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Takayuki Sugiura - One of the best experts on this subject based on the ideXlab platform.
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involvement of the cannabinoid cb2 receptor and its endogenous ligand 2 Arachidonoylglycerol in oxazolone induced contact dermatitis in mice
Journal of Immunology, 2006Co-Authors: Saori Oka, Junichi Wakui, Maiko Gokoh, Seishi Kishimoto, Shinobu Ikeda, Shin Yanagimoto, Miwako Nasui, Takayuki SugiuraAbstract:The possible involvement of 2-Arachidonoylglycerol (2-AG), an endogenous ligand for the cannabinoid receptors (CB1 and CB2), in contact dermatitis in mouse ear was investigated. We found that the level of 2-AG was markedly elevated in the ear following a challenge with oxazolone in sensitized mice. Of note, the swelling following the challenge was suppressed by either the administration of SR144528, a CB2 receptor antagonist, immediately after sensitization, or the administration of SR144528 upon the challenge. The effect of AM251, a CB1 receptor antagonist, was marginal in either case. It seems apparent, therefore, that the CB2 receptor and its endogenous ligand 2-AG are closely involved in both the sensitization phase and the elicitation phase of oxazolone-induced contact dermatitis. In line with this, we found that Langerhans cells (MHC class II + ) contain a substantial amount of CB2 receptor mRNA, whereas keratinocytes (MHC class II − ) do not. We also obtained evidence that the expression of mRNAs for proinflammatory cytokines following a challenge with oxazolone was markedly suppressed by treatment with SR144528. We next examined whether the CB2 receptor and 2-AG participate in chronic contact dermatitis accompanied by the infiltration of tissues by eosinophils. The amount of 2-AG in mouse ear dramatically increased following repeated challenge with oxazolone. Importantly, treatment with SR144528 attenuated both the recruitment of eosinophils and ear swelling in chronic contact dermatitis induced by repeated challenge with oxazolone. These results strongly suggest that the CB2 receptor and 2-AG play important stimulative roles in the sensitization, elicitation, and exacerbation of allergic inflammation.
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Suppression by WIN55212-2, a cannabinoid receptor agonist, of inflammatory reactions in mouse ear: Interference with the actions of an endogenous ligand, 2-Arachidonoylglycerol.
European journal of pharmacology, 2006Co-Authors: Saori Oka, Junichi Wakui, Maiko Gokoh, Seishi Kishimoto, Takayuki SugiuraAbstract:The effect of WIN55212-2, a cannabinoid receptor agonist, on acute inflammation of mouse ear was investigated. We found that topical application of WIN55212-2 suppressed ear swelling induced by 12-O-tetradecanoylphorbol 13-acetate or 2-Arachidonoylglycerol. Similar inhibition was observed with CP55940, another cannabinoid receptor agonist, and HU-308, a cannabinoid CB(2) receptor-selective agonist. WIN55212-2 also suppressed the infiltration of leukocytes induced by 12-O-tetradecanoylphorbol 13-acetate. On the other hand, WIN55212-3, an inactive enantiomer of WIN55212-2, exerted only small effects on inflammation. Notably, SR144528, a cannabinoid CB(2) receptor antagonist, also suppressed inflammatory reactions in mouse ear. Thus, both the cannabinoid CB(2) receptor agonist and antagonist are capable of reducing inflammatory reactions. We then investigated the mechanism underlying WIN55212-2-induced suppression of inflammation using cultured cells. We found that the addition of WIN55212-2 together with 2-Arachidonoylglycerol blocked 2-Arachidonoylglycerol-induced migration of human promyelocytic leukemia HL-60 cells that had been differentiated into macrophage-like cells. The restoration of 2-Arachidonoylglycerol-desensitized cells and WIN55212-2-desensitized cells from an anergic condition was examined next. We found that 2-Arachidonoylglycerol-treated cells rapidly recovered the capacity to respond to 2-Arachidonoylglycerol. On the other hand, the anergic condition toward 2-Arachidonoylglycerol continued for a longer period after pretreatment with WIN55212-2. These results suggest that the anti-inflammatory activity of WIN55212-2 is attributable, at least in part, to interference with the actions of the endogenous ligand, 2-Arachidonoylglycerol.
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2 Arachidonoylglycerol an endogenous cannabinoid receptor ligand induces the migration of eol 1 human eosinophilic leukemia cells and human peripheral blood eosinophils
Journal of Leukocyte Biology, 2004Co-Authors: Takayuki Sugiura, Keizo Waku, Saori Oka, Maiko Gokoh, Seishi Kishimoto, Shinobu Ikeda, Shin YanagimotoAbstract:2-Arachidonoylglycerol (2-AG) is an endogenous cannabinoid receptor ligand. To date, two types of cannabinoid receptors have been identified: the CB1 receptor, abundantly expressed in the brain, and the CB2 receptor, expressed in various lymphoid tissues such as the spleen. The CB1 receptor has been assumed to play an important role in the regulation of synaptic transmission, whereas the physiological roles of the CB2 receptor remain obscure. In this study, we examined whether the CB2 receptor is present in human eosinophils and found that the CB2 receptor is expressed in human peripheral blood eosinophils. In contrast, human neutrophils do not contain a significant amount of the CB2 receptor. We then examined the effect of 2-AG on the motility of eosinophils. We found that 2-AG induces the migration of human eosinophilic leukemia EoL-1 cells. The migration evoked by 2-AG was abolished in the presence of SR144528, a CB2 receptor antagonist, or by pretreatment of the cells with pertussis toxin, suggesting that the CB2 receptor and Gi/o are involved in the 2-AG-induced migration. The migration of EoL-1 cells induced by 2-AG was suggested to be a result of chemotaxis. In contrast to 2-AG, neither anandamide nor free arachidonic acid elicited the migration. Finally, we examined the effect of 2-AG on human peripheral blood eosinophils and neutrophils and found that 2-AG induces migration of eosinophils but not neutrophils. These results suggest that the CB2 receptor and its endogenous ligand 2-AG may be closely involved in allergic inflammation accompanied by the infiltration of eosinophils.
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Rapid generation of 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, in rat brain after decapitation
Neuroscience letters, 2001Co-Authors: Takayuki Sugiura, Naoki Yoshinaga, Keizo WakuAbstract:Rat brain, frozen in liquid nitrogen immediately after decapitation, contains a substantial amount of 2-Arachidonoylglycerol (0.34 nmol/g tissue), an endogenous cannabinoid receptor ligand. The level of 2-Arachidonoylglycerol in the brain was rapidly augmented after decapitation, the peak being noted 30 s after decapitation (1.54 nmol/g tissue). Noticeably, there are two phases during the increase in the levels of 2-Arachidonoylglycerol: a rapid transient increase and a subsequent gradual sustained increase, suggesting that at least two separate mechanisms are involved in the generation of 2-Arachidonoylglycerol in the decapitated brain. Gradual sustained formation was also observed for other monoacylglycerols, (e.g. 2-palmitoylglycerol plus 2-oleoylglycerol and 2-cis-vaccenoylglycerol). Thus, it is important to minimize post-mortem changes to estimate the exact tissue levels of 2-Arachidonoylglycerol as well as other monoacylglycerols in the brain.
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Generation of 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, in picrotoxinin-administered rat brain.
Biochemical and biophysical research communications, 2000Co-Authors: Takayuki Sugiura, Sachiko Kondo, Keizo Waku, Naoki Yoshinaga, Yoshio IshimaAbstract:Abstract The levels of 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, and other molecular species of monoacylglycerols in rat brain were examined. In this study, we sacrificed the animals in liquid nitrogen to minimize postmortem changes. We found that rat brain contains 0.23 nmol/g tissue of 2-Arachidonoylglycerol, which accounts for 10.5% of the total monoacylglycerol present in this tissue. We next investigated the level of 2-Arachidonoylglycerol after in vivo stimulation with picrotoxinin. We found that the level of 2-Arachidonoylglycerol was elevated markedly in picrotoxinin-administered rat brain (4- to 6-fold over the control level). Changes in the levels of other molecular species were relatively small or negligible. Several cannabimimetic molecules as well as Δ 9 -tetrahydrocannabinol are known to depress neurotransmission and to exert anticonvulsant activities; endogenous 2-Arachidonoylglycerol produced during neural excitation may play a regulatory role in calming the enhanced synaptic transmission.
Vincenzo Di Marzo - One of the best experts on this subject based on the ideXlab platform.
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genetic manipulation of sn 1 diacylglycerol lipase and cb1 cannabinoid receptor gain of function uncover neuronal 2 linoleoyl glycerol signaling in drosophila melanogaster
Cannabis and Cannabinoid Research, 2020Co-Authors: Giuseppe Tortoriello, Ken Mackie, Vincenzo Di Marzo, Erik Keimpema, Johannes Beiersdorf, Susana Romani, Gareth Williams, Gary A Cameron, Michael J Williams, Patrick DohertyAbstract:Introduction: In mammals, sn-1-diacylglycerol lipases (DAGL) generate 2-Arachidonoylglycerol (2-AG) that, as the major endocannabinoid, modulates synaptic neurotransmission by acting on CB1 cannabi...
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acute inhibition of diacylglycerol lipase blocks endocannabinoid mediated retrograde signalling evidence for on demand biosynthesis of 2 Arachidonoylglycerol
The Journal of Physiology, 2013Co-Authors: Yuki Hashimotodani, Takako Ohnoshosaku, Asami Tanimura, Yoshikazu Sano, Yoshihiro Kita, Vincenzo Di Marzo, Masanobu KanoAbstract:Key points • 2-Arachidonoylglycerol (2-AG), one of the best-characterized retrograde messengers at central synapses, has been thought to be produced ‘on demand’ through a diacylglycerol lipase α (DGLα)-dependent pathway upon activation of postsynaptic neurons (on-demand synthesis hypothesis). • However, recent studies propose an alternative hypothesis that 2-AG is pre-synthesized by DGLα, stored in neurons, and released from such ‘pre-formed pools’ without the participation of DGLα (pre-formed pool hypothesis). • To test these hypotheses, we examined the effects of acute pharmacological inhibition of DGL by a novel potent DGL inhibitor, OMDM-188, on retrograde 2-AG signalling. • We found that 2-AG-mediated retrograde signalling was blocked after 1 h treatment with OMDM-188 in acute slices from the hippocampus, striatum and cerebellum, and was blocked several minutes after OMDM-188 application in cultured hippocampal neurons. • These results fit well with the on-demand synthesis hypothesis, rather than the pre-formed pool hypothesis. Abstract The endocannabinoid (eCB) 2-Arachidonoylglycerol (2-AG) produced by diacylglycerol lipase α (DGLα) is one of the best-characterized retrograde messengers at central synapses. It has been thought that 2-AG is produced ‘on demand’ upon activation of postsynaptic neurons. However, recent studies propose that 2-AG is pre-synthesized by DGLα and stored in neurons, and that 2-AG is released from such ‘pre-formed pools’ without the participation of DGLα. To address whether the 2-AG source for retrograde signalling is the on-demand biosynthesis by DGLα or the mobilization from pre-formed pools, we examined the effects of acute pharmacological inhibition of DGL by a novel potent DGL inhibitor, OMDM-188, on retrograde eCB signalling triggered by Ca2+ elevation, Gq/11 protein-coupled receptor activation or synergy of these two stimuli in postsynaptic neurons. We found that pretreatment for 1 h with OMDM-188 effectively blocked depolarization-induced suppression of inhibition (DSI), a purely Ca2+-dependent form of eCB signalling, in slices from the hippocampus, striatum and cerebellum. We also found that at parallel fibre–Purkinje cell synapses in the cerebellum OMDM-188 abolished synaptically induced retrograde eCB signalling, which is known to be caused by the synergy of postsynaptic Ca2+ elevation and group I metabotropic glutamate receptor (I-mGluR) activation. Moreover, brief OMDM-188 treatments for several minutes were sufficient to suppress both DSI and the I-mGluR-induced retrograde eCB signalling in cultured hippocampal neurons. These results are consistent with the hypothesis that 2-AG for synaptic retrograde signalling is supplied as a result of on-demand biosynthesis by DGLα rather than mobilization from presumptive pre-formed pools.
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dietary krill oil increases docosahexaenoic acid and reduces 2 Arachidonoylglycerol but not n acylethanolamine levels in the brain of obese zucker rats
International Dairy Journal, 2010Co-Authors: Vincenzo Di Marzo, Tiziana Bisogno, Gianfranca Carta, Elisabetta Murru, Lina Cordeddu, Mikko Griinari, Alessia Ligresti, Elena Giordano, Maria Collu, Barbara BatettaAbstract:Abstract Evidence suggests that dietary long chain polyunsaturated fatty acids (LCPUFAs), and particularly those belonging to the n-3 family, may influence the brain fatty acid profile and, thereby, the biosynthesis of endocannabinoids in rodents. However, the doses used are usually quite high and not comparable with human intake. Recently, we have shown that relatively low doses of dietary n-3 LCPUFAs (4 weeks), in the form of either fish or krill oil, balanced for EPA and DHA content, and against a control diet with no EPA and DHA and similar contents of oleic, linoleic and α-linolenic acids, lower the concentrations of the endocannabinoids, anandamide (AEA) and 2-Arachidonoylglycerol (2-AG), in the visceral adipose tissue, and of AEA in the liver and heart, of obese Zucker rats. This, in turn, is associated with lower levels of arachidonic acid in membrane phospholipids and with amelioration of some metabolic syndrome parameters. We investigated here whether in Zucker rats, under the same conditions, fish and krill oil are also able to influence LCPUFA and endocannabinoid profiles in brain. Only krill oil was able to increase significantly DHA levels in brain phospholipids, with no changes in arachidonic acid. DHA increase was associated with lower levels of 2-AG in the brain, whereas AEA and its congeners, N -palmitoylethanolamine and N -oleoylethanolamine, were unchanged. We conclude that, despite the strong impact of dietary n-3 fatty acid on endocannabinoid levels previously observed in peripheral tissues, in the brain only 2-AG is affected by dietary krill oil, suggesting that the beneficial effect of the latter on the metabolic syndrome is mostly exerted by modifying peripheral endocannabinoids. Nevertheless, possible effects of dietary krill oil in the brain through modification of 2-AG levels deserve further investigation.
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Development of a potent inhibitor of 2-Arachidonoylglycerol hydrolysis with antinociceptive activity in vivo
'Elsevier BV', 2009Co-Authors: Tiziana Bisogno, Stefania Petrosino, Giorgio Ortar, Enrico Morera, Marianna Nalli, Enza Palazzo, Sabatino Maione, Vincenzo Di MarzoAbstract:Although inhibitors of the enzymatic hydrolysis of the endocannabinoid 2-Arachidonoylglycerol are available, they are either rather weak in vitro (IC(50) > 30 mu M) or their selectivity towards other proteins of the endocannabinoid system has not been tested. Here we describe the synthesis and activity in vitro and in vivo of a tetrahydrolipstatin analogue, OMDM169, as a potent inhibitor of 2-AG hydrolysis, capable of enhancing 2-AG levels and of exerting analgesic activity via indirect activation of cannabinoid receptors. OMDM169 exhibited 0.13 mu M 10 mu M) at human CB(1) and CB(2) receptors. However, OMDM169 shared with tetrahydrolipstatin the capability of inhibiting the human pancreatic lipase (IC(50) = 0.6 mu M). OMDM169 inhibited fatty acid amide hydrolase and diacylglycerol lipase only at higher concentrations (IC(50) = 3.0 and 2.8 mu M, respectively), and, accordingly, it increased by similar to 1.6-fold the levels of 2-AG, but not anandamide, in intact ionomycin-stimulated N18TG2 neuroblastoma cells. Acute intraperitoneal (i.p.) administration of OMDM169 to mice inhibited the second phase of the formalin-induced nocifensive response with an IC(50) of similar to 2.5 mg/kg, and concomitantly elevated 2-AG, but not anandamide, levels in the ipsilateral paw of formalin-treated mice. The antinociceptive effect of OMDM169 was antagonized by antagonists of CB(1) and CB(2) receptors, AM251 and AM630, respectively (1 mg/kg, i.p.). OMDM69 might represent a template for the development of selective and even more potent inhibitors of 2-AG hydrolysis. (C) 2008 Elsevier B.V. All rights reserved
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Tetrahydrolipstatin Analogues as Modulators of Endocannabinoid 2-Arachidonoylglycerol Metabolism
Journal of medicinal chemistry, 2008Co-Authors: Giorgio Ortar, T. Bisogno, Alessia Ligresti, Enrico Morera, Marianna Nalli, Vincenzo Di MarzoAbstract:A series of 21 analogues of tetrahydrolipstatin (THL, 1) were synthesized and tested as inhibitors of the formation or hydrolysis of the endocannabinoid 2-Arachidonoylglycerol (2-AG). Three of the novel compounds, i.e., 11, 13, and 15, inhibited 2-AG formation via the diacylglycerol lipase α (DAGLα) with IC50 values lower than 50 nM (IC50 of THL = 1 μM) and were between 23- and 375-fold selective vs 2-AG hydrolysis by monoacylglycerol lipase (MAGL) as well as vs cannabinoid CB1 and CB2 receptors and anandamide hydrolysis by fatty acid amide hydrolase (FAAH). Three other THL analogues, i.e., 14, 16, and 18, were slightly more potent than THL against DAGLα and appreciably selective vs MAGL, CB receptors, and FAAH (15−26-fold). One compound, i.e., 8, was a potent inhibitor of MAGL-like activity (IC50 = 0.41 μM), and relatively (∼7-fold) selective vs the other targets tested.
Keizo Waku - One of the best experts on this subject based on the ideXlab platform.
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2 Arachidonoylglycerol an endogenous cannabinoid receptor ligand induces the migration of eol 1 human eosinophilic leukemia cells and human peripheral blood eosinophils
Journal of Leukocyte Biology, 2004Co-Authors: Takayuki Sugiura, Keizo Waku, Saori Oka, Maiko Gokoh, Seishi Kishimoto, Shinobu Ikeda, Shin YanagimotoAbstract:2-Arachidonoylglycerol (2-AG) is an endogenous cannabinoid receptor ligand. To date, two types of cannabinoid receptors have been identified: the CB1 receptor, abundantly expressed in the brain, and the CB2 receptor, expressed in various lymphoid tissues such as the spleen. The CB1 receptor has been assumed to play an important role in the regulation of synaptic transmission, whereas the physiological roles of the CB2 receptor remain obscure. In this study, we examined whether the CB2 receptor is present in human eosinophils and found that the CB2 receptor is expressed in human peripheral blood eosinophils. In contrast, human neutrophils do not contain a significant amount of the CB2 receptor. We then examined the effect of 2-AG on the motility of eosinophils. We found that 2-AG induces the migration of human eosinophilic leukemia EoL-1 cells. The migration evoked by 2-AG was abolished in the presence of SR144528, a CB2 receptor antagonist, or by pretreatment of the cells with pertussis toxin, suggesting that the CB2 receptor and Gi/o are involved in the 2-AG-induced migration. The migration of EoL-1 cells induced by 2-AG was suggested to be a result of chemotaxis. In contrast to 2-AG, neither anandamide nor free arachidonic acid elicited the migration. Finally, we examined the effect of 2-AG on human peripheral blood eosinophils and neutrophils and found that 2-AG induces migration of eosinophils but not neutrophils. These results suggest that the CB2 receptor and its endogenous ligand 2-AG may be closely involved in allergic inflammation accompanied by the infiltration of eosinophils.
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Rapid generation of 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, in rat brain after decapitation
Neuroscience letters, 2001Co-Authors: Takayuki Sugiura, Naoki Yoshinaga, Keizo WakuAbstract:Rat brain, frozen in liquid nitrogen immediately after decapitation, contains a substantial amount of 2-Arachidonoylglycerol (0.34 nmol/g tissue), an endogenous cannabinoid receptor ligand. The level of 2-Arachidonoylglycerol in the brain was rapidly augmented after decapitation, the peak being noted 30 s after decapitation (1.54 nmol/g tissue). Noticeably, there are two phases during the increase in the levels of 2-Arachidonoylglycerol: a rapid transient increase and a subsequent gradual sustained increase, suggesting that at least two separate mechanisms are involved in the generation of 2-Arachidonoylglycerol in the decapitated brain. Gradual sustained formation was also observed for other monoacylglycerols, (e.g. 2-palmitoylglycerol plus 2-oleoylglycerol and 2-cis-vaccenoylglycerol). Thus, it is important to minimize post-mortem changes to estimate the exact tissue levels of 2-Arachidonoylglycerol as well as other monoacylglycerols in the brain.
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Generation of 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, in picrotoxinin-administered rat brain.
Biochemical and biophysical research communications, 2000Co-Authors: Takayuki Sugiura, Sachiko Kondo, Keizo Waku, Naoki Yoshinaga, Yoshio IshimaAbstract:Abstract The levels of 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, and other molecular species of monoacylglycerols in rat brain were examined. In this study, we sacrificed the animals in liquid nitrogen to minimize postmortem changes. We found that rat brain contains 0.23 nmol/g tissue of 2-Arachidonoylglycerol, which accounts for 10.5% of the total monoacylglycerol present in this tissue. We next investigated the level of 2-Arachidonoylglycerol after in vivo stimulation with picrotoxinin. We found that the level of 2-Arachidonoylglycerol was elevated markedly in picrotoxinin-administered rat brain (4- to 6-fold over the control level). Changes in the levels of other molecular species were relatively small or negligible. Several cannabimimetic molecules as well as Δ 9 -tetrahydrocannabinol are known to depress neurotransmission and to exert anticonvulsant activities; endogenous 2-Arachidonoylglycerol produced during neural excitation may play a regulatory role in calming the enhanced synaptic transmission.
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evidence that 2 Arachidonoylglycerol but not n palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid cb2 receptor comparison of the agonistic activities of various cannabinoid receptor ligands in hl 60 cells
Journal of Biological Chemistry, 2000Co-Authors: Takayuki Sugiura, Sachiko Kondo, Shinji Nakane, Tomoko Kodaka, Seishi Kishimoto, Tomoyuki Miyashita, Yoshitomo Suhara, Hiroaki Takayama, Keizo WakuAbstract:Abstract We examined the effect of 2-Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, on the intracellular free Ca2+ concentrations in HL-60 cells that express the cannabinoid CB2 receptor. We found that 2-Arachidonoylglycerol induces a rapid transient increase in intracellular free Ca2+concentrations in HL-60 cells. The response was affected by neither cyclooxygenase inhibitors nor lipoxygenase inhibitors, suggesting that arachidonic acid metabolites are not involved. Consistent with this notion, free arachidonic acid was devoid of any agonistic activity. Importantly, the Ca2+ transient induced by 2-Arachidonoylglycerol was blocked by pretreatment of the cells with SR144528, a CB2 receptor-specific antagonist, but not with SR141716A, a CB1 receptor-specific antagonist, indicating the involvement of the CB2 receptor but not the CB1 receptor in this cellular response. Gi or Go is also assumed to be involved, because pertussis toxin treatment of the cells abolished the response. We further examined the structure-activity relationship. We found that 2-Arachidonoylglycerol is the most potent compound among a number of naturally occurring cannabimimetic molecules. Interestingly, anandamide and N-palmitoylethanolamine, other putative endogenous ligands, were found to be a weak partial agonist and an inactive ligand, respectively. These results strongly suggest that the CB2 receptor is originally a 2-Arachidonoylglycerol receptor, and 2-Arachidonoylglycerol is the intrinsic natural ligand for the CB2 receptor that is abundant in the immune system.
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2 Arachidonoylglycerol an endogenous cannabinoid receptor agonist identification as one of the major species of monoacylglycerols in various rat tissues and evidence for its generation through ca2 dependent and independent mechanisms
FEBS Letters, 1998Co-Authors: Sachiko Kondo, Hironori Kondo, Shinji Nakane, Tomoko Kodaka, Akira Tokumura, Keizo Waku, Takayuki SugiuraAbstract:The molecular species compositions of monoacylglycerols obtained from various rat tissues were examined by reverse-phase high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS) analyses. We confirmed that 2-Arachidonoylglycerol, an endogenous cannabinoid receptor agonist, is one of the most abundant molecular species of monoacylglycerols in the brain. Substantial amounts of 2-Arachidonoylglycerol were also found in the liver, spleen, lung and kidney, but the levels were considerably lower than that in the brain. We found that a small amount of 2-Arachidonoylglycerol was generated in a brain homogenate during incubation in the absence of Ca2+. Importantly, the generation of 2-Arachidonoylglycerol was markedly augmented in the presence of Ca2+, suggesting that Ca2+ plays a key role in regulation of the generation of 2-Arachidonoylglycerol in this tissue.
Kouichi Hashimoto - One of the best experts on this subject based on the ideXlab platform.
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the endocannabinoid 2 Arachidonoylglycerol produced by diacylglycerol lipase α mediates retrograde suppression of synaptic transmission
Neuron, 2010Co-Authors: Asami Tanimura, Shinya Kawata, Yuki Hashimotodani, Motokazu Uchigashima, Maya Yamazaki, Kouichi Hashimoto, Yoshihiro Kita, Masahiko WatanabeAbstract:Summary Endocannabinoids are released from postsynaptic neurons and cause retrograde suppression of synaptic transmission. Anandamide and 2-Arachidonoylglycerol (2-AG) are regarded as two major endocannabinoids. To determine to what extent 2-AG contributes to retrograde signaling, we generated and analyzed mutant mice lacking either of the two 2-AG synthesizing enzymes diacylglycerol lipase α (DGLα) and β (DGLβ). We found that endocannabinoid-mediated retrograde synaptic suppression was totally absent in the cerebellum, hippocampus, and striatum of DGLα knockout mice, whereas the retrograde suppression was intact in DGLβ knockout brains. The basal 2-AG content was markedly reduced and stimulus-induced elevation of 2-AG was absent in DGLα knockout brains, whereas the 2-AG content was normal in DGLβ knockout brains. Morphology of the brain and expression of molecules required for 2-AG production other than DGLs were normal in the two knockout mice. We conclude that 2-AG produced by DGLα, but not by DGLβ, mediates retrograde suppression at central synapses.
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the endocannabinoid 2 Arachidonoylglycerol produced by diacylglycerol lipase α mediates retrograde suppression of synaptic transmission
Neuron, 2010Co-Authors: Asami Tanimura, Shinya Kawata, Yuki Hashimotodani, Motokazu Uchigashima, Maya Yamazaki, Kouichi Hashimoto, Yoshihiro Kita, Manabu Abe, Takao ShimizuAbstract:Endocannabinoids are released from postsynaptic neurons and cause retrograde suppression of synaptic transmission. Anandamide and 2-Arachidonoylglycerol (2-AG) are regarded as two major endocannabinoids. To determine to what extent 2-AG contributes to retrograde signaling, we generated and analyzed mutant mice lacking either of the two 2-AG synthesizing enzymes diacylglycerol lipase alpha (DGLalpha) and beta (DGLbeta). We found that endocannabinoid-mediated retrograde synaptic suppression was totally absent in the cerebellum, hippocampus, and striatum of DGLalpha knockout mice, whereas the retrograde suppression was intact in DGLbeta knockout brains. The basal 2-AG content was markedly reduced and stimulus-induced elevation of 2-AG was absent in DGLalpha knockout brains, whereas the 2-AG content was normal in DGLbeta knockout brains. Morphology of the brain and expression of molecules required for 2-AG production other than DGLs were normal in the two knockout mice. We conclude that 2-AG produced by DGLalpha, but not by DGLbeta, mediates retrograde suppression at central synapses.
Maya Yamazaki - One of the best experts on this subject based on the ideXlab platform.
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task specific enhancement of hippocampus dependent learning in mice deficient in monoacylglycerol lipase the major hydrolyzing enzyme of the endocannabinoid 2 Arachidonoylglycerol
Frontiers in Behavioral Neuroscience, 2015Co-Authors: Yasushi Kishimoto, Maya Yamazaki, Kenji Sakimura, Barbara Cagniard, Junko Nakayama, Yutaka Kirino, Masanobu KanoAbstract:Growing evidence indicates that the endocannabinoid system is important for the acquisition and/or extinction of learning and memory. However, it is unclear which endocannabinoid(s) play(s) a crucial role in these cognitive functions, especially memory extinction. To elucidate the physiological role of 2-Arachidonoylglycerol (2-AG), a major endocannabinoid, in behavioral and cognitive functions, we conducted a comprehensive behavioral test battery in knockout (KO) mice deficient in monoacylglycerol lipase (MGL), the major hydrolyzing enzyme of 2-AG. We found age-dependent increases in spontaneous physical activity (SPA) in MGL KO mice. Next, we tested the MGL KO mice using 5 hippocampus-dependent learning paradigms (i.e., Morris water maze (MWM), contextual fear conditioning, novel object recognition test, trace eyeblink conditioning, and water-finding test). In the MWM, MGL KO mice showed normal acquisition of reference memory, but exhibited significantly faster extinction of the learned behavior. Moreover, they showed faster memory acquisition on the reversal-learning task of the MWM. In contrast, in the contextual fear conditioning, MGL KO mice tended to show slower memory extinction. In the novel object recognition and water-finding tests, MGL KO mice exhibited enhanced memory acquisition. Trace eyeblink conditioning was not altered in MGL KO mice throughout the acquisition and extinction phases. These results indicate that 2-AG signaling is important for hippocampus-dependent learning and memory, but its contribution is highly task-dependent.
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augmented tonic pain related behavior in knockout mice lacking monoacylglycerol lipase a major degrading enzyme for the endocannabinoid 2 Arachidonoylglycerol
Behavioural Brain Research, 2014Co-Authors: Andrey B Petrenko, Maya Yamazaki, Masanobu Kano, Kenji Sakimura, Hiroshi BabaAbstract:Monoacylglycerol lipase (MGL) is the main enzyme responsible for degradation of the endocannabinoid 2-Arachidonoylglycerol (2-AG). Selective inhibitors of MGL have antinociceptive effects upon acute administration and, therefore, hold promise as analgesics. To gain insight into the possible consequences of their prolonged administration, genetically modified mice with the knocked-out MGL gene were tested in several models of acute (phasic, tonic) and chronic (inflammatory, neuropathic) pain. MGL knockout mice showed normal acute phasic pain perception (pain thresholds) and no alleviation of pain perception in models of inflammatory and neuropathic pain. However, compared with wild-type controls, they showed significantly augmented nociceptive behavior in models of acute somatic and visceral tonic pain (formalin and acetic acid tests). The observed proalgesic changes in perception of tonic pain in MGL knockouts could have resulted from desensitization of cannabinoid receptors (known to occur after genetic inactivation of MGL). Supporting this notion, chronic pretreatment with the selective CB1 receptor antagonist AM 251 (employed to re-sensitize cannabinoid receptors in MGL knockouts) resulted in normalization of their tonic pain-related behaviors. Similar augmentation of tonic pain-related behaviors was replicated in C57BL/6N mice pretreated chronically with the selective MGL inhibitor JZL 184 (employed to pharmacologically desensitize CB1 receptors). These findings imply that prolonged use of MGL inhibitors, at doses causing close to complete inhibition of MGL enzymatic activity, not only have no beneficial analgesic effects, they may lead to exacerbation of some types of pain (particularly those with a tonic component).
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molecular and morphological configuration for 2 Arachidonoylglycerol mediated retrograde signaling at mossy cell granule cell synapses in the dentate gyrus
The Journal of Neuroscience, 2011Co-Authors: Motokazu Uchigashima, Asami Tanimura, Maya Yamazaki, Masanobu Kano, Miwako Yamasaki, Kenji Sakimura, Masahiko WatanabeAbstract:2-Arachidonoylglycerol (2-AG) is the endocannabinoid that mediates retrograde suppression of neurotransmission in the brain. In the present study, we investigated the 2-AG signaling system at mossy cell (MC)–granule cell (GC) synapses in the mouse dentate gyrus, an excitatory recurrent circuit where endocannabinoids are thought to suppress epileptogenesis. First, we showed by electrophysiology that 2-AG produced by diacylglycerol lipase α (DGLα) mediated both depolarization-induced suppression of excitation and its enhancement by group I metabotropic glutamate receptor activation at MC–GC synapses, as they were abolished in DGLα-knock-out mice. Immunohistochemistry revealed that DGLα was enriched in the neck portion of GC spines forming synapses with MC terminals, whereas cannabinoid CB1 receptors accumulated in the terminal portion of MC axons. On the other hand, the major 2-AG-degrading enzyme, monoacylglycerol lipase (MGL), was absent at MC–GC synapses but was expressed in astrocytes and some inhibitory terminals. Serial electron microscopy clarified that a given GC spine was innervated by a single MC terminal and also contacted nonsynaptically by other MC terminals making synapses with other GC spines in the neighborhood. MGL-expressing elements, however, poorly covered GC spines, amounting to 17% of the total surface of GC spines by astrocytes and 4% by inhibitory terminals. Our findings provide a basis for 2-AG-mediated retrograde suppression of MC–GC synaptic transmission and also suggest that 2-AG released from activated GC spines is readily accessible to nearby MC–GC synapses by escaping from enzymatic degradation. This molecular–anatomical configuration will contribute to adjust network activity in the dentate gyrus after enhanced excitation.
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the endocannabinoid 2 Arachidonoylglycerol produced by diacylglycerol lipase α mediates retrograde suppression of synaptic transmission
Neuron, 2010Co-Authors: Asami Tanimura, Shinya Kawata, Yuki Hashimotodani, Motokazu Uchigashima, Maya Yamazaki, Kouichi Hashimoto, Yoshihiro Kita, Masahiko WatanabeAbstract:Summary Endocannabinoids are released from postsynaptic neurons and cause retrograde suppression of synaptic transmission. Anandamide and 2-Arachidonoylglycerol (2-AG) are regarded as two major endocannabinoids. To determine to what extent 2-AG contributes to retrograde signaling, we generated and analyzed mutant mice lacking either of the two 2-AG synthesizing enzymes diacylglycerol lipase α (DGLα) and β (DGLβ). We found that endocannabinoid-mediated retrograde synaptic suppression was totally absent in the cerebellum, hippocampus, and striatum of DGLα knockout mice, whereas the retrograde suppression was intact in DGLβ knockout brains. The basal 2-AG content was markedly reduced and stimulus-induced elevation of 2-AG was absent in DGLα knockout brains, whereas the 2-AG content was normal in DGLβ knockout brains. Morphology of the brain and expression of molecules required for 2-AG production other than DGLs were normal in the two knockout mice. We conclude that 2-AG produced by DGLα, but not by DGLβ, mediates retrograde suppression at central synapses.
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the endocannabinoid 2 Arachidonoylglycerol produced by diacylglycerol lipase α mediates retrograde suppression of synaptic transmission
Neuron, 2010Co-Authors: Asami Tanimura, Shinya Kawata, Yuki Hashimotodani, Motokazu Uchigashima, Maya Yamazaki, Kouichi Hashimoto, Yoshihiro Kita, Manabu Abe, Takao ShimizuAbstract:Endocannabinoids are released from postsynaptic neurons and cause retrograde suppression of synaptic transmission. Anandamide and 2-Arachidonoylglycerol (2-AG) are regarded as two major endocannabinoids. To determine to what extent 2-AG contributes to retrograde signaling, we generated and analyzed mutant mice lacking either of the two 2-AG synthesizing enzymes diacylglycerol lipase alpha (DGLalpha) and beta (DGLbeta). We found that endocannabinoid-mediated retrograde synaptic suppression was totally absent in the cerebellum, hippocampus, and striatum of DGLalpha knockout mice, whereas the retrograde suppression was intact in DGLbeta knockout brains. The basal 2-AG content was markedly reduced and stimulus-induced elevation of 2-AG was absent in DGLalpha knockout brains, whereas the 2-AG content was normal in DGLbeta knockout brains. Morphology of the brain and expression of molecules required for 2-AG production other than DGLs were normal in the two knockout mice. We conclude that 2-AG produced by DGLalpha, but not by DGLbeta, mediates retrograde suppression at central synapses.