Zvi Vogel

• Prof.
• Professor Emeritus at Weizmann Institute of Science

Rationale: The endocannabinoid system is known to be involved in learning, memory, emotional processing and regulation of personality patterns. Here we assessed the endocannabinoid profile in the brains of mice with strong characteristics of social dominance and submissiveness. Methods: A lipidomics approach was employed to assess the endocannabino...

The endocannabinoid system consists mainly of 2-arachidonoylglycerol and anandamide, as well as cannabinoid receptor type 1 (CB1) and type 2 (CB2). Based on previous studies, we hypothesized that a circulating peptide previously identified as Osteogenic Growth Peptide (OGP) maintains a bone-protective CB2 tone. We tested OGP activity in mouse model...

Cannabidiol (CBD), a non-psychotropic cannabinoid, demonstrates antipsychotic-like and procognitive activities in humans and in animal models of schizophrenia. The mechanisms of these beneficial effects of CBD are unknown. Here, we examined behavioral effects of CBD in a pharmacological model of schizophrenia-like cognitive deficits induced by repe...

Mammalian microRNAs (miRNAs) play a critical role in modulating the response of immune cells to stimuli. Cannabinoids are known to exert beneficial actions such as neuroprotection and immunosuppressive activities. However, the underlying mechanisms which contribute to these effects are not fully understood. We previously reported that the psychoact...

Selected miR-146a target genes. (PDF)

Selected miR-34a target genes. (PDF)

Selected miR-155 target genes. (PDF)

The astrocytes have gained in recent decades an enormous interest as a potential target for neurotherapies, due to their essential and pleiotropic roles in brain physiology and pathology. Their precise regulation is still far from understood, although several candidate molecules/systems arise as promising targets for astrocyte-mediated neuroregulat...

Background Our previous studies showed that the non-psychoactive cannabinoid, cannabidiol (CBD), ameliorates the clinical symptoms in mouse myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis model of multiple sclerosis (MS) as well as decreases the memory MOG35-55-specific T cell (TMOG) proliferation an...

Multiple Sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases driven by pathogenic memory T cells. Using myelin oligodendrocyte glycoprotein (MOG) 35-55-specific encephalitogenic T cells (TMOG) isolated from MOG35-55-immunized EAE mice we describe here their gene expression profile following...

Cannabidiol (CBD), the main non-psychoactive cannabinoid, has been previously shown by us to ameliorate clinical symptoms and to decrease inflammation in myelin oligodendrocyte glycoprotein (MOG)35-55-induced mouse experimental autoimmune encephalomyelitis model of multiple sclerosis as well as to decrease MOG35-55-induced T cell proliferation and...

Dimethylheptyl-cannabidiol (DMH-CBD), a non-psychoactive, synthetic derivative of the phytocannabinoid cannabidiol (CBD), has been reported to be anti-inflammatory in RAW macrophages. Here, we evaluated the effects of DMH-CBD at the transcriptional level in BV-2 microglial cells as well as on the proliferation of encephalitogenic T cells. BV-2 cell...

Cannabidiol (CBD), the non-psychoactive cannabinoid, has been previously shown by us to decrease peripheral inflammation and neuroinflammation in mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Here we have studied the anti-inflammatory effects of newly synthesized derivatives of natural (-)-CBD ((-)-8,9-dihy...

Cannabidiol (CBD), the non-psychoactive cannabinoid, has been previously shown by us to decrease peripheral inflammation and neuroinflammation in mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Here we have studied the anti-inflammatory effects of newly synthesized derivatives of natural (-)-CBD ((-)-8,9-dihy...

Several derivatives of cannabinol and the 1,1-dimethylheptyl homolog (DMH) of cannabinol were prepared and assayed for binding to the brain and the peripheral cannabinoid receptors (CB 1 and CB 2), as well as for activation of CB 1 -and CB 2 -mediated inhibition of adenylylcyclase. The DMH derivatives were much more potent than the pentyl (i.e., ca...

Cannabidiol (CBD) is a non-psychoactive plant cannabinoid that inhibits cell proliferation and induces cell death of cancer cells and activated immune cells. It is not an agonist of the classical CB1/CB2 cannabinoid receptors and the mechanism by which it functions is unknown. Here, we studied the effects of CBD on various mitochondrial functions i...

Cannabinoids, the Cannabis constituents, are known to possess anti-inflammatory properties but the mechanisms involved are not understood. Here we show that the main psychoactive cannabinoid, Δ-9-tetrahydrocannabinol (THC), and the main nonpsychoactive cannabinoid, cannabidiol (CBD), markedly reduce the Th17 phenotype which is known to be increased...

Cannabinoids are known to exert immunosuppressive activities. However, the mechanisms which contribute to these effects are unknown. Using lipopolysaccharide (LPS) to activate BV-2 microglial cells, we examined how D 9 -tetrahydrocannabinol (THC), the major psychoactive component of marijuana, and cannabidiol (CBD) the non-psychoactive component, m...

Cannabinoids are known to exert immunosuppressive activities. However, the mechanisms which contribute to these effects are unknown. Using lipopolysaccharide (LPS) to activate BV-2 microglial cells, we examined how Δ(9)-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, and cannabidiol (CBD) the non-psychoactive component, m...

Primer sequences for qPCR. a Amplicon length in base pairs; b Genbank accession number of cDNA and corresponding gene, available at http://www.ncbi.nlm.nih.gov/http://www.ncbi.nlm.nih.gov/; c FW, forward primer; RV, reverse primer (DOC)

Effect of CBD and THC on LPS-downregulated genes. Some genes were validated by qPCR, using β2-microglobulin mRNA as a reference gene. (XLS)

Functional and pathway annotations according to DAVID Bioinformatics Resources of affected gene products following LPS treatment. Gene Ontology (GO) analysis was performed separately for upregulated (red) and downregulated (green) genes, to identify functional categories and cluster of genes significantly affected by LPS treatment. The GO terms wer...

Distribution of differentially expressed genes by global functional annotation and pathway association according to IPA analysis. IPA global functional and pathway analysis was used to examine the enriched functional classes of upregulated (warm colors) and downregulated (cold colors) gene transcripts among the LPS-stimulated genes. The y axis show...

Effect of CBD and THC on LPS-upregulated genes. Some genes were validated by qPCR, using β2-microglobulin mRNA as a reference gene. (XLS)

Microglia are the resident macrophage-like cells of the central nervous system (CNS). They exhibit a rami fi ed resting phenotype and perform continuous surveil-lance in order to maintain CNS homeostasis. However, under pathological condi-tions, they undergo a series of morphological changes leading to retraction of their rami fi cations and reachi...

Microglia are the resident macrophage-like cells of the central nervous system (CNS). They exhibit a rami fi ed resting phenotype and perform continuous surveil-lance in order to maintain CNS homeostasis. However, under pathological condi-tions, they undergo a series of morphological changes leading to retraction of their rami fi cations and reachi...

Microglia are the resident macrophage-like cells of the central nervous system (CNS). They exhibit a rami fi ed resting phenotype and perform continuous surveil-lance in order to maintain CNS homeostasis. However, under pathological condi-tions, they undergo a series of morphological changes leading to retraction of their rami fi cations and reachi...

Microglia are the resident macrophage-like cells of the central nervous system (CNS). They exhibit a rami fi ed resting phenotype and perform continuous surveil-lance in order to maintain CNS homeostasis. However, under pathological condi-tions, they undergo a series of morphological changes leading to retraction of their rami fi cations and reachi...

Cannabidiol (CBD) has been shown to exhibit anti-inflammatory, antioxidant and neuroprotective properties. Unlike Δ(9)-tetrahydrocannabinol (THC), CBD is devoid of psychotropic effects and has very low affinity for both cannabinoid receptors, CB(1) and CB(2). We have previously reported that CBD and THC have different effects on anti-inflammatory p...

Background and purpose: Cannabis extracts and several cannabinoids have been shown to exert broad anti-inflammatory activities in experimental models of inflammatory CNS degenerative diseases. Clinical use of many cannabinoids is limited by their psychotropic effects. However, phytocannabinoids like cannabidiol (CBD), devoid of psychoactive activi...

Background and purpose: Apart from their effects on mood and reward, cannabinoids exert beneficial actions such as neuroprotection and attenuation of inflammation. The immunosuppressive activity of cannabinoids has been well established. However, the underlying mechanisms are largely unknown. We previously showed that the psychoactive cannabinoid...

Cannabidiol (CBD) is a non-psychoactive plant cannabinoid that is clinically used in a 1:1 mixture with the psychoactive cannabinoid Δ(9)-tetrahydrocannabinol (THC) for the treatment of neuropathic pain and spasticity in multiple sclerosis. Our group previously reported that CBD exerts anti-inflammatory effects on microglial cells. In addition, we...

N-acyl ethanolamines (NAEs) and 2-arachidonoyl glycerol (2-AG) are endogenous cannabinoids and along with related lipids are synthesized on demand from membrane phospholipids. Here, we have studied the compartmentalization of NAEs and 2-AG into lipid raft fractions isolated from the caveolin-1-lacking microglial cell line BV-2, following vehicle or...

Whisking is controlled by multiple, possibly functionally segregated, motor sensory-motor loops. While testing for effects of endocannabinoids on whisking, we uncovered the first known functional segregation of channels controlling whisking amplitude and timing. Channels controlling amplitude, but not timing, were modulated by cannabinoid receptor...

Microglia provide continuous immune surveillance of the CNS and upon activation rapidly change phenotype to express receptors that respond to chemoattractants during CNS damage or infection. These activated microglia undergo directed migration towards affected tissue. Importantly, the molecular species of chemoattractant encountered determines if m...

Cannabinoids have been shown to exert antiinflammatory activities in various in vivo and in vitro experimental models as well as ameliorate various inflammatory degenerative diseases. However, the mechanisms of these effects are currently unknown. Using the BV-2 mouse microglial cell line and lipopolysaccharide (LPS) to induce an inflammatory respo...

Cannabinoids have been shown to exert anti-inflammatory activities in various in vivo and in vitro experimental models as well as ameliorate various inflammatory degenerative diseases. However, the mechanisms of these effects are not completely understood. Using the BV-2 mouse microglial cell line and lipopolysaccharide (LPS) to induce an inflammat...

We examined how lipopolysaccharide (LPS) and interferon gamma (IFN-gamma), known to differentially activate microglia, affect the expression of G protein-coupled receptor 55 (GPR55), a novel cannabinoid receptor. We found that GPR55 mRNA is significantly expressed in both primary mouse microglia and the BV-2 mouse microglial cell line, and that LPS...

The notion of functional interactions between the α7 nicotinic acetylcholine (α7 nACh) and the cannabinoid systems is emerging from recent in vitro and in vivo studies. Both the α7 nACh receptor and the cannabinoid receptor 1 (CB1) are highly expressed in the hippocampus. To begin addressing possible anatomical interactions between the α7 nACh and...

Anandamide (AEA) is a lipid molecule belonging to the family of endocannabinoids. Various studies report neuroprotective activity of AEA against toxic insults, such as ischemic conditions and excitotoxicity, whereas some show that AEA has pro-apoptotic effects. Here we have shown that AEA confers a protective activity in N18TG2 murine neuroblastoma...

The AF series compounds, AF102B and congeners of AF150(S), are functionally selective agonists for m1 muscarinic receptors (m1AChRs). This is shown in stable transfected CHO and PC12 cells (PC12M1) with m1-m5AChRs and m1AChRs, respectively. AF102B and AF150(S) are partial agonists, but AF150, AF151, and AF151(S) are full agonists in stimulating pho...

We have reviewed the effects of two endogenous cannabinoid constituents, anandamide and 2-Ara-G1, and of two synthetic cannabinoids, HU-211 and HU- 210. Anandamide partly parallels THC in most CNS activities; the lack of published data prevents comparison of 2-Ara-G1 with THC. Anandamide probably serves as a mediator in motor functions, in memory a...

Acute and chronic activation of opioid receptors differentially regulate the activity of the various adenylyl cyclase (AC) isoforms. In several AC isoforms (I, V, VI and VIII) acute opioid activation (by agonists such as morphine) leads to AC inhibition, while prolonged opioid activation leads to increase in AC activity, a phenomenon known as AC se...

Cannabinoids are widely abused drugs. Our goal was to identify genes modulated by Delta9-tetrahydrocannabinol (Delta9-THC) treatment. We found that chronic administration of Delta9-THC (1.5 mg/kg/day, i.p.; 7 days) to rats, downregulates the expression of oxytocin-neurophysin (OT-NP) mRNA and of OT and oxytocin-associated NP (NPOT) immunoreactivity...

Delta-9-tetrahydrocannabinol (THC), the major active component of marijuana, has a beneficial effect on the cardiovascular system during stress conditions, but the defence mechanism is still unclear. The present study was designed to investigate the central (CB1) and the peripheral (CB2) cannabinoid receptor expression in neonatal cardiomyoctes and...

Chronic exposure to opiate agonists (followed by agonist withdrawal) leads to a large increase in the activity of adenylyl cyclase (AC) isozymes I, V, VI, and VIII, a phenomenon defined as AC superactivation (or supersensitization). On the other hand, AC isozymes belonging to the AC-II family (AC-II, AC-IV, and AC-VII) show decreased activity, refe...

The Ca2+-activated adenylyl cyclase type VIII (AC-VIII) has been implicated in several forms of neural plasticity, including drug addiction and learning and memory. It has not been clear whether Gi/o proteins and G-protein coupled receptors regulate the activity of AC-VIII. Here we show in intact mammalian cell system that AC-VIII is inhibited by m...

Cannabinoids are widely abused drugs. Our goal was to identify genes modulated by Delta9-tetrahydrocannabinol (Delta9-THC) treatment. We found that chronic administration of Delta9-THC (1.5 mg/kg/day, i.p.; 7 days) to rats, downregulates the expression of oxytocin-neurophysin (OT-NP) mRNA and of OT and oxytocin-associated NP (NPOT) immunoreactivity...

It was shown previously that chronic exposure to opiate agonists increases adenylyl cyclase (AC) activity, a phenomenon termed AC superactivation (or supersensitization). More recently, we showed that acute Gi/o-coupled receptor activation inhibits the activity of several AC isozymes, including Ca2+/calmodulin-stimulated AC-I and -VIII, whereas chr...

Cannabinoids are widely abused drugs. Here we show that chronic administration of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the active psychotropic agent in marijuana and hashish, at 1.5 mg per kg per day intraperitoneally for 7 days, increases the expression, at both mRNA and protein levels, of brain-derived neurotrophic factor (BDNF), in spec...

We previously reported that acute agonist activation of G(i/o)-coupled receptors inhibits adenylate cyclase (AC) type VIII activity, whereas agonist withdrawal following chronic activation of these receptors induces AC-VIII superactivation. Three splice variants of AC-VIII have been identified, which are called AC-VIII-A, -B and -C (with AC-VIII-B...

It was shown previously that chronic exposure to opiate agonists increases adenylyl cyclase (AC) activity, a phenomenon termed AC superactivation (or supersensitization). More recently, we showed that acute Gi/o- coupled receptor activation inhibits the activity of several AC isozymes, including Ca2+/calmodulin-stimulated AC-I and -VIII, whereas ch...

(-)Delta9-tetrahydrocannabinol is a scavenger of free radicals. However, the activation of the CB1 receptor in cultured C6 glioma cells by (-)delta9-tetrahydrocannabinol in the presence of reagents generating reactive oxygen species leads to amplification of the cellular damage from oxidative stress. This was evident by increased loss of cell wall...

Although it is well-established that G protein-coupled receptor signaling systems can network with those of tyrosine kinase receptors by several mechanisms, the point(s) of convergence of the two pathways remains largely undelineated, particularly for opioids. Here we demonstrate that opioid agonists modulate the activity of the extracellular signa...

Palmitoylethanolamide (PEA) has been shown to act in synergy with anandamide (arachidonoylethanolamide; AEA), an endogenous agonist of cannabinoid receptor type 1 (CB(1)). This synergistic effect was reduced by the CB(2) cannabinoid receptor antagonist SR144528, although PEA does not activate either CB(1) or CB(2) receptors. Here we show that PEA p...

Evidence for heterodimerization has recently been provided for dopamine D1 and adenosine A1 receptors as well as for dopamine D2 and somatostatin SSTR5 receptors. In this paper, we have studied the possibility that D2 and D3receptors interact functionally by forming receptor heterodimers. Initially, we split the two receptors at the level of the th...

Two types of endogenous cannabinoid-receptor agonists have been identified thus far. They are the ethanolamides of polyunsaturated fatty acids--arachidonoyl ethanolamide (anandamide) is the best known compound in the amide series--and 2-arachidonoyl glycerol, the only known endocannabinoid in the ester series. We report now an example of a third, e...

Several tryptophan (Trp) residues are conserved in G protein-coupled receptors (GPCRs). Relatively little is known about the contribution of these residues and especially of those in the fourth transmembrane domain in the function of the CB(2) cannabinoid receptor. Replacing W158 (very highly conserved in GPCRs) and W172 (conserved in CB(1) and CB(...

Several tryptophan (Trp) residues are conserved in Gprotein-coupled receptors (GPCRs). Relatively little is known about thecontribution of these residues and especially of those in the fourthtransmembrane domain in the function of the CB2 cannabinoidreceptor. Replacing W158 (very highly conserved in GPCRs) and W172 (conservedin CB1 and CB2 cannabin...

1. Opioid (μ, δ, κ) and cannabinoid (CB1, CB2) receptors are coupled mainly toGi/Go GTP-binding proteins. The goal of the present study was to determine whether different subtypes of opioid and cannabinoid receptors, when coexpressed in the same cell, share a common reservoir, or utilize different pools, of G proteins. 2. The stimulation of [35S]GT...

Many types of cells exhibit increased adenylyl cyclase (AC) activity after chronic agonist treatment of G(i/o)-coupled receptors. This phenomenon, defined as AC superactivation or sensitization, has mostly been studied for the opioid receptors and is implicated in opiate addiction. Here we show that this phenomenon is also observed on chronic activ...

Prolonged G(i/o) protein-coupled receptor activation has been shown to lead to receptor internalization and receptor desensitization. In addition, it is well established that although acute activation of these receptors leads to inhibition of adenylyl cyclase (AC), long-term activation results in increased AC activity (especially evident on removal...

Morphine-3- and morphine-6-glucuronide are morphine's major metabolites. As morphine-6-glucuronide produces stronger analgesia than morphine, we investigated the effects of acute and chronic morphine glucuronides on adenylyl cyclase (AC) activity. Using COS-7 cells cotransfected with representatives of the nine cloned AC isozymes, we show that AC-I...

While acute activation of G(i/o)-coupled receptors leads to inhibition of adenylyl cyclase, chronic activation of such receptors produces an increase in cyclic AMP accumulation, particularly evident upon withdrawal of the inhibitory agonist. This phenomenon has been referred to as adenylyl cyclase superactivation and is believed to play an importan...

The DRY motif, at the junction of transmembrane helix 3 and intracellular loop 2 of G protein-coupled receptors, is highly conserved. Mutations were introduced into the CB2 cannabinoid receptor to study the role of this motif in CB2 signaling. D mutations (DRY130-132AAA and D130A) markedly reduced binding of cannabinoid agonists, while no significa...

1.The D2-type dopamine receptors are thought to inhibit adenylyl cyclase (AC), via coupling to pertussis toxin (PTX)-sensitive G proteins of the Gi family. We examined whether and to what extent the various D2 receptors (D2S, D2L, D3S, D3L, and D4) couple to the PTX-insensitive G protein Gz, to produce inhibition of AC activity. 2.COS-7 cells were...

Two cannabinoid receptors belonging to the superfamily of G protein-coupled membrane receptors have been identified and cloned: the neuronal cannabinoid receptor (CB1) and the peripheral cannabinoid receptor (CB2). They have been shown to couple directly to the G(i/o) subclass of G proteins and to mediate inhibition of adenylyl cyclase upon binding...

An intriguing development in the G-protein signaling field has been the finding that not only the Galpha subunit, but also Gbetagamma subunits, affect a number of downstream target molecules. One of the downstream targets of Gbetagamma is adenylyl cyclase, and it has been demonstrated that a number of isoforms of adenylyl cyclase can be either inhi...

Adenylyl cyclase superactivation, a phenomenon by which chronic activation of inhibitory Gi/o-coupled receptors leads to an increase in cAMP accumulation, is believed to play an important role as a compensatory response of the cAMP signaling system in the cell. However, to date, the mechanism by which adenylyl cyclase activity is regulated by chron...

The hypothesis that the naturally occurring analgesic peptide, beta-endorphin, is released in the brain in response to pain had never been directly validated. In this study, we applied a brain microdialysis method for monitoring beta-endorphin release in vivo, to test this hypothesis in the brains of conscious, freely moving rats. Herein we first s...

2-Arachidonoyl-glycerol (2-Ara-Gl) has been isolated from various tissues and identified as an endogenous ligand for both cannabinoid receptors, CB1 and CB2. Here we report that in spleen, as in brain and gut, 2-Ara-Gl is accompanied by several 2-acyl-glycerol esters, two major ones being 2-linoleoyl-glycerol (2-Lino-Gl) and 2-palmitoyl-glycerol (2...

An intriguing development in the G- protein signaling field has been the finding that not only the Ga subunit, but also Gbg subunits, affect a number of downstream target molecules. One of the downstream targets of Gbg is adenylyl cyclase, and it has been demonstrated that a number of isoforms of adenylyl cyclase can be either inhibited or stimulat...

Opioid receptor binding properties of [3H]Tyr-d-Ala-Phe-Phe-NH2 (TAPP) were characterized in rat brain and Chinese hamster ovary (CHO) cells expressing the rat μ-receptor. In rat brain, [3H]TAPP labeled a single class of opioid sites with a dissociation constant (Kd) of 0.31 nM and maximal number of binding sites (Bmax) of 119 fmol/mg protein. In C...

Although it is well-established that G protein-coupled receptor signaling systems can network with those of tyrosine kinase receptors by several mechanisms, the point(s) of convergence of the two pathways remains largely undelineated, particularly for opioids. Here we demonstrate that opioid agonists modulate the activity of the extracellular signa...

The accepted dogma concerning the regulation of adenylyl cyclase (AC) activity by G beta gamma dimers states that the various isoforms of AC respond differently to the presence of free G beta gamma. It has been demonstrated that AC I activity is inhibited and AC II activity is stimulated by G beta gamma subunits. This result does not address the po...

The accepted dogma concerning the regulation of adenylyl cyclase (AC) activity by Gβγ dimers states that the various isoforms of AC respond differently to the presence of free Gβγ. It has been demonstrated that AC I activity is inhibited and AC II activity is stimulated by Gβγ subunits. This result does not address the possible differences in modul...

The accepted dogma concerning the regulation of adenylyl cyclase (AC) activity by Gβγ dimers states that the various isoforms of AC respond differently to the presence of free Gβγ. It has been demonstrated that AC I activity is inhibited and AC II activity is stimulated by Gβγ subunits. This result does not address the possible differences in modul...

Selective muscarinic agonists that are directed at the ml muscarinic acetylcholine receptor (Ml mAChR) have been suggested as a rational treatment of Alzheimer’s disease (AD) (Fisher and Barak, 1995). Such muscarinic receptor agonists may activate a variety of transduction pathways, some of which are beneficial while others may be deleterious to AD...