The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Mauro Maccarrone - One of the best experts on this subject based on the ideXlab platform.
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excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type 2 Cannabinoid Receptors
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Femke Den S Boon, Pascal Chameau, Qiluan Schaafsmazhao, Willem Van Aken, Monica Bari, Sergio Oddi, Chris G Kruse, Mauro Maccarrone, Wytse J Wadman, Taco R WerkmanAbstract:The endoCannabinoid (eCB) system is widely expressed throughout the central nervous system (CNS) and the functionality of type-1 Cannabinoid Receptors in neurons is well documented. In contrast, there is little knowledge about type-2 Cannabinoid Receptors (CB2Rs) in the CNS. Here, we show that CB2Rs are located intracellularly in layer II/III pyramidal cells of the rodent medial prefrontal cortex (mPFC) and that their activation results in IP3R-dependent opening of Ca2+-activated Cl− channels. To investigate the functional role of CB2R activation, we induced neuronal firing and observed a CB2R-mediated reduction in firing frequency. The description of this unique CB2R-mediated signaling pathway, controlling neuronal excitability, broadens our knowledge of the influence of the eCB system on brain function.
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type 1 Cannabinoid Receptors reduce membrane fluidity of capacitated boar sperm by impairing their activation by bicarbonate
PLOS ONE, 2011Co-Authors: Barbara Barboni, Mauro Maccarrone, Natalia Battista, Nicola Bernabo, Paola Palestini, Laura Botto, M G Pistilli, Marco Charini, Enzo Tettamanti, Mauro MattioliAbstract:Background: Mammalian spermatozoa acquire their full fertilizing ability (so called capacitation) within the female genital tract, where they are progressively exposed to inverse gradients of inhibiting and stimulating molecules. Methodology/Principal Findings: In the present research, the effect on this process of anandamide, an endoCannabinoid that can either activate or inhibit Cannabinoid Receptors depending on its concentration, and bicarbonate, an oviductal activatory molecule, was assessed, in order to study the role exerted by the type 1 Cannabinoid receptor (CB1R) in the process of lipid membrane remodeling crucial to complete capacitation. To this aim, boar sperm were incubated in vitro under capacitating conditions (stimulated by bicarbonate) in the presence or in the absence of methanandamide (Met-AEA), a non-hydrolysable analogue of anandamide. The CB1R involvement was studied by using the specific inhibitor (SR141716) or mimicking its activation by adding a permeable cAMP analogue (8Br-cAMP). By an immunocytochemistry approach it was shown that the Met-AEA inhibits the bicarbonate-dependent translocation of CB1R from the post-equatorial to equatorial region of sperm head. In addition it was found that Met-AEA is able to prevent the bicarbonate-induced increase in membrane disorder and the cholesterol extraction, both preliminary to capacitation, acting through a CB1R-cAMP mediated pathway, as indicated by MC540 and filipin staining, EPR spectroscopy and biochemical analysis on whole membranes (CB1R activity) and on membrane enriched fraction (C/P content and anisotropy). Conclusions/Significance: Altogether, these data demonstrate that the endoCannabinoid system strongly inhibits the process of sperm capacitation, acting as membrane stabilizing agent, thus increasing the basic knowledge on capacitationrelated signaling and potentially opening new perspectives in diagnostics and therapeutics of male infertility.
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jekyll and hyde two faces of Cannabinoid signaling in male and female fertility
Endocrine Reviews, 2006Co-Authors: Haibin Wang, Mauro Maccarrone, Sudhansu K DeyAbstract:Mammalian reproduction is a complicated process designed to diversify and strengthen the genetic complement of the offspring and to safeguard regulatory systems at various steps for propagating procreation. An emerging concept in mammalian reproduction is the role of endoCannabinoids, a group of endogenously produced lipid mediators, that bind to and activate Cannabinoid Receptors. Although adverse effects of Cannabinoids on fertility have been implicated for years, the mechanisms by which they exert these effects were not clearly understood. With the identification of Cannabinoid Receptors, endoCannabinoid ligands, their key synthetic and hydrolytic pathways, and the generation of mouse models missing Cannabinoid Receptors, a wealth of information on the significance of Cannabinoid/endoCannabinoid signaling in spermatogenesis, fertilization, preimplantation embryo development, implantation, and postimplantation embryonic growth has been generated. This review focuses on various aspects of the endocannabi...
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lipid rafts control signaling of type 1 Cannabinoid Receptors in neuronal cells implications for anandamide induced apoptosis
Journal of Biological Chemistry, 2005Co-Authors: M Bari, Alessandro Finazziagro, Natalia Battista, Filomena Fezza, Mauro MaccarroneAbstract:Abstract Several G protein-coupled Receptors function within lipid rafts plasma membrane microdomains, which may be important in limiting signal transduction. Here we show that treatment of rat C6 glioma cells with the raft disruptor methyl-β-cyclodextrin (MCD) doubles the binding efficiency (i.e. the ratio between maximum binding and dissociation constant) of type-1 Cannabinoid Receptors (CB1R), which belong to the rhodopsin family of G protein-coupled Receptors. In parallel, activation of CB1R by the endogenous agonist anandamide (AEA) leads to ∼3-fold higher [35S]GTPγS binding in MCD-treated cells than in controls, and CB1R-dependent signaling via adenylate cyclase, and p42/p44 MAPK is almost doubled by MCD. Unlike CB1R, the other AEA-binding receptor TRPV1, the AEA synthetase NAPE-PLD, and the AEA hydrolase FAAH are not modulated by MCD, whereas the activity of the AEA membrane transporter (AMT) is reduced to ∼50% of the controls. We also show that MCD reduces dose-dependently AEA-induced apoptosis in C6 cells but not in human CHP100 neuroblastoma cells, which mirror the endoCannabinoid system of C6 cells but are devoid of CB1R. MCD reduces also cytochrome c release from mitochondria of C6 cells, and this effect is CB1R-dependent and partly mediated by activation of p42/p44 MAPK. Altogether, the present data suggest that lipid rafts control CB1R binding and signaling, and that CB1R activation underlies the protective effect of MCD against apoptosis.
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anandamide induces apoptosis in human cells via vanilloid Receptors evidence for a protective role of Cannabinoid Receptors
Journal of Biological Chemistry, 2000Co-Authors: Mauro Maccarrone, Monica Bari, Tatiana Lorenzon, Gerry Melino, Alessandro FinazziagroAbstract:Abstract The endoCannabinoid anandamide (AEA) is shown to induce apoptotic bodies formation and DNA fragmentation, hallmarks of programmed cell death, in human neuroblastoma CHP100 and lymphoma U937 cells. RNA and protein synthesis inhibitors like actinomycin D and cycloheximide reduced to one-fifth the number of apoptotic bodies induced by AEA, whereas the AEA transporter inhibitor AM404 or the AEA hydrolase inhibitor ATFMK significantly increased the number of dying cells. Furthermore, specific antagonists of Cannabinoid or vanilloid Receptors potentiated or inhibited cell death induced by AEA, respectively. Other endoCannabinoids such as 2-arachidonoylglycerol, linoleoylethanolamide, oleoylethanolamide, and palmitoylethanolamide did not promote cell death under the same experimental conditions. The formation of apoptotic bodies induced by AEA was paralleled by increases in intracellular calcium (3-fold over the controls), mitochondrial uncoupling (6-fold), and cytochrome c release (3-fold). The intracellular calcium chelator EGTA-AM reduced the number of apoptotic bodies to 40% of the controls, and electrotransferred anti-cytochrome c monoclonal antibodies fully prevented apoptosis induced by AEA. Moreover, 5-lipoxygenase inhibitors 5,8,11,14-eicosatetraynoic acid and MK886, cyclooxygenase inhibitor indomethacin, caspase-3 and caspase-9 inhibitors Z-DEVD-FMK and Z-LEHD-FMK, but not nitric oxide synthase inhibitorNω-nitro-l-arginine methyl ester, significantly reduced the cell death-inducing effect of AEA. The data presented indicate a protective role of Cannabinoid Receptors against apoptosis induced by AEA via vanilloid Receptors.
Christine Borner - One of the best experts on this subject based on the ideXlab platform.
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loss of striatal type 1 Cannabinoid Receptors is a key pathogenic factor in huntington s disease
Brain, 2011Co-Authors: Cristina Blazquez, Anna Chiarlone, Onintza Sagredo, Tania Aguado, Ruth M Pazos, Eva Resel, Javier Palazuelos, Boris Julien, Maria Salazar, Christine BornerAbstract:EndoCannabinoids act as neuromodulatory and neuroprotective cues by engaging type 1 Cannabinoid Receptors. These Receptors are highly abundant in the basal ganglia and play a pivotal role in the control of motor behaviour. An early downregulation of type 1 Cannabinoid Receptors has been documented in the basal ganglia of patients with Huntington's disease and animal models. However, the pathophysiological impact of this loss of Receptors in Huntington's disease is as yet unknown. Here, we generated a double-mutant mouse model that expresses human mutant huntingtin exon 1 in a type 1 Cannabinoid receptor-null background, and found that receptor deletion aggravates the symptoms, neuropathology and molecular pathology of the disease. Moreover, pharmacological administration of the Cannabinoid Δ(9)-tetrahydrocannabinol to mice expressing human mutant huntingtin exon 1 exerted a therapeutic effect and ameliorated those parameters. Experiments conducted in striatal cells show that the mutant huntingtin-dependent downregulation of the Receptors involves the control of the type 1 Cannabinoid receptor gene promoter by repressor element 1 silencing transcription factor and sensitizes cells to excitotoxic damage. We also provide in vitro and in vivo evidence that supports type 1 Cannabinoid receptor control of striatal brain-derived neurotrophic factor expression and the decrease in brain-derived neurotrophic factor levels concomitant with type 1 Cannabinoid receptor loss, which may contribute significantly to striatal damage in Huntington's disease. Altogether, these results support the notion that downregulation of type 1 Cannabinoid Receptors is a key pathogenic event in Huntington's disease, and suggest that activation of these Receptors in patients with Huntington's disease may attenuate disease progression.
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loss of striatal type 1 Cannabinoid Receptors is a key pathogenic factor in huntington s disease
Brain, 2011Co-Authors: Cristina Blazquez, Anna Chiarlone, Onintza Sagredo, Tania Aguado, Ruth M Pazos, Eva Resel, Javier Palazuelos, Boris Julien, Maria Salazar, Christine BornerAbstract:EndoCannabinoids act as neuromodulatory and neuroprotective cues by engaging type 1 Cannabinoid Receptors. These Receptors are highly abundant in the basal ganglia and play a pivotal role in the control of motor behaviour. An early downregulation of type 1 Cannabinoid Receptors has been documented in the basal ganglia of patients with Huntington’s disease and animal models. However, the pathophysiological impact of this loss of Receptors in Huntington’s disease is as yet unknown. Here, we generated a double-mutant mouse model that expresses human mutant huntingtin exon 1 in a type 1 Cannabinoid receptor-null background, and found that receptor deletion aggravates the symptoms, neuropathology and molecular pathology of the disease. Moreover, pharmacological administration of the Cannabinoid Δ9-tetrahydrocannabinol to mice expressing human mutant huntingtin exon 1 exerted a therapeutic effect and ameliorated those parameters. Experiments conducted in striatal cells show that the mutant huntingtin-dependent downregulation of the Receptors involves the control of the type 1 Cannabinoid receptor gene promoter by repressor element 1 silencing transcription factor and sensitizes cells to excitotoxic damage. We also provide in vitro and in vivo evidence that supports type 1 Cannabinoid receptor control of striatal brain-derived neurotrophic factor expression and the decrease in brain-derived neurotrophic factor levels concomitant with type 1 Cannabinoid receptor loss, which may contribute significantly to striatal damage in Huntington’s disease. Altogether, these results support the notion that downregulation of type 1 Cannabinoid Receptors is a key pathogenic event in Huntington’s disease, and suggest that activation of these Receptors in patients with Huntington’s disease may attenuate disease progression. * Abbreviations : BDNF : brain-derived neurotrophic factor CAT : chloramphenicol acetyltransferase CB1 : type 1 Cannabinoid FAAH : fatty acid amide hydrolase GABA : gamma-aminobutyric acid GAD67 : glutamic acid decarboxylase 67 KDa isoform GFP : green fluorescent protein NMDA : N -methyl-D-aspartate PSD95 : post-synaptic density protein 95 RE1 : repressor element 1 REST : repressor element 1 silencing transcription factor THC : Δ9-tetrahydrocannabinol
Cristina Blazquez - One of the best experts on this subject based on the ideXlab platform.
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loss of striatal type 1 Cannabinoid Receptors is a key pathogenic factor in huntington s disease
Brain, 2011Co-Authors: Cristina Blazquez, Anna Chiarlone, Onintza Sagredo, Tania Aguado, Ruth M Pazos, Eva Resel, Javier Palazuelos, Boris Julien, Maria Salazar, Christine BornerAbstract:EndoCannabinoids act as neuromodulatory and neuroprotective cues by engaging type 1 Cannabinoid Receptors. These Receptors are highly abundant in the basal ganglia and play a pivotal role in the control of motor behaviour. An early downregulation of type 1 Cannabinoid Receptors has been documented in the basal ganglia of patients with Huntington’s disease and animal models. However, the pathophysiological impact of this loss of Receptors in Huntington’s disease is as yet unknown. Here, we generated a double-mutant mouse model that expresses human mutant huntingtin exon 1 in a type 1 Cannabinoid receptor-null background, and found that receptor deletion aggravates the symptoms, neuropathology and molecular pathology of the disease. Moreover, pharmacological administration of the Cannabinoid Δ9-tetrahydrocannabinol to mice expressing human mutant huntingtin exon 1 exerted a therapeutic effect and ameliorated those parameters. Experiments conducted in striatal cells show that the mutant huntingtin-dependent downregulation of the Receptors involves the control of the type 1 Cannabinoid receptor gene promoter by repressor element 1 silencing transcription factor and sensitizes cells to excitotoxic damage. We also provide in vitro and in vivo evidence that supports type 1 Cannabinoid receptor control of striatal brain-derived neurotrophic factor expression and the decrease in brain-derived neurotrophic factor levels concomitant with type 1 Cannabinoid receptor loss, which may contribute significantly to striatal damage in Huntington’s disease. Altogether, these results support the notion that downregulation of type 1 Cannabinoid Receptors is a key pathogenic event in Huntington’s disease, and suggest that activation of these Receptors in patients with Huntington’s disease may attenuate disease progression. * Abbreviations : BDNF : brain-derived neurotrophic factor CAT : chloramphenicol acetyltransferase CB1 : type 1 Cannabinoid FAAH : fatty acid amide hydrolase GABA : gamma-aminobutyric acid GAD67 : glutamic acid decarboxylase 67 KDa isoform GFP : green fluorescent protein NMDA : N -methyl-D-aspartate PSD95 : post-synaptic density protein 95 RE1 : repressor element 1 REST : repressor element 1 silencing transcription factor THC : Δ9-tetrahydrocannabinol
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loss of striatal type 1 Cannabinoid Receptors is a key pathogenic factor in huntington s disease
Brain, 2011Co-Authors: Cristina Blazquez, Anna Chiarlone, Onintza Sagredo, Tania Aguado, Ruth M Pazos, Eva Resel, Javier Palazuelos, Boris Julien, Maria Salazar, Christine BornerAbstract:EndoCannabinoids act as neuromodulatory and neuroprotective cues by engaging type 1 Cannabinoid Receptors. These Receptors are highly abundant in the basal ganglia and play a pivotal role in the control of motor behaviour. An early downregulation of type 1 Cannabinoid Receptors has been documented in the basal ganglia of patients with Huntington's disease and animal models. However, the pathophysiological impact of this loss of Receptors in Huntington's disease is as yet unknown. Here, we generated a double-mutant mouse model that expresses human mutant huntingtin exon 1 in a type 1 Cannabinoid receptor-null background, and found that receptor deletion aggravates the symptoms, neuropathology and molecular pathology of the disease. Moreover, pharmacological administration of the Cannabinoid Δ(9)-tetrahydrocannabinol to mice expressing human mutant huntingtin exon 1 exerted a therapeutic effect and ameliorated those parameters. Experiments conducted in striatal cells show that the mutant huntingtin-dependent downregulation of the Receptors involves the control of the type 1 Cannabinoid receptor gene promoter by repressor element 1 silencing transcription factor and sensitizes cells to excitotoxic damage. We also provide in vitro and in vivo evidence that supports type 1 Cannabinoid receptor control of striatal brain-derived neurotrophic factor expression and the decrease in brain-derived neurotrophic factor levels concomitant with type 1 Cannabinoid receptor loss, which may contribute significantly to striatal damage in Huntington's disease. Altogether, these results support the notion that downregulation of type 1 Cannabinoid Receptors is a key pathogenic event in Huntington's disease, and suggest that activation of these Receptors in patients with Huntington's disease may attenuate disease progression.
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Cannabinoid Receptors as novel targets for the treatment of melanoma
The FASEB Journal, 2006Co-Authors: Cristina Blazquez, Arkaitz Carracedo, Lucia Barrado, Pedro Real, Jose L Fernandezluna, Guillermo Velasco, Marcos Malumbres, Manuel GuzmanAbstract:Melanoma causes the greatest number of skin cancer-related deaths worldwide. Despite intensive research, prevention and early detection are the only effective measures against melanoma, so new therapeutic strategies are necessary for the management of this devastating disease. Here, we evaluated the efficacy of Cannabinoid receptor agonists, a new family of potential antitumoral compounds, at skin melanoma. Human melanomas and melanoma cell lines express CB1 and CB2 Cannabinoid Receptors. Activation of these Receptors decreased growth, proliferation, angiogenesis and metastasis, and increased apoptosis, of melanomas in mice. Cannabinoid antimelanoma activity was independent of the immune status of the animal, could be achieved without overt psychoactive effects and was selective for melanoma cells vs. normal melanocytes. Cannabinoid antiproliferative action on melanoma cells was due, at least in part, to cell cycle arrest at the G1-S transition via inhibition of the prosurvival protein Akt and hypophosphorylation of the pRb retinoblastoma protein tumor suppressor. These findings may contribute to the design of new chemotherapeutic strategies for the management of melanoma.
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inhibition of skin tumor growth and angiogenesis in vivo by activation of Cannabinoid Receptors
Journal of Clinical Investigation, 2003Co-Authors: Llanos M Casanova, Cristina Blazquez, Jesus Martinezpalacio, Concepcion Villanueva, Jesus M Fernandezacenero, John W Huffman, Jose L Jorcano, Manuel GuzmanAbstract:Nonmelanoma skin cancer is one of the most common malignancies in humans. Different therapeutic strategies for the treatment of these tumors are currently being investigated. Given the growthinhibiting effects of Cannabinoids on gliomas and the wide tissue distribution of the two subtypes of Cannabinoid Receptors (CB1 and CB2), we studied the potential utility of these compounds in anti‐skin tumor therapy. Here we show that the CB1 and the CB2 receptor are expressed in normal skin and skin tumors of mice and humans. In cell culture experiments pharmacological activation of Cannabinoid Receptors induced the apoptotic death of tumorigenic epidermal cells, whereas the viability of nontransformed epidermal cells remained unaffected. Local administration of the mixed CB1/CB2 agonist WIN-55,212-2 or the selective CB2 agonist JWH-133 induced a considerable growth inhibition of malignant tumors generated by inoculation of epidermal tumor cells into nude mice. Cannabinoid-treated tumors showed an increased number of apoptotic cells. This was accompanied by impairment of tumor vascularization, as determined by altered blood vessel morphology and decreased expression of proangiogenic factors (VEGF, placental growth factor, and angiopoietin 2). Abrogation of EGF-R function was also observed in Cannabinoid-treated tumors. These results support a new therapeutic approach for the treatment of skin tumors.
Ken Mackie - One of the best experts on this subject based on the ideXlab platform.
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cb2 Cannabinoid Receptors as a therapeutic target what does the future hold
Molecular Pharmacology, 2014Co-Authors: Amey Dhopeshwarkar, Ken MackieAbstract:The past decades have seen an exponential rise in our understanding of the endoCannabinoid system, comprising CB1 and CB2 Cannabinoid Receptors, endogenous Cannabinoids (endoCannabinoids), and the enzymes that synthesize and degrade endoCannabinoids. The primary focus of this review is the CB2 receptor. CB2 Receptors have been the subject of considerable attention, primarily due to their promising therapeutic potential for treating various pathologies while avoiding the adverse psychotropic effects that can accompany CB1 receptor–based therapies. With the appreciation that CB2-selective ligands show marked functional selectivity, there is a renewed opportunity to explore this promising area of research from both a mechanistic as well as a therapeutic perspective. In this review, we summarize our present knowledge of CB2 receptor signaling, localization, and regulation. We discuss the availability of genetic tools (and their limitations) to study CB2 Receptors and also provide an update on preclinical data on CB2 agonists in pain models. Finally, we suggest possible reasons for the failure of CB2 ligands in clinical pain trials and offer possible ways to move the field forward in a way that can help reconcile the inconsistencies between preclinical and clinical data.
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cb1 Cannabinoid Receptors couple to focal adhesion kinase to control insulin release
Journal of Biological Chemistry, 2013Co-Authors: Ken Mackie, Katarzyna Malenczyk, Magdalena Jazurek, Erik Keimpema, Cristoforo Silvestri, Justyna Janikiewicz, Vincenzo Di Marzo, Maria Jolanta Redowicz, Tibor HarkanyAbstract:EndoCannabinoid signaling has been implicated in modulating insulin release from β cells of the endocrine pancreas. β Cells express CB1 Cannabinoid Receptors (CB1Rs), and the enzymatic machinery regulating anandamide and 2-arachidonoylglycerol bioavailability. However, the molecular cascade coupling agonist-induced Cannabinoid receptor activation to insulin release remains unknown. By combining molecular pharmacology and genetic tools in INS-1E cells and in vivo, we show that CB1R activation by endoCannabinoids (anandamide and 2-arachidonoylglycerol) or synthetic agonists acutely or after prolonged exposure induces insulin hypersecretion. In doing so, CB1Rs recruit Akt/PKB and extracellular signal-regulated kinases 1/2 to phosphorylate focal adhesion kinase (FAK). FAK activation induces the formation of focal adhesion plaques, multimolecular platforms for second-phase insulin release. Inhibition of endoCannabinoid synthesis or FAK activity precluded insulin release. We conclude that FAK downstream from CB1Rs mediates endoCannabinoid-induced insulin release by allowing cytoskeletal reorganization that is required for the exocytosis of secretory vesicles. These findings suggest a mechanistic link between increased circulating and tissue endoCannabinoid levels and hyperinsulinemia in type 2 diabetes.
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international union of basic and clinical pharmacology lxxix Cannabinoid Receptors and their ligands beyond cb1 and cb2
Pharmacological Reviews, 2010Co-Authors: Roger G Pertwee, Allyn C. Howlett, Mary E Abood, George Kunos, Stephen P H Alexander, V Di Marzo, Maurice R Elphick, Peter J Greasley, Harald S Hansen, Ken MackieAbstract:There are at least two types of Cannabinoid Receptors (CB1 and CB2). Ligands activating these G protein-coupled Receptors (GPCRs) include the phytoCannabinoid Δ9-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endoCannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of Cannabinoid receptor more potently than the other type. This review summarizes current data indicating the extent to which Cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB1, non-CB2 established GPCRs, deorphanized Receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear Receptors. From these data, it is clear that some ligands that interact similarly with CB1 and/or CB2 Receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel “CB3” Cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB1, non-CB2 pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB3 Receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic Cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB1 Receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB1/CB2 Receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB1, non-CB2 Cannabinoid Receptors; and 4) current Cannabinoid receptor nomenclature.
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cb1 Cannabinoid Receptors promote oxidative stress and cell death in murine models of doxorubicin induced cardiomyopathy and in human cardiomyocytes
Cardiovascular Research, 2010Co-Authors: Partha Mukhopadhyay, Ken Mackie, Sandor Batkai, Mohanraj Rajesh, Vivek Patel, Yoshihiro Kashiwaya, Lucas Liaudet, Oleg V Evgenov, Gyorgy Hasko, Pal PacherAbstract:Aims Here we investigated the mechanisms by which cardiovascular CB1 Cannabinoid Receptors may modulate the cardiac dysfunction, oxidative stress, and interrelated cell death pathways associated with acute/chronic cardiomyopathy induced by the widely used anti-tumour compound doxorubicin (DOX). Methods and results Both load-dependent and -independent indices of left-ventricular function were measured by the Millar pressure–volume conductance system. Mitogen-activated protein kinase (MAPK) activation, cell-death markers, and oxidative/nitrosative stress were measured by molecular biology/biochemical methods and flow cytometry. DOX induced left-ventricular dysfunction, oxidative/nitrosative stress coupled with impaired antioxidant defense, activation of MAPK (p38 and JNK), and cell death and/or fibrosis in hearts of wide-type mice (CB1+/+), and these effects were markedly attenuated in CB1 knockouts (CB1−/−). In human primary cardiomyocytes expressing CB1 Receptors (demonstrated by RT–PCR, western immunoblot, and flow cytometry) DOX, likewise the CB1 receptor agonist HU210 and the endoCannabinoid anandamide (AEA), induced MAPK activation and cell death. The DOX-induced MAPK activation and cell death were significantly enhanced when DOX was co-administered with CB1 agonists AEA or HU210. Remarkably, cell death and MAPK activation induced by AEA, HU210, and DOX ± AEA/HU210 were largely attenuated by either CB1 antagonists (rimonabant and AM281) or by inhibitors of p38 and JNK MAPKs. Furthermore, AEA or HU210 in primary human cardiomyocytes triggered increased reactive oxygen species generation. Conclusion CB1 activation in cardiomyocytes may amplify the reactive oxygen/nitrogen species-MAPK activation-cell death pathway in pathological conditions when the endoCannabinoid synthetic or metabolic pathways are dysregulated by excessive inflammation and/or oxidative/nitrosative stress, which may contribute to the pathophysiology of various cardiovascular diseases.
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Cannabinoid Receptors where they are and what they do
Journal of Neuroendocrinology, 2008Co-Authors: Ken MackieAbstract:The endoCannabinoid system consists of the endogenous Cannabinoids (endoCannabinoids), Cannabinoid Receptors and the enzymes that synthesise and degrade endoCannabinoids. Many of the effects of Cannabinoids and endoCannabinoids are mediated by two G protein-coupled Receptors (GPCRs), CB(1) and CB(2), although additional Receptors may be involved. CB(1) Receptors are present in very high levels in several brain regions and in lower amounts in a more widespread fashion. These Receptors mediate many of the psychoactive effects of Cannabinoids. CB(2) Receptors have a more restricted distribution, being found in a number of immune cells and in a few neurones. Both CB(1) and CB(2) couple primarily to inhibitory G proteins and are subject to the same pharmacological influences as other GPCRs. Thus, partial agonism, functional selectivity and inverse agonism all play important roles in determining the cellular response to specific Cannabinoid receptor ligands.
Javier Palazuelos - One of the best experts on this subject based on the ideXlab platform.
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cb2 Cannabinoid Receptors promote neural progenitor cell proliferation via mtorc1 signaling
Journal of Biological Chemistry, 2012Co-Authors: Javier Palazuelos, Manuel Guzman, Zaira Ortega, Javier Diazalonso, Ismael GalveroperhAbstract:The endoCannabinoid system is known to regulate neural progenitor (NP) cell proliferation and neurogenesis. In particular, CB2 Cannabinoid Receptors have been shown to promote NP proliferation. As CB2 Receptors are not expressed in differentiated neurons, CB2-selective agonists are promising candidates to manipulate NP proliferation and indirectly neurogenesis by overcoming the undesired psychoactive effects of neuronal CB1 Cannabinoid receptor activation. Here, by using NP cells, brain organotypic cultures, and in vivo animal models, we investigated the signal transduction mechanism involved in CB2 receptor-induced NP cell proliferation and neurogenesis. Exposure of hippocampal HiB5 NP cells to the CB2 receptor-selective agonist HU-308 led to the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway, which, by inhibiting its downstream target p27Kip1, induced NP proliferation. Experiments conducted with the CB2 receptor-selective antagonist SR144528, inhibitors of the PI3K/Akt/mTORC1 axis, and CB2 receptor transient-transfection vector further supported that CB2 Receptors control NP cell proliferation via activation of mTORC1 signaling. Likewise, CB2 receptor engagement induced cell proliferation in an mTORC1-dependent manner both in embryonic cortical slices and in adult hippocampal NPs. Thus, HU-308 increased ribosomal protein S6 phosphorylation and 5-bromo-2′-deoxyuridine incorporation in wild-type but not CB2 receptor-deficient NPs of the mouse subgranular zone. Moreover, adult hippocampal NP proliferation induced by HU-308 and excitotoxicity was blocked by the mTORC1 inhibitor rapamycin. Altogether, these findings provide a mechanism of action and a rationale for the use of nonpsychotomimetic CB2 receptor-selective ligands as a novel strategy for the control of NP cell proliferation and neurogenesis.
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loss of striatal type 1 Cannabinoid Receptors is a key pathogenic factor in huntington s disease
Brain, 2011Co-Authors: Cristina Blazquez, Anna Chiarlone, Onintza Sagredo, Tania Aguado, Ruth M Pazos, Eva Resel, Javier Palazuelos, Boris Julien, Maria Salazar, Christine BornerAbstract:EndoCannabinoids act as neuromodulatory and neuroprotective cues by engaging type 1 Cannabinoid Receptors. These Receptors are highly abundant in the basal ganglia and play a pivotal role in the control of motor behaviour. An early downregulation of type 1 Cannabinoid Receptors has been documented in the basal ganglia of patients with Huntington's disease and animal models. However, the pathophysiological impact of this loss of Receptors in Huntington's disease is as yet unknown. Here, we generated a double-mutant mouse model that expresses human mutant huntingtin exon 1 in a type 1 Cannabinoid receptor-null background, and found that receptor deletion aggravates the symptoms, neuropathology and molecular pathology of the disease. Moreover, pharmacological administration of the Cannabinoid Δ(9)-tetrahydrocannabinol to mice expressing human mutant huntingtin exon 1 exerted a therapeutic effect and ameliorated those parameters. Experiments conducted in striatal cells show that the mutant huntingtin-dependent downregulation of the Receptors involves the control of the type 1 Cannabinoid receptor gene promoter by repressor element 1 silencing transcription factor and sensitizes cells to excitotoxic damage. We also provide in vitro and in vivo evidence that supports type 1 Cannabinoid receptor control of striatal brain-derived neurotrophic factor expression and the decrease in brain-derived neurotrophic factor levels concomitant with type 1 Cannabinoid receptor loss, which may contribute significantly to striatal damage in Huntington's disease. Altogether, these results support the notion that downregulation of type 1 Cannabinoid Receptors is a key pathogenic event in Huntington's disease, and suggest that activation of these Receptors in patients with Huntington's disease may attenuate disease progression.
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loss of striatal type 1 Cannabinoid Receptors is a key pathogenic factor in huntington s disease
Brain, 2011Co-Authors: Cristina Blazquez, Anna Chiarlone, Onintza Sagredo, Tania Aguado, Ruth M Pazos, Eva Resel, Javier Palazuelos, Boris Julien, Maria Salazar, Christine BornerAbstract:EndoCannabinoids act as neuromodulatory and neuroprotective cues by engaging type 1 Cannabinoid Receptors. These Receptors are highly abundant in the basal ganglia and play a pivotal role in the control of motor behaviour. An early downregulation of type 1 Cannabinoid Receptors has been documented in the basal ganglia of patients with Huntington’s disease and animal models. However, the pathophysiological impact of this loss of Receptors in Huntington’s disease is as yet unknown. Here, we generated a double-mutant mouse model that expresses human mutant huntingtin exon 1 in a type 1 Cannabinoid receptor-null background, and found that receptor deletion aggravates the symptoms, neuropathology and molecular pathology of the disease. Moreover, pharmacological administration of the Cannabinoid Δ9-tetrahydrocannabinol to mice expressing human mutant huntingtin exon 1 exerted a therapeutic effect and ameliorated those parameters. Experiments conducted in striatal cells show that the mutant huntingtin-dependent downregulation of the Receptors involves the control of the type 1 Cannabinoid receptor gene promoter by repressor element 1 silencing transcription factor and sensitizes cells to excitotoxic damage. We also provide in vitro and in vivo evidence that supports type 1 Cannabinoid receptor control of striatal brain-derived neurotrophic factor expression and the decrease in brain-derived neurotrophic factor levels concomitant with type 1 Cannabinoid receptor loss, which may contribute significantly to striatal damage in Huntington’s disease. Altogether, these results support the notion that downregulation of type 1 Cannabinoid Receptors is a key pathogenic event in Huntington’s disease, and suggest that activation of these Receptors in patients with Huntington’s disease may attenuate disease progression. * Abbreviations : BDNF : brain-derived neurotrophic factor CAT : chloramphenicol acetyltransferase CB1 : type 1 Cannabinoid FAAH : fatty acid amide hydrolase GABA : gamma-aminobutyric acid GAD67 : glutamic acid decarboxylase 67 KDa isoform GFP : green fluorescent protein NMDA : N -methyl-D-aspartate PSD95 : post-synaptic density protein 95 RE1 : repressor element 1 REST : repressor element 1 silencing transcription factor THC : Δ9-tetrahydrocannabinol
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microglial cb2 Cannabinoid Receptors are neuroprotective in huntington s disease excitotoxicity
Brain, 2009Co-Authors: Javier Palazuelos, Onintza Sagredo, Tania Aguado, Ruth M Pazos, Eva Resel, Boris Julien, Carolina Carrasco, Cristina Benito, Julian Romero, Inigo AzcoitiaAbstract:Cannabinoid-derived drugs are promising agents for the development of novel neuroprotective strategies. Activation of neuronal CB(1) Cannabinoid Receptors attenuates excitotoxic glutamatergic neurotransmission, triggers prosurvival signalling pathways and palliates motor symptoms in animal models of neurodegenerative disorders. However, in Huntington's disease there is a very early downregulation of CB(1) Receptors in striatal neurons that, together with the undesirable psychoactive effects triggered by CB(1) receptor activation, foster the search for alternative pharmacological treatments. Here, we show that CB(2) Cannabinoid receptor expression increases in striatal microglia of Huntington's disease transgenic mouse models and patients. Genetic ablation of CB(2) Receptors in R6/2 mice, that express human mutant huntingtin exon 1, enhanced microglial activation, aggravated disease symptomatology and reduced mice lifespan. Likewise, induction of striatal excitotoxicity in CB(2) receptor-deficient mice by quinolinic acid administration exacerbated brain oedema, microglial activation, proinflammatory-mediator state and medium-sized spiny neuron degeneration. Moreover, administration of CB(2) receptor-selective agonists to wild-type mice subjected to excitotoxicity reduced neuroinflammation, brain oedema, striatal neuronal loss and motor symptoms. Studies on ganciclovir-induced depletion of astroglial proliferation in transgenic mice expressing thymidine kinase under the control of the glial fibrillary acidic protein promoter excluded the participation of proliferating astroglia in CB(2) receptor-mediated actions. These findings support a pivotal role for CB(2) Receptors in attenuating microglial activation and preventing neurodegeneration that may pave the way to new therapeutic strategies for neuroprotection in Huntington's disease as well as in other neurodegenerative disorders with a significant excitotoxic component.
