Publications

2019
A. Di Pizio, Y. Ben Shoshan-Galeczki, J.E. Hayes, and M.Y. Niv. 2019. “Bitter and sweet tasting molecules: It's complicated.” Neuroscience Letters, 700, Pp. 56-63. Abstract
“Bitter” and “sweet” are frequently framed in opposition, both functionally and metaphorically, in regard to affective responses, emotion, and nutrition. This oppositional relationship is complicated by the fact that some molecules are simultaneously bitter and sweet. In some cases, a small chemical modification, or a chirality switch, flips the taste from sweet to bitter. Molecules humans describe as bitter are recognized by a 25-member subfamily of class A G-protein coupled receptors (GPCRs) known as TAS2Rs. Molecules humans describe as sweet are recognized by a TAS1R2/TAS1R3 heterodimer of class C GPCRs. Here we characterize the chemical space of bitter and sweet molecules: the majority of bitter compounds show higher hydrophobicity compared to sweet compounds, while sweet molecules have a wider range of sizes. Importantly, recent evidence indicates that TAS1Rs and TAS2Rs are not limited to the oral cavity; moreover, some bitterants are pharmacologically promiscuous, with the hERG potassium channel, cytochrome P450 enzymes, and carbonic anhydrases as common off-targets. Further focus on polypharmacology may unravel new physiological roles for tastant molecules. © 2018 Elsevier B.V.
M. Eger, M. Bader, D. Bree, R. Hadar, A. Nemerovski, J. Tam, D. Levy, C.G. Pick, and Y. Gabet. 2019. “Bone Anabolic Response in the Calvaria Following Mild Traumatic Brain Injury is Mediated by the Cannabinoid-1 Receptor.” Scientific Reports, 9, 1. Abstract
Brain trauma was clinically associated with increased osteogenesis in the appendicular skeleton. We showed previously in C57BL/6J mice that mild traumatic brain injury (mTBI) transiently induced bone formation in the femur via the cannabinoid-1 (CB1) receptor. Here, we subjected ICR mice to mTBI and examined the bone response in the skull using microCT. We also measured mast cell degranulation (MCD)72 h post-injury. Finally, we measured brain and calvarial endocannabinoids levels post-mTBI. mTBI led to decreased bone porosity on the contralateral (untouched) side. This effect was apparent both in young and mature mice. Administration of rimonabant (CB1 inverse agonist) completely abrogated the effect of mTBI on calvarial porosity and significantly reduced MCD, compared with vehicle-treated controls. We also found that mTBI resulted in elevated levels of anandamide, but not 2-arachidonoylglycerol, in the contralateral calvarial bone, whereas brain levels remained unchanged. In C57BL/6J CB1 knockout mice, mTBI did not reduce porosity but in general the porosity was significantly lower than in WT controls. Our findings suggest that mTBI induces a strain-specific CB1-dependent bone anabolic response in the skull, probably mediated by anandamide, but seemingly unrelated to inflammation. The endocannabinoid system is therefore a plausible target in management of bone response following head trauma. © 2019, The Author(s).
E. Murillo-Rodríguez, D. Millán-Aldaco, M. Palomero-Rivero, D. Morales-Lara, R. Mechoulam, and R. Drucker-Colín. 2019. “Cannabidiol partially blocks the excessive sleepiness in hypocretin-deficient rats: Preliminary data.” CNS and Neurological Disorders - Drug Targets, 18, 9, Pp. 705-712. Abstract
Background: Excessive daytime sleepiness and cataplexy are among the symptoms of narcolepsy, a sleep disorder caused by the loss of hypocretin/orexin (HCRT/OX) neurons placed into the Hypothalamus (LH). Several treatments for managing narcolepsy include diverse drugs to induce alertness, such as antidepressants, amphetamine, or modafinil, etc. Recent evidence has shown that cannabidiol (CBD), a non-psychotropic derived from Cannabis sativa, shows positive therapeutic effects in neurodegenerative disorders, including Parkinson´s disease. Furthermore, CBD provokes alertness and enhances wake-related neurochemicals in laboratory animals. Thus, it is plausible to hypothesize that excessive somnolence observed in narcolepsy might be blocked by CBD. Objective: Here, we determined whether the systemic injection of CBD (5mg/kg, i.p.) would block the excessive sleepiness in a narcoleptic model. Methods: To test this idea, the neurotoxin hypocretin-2-saporin (HCRT2/SAP) was bilaterally injected into the LH of rats to eliminate HCRT leading to the establishment of narcoleptic-like behavior. Since excessive somnolence in HCRT2/SAP lesioned rats has been observed during the lights-off period, CBD was administered at the beginning of the dark phase. Results: Hourly analysis of sleep data showed that CBD blocked the sleepiness during the lights-off period across 7h post-injection in lesioned rats. Conclusion: Taking together, these preliminary findings suggest that CBD might prevent sleepiness in narcolepsy. © 2019 Bentham Science Publishers.
I.M. Linares, A.W. Zuardi, L.C. Pereira, R.H. Queiroz, R. Mechoulam, F.S. Guimarães, and J.A. Crippa. 2019. “Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test.” Revista Brasileira de Psiquiatria, 41, 1, Pp. 9-14. Abstract
Objective: Cannabidiol (CBD), one of the non-psychotomimetic compounds of Cannabis sativa, causes anxiolytic-like effects in animals, with typical bell-shaped dose-response curves. No study, however, has investigated whether increasing doses of this drug would also cause similar curves in humans. The objective of this study was to compare the acute effects of different doses of CBD and placebo in healthy volunteers performing a simulated public speaking test (SPST), a well-tested anxiety-inducing method. Method: A total of 57 healthy male subjects were allocated to receive oral CBD at doses of 150 mg (n=15), 300 mg (n=15), 600 mg (n=12) or placebo (n=15) in a double-blind procedure. During the SPST, subjective ratings on the Visual Analogue Mood Scale (VAMS) and physiological measures (systolic and diastolic blood pressure, heart rate) were obtained at six different time points. Results: Compared to placebo, pretreatment with 300 mg of CBD significantly reduced anxiety during the speech. No significant differences in VAMS scores were observed between groups receiving CBD 150 mg, 600 mg and placebo. Conclusion: Our findings confirm the anxiolytic-like properties of CBD and are consonant with results of animal studies describing bell-shaped dose-response curves. Optimal therapeutic doses of CBD should be rigorously determined so that research findings can be adequately translated into clinical practice. © 2019, Associacao Brasileira de Psiquiatria. All rights reserved.
A. Drori, A. Permyakova, R. Hadar, S. Udi, A. Nemirovski, and J. Tam. 2019. “Cannabinoid-1 receptor regulates mitochondrial dynamics and function in renal proximal tubular cells.” Diabetes, Obesity and Metabolism, 21, 1, Pp. 146-159. Abstract
Aims: To evaluate the specific role of the endocannabinoid/cannabinoid type-1 (CB1R) system in modulating mitochondrial dynamics in the metabolically active renal proximal tubular cells (RPTCs). Materials and methods: We utilized mitochondrially-targeted GFP in live cells (wild-type and null for the CB1R) and electron microscopy in kidney sections of RPTC-CB1R-/- mice and their littermate controls. In both in vitro and in vivo conditions, we assessed the ability of CB1R agonism or fatty acid flux to modulate mitochondrial architecture and function. Results: Direct stimulation of CB1R resulted in mitochondrial fragmentation in RPTCs. This process was mediated, at least in part, by modulating the phosphorylation levels of the canonical fission protein dynamin-related protein 1 on both S637 and S616 residues. CB1R-induced mitochondrial fission was associated with mitochondrial dysfunction, as documented by reduced oxygen consumption and ATP production, increased reactive oxygen species and cellular lactate levels, as well as a decline in mitochondrial biogenesis. Likewise, we documented that exposure of RPTCs to a fatty acid flux induced CB1R-dependent mitochondrial fission, lipotoxicity and cellular dysfunction. Conclusions: CB1R plays a key role in inducing mitochondrial fragmentation in RPTCs, leading to a decline in the organelle's function and contributing to the renal tubular injury associated with lipotoxicity and other metabolic diseases. © 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
I. Khuja, Z. Yekhtin, R. Or, and O. Almogi-Hazan. 2019. “Cannabinoids reduce inflammation but inhibit lymphocyte recovery in murine models of bone marrow transplantation.” International Journal of Molecular Sciences, 20, 3. Abstract
Cannabinoids, the biologically active constituents of Cannabis, have potent neuronal and immunological effects. However, the basic and medical research dedicated to medical cannabis and cannabinoids is limited. The influence of these treatments on hematologic reconstitution and on the development of graft versus host disease (GVHD) after bone marrow transplantation (BMT) is largely unknown. In this research, we compared the influence of D9 tetrahydrocannabinol (THC) and cannabidiol (CBD) on lymphocyte activation in vitro and in murine BMT models. Our in vitro results demonstrate that these treatments decrease activated lymphocyte proliferation and affect cytokine secretion. We also discovered that CBD and THC utilize different receptors to mediate these effects. In vivo, in a syngeneic transplantation model, we demonstrate that all treatments inhibit lymphocyte reconstitution and show the inhibitory role of the cannabinoid receptor type 2 (CB2) on lymphocyte recovery. Although pure cannabinoids exhibited a superior effect in vitro, in an allogeneic (C57BL/6 to BALB/c) BMT mouse model, THC-high and CBD-high cannabis extracts treatment reduced the severity of GVHD and improved survival significantly better than the pure cannabinoids. Our results highlights the complexity of using cannabinoids-based treatments and the need for additional comparative scientific results. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
In this review, we discuss the role of the endocannabinoid (eCB) system in regulating energy and metabolic homeostasis. Endocannabinoids, via activating the cannabinoid type-1 receptor (CB1R), are commonly known as mediators of the thrifty phenotype hypothesis due to their activity in the central nervous system, which in turn regulates food intake and underlies the development of metabolic syndrome. Indeed, these findings led to the clinical testing of globally acting CB1R blockers for obesity and various metabolic complications. However, their therapeutic potential was halted due to centrally mediated adverse effects. Recent observations that highlighted the key role of the peripheral eCB system in metabolic regulation led to the preclinical development of various novel compounds that block CB1R only in peripheral organs with very limited brain penetration and without causing behavioral side effects. These unique molecules, which effectively ameliorate obesity, type II diabetes, fatty liver, insulin resistance, and chronic kidney disease in several animal models, are likely to be further developed in the clinic and may revive the therapeutic potential of blocking CB1R once again. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
M.T. Joy, E. Ben Assayag, D. Shabashov-Stone, S. Liraz-Zaltsman, J. Mazzitelli, M. Arenas, N. Abduljawad, E. Kliper, A.D. Korczyn, N.S. Thareja, E.L. Kesner, M. Zhou, S. Huang, T.K. Silva, N. Katz, N.M. Bornstein, A.J. Silva, E. Shohami, and S.T. Carmichael. 2019. “CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury.” Cell, 176, 5, Pp. 1143-1157.e13. Abstract
We tested a newly described molecular memory system, CCR5 signaling, for its role in recovery after stroke and traumatic brain injury (TBI). CCR5 is uniquely expressed in cortical neurons after stroke. Post-stroke neuronal knockdown of CCR5 in pre-motor cortex leads to early recovery of motor control. Recovery is associated with preservation of dendritic spines, new patterns of cortical projections to contralateral pre-motor cortex, and upregulation of CREB and DLK signaling. Administration of a clinically utilized FDA-approved CCR5 antagonist, devised for HIV treatment, produces similar effects on motor recovery post stroke and cognitive decline post TBI. Finally, in a large clinical cohort of stroke patients, carriers for a naturally occurring loss-of-function mutation in CCR5 (CCR5-Δ32) exhibited greater recovery of neurological impairments and cognitive function. In summary, CCR5 is a translational target for neural repair in stroke and TBI and the first reported gene associated with enhanced recovery in human stroke. © 2019 Elsevier Inc. Genetic and small molecule-based perturbation of CCR5 promotes functional recovery from stroke and traumatic brain injury. © 2019 Elsevier Inc.
L. Karra, R.S. Gangwar, P.G. Puzzovio, N. Fyhrquist, Y. Minai-Fleminger, N. Landolina, H.-U. Simon, H. Alenius, V. Leibovici, D. Simon, and F. Levi-Schaffer. 2019. “CD300a expression is modulated in atopic dermatitis and could influence the inflammatory response.” Allergy: European Journal of Allergy and Clinical Immunology, 74, 7, Pp. 1377-1380.
S. Azar, S. Sherf-Dagan, A. Nemirovski, M. Webb, A. Raziel, A. Keidar, D. Goitein, N. Sakran, O. Shibolet, J. Tam, and S. Zelber-Sagi. 2019. “Circulating Endocannabinoids Are Reduced Following Bariatric Surgery and Associated with Improved Metabolic Homeostasis in Humans.” Obesity Surgery, 29, 1, Pp. 268-276. Abstract
Background: The endocannabinoid (eCB) system plays a key role in the development of obesity and its comorbidities. Limited information exists on the changes in circulating eCBs following bariatric surgery. Objectives: This study aims to (i) assess the circulating levels of eCBs and related molecules and (ii) examine the association between their levels and numerous clinical/metabolic features pre- and post-operatively. Methods: Sixty-five morbidly obese patients (age 42.78 ± 9.27 years; BMI 42.00 ± 5.01 kg/m 2 ) underwent laparoscopic sleeve gastrectomy (LSG) surgery, and were followed up for 12 months. Data collected included anthropometrics and metabolic parameters. The serum levels of the eCBs, 2-arachidonoylglycerol (2-AG), anandamide (AEA); and their related molecules, arachidonic acid (AA) and oleoylethanolamine (OEA) were measured by liquid chromatography-mass spectrometry. Results: Levels of 2-AG, AEA, and AA were reduced post operatively with no differences in serum OEA levels. The delta changes in eCB levels between pre- and post-operation were correlated with the delta of different metabolic parameters. Positive correlations were found between delta AA and waist circumference (WC) (r = 0.28, P < 0.05), free fat mass (r = 0.26, P < 0.05), SteatoTest score (r = 0.45, P < 0.05), and ALT (r = 0.32, P < 0.05). Delta AEA levels positively correlated with WC (r = 0.30, P < 0.05). Delta 2-AG levels positively correlated with total cholesterol (r = 0.27, P < 0.05), triglycerides (r = 0.55, P < 0.05), and SteatoTest score (r = 0.27, P < 0.05). Delta OEA levels negatively correlated with fasting glucose levels (r = − 0.27, P < 0.05). Conclusions: This study provides compelling evidence that LSG surgery induces reductions in the circulating 2-AG, AEA, and AA levels, and that these changes are associated with clinical benefits related to the surgery including reduced fat mass, hepatic steatosis, glucose, and improved lipid profile. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.
L. Hinden and J. Tam. 2019. “Do endocannabinoids regulate glucose reabsorption in the kidney?” Nephron, 143, 1, Pp. 24-27. Abstract
Diabetic nephropathy (DN), a distinct manifestation of diabetic kidney disease, affects approximately 30% of patients with diabetes. While most attention has been focused on glomerular changes related to DN, there is growing evidence that tubulopathy is a key feature in the pathogenesis of this disease. The renal proximal tubule cells (RPTCs) are particularly sensitive to the deleterious effect of chronic hyperglycemia. However, the cellular changes that control the dysfunction of the RPTCs are not fully understood. Controlling glucose reabsorption in the proximal tubules via inhibition of glucose transporters (GLUT) has emerged as a promising therapeutic in ameliorating DN. Overactivation of the renal endocannabinoid (eCB) system via the cannabinoid-1 receptor (CB1R) contributes to the development of DN, and its blockade by globally acting or peripherally restricted CB1R antagonists has been shown to ameliorate renal dysfunction in different murine models for diabetes. Recently, we have utilized various pharmacological and genetic tools to show that the eCB/CB1R system contributes to the development of DN via regulating the expression, translocation, and activity of the facilitative GLUT2 located in the RPTCs. These findings have the potential to be translated into therapy, and support the rationale for the preclinical development of novel renal-specific CB1R and/or GLUT2 inhibitors for the treatment of DN. © 2019 S. Karger AG, Basel. All rights reserved.
L. Friedman, R. Smoum, M. Feldman, R. Mechoulam, and D. Steinberg. 2019. “Does the Endocannabinoid Anandamide Affect Bacterial Quorum Sensing, Vitality, and Motility?” Cannabis and Cannabinoid Research, 4, 2, Pp. 102-109. Abstract
Introduction: The endocannabinoid anandamide (AEA) is a neurotransmitter produced and released "on demand." Numerous studies have been conducted on AEA and on the endocannabinoid system (ECS), but none of them have investigated their effect on prokaryotes. Quorum sensing (QS) is a process of bacteria-bacteria communication. In this cross-Talk, the bacteria secrete and recognize signal molecules termed autoinducers (AIs). It has been shown that the QS system regulates expression of many physiological and virulence factors of bacteria. Materials and Methods: QS was measured using the bioluminescence property of the bacterium Vibrio harveyi. The effect of AEA on QS-related gene expression was measured using real-Time polymerase chain reaction. 0.18% agar plates were used for surface movement assay. Results: No dose response of AEA could be determined up to 100 μg/mL on bacterial growth either wild-Type (WT) V. harveyi or mutant strains. However on addition of AEA, QS was reduced significantly for WT and other V. harveyi strains mutated at different locations of the QS cascade (BB152; HAI-1 synthase mutant, BB886; Sensor-2-, BB170; Sensor-1-, MM30; AI-2). Genes related to the QS pathway, such as luxS, showed significant reduction in expression in the presence of AEA. Motility tests showed that continuous exposure to AEA reduced V. harveyi ability to spread on a soft agar surface, but pre-exposure to AEA did not have any effect on its motility. Conclusions: This study presents the first evidence that the endocannabinoid AEA affects specific functions of a prokaryotic organism (e.g., QS and motility). Our results present novel, not yet been observed biological functions of the ECS, namely as a possible line of defense against bacteria. © Copyright 2019, Mary Ann Liebert, Inc., publishers 2019.
L. Shbiro, D. Hen-Shoval, N. Hazut, K. Rapps, S. Dar, G. Zalsman, R. Mechoulam, A. Weller, and G. Shoval. 2019. “Effects of cannabidiol in males and females in two different rat models of depression.” Physiology and Behavior, 201, Pp. 59-63. Abstract
The current study explores the therapeutic potential of Cannabidiol (CBD), a compound in the Cannabis plant, using both sexes of 2 “depressive-like” genetic models, Wistar Kyoto (WKY) and Flinders Sensitive Line (FSL) rats. Rats ingested CBD (30 mg/kg) orally. In the saccharin preference test, following a previous report of a pro-hedonic effect of CBD in male WKY, we now found similar results in female WKY. CBD also decreased immobility in the forced swim test in males (both strains) and in female WKY. These findings suggest a role for CBD in treating mental disorders with prominent symptoms of helplessness and anhedonia. © 2018 Elsevier Inc.
S. Baraghithy, R. Smoum, M. Attar-Namdar, R. Mechoulam, I. Bab, and J. Tam. 2019. “Hu-671, a novel oleoyl serine derivative, exhibits enhanced efficacy in reversing ovariectomy-induced osteoporosis and bone marrow adiposity.” Molecules, 24, 20. Abstract
Oleoyl serine (OS), an endogenous fatty acyl amide (FAA) found in bone, has been shown to have an anti-osteoporotic effect. OS, being an amide, can be hydrolyzed in the body by amidases. Hindering its amide bond by introducing adjacent substituents has been demonstrated as a successful method for prolonging its skeletal activity. Here, we tested the therapeutic efficacy of two methylated OS derivatives, oleoyl α-methyl serine (HU-671) and 2-methyl-oleoyl serine (HU-681), in an ovariectomized mouse model for osteoporosis by utilizing combined micro-computed tomography, histomorphometry, and cell culture analyses. Our findings indicate that daily treatment for 6 weeks with OS or HU-671 completely rescues bone loss, whereas HU-681 has only a partial effect. The increased bone density was primarily due to enhanced trabecular thickness and number. Moreover, the most effective dose of HU-671 was 0.5 mg/kg/day, an order of magnitude lower than with OS. The reversal of bone loss resulted from increased bone formation and decreased bone resorption, as well as reversal of bone marrow adiposity. These results were further confirmed by determining the serum levels of osteocalcin and type 1 collagen C-terminal crosslinks, as well as demonstrating the enhanced antiadipogenic effect of HU-671. Taken together, these data suggest that methylation interferes with OS’s metabolism, thus enhancing its effects by extending its availability to its target cells. © 2019 by the authors.
V. Vetvicka, G. Gover, H. Hayby, O. Danay, N. Ezov, Y. Hadar, and B. Schwartz. 2019. “Immunomodulating effects exerted by glucans extracted from the king oyster culinary-medicinal mushroom pleurotus eryngii (agaricomycetes) grown in substrates containing various concentrations of olive mill waste.” International Journal of Medicinal Mushrooms, 21, 8, Pp. 765-781. Abstract
We have recently demonstrated that we could enhance glucan content in Pleurotus eryngii following cultivation of the mushrooms on a substrate containing different concentrations of olive mill solid waste (OMSW). These changes are directly related to the content of OMSW in the growing substrate. Using dextran sulfate sodium (DSS)-inflammatory bowel disease (IBD) mice model, we measured the colonic inflammatory response to the different glucan preparations. We found that the histology damaging score (HDS) resulting from DSS treatment reach a value of 11.8 ± 2.3 were efficiently downregulated by treatment with the fungal extracted glucans. Glucans extracted from stalks cultivated at 20% OMSW downregulated to a HDS value of 6.4 ± 0.5 whereas those cultivated at 80% OMSW showed the strongest effects (5.5 ± 0.6). Similar downregulatory effects were obtained for expression of various intestinal cytokines. All tested glucans were equally effective in regulating the number of CD14/CD16 monocytes from 18.2 ± 2.7% for DSS to 6.4 ± 2.0 for DSS + glucans extracted from stalks cultivated at 50% OMSW. We tested the effect of glucans on lipopolysaccharide- induced production of TNF-α, which demonstrated that stalk-derived glucans were more effective than caps-derived glucans. Isolated glucans competed with anti-Dectin-1 and anti-CR3 antibodies, indicating that they contain β-glucans recognized by these receptors. In conclusion, the most effective glucans in ameliorating IBD-associated symptoms induced by DSS treatment in mice were glucan extracts prepared from the stalk of P. eryngii grown at higher concentrations of OMSW. We conclude that these stress-induced growing conditions may be helpful in selecting more effective glucans derived from edible mushrooms. © 2019 by Begell House, Inc.
N.Y. Steinman and A.J. Domb. 2019. “Injectable pasty biodegradable polyesters derived from castor oil and hydroxyl-acid lactones.” Journal of Pharmacology and Experimental Therapeutics, 370, 3, Pp. 736-741. Abstract
Pasty polymers offer a platform for injectable implants for drug delivery. A library of biodegradable pasty polymers was synthesized by bulk ring-opening polymerization of lactide, glycolide, trimethylene carbonate, or caprolactone using castor oil or 12-hydroxy stearic acid as hydroxyl initiators and stannous octoate as the catalyst. Some of the polymers behaved as Newtonian liquids. Pasty polymers of poly(caprolactone) and poly(trimethylene carbonate) were stable under physiologic conditions for over 1 month in vitro, whereas polymers of poly(lactic-co-glycolic acid) degraded within 10 days. These pasty polymers offer a platform for pasty injectable biodegradable carriers for drugs and fillers. Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.
A. Keren, A. Gilhar, Y. Ullmann, M. Zlotkin-Frušić, Y. Soroka, A.J. Domb, and M. Levite. 2019. “Instantaneous depolarization of T cells via dopamine receptors, and inhibition of activated T cells of Psoriasis patients and inflamed human skin, by D1-like receptor agonist: Fenoldopam.” Immunology, 158, 3, Pp. 171-193. Abstract
Activated T cells are pathological in various autoimmune and inflammatory diseases including Psoriasis, and also in graft rejection and graft-versus-host-disease. In these pathological conditions, selective silencing of activated T cells through physiological receptors they express remains a clinical challenge. In our previous studies we found that activation of dopamine receptors (DRs) in resting human T cells activates these cells, and induces by itself many beneficial T cell functions. In this study, we found that normal human T cells express all types of DRs, and that expression of D1R, D4R and D5R increases profoundly after T cell receptor (TCR) activation. Interestingly, DR agonists shift the membrane potential (Vm) of both resting and activated human T cells, and induces instantaneous T cell depolarization within 15 seconds only. Thus, activation of DRs in T cells depolarize these immune cells, alike activation of DRs in neural cells. The skin of Psoriasis patients contains 20-fold more D1R+ T cells than healthy human skin. In line with that, 25-fold more D1R+ T cells are present in Psoriasis humanized mouse model. Highly selective D1-like receptor agonists, primarily Fenoldopam (Corlopam) – a D1-like receptor agonist and a drug used in hypertension, induced the following suppressive effects on activated T cells of Psoriasis patients: reduced chemotactic migration towards the chemokine SDF-1/CXCL12; reduced dramatically the secretion of eight cytokines: tumor necrosis factor-α, interferon-γ, interleukin-1β (IL-1β), IL-2, IL-4, IL-6, IL-8 and IL-10; and reduced three T cell activation proteins/markers: CD69, CD28 and IL-2. Next, we invented a novel topical/dermal Fenoldopam formulation, allowing it to be spread on, and providing prolonged and regulated release in, diseased skin. Our novel topical/dermal Fenoldopam: reduced secretion of the eight cytokines by activated human T cells; reduced IL-1β and IL-6 secretion by human lipopolysaccharide-inflamed skin; eliminated preferentially >90% of live and large/proliferating human T cells. Together, our findings show for the first time that both resting and activated T cells are depolarized instantaneously via DRs, and that targeting D1-like receptors in activated T cells and inflamed human skin by Fenoldopam, in Psoriasis, and potentially in other T cell-mediated diseases, could be therapeutic. Validation in vivo is required. © 2019 John Wiley & Sons Ltd
A. Aran, M. Eylon, M. Harel, L. Polianski, A. Nemirovski, S. Tepper, A. Schnapp, H. Cassuto, N. Wattad, and J. Tam. 2019. “Lower circulating endocannabinoid levels in children with autism spectrum disorder.” Molecular Autism, 10, 1. Abstract
Background: The endocannabinoid system (ECS) is a major regulator of synaptic plasticity and neuromodulation. Alterations of the ECS have been demonstrated in several animal models of autism spectrum disorder (ASD). In some of these models, activating the ECS rescued the social deficits. Evidence for dysregulations of the ECS in human ASD are emerging, but comprehensive assessments and correlations with disease characteristics have not been reported yet. Methods: Serum levels of the main endocannabinoids, N-arachidonoylethanolamine (AEA or anandamide) and 2-arachidonoylglycerol (2-AG), and their related endogenous compounds, arachidonic acid (AA), N-palmitoylethanolamine (PEA), and N-oleoylethanolamine (OEA), were analyzed by liquid chromatography/tandem mass spectrometry in 93 children with ASD (age = 13.1 ± 4.1, range 6-21; 79% boys) and 93 age- and gender-matched neurotypical children (age = 11.8 ± 4.3, range 5.5-21; 79% boys). Results were associated with gender and use of medications, and were correlated with age, BMI, and adaptive functioning of ASD participants as reflected by scores of Autism Diagnostic Observation Schedule (ADOS-2), Vineland Adaptive Behavior Scale-II (VABS-II), and Social Responsiveness Scale-II (SRS-2). Results: Children with ASD had lower levels (pmol/mL, mean ± SEM) of AEA (0.722 ± 0.045 vs. 1.252 ± 0.072, P < 0.0001, effect size 0.91), OEA (17.3 ± 0.80 vs. 27.8 ± 1.44, P < 0.0001, effect size 0.94), and PEA (4.93 ± 0.32 vs. 7.15 ± 0.37, P < 0.0001, effect size 0.65), but not AA and 2-AG. Serum levels of AEA, OEA, and PEA were not significantly associated or correlated with age, gender, BMI, medications, and adaptive functioning of ASD participants. In children with ASD, but not in the control group, younger age and lower BMI tended to correlate with lower AEA levels. However, these correlations were not statistically significant after a correction for multiple comparisons. Conclusions: We found lower serum levels of AEA, PEA, and OEA in children with ASD. Further studies are needed to determine whether circulating endocannabinoid levels can be used as stratification biomarkers that identify clinically significant subgroups within the autism spectrum and if they reflect lower endocannabinoid "tone" in the brain, as found in animal models of ASD. © 2019 The Author(s).
S. Baraghithy, R. Smoum, A. Drori, R. Hadar, A. Gammal, S. Hirsch, M. Attar-Namdar, A. Nemirovski, Y. Gabet, Y. Langer, Y. Pollak, C.P. Schaaf, M.E. Rech, V. Gross-Tsur, I. Bab, R. Mechoulam, and J. Tam. 2019. “Magel2 Modulates Bone Remodeling and Mass in Prader-Willi Syndrome by Affecting Oleoyl Serine Levels and Activity.” Journal of Bone and Mineral Research, 34, 1, Pp. 93-105. Abstract
Among a multitude of hormonal and metabolic complications, individuals with Prader-Willi syndrome (PWS) exhibit significant bone abnormalities, including decreased BMD, osteoporosis, and subsequent increased fracture risk. Here we show in mice that loss of Magel2, a maternally imprinted gene in the PWS critical region, results in reduced bone mass, density, and strength, corresponding to that observed in humans with PWS, as well as in individuals suffering from Schaaf-Yang syndrome (SYS), a genetic disorder caused by a disruption of the MAGEL2 gene. The low bone mass phenotype in Magel2 -/- mice was attributed to reduced bone formation rate, increased osteoclastogenesis and osteoclast activity, and enhanced trans-differentiation of osteoblasts to adipocytes. The absence of Magel2 in humans and mice resulted in reduction in the fatty acid amide bone homeostasis regulator, N-oleoyl serine (OS), whose levels were positively linked with BMD in humans and mice as well as osteoblast activity. Attenuating the skeletal abnormalities in Magel2 -/- mice was achieved with chronic administration of a novel synthetic derivative of OS. Taken together, Magel2 plays a key role in modulating bone remodeling and mass in PWS by affecting OS levels and activity. The use of potent synthetic analogs of OS should be further tested clinically as bone therapeutics for treating bone loss. © 2018 American Society for Bone and Mineral Research. © 2018 American Society for Bone and Mineral Research
Introduction: Sativex® spray is clinically utilized to deliver delta9-tetrahydrocannabinol and cannabidiol to oral mucosa for systemic absorption. We challenge the consensus that the mechanism of absorption following the oro-mucosal application occurs via the buccal tissue. Areas covered: Correctness of the consensus of this absorption pathway arose when reviewing publications regarding the influence fed versus fasting states have on pharmacokinetics of these cannabinoids administered to the oral mucosa. This finding is more suitable for peroral administration, where stomach content affects the absorption profile. We hypothesize that these cannabinoids are ingested and absorbed in the gastrointestinal tract. Expert opinion: Although clinical importance of Sativex® is not disputed, the wide acceptance of its being a successful example of drug delivery through oral mucosa is questionable. Sativex® acts as an example for other drugs delivered to oral mucosa for systemic absorption and unintentionally washed by the saliva flow into the gastrointestinal tract. Delivery of each medicine through oral mucosa should be validated in-vivo to ensure this route to be the predominant one. Revealing the underlying absorption mechanisms would enable predicting the impact of different physiological parameters such as saliva flow and fed/fasting states on the pharmacokinetics of the delivered medication. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.

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