorders, including Parkinson disease, Alzheimer disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy and glioblastoma. In this Review, Cristino, Bisogno and Di Marzo outline the biology of cannabinoids, the Endocannabinoid system and the expanded Endocannabinoid system and discuss the involvement of these systems and the therapeutic potential of cannabinoids across the spectrum of neurological disease. Cannabinoid receptors 1 and 2 (CB1 and CB2), the two Endocannabinoids anandamide and 2-arachidonoylglycerol, and Endocannabinoid anabolic and catabolic enzymes form the Endocannabinoid system. Endocannabinoid signalling is involved in regulation of cell, tissue, organ and organism homeostasis, brain development, neurotransmitter release and synaptic plasticity, and cytokine release from microglia, and hence is implicated in multiple neurological disorders. Endocannabinoid signalling is altered in most neurological disorders; enhancers or inhibitors of Endocannabinoid signalling can have therapeutic effects in preclinical models, depending on disease characteristics and the roles of CB1 and CB2. Endocannabinoids can activate different receptors and their biosynthetic and catabolic pathways are often shared with other mediators. Consequently, the system is considered to be part of an expanded signalling system, the Endocannabinoidome. The Endocannabinoidome hinders therapeutic targeting of Endocannabinoid anabolic or catabolic enzymes but inhibitors of Endocannabinoid inactivation and allosteric modulators of CB1 and CB2 are being actively investigated in neurological disorders. The existence of the Endocannabinoidome explains in part why some non-euphoric cannabinoids, which affect several Endocannabinoidome proteins, are useful for the treatment of neurological disorders, such as multiple sclerosis and epilepsy.
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cannabinoids and the expanded Endocannabinoid system in neurological disorders
Nature Reviews Neurology, 2020Co-Authors: Luigia Cristino, Tiziana Bisogno, Vincenzo Di MarzoAbstract:Anecdotal evidence that cannabis preparations have medical benefits together with the discovery of the psychotropic plant cannabinoid Δ9-tetrahydrocannabinol (THC) initiated efforts to develop cannabinoid-based therapeutics. These efforts have been marked by disappointment, especially in relation to the unwanted central effects that result from activation of cannabinoid receptor 1 (CB1), which have limited the therapeutic use of drugs that activate or inactivate this receptor. The discovery of CB2 and of endogenous cannabinoid receptor ligands (Endocannabinoids) raised new possibilities for safe targeting of this Endocannabinoid system. However, clinical success has been limited, complicated by the discovery of an expanded Endocannabinoid system — known as the Endocannabinoidome — that includes several mediators that are biochemically related to the Endocannabinoids, and their receptors and metabolic enzymes. The approvals of nabiximols, a mixture of THC and the non-psychotropic cannabinoid cannabidiol, for the treatment of spasticity and neuropathic pain in multiple sclerosis, and of purified botanical cannabidiol for the treatment of otherwise untreatable forms of paediatric epilepsy, have brought the therapeutic use of cannabinoids and Endocannabinoids in neurological diseases into the limelight. In this Review, we provide an overview of the Endocannabinoid system and the Endocannabinoidome before discussing their involvement in and clinical relevance to a variety of neurological disorders, including Parkinson disease, Alzheimer disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy and glioblastoma. In this Review, Cristino, Bisogno and Di Marzo outline the biology of cannabinoids, the Endocannabinoid system and the expanded Endocannabinoid system and discuss the involvement of these systems and the therapeutic potential of cannabinoids across the spectrum of neurological disease.
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effect of dietary krill oil supplementation on the Endocannabinoidome of metabolically relevant tissues from high fat fed mice
Nutrition & Metabolism, 2011Co-Authors: Fabiana Piscitelli, Tiziana Bisogno, Gianfranca Carta, Elisabetta Murru, Lina Cordeddu, Kjetil Berge, Sally Tandy, Jeffrey S Cohn, Mikko Griinari, Sebastiano BanniAbstract:Omega-3 polyunsaturated fatty acids (ω-3-PUFA) are known to ameliorate several metabolic risk factors for cardiovascular disease, and an association between elevated peripheral levels of endogenous ligands of cannabinoid receptors (Endocannabinoids) and the metabolic syndrome has been reported. We investigated the dose-dependent effects of dietary ω-3-PUFA supplementation, given as krill oil (KO), on metabolic parameters in high fat diet (HFD)-fed mice and, in parallel, on the levels, in inguinal and epididymal adipose tissue (AT), liver, gastrocnemius muscle, kidneys and heart, of: 1) the Endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), 2) two anandamide congeners which activate PPARα but not cannabinoid receptors, N-oleoylethanolamine and N-palmitoylethanolamine, and 3) the direct biosynthetic precursors of these compounds. Lipids were identified and quantified using liquid chromatography coupled to atmospheric pressure chemical ionization single quadrupole mass spectrometry (LC-APCI-MS) or high resolution ion trap-time of flight mass spectrometry (LC-IT-ToF-MS). Eight-week HFD increased Endocannabinoid levels in all tissues except the liver and epididymal AT, and KO reduced anandamide and/or 2-AG levels in all tissues but not in the liver, usually in a dose-dependent manner. Levels of Endocannabinoid precursors were also generally down-regulated, indicating that KO affects levels of Endocannabinoids in part by reducing the availability of their biosynthetic precursors. Usually smaller effects were found of KO on OEA and PEA levels. Our data suggest that KO may promote therapeutic benefit by reducing Endocannabinoid precursor availability and hence Endocannabinoid biosynthesis.
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Endogenous cannabinoids in the brain and peripheral tissues: regulation of their levels and control of food intake
International Journal of Obesity, 2006Co-Authors: Isabelle Matias, Tiziana Bisogno, Vincenzo Di MarzoAbstract:Endocannabinoids were first defined in 1995 as ‘endogenous substances capable of binding to and functionally activating the cannabinoid receptors’. To date, two well-established Endocannabinoids, N -arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), as well as a few other putative ligands, all derived from long-chain polyunsaturated fatty acids, have been identified in animal tissues. The biosynthetic and metabolic pathways for anandamide and 2-AG have been elucidated, and most of the enzymes therein involved have been cloned. We now know that CB_1 receptors, and Endocannabinoids in tissue concentrations sufficient to activate them, are more widely distributed than originally thought, and are found in brain and peripheral organs involved in the control of energy intake and processing, including the hypothalamus, nucleus accumbens, brainstem, vagus nerve, gastrointestinal tract, adipose tissue and liver. Endocannabinoid biosynthetic and inactivating pathways are under the regulation of neuropeptides and hormones involved in energy homeostasis, and Endocannabinoid levels are directly affected by the diet. Endocannabinoids, in turn, regulate the expression and action of mediators involved in nutrient intake and processing. These cross-talks are at the basis of the proposed role of Endocannabinoid signalling in the control of food intake, from invertebrates to lower vertebrates and mammals, and their perturbation appears to contribute to the development of eating disorders.
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The Endocannabinoid signalling system: biochemical aspects.
Pharmacology Biochemistry and Behavior, 2005Co-Authors: Tiziana Bisogno, Alessia Ligresti, Vincenzo Di MarzoAbstract:Knowledge of the endogenous cannabinoid system has expanded greatly during the past years. After the discovery of the cannabinoid receptors, of their endogenous agonists and of the proteins for their synthesis and inactivation, significant progress has been made towards the understanding of the role of the Endocannabinoid system in vital functions. Subsequently, an increasing number of papers has been published on the biochemistry and pharmacology of Endocannabinoids. This article overviews the Endocannabinoid signalling system with focus on its biochemical aspects. In particular we review the mechanisms for the biosynthesis and inactivation of the Endocannabinoids, as well as the various molecular targets for some of the Endocannabinoids described so far.
Andrea G. Hohmann - One of the best experts on this subject based on the ideXlab platform.
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The Endocannabinoid System and Pain
CNS & neurological disorders drug targets, 2009Co-Authors: Josée Guindon, Andrea G. HohmannAbstract:The therapeutic potential of cannabinoids has been the topic of extensive investigation following the discovery of cannabinoid receptors and their endogenous ligands. Cannabinoid receptors and their endogenous ligands are present at supraspinal, spinal and peripheral levels. Cannabinoids suppress behavioral responses to noxious stimulation and suppress nociceptive processing through activation of cannabinoid CB(1) and CB(2) receptor subtypes. Endocannabinoids, the brain's own cannabis-like substances, share the same molecular target as Delta(9)-tetrahydrocannabinol, the main psychoactive component in cannabis. Endocannabinoids serve as synaptic circuit breakers and regulate multiple physiological and pathological conditions, e.g. regulation of food intake, immunomodulation, inflammation, analgesia, cancer, addictive behavior, epilepsy and others. This review will focus on uncovering the roles of anandamide and 2-arachidonoylglycerol, the two best characterized Endocannabinoids identified to date, in controlling nociceptive responding. The roles of anandamide and 2-arachidonoylglycerol, released under physiological conditions, in modulating nociceptive responding at different levels of the neuraxis will be emphasized in this review. Effects of modulation of Endocannabinoid levels through inhibition of Endocannabinoid hydrolysis and uptake is also compared with effects of exogenous administration of synthetic Endocannabinoids in acute, inflammatory and neuropathic pain models. Finally, the therapeutic potential of the Endocannabinoid signaling system is discussed in the context of identifying novel pharmacotherapies for the treatment of pain.
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The Endocannabinoid System and Pain
Cns & Neurological Disorders-drug Targets, 2009Co-Authors: Josée Guindon, Andrea G. HohmannAbstract:The therapeutic potential of cannabinoids has been the topic of extensive investigation following the discovery of cannabinoid receptors and their endogenous ligands. Cannabinoid receptors and their endogenous ligands are present at supraspinal, spinal and peripheral levels. Cannabinoids suppress behavioral responses to noxious stimulation and suppress nociceptive processing through activation of cannabinoid CB1 and CB2 receptor subtypes. Endocannabinoids, the brain’s own cannabis-like substances, share the same molecular target as Δ9-tetrahydrocannabinol, the main psychoactive component in cannabis. Endocannabinoids serve as synaptic circuit breakers and regulate multiple physiological and pathological conditions, e.g. regulation of food intake, immunomodulation, inflammation, analgesia, cancer, addictive behavior, epilepsy and others. This review will focus on uncovering the roles of anandamide (AEA) and 2-arachidonoylglycerol (2-AG), the two best characterized Endocannabinoids identified to date, in controlling nociceptive responding. The roles of AEA and 2-AG, released under physiological conditions, in modulating nociceptive responding at different levels of the neuraxis will be emphasized in this review. Effects of modulation of Endocannabinoid levels through inhibition of Endocannabinoid hydrolysis and uptake is also compared with effects of exogenous administration of synthetic Endocannabinoids in acute, inflammatory and neuropathic pain models. Finally, the therapeutic potential of the Endocannabinoid signaling system is discussed in the context of identifying novel pharmacotherapies for the treatment of pain.
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Endocannabinoid mechanisms of pain modulation.
Aaps Journal, 2006Co-Authors: Andrea G. Hohmann, Richard L. SuplitaAbstract:Cannabinoids are antinociceptive in animal models of acute, tissue injury-, and nerve injury-induced nociception. This review examines the biology of endogenous cannabinoids (Endocannabinoids) and behavioral, neurophysiological, and neuroanatomical evidence supporting the notion that cannabioids play a role in pain modulation. Behavioral pharmacological approaches, in conjunction with the identification and quantification of Endocannabinoids through the use of liquid and gas chromatography mass spectrometry, have providedinsight into the functional roles of Endocannabinoids in pain modulation. Here we examine the distribution of cannabinoid receptors and Endocannabinoid-hydrolyzing enzymes within pain modulatory circuits together with behavioral, neurochemical, and neurophysiological studies that suggest a role for Endocannabinoid signaling in pain modulation. This review will provide a comprehensive evaluation of the roles of the Endocannabinoids 2-arachidonoyl-glycerol and anandamide in stress-induced analgesia. These findings provide a functional framework with which to understand the roles of Endocannabinoids in nociceptive processing at the supraspinal level.