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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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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.
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fetal Endocannabinoids orchestrate the organization of pancreatic islet microarchitecture
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Vincenzo Di Marzo, Ken Mackie, Katarzyna Malenczyk, Erik Keimpema, Fabiana Piscitelli, Daniela Calvigioni, Peyman Bjorklund, Tomas HokfeltAbstract:Endocannabinoids are implicated in the control of glucose utilization and energy homeostasis by orchestrating pancreatic hormone release. Moreover, in some cell niches, Endocannabinoids regulate cell proliferation, fate determination, and migration. Nevertheless, endocannabinoid contributions to the development of the endocrine pancreas remain unknown. Here, we show that α cells produce the endocannabinoid 2-arachidonoylglycerol (2-AG) in mouse fetuses and human pancreatic islets, which primes the recruitment of β cells by CB1 cannabinoid receptor (CB1R) engagement. Using subtractive pharmacology, we extend these findings to anandamide, a promiscuous endocannabinoid/endovanilloid ligand, which impacts both the determination of islet size by cell proliferation and α/β cell sorting by differential activation of transient receptor potential cation channel subfamily V member 1 (TRPV1) and CB1Rs. Accordingly, genetic disruption of TRPV1 channels increases islet size whereas CB1R knockout augments cellular heterogeneity and favors insulin over glucagon release. Dietary enrichment in ω-3 fatty acids during pregnancy and lactation in mice, which permanently reduces endocannabinoid levels in the offspring, phenocopies CB1R−/− islet microstructure and improves coordinated hormone secretion. Overall, our data mechanistically link Endocannabinoids to cell proliferation and sorting during pancreatic islet formation, as well as to life-long programming of hormonal determinants of glucose homeostasis.
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Endocannabinoids and neuropathic pain: focus on neuron-glia and endocannabinoid-neurotrophin interactions.
European Journal of Neuroscience, 2014Co-Authors: Livio Luongo, Sabatino Maione, Vincenzo Di MarzoAbstract:Although originally described as a signalling system encompassing the cannabinoid CB1 and CB2 receptors, their endogenous agonists (the Endocannabinoids), and metabolic enzymes regulating the levels of such agonists, the endocannabinoid system is now viewed as being more complex, and including metabolically related endocannabinoid-like mediators and their molecular targets as well. The function and dysfunction of this complex signalling system in the molecular and cellular mechanisms of pain transduction and control has been widely studied over the last two decades. In this review article, we describe some of the latest advances in our knowledge on the role of the endocannabinoid system, in its most recent and wider conception, in pain pathways, by focusing on: (1) neuron-glia interactions; and (2) emerging data on endocannabinoid cross-talk with neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor.
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Endocannabinoid system and mood disorders: Priming a target for new therapies
Pharmacology and Therapeutics, 2013Co-Authors: Vincenzo Micale, Carsten T Wotjak, Vincenzo Di Marzo, Alexandra Sulcova, Filippo DragoAbstract:The endocannabinoid system (ECS), comprising two G protein-coupled receptors (the cannabinoid receptors 1 and 2 [CB1 and CB2] for marijuana's psychoactive principle ??9-tetrahydrocannabinol [??9-THC]), their endogenous small lipid ligands (namely anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as Endocannabinoids), and the proteins for endocannabinoid biosynthesis and degradation, has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during physiopathological conditions. In the brain activation of this system modulates the release of excitatory and inhibitory neurotransmitters and of cytokines from glial cells. As such, the ECS is strongly involved in neuropsychiatric disorders, particularly in affective disturbances such as anxiety and depression. It has been proposed that synthetic molecules that inhibit endocannabinoid degradation can exploit the selectivity of endocannabinoid action, thus activating cannabinoid receptors only in those tissues where there is perturbed endocannabinoid turnover due to the disorder, and avoiding the potential side effects of direct CB1 and CB2 activation. However, the realization that Endocannabinoids, and AEA in particular, also act at other molecular targets, and that these mediators can be deactivated by redundant pathways, has recently led to question the efficacy of such approach, thus opening the way to new multi-target therapeutic strategies, and to the use of non-psychotropic cannabinoids, such as cannabidiol (CBD), which act via several parallel mechanisms, including indirect interactions with the ECS. The state of the art of the possible therapeutic use of endocannabinoid deactivation inhibitors and phytocannabinoids in mood disorders is discussed in this review article. ?? 2012 Elsevier Inc.
Stefania Petrosino - One of the best experts on this subject based on the ideXlab platform.
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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.
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Endocannabinoids in amygdala and nucleus accumbens mediate social play reward in adolescent rats
The Journal of Neuroscience, 2012Co-Authors: Viviana Trezza, Stefania Petrosino, Ruth Damsteegt, Antonia Manduca, Linda W M Van Kerkhof, Jeroen R Pasterkamp, Yeping Zhou, Patrizia Campolongo, Vincenzo Cuomo, Vincenzo Di MarzoAbstract:The brain endocannabinoid system plays a crucial role in emotional processes. We have previously identified an important role for Endocannabinoids in social play behavior, a highly rewarding form of social interaction in adolescent rats. Here, we tested the hypothesis that endocannabinoid modulation of social play behavior occurs in brain regions implicated in emotion and motivation. Social play increased levels of the endocannabinoid anandamide in the amygdala and nucleus accumbens (NAc), but not in prefrontal cortex or hippocampus of 4- to 5-week-old male Wistar rats. Furthermore, social play increased phosphorylation of CB1 cannabinoid receptors in the amygdala. Systemic administration of the anandamide hydrolysis inhibitor URB597 increased social play behavior, and augmented the associated elevation in anandamide levels in the amygdala, but not the NAc. Infusion of URB597 into the basolateral amygdala (BLA) increased social play behavior, and blockade of BLA CB1 cannabinoid receptors with the antagonist/inverse agonist SR141716A prevented the play-enhancing effects of systemic administration of URB597. Infusion of URB597 into the NAc also increased social play, but blockade of NAc CB1 cannabinoid receptors did not antagonize the play-enhancing effects of systemic URB597 treatment. Last, SR141716A did not affect social play after infusion into the core and shell subregions of the NAc, while it reduced social play when infused into the BLA. These data show that increased anandamide signaling in the amygdala and NAc augments social play, and identify the BLA as a prominent site of action for Endocannabinoids to modulate the rewarding properties of social interactions in adolescent rats.
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circulating and hepatic Endocannabinoids and endocannabinoid related molecules in patients with cirrhosis
Liver International, 2009Co-Authors: Paolo Caraceni, Stefania Petrosino, Fabiana Piscitelli, Antonella Viola, F A Giannone, Annalisa Berzigotti, Matteo Cescon, M Domenicali, Emanuela Giampalma, A RiiliAbstract:Background/Aims: Endocannabinoids include anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Endocannabinoid-related molecules like oleoyl-ethanolamine (OEA) and palmitoyl-ethanolamine (PEA) have also been identified. AEA contributes to the pathogenesis of cardiovascular alterations in experimental cirrhosis, but data on the endocannabinoid system in human cirrhosis are lacking. Thus, we aimed to assess whether circulating and hepatic Endocannabinoids are upregulated in cirrhotic patients and whether their levels correlate with systemic haemodynamics and liver function. Methods: The endocannabinoid levels were measured in peripheral and hepatic veins and liver tissue by isotope-dilution liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry. Systemic haemodynamics were assessed by the transthoracic electrical bioimpedance technique. Portal pressure was evaluated by hepatic venous pressure gradient. Results: Circulating AEA and, to a greater extent, PEA and OEA were significantly higher in cirrhotic patients than in controls. PEA and OEA were also increased in the cirrhotic liver tissue. AEA, OEA and PEA levels were significantly higher in peripheral than in the hepatic veins of cirrhotic patients, while the opposite occurred for 2-AG. Finally, circulating AEA, OEA and PEA correlated with parameters of liver function, such as serum bilirubin and international normalized ratio. No correlations were found with systemic haemodynamics. Conclusions: The endocannabinoid system is upregulated in human cirrhosis. Peripheral AEA is increased in patients with a high model of end-stage liver disease score and may reflect the extent of liver dysfunction. In contrast, the 2-AG levels, the other major endocannabinoid, are not affected by cirrhosis. The upregulation of the endocannabinoid-related molecules, OEA and PEA, is even greater than that of AEA, prompting pharmacological studies on these compounds.
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From endocannabinoid profiling to ‘endocannabinoid therapeutics’
Current Opinion in Chemical Biology, 2009Co-Authors: Alessia Ligresti, Stefania Petrosino, Vincenzo Di MarzoAbstract:The discovery of the endocannabinoid signalling system, that is, of cannabinoid receptors, their endogenous ligands, known as Endocannabinoids, and of endocannabinoid anabolic and catabolic enzymes, raised several questions regarding the physiopathological role of these mediators. Several of these questions were answered by investigating alterations in the levels of the most studied Endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), in tissues of animal models of disorders, and in bioptic samples and biological fluids (cerebrospinal fluid and blood) of human volunteers. Subsequently, the pharmacological effects of synthetic compounds that selectively target the cannabinoid CB1 and CB2 receptors, and endocannabinoid anabolic and catabolic enzymes, established cause–effect relationships between pathological alterations in endocannabinoid levels and the symptoms and progress of several disorders, including emesis, obesity, metabolic disorders, hepatic diseases, pain, inflammation and neurological and neuropsychiatric disorders. These new developments are discussed in this second review on the Endocannabinoids, together with the results of pre-clinical and clinical studies on the potential therapeutic use of plant-derived cannabinoids and synthetic agents that manipulate pharmacologically the action at cannabinoid receptors or the tissue levels of AEA and 2-AG.
V. Di Marzo - One of the best experts on this subject based on the ideXlab platform.
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Endocannabinoid overactivity and intestinal inflammation
Gut, 2006Co-Authors: V. Di Marzo, Angelo A IzzoAbstract:Cannabinoid receptors of type 1 and 2 (CB1 and CB2), endogenous ligands that activate them (Endocannabinoids), and mechanisms for endocannabinoid biosynthesis and inactivation have been identified in the gastrointestinal system. Activation of CB1 receptors by Endocannabinoids produces relaxation of the lower oesophageal sphincter and inhibition of gastric acid secretion, intestinal motility, and fluid stimulated secretion. However, stimulation of cannabinoid receptors impacts on gastrointestinal functions in several other ways. Recent data indicate that the endocannabinoid system in the small intestine and colon becomes over stimulated during inflammation in both animal models and human inflammatory disorders. The pathological significance of this “endocannabinoid overactivity” and its possible exploitation for therapeutic purposes are discussed here.
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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: I Matias, T Bisogno, V. 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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Endocannabinoids synthesis and degradation
Reviews of Physiology Biochemistry and Pharmacology, 2006Co-Authors: V. Di MarzoAbstract:Endocannabinoids were defined in 1995 as endogenous agonists of cannabinoid receptors, i.e. of the G protein-coupled receptors for cannabis's psychoactive principle, Δ9-tetrahydrocannabinol. Although there appear to be several Endocannabinoids, only two of such endogenous mediators have been thoroughly studied so far: anandamide and 2-arachidonoylglycerol (2-AG). A general strategy seems to apply to the biosynthesis and degradation of anandamide and 2-AG, although the levels of these two compounds appear to be regulated in different, and sometimes even opposing, ways. “Endocannabinoid enzymes”, that is to say enzymes that catalyse endocannabinoid biosynthesis or degradation, have been identified and in some cases cloned, and will be described in this review together with their possible pharmacological targeting for therapeutic purposes. The cellular and subcellular localization and the modes for the regulation of the expression and activity of these enzymes play an important role in the functions played by the Endocannabinoids under physiological and pathological conditions.
E Fride - One of the best experts on this subject based on the ideXlab platform.
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Endocannabinoids in the central nervous system an overview
Prostaglandins Leukotrienes and Essential Fatty Acids, 2002Co-Authors: E FrideAbstract:Abstract Many aspects of the physiology and pharmacology of anandamide (arachidonoyl ethanol amide), the first endogenous cannabinoid ligand (‘endocannabinoid’) isolated from pig brain, have been studied since its discovery in 1992. Ethanol amides from other fatty acids have also been identified as Endocannabinoids with similar in vivo and in vitro pharmacological properties. 2-Arachidonoyl glycerol and noladin ether (2-arachidonyl glyceryl ether), isolated in 1995 and 2001, respectively, so far, display pharmacological properties in the central nervous system, similar to those of anandamide. The Endocannabinoids are widely distributed in brain, they are synthesized and released upon neuronal stimulation, undergo reuptake and are hydrolyzed intracellularly by fatty acid amide hydrolase (FAAH). For therapeutic purposes, inhibitors of FAAH may provide more specific cannabinoid activities than direct agonists, and several such molecules have already been developed. Pharmacological effects of the Endocannabinoids are very similar, yet not identical, to those of the plant-derived and synthetic cannabinoid receptor ligands. In addition to pharmacokinetic explanations, direct or indirect interactions with other receptors have been considered to explain some of these differences, including activities at serotonin and GABA receptors. Binding affinities for other receptors such as the vanilloid receptor, have to be taken into account in order to fully understand endocannabinoid physiology. Moreover, possible interactions with receptors for the lysophosphatidic acids deserve attention in future studies. Endocannabinoids have been implicated in a variety of physiological functions. The areas of central activities include pain reduction, motor regulation, learning/memory, and reward. Finally, the role of the endocannabinoid system in appetite stimulation in the adult organism, and perhaps more importantly, its critical involvement in milk ingestion and survival of the newborn, may not only further our understanding of the physiology of food intake and growth, but may also find therapeutic applications in wasting disease and infant's ‘failure to thrive’.
Aron H Lichtman - One of the best experts on this subject based on the ideXlab platform.
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The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain
Neuropsychopharmacology, 2018Co-Authors: Giulia Donvito, Sara R Nass, Jenny L Wilkerson, Zachary A Curry, Lesley D Schurman, Steven G Kinsey, Aron H LichtmanAbstract:A great need exists for the development of new medications to treat pain resulting from various disease states and types of injury. Given that the endogenous cannabinoid (that is, endocannabinoid) system modulates neuronal and immune cell function, both of which play key roles in pain, therapeutics targeting this system hold promise as novel analgesics. Potential therapeutic targets include the cannabinoid receptors, type 1 and 2, as well as biosynthetic and catabolic enzymes of the Endocannabinoids N -arachidonoylethanolamine and 2-arachidonoylglycerol. Notably, cannabinoid receptor agonists as well as inhibitors of endocannabinoid-regulating enzymes fatty acid amide hydrolase and monoacylglycerol lipase produce reliable antinociceptive effects, and offer opioid-sparing antinociceptive effects in myriad preclinical inflammatory and neuropathic pain models. Emerging clinical studies show that ‘medicinal’ cannabis or cannabinoid-based medications relieve pain in human diseases such as cancer, multiple sclerosis, and fibromyalgia. However, clinical data have yet to demonstrate the analgesic efficacy of inhibitors of endocannabinoid-regulating enzymes. Likewise, the question of whether pharmacotherapies aimed at the endocannabinoid system promote opioid-sparing effects in the treatment of pain reflects an important area of research. Here we examine the preclinical and clinical evidence of various endocannabinoid system targets as potential therapeutic strategies for inflammatory and neuropathic pain conditions.
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increased seizure susceptibility and proconvulsant activity of anandamide in mice lacking fatty acid amide hydrolase
The Journal of Neuroscience, 2003Co-Authors: Angela B Clement, Gregory E Hawkins, Aron H Lichtman, Benjamin F CravattAbstract:A number of recent in vitro studies have described a role for endogenous cannabinoids (“Endocannabinoids”) as transsynaptic modulators of neuronal activity in the hippocampus and other brain regions. However, the impact that endocannabinoid signals may have on activity-dependent neural events in vivoremains mostly unknown and technically challenging to address because of the short half-life of these chemical messengers in the brain. Mice lacking the enzyme fatty acid amide hydrolase [FAAH (−/−) mice] are severely impaired in their ability to degrade the endocannabinoid anandamide and therefore represent a unique animal model in which to examine the function of this signaling lipidin vivo. Here, we show that the administration of anandamide dramatically augments the severity of chemically induced seizures in FAAH (−/−) mice but not in wild-type mice. Anandamide-enhanced seizures in FAAH (−/−) mice resulted in significant neuronal damage in the CA1 and CA3 regions of the hippocampus for the bicuculline and kainate models, respectively. Notably, in the absence of anandamide treatment, FAAH (−/−) mice exhibited enhanced seizure responses to high doses of kainate that correlated with greatly elevated endogenous levels of anandamide in the hippocampus of these animals. Collectively, these studies suggest that both exogenously administered and endogenously produced anandamide display FAAH-regulated proconvulsant activity and do not support a general neuroprotective role for this endocannabinoid in response to excitotoxic stimuli in vivo. More generally, these findings demonstrate that the disinhibitory actions of Endocannabinoids observed in hippocampal slices in vitro may also occurin vivo.