Biotech / MedicalIndications -- obesity/erectile dysfunction

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From: scaram(o)uche9/13/2011 6:28:21 PM
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Sanofi Scientists Bewildered!!!......

Dr. Le Strat sounds like a fun guy. Sanofi should hire him and his brain, which appears to be characterized by a lack of plasticity.....

J Biol Chem. 2011 Sep 9. [Epub ahead of print]

Hetero-multimerization of the cannabinoid CB1 receptor and the orexin OX1 receptor generates a unique complex in which both protomers are regulated by orexin A.

Ward RJ, Pediani JD, Milligan G.

University of Glasgow, United Kingdom

Agonist-induced internalization was observed for both inducible and constitutively expressed forms of the cannabinoid CB1 receptor. These were also internalized by the peptide orexin A, which has no direct affinity for the cannabinoid CB1 receptor, but only when the orexin OX1 receptor was co-expressed along with the cannabinoid CB1 receptor. This effect of orexin A was concentration-dependent and blocked by OX1 receptor antagonists. Moreover, the ability of orexin A to internalize the CB1 receptor was also blocked by CB1 receptor antagonists. Remarkably, orexin A was substantially more potent in producing internalization of the CB1 receptor than in causing internalization of the bulk OX1 receptor population and this was true in cells in which the CB1 receptor was maintained at a constant level whilst levels of OX1 could be varied and vice versa. Both co-immunoprecipitation and cell surface, homogenous time-resolved fluorescence resonance energy transfer based on covalent labelling of N-terminal SNAP- and CLIP-tags present in the extracellular N-terminal domain of the receptors confirmed the capacity of these two receptors to hetero-multimerize. These studies confirm the capacity of the CB1 and OX1 receptors to interact directly and demonstrate that this complex has unique regulatory characteristics. The higher potency of the agonist orexin A to regulate the CB1-OX1 heteromer than the OX1-OX1 homomer present in the same cells and the effects of CB1 receptor antagonists on the function of orexin A suggests an interplay between these two systems that may modulate appetite, feeding and wakefulness.

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To: scaram(o)uche who wrote (305)9/13/2011 9:47:23 PM
From: scaram(o)uche
   of 414
grain of salt.....

J Endocrinol.
2011 Sep 1. [Epub ahead of print]

A role for the putative cannabinoid receptor GPR55 in the islets of Langerhans.

Romero-Zerbo SY, Rafacho A, Diaz-Arteaga A, Suarez J, Quesada I, Imbernón M, Ross R, Diéguez C, Rodriguez de Fonseca F, Nogueiras R, Nadal A, Bermudez-Silva FJ.

S Romero-Zerbo, Laboratorio de Medicina Regenerativa, Fundacion IMABIS, 29010, Spain.

The cannabinoid CB1 receptor is a well known player in energy homeostasis and its specific antagonism has been used in clinical practice for the treatment of obesity. The G-protein-coupled receptor GPR55 has been recently proposed as a new cannabinoid receptor and, by contrast, its pharmacology is still enigmatic and its physiological role is largely unexplored, with no reports investigating its putative role in metabolism. Thus, we aim to investigate in rats the presence, distribution and putative physiological role of GPR55 in a key metabolic tissue, the endocrine pancreas. We found high GPR55 mRNA content in pancreatic islets and considerable protein distribution in insulin-secreting beta cells. Activation of GPR55 by the agonist O-1602 increased calcium transients (P<0.01) and insulin secretion (P<0.001) stimulated by glucose. This latter effect was blunted in GPR55 KO mice suggesting that O-1602 is acting, at least in part, through GPR55. Indeed, acute in vivo experiments showed that GPR55 activation increases glucose tolerance (P<0.05) and plasma insulin levels (P<0.05), suggesting an in vivo physiological relevance of GPR55 systemic stimulation. Taken together, these results reveal the expression of GPR55 receptors in the endocrine pancreas as well as its function at stimulus-secretion coupling of insulin secretion suggesting a role in glucose homeostasis. In this context, it may also represent a new target for consideration in the management of type 2 diabetes and related diseases.

J Mol Cell Cardiol. 2011 Aug 18. [Epub ahead of print]

Atheroprotection via cannabinoid receptor-2 is mediated by circulating and vascular cells in vivo.

Hoyer FF, Steinmetz M, Zimmer S, Becker A, Lütjohann D, Buchalla R, Zimmer A, Nickenig G.

Department for Cardiology, University of Bonn, 53125 Bonn, Germany.

Abstract Low-dose oral tetrahydrocannabinol (THC) reduces progression of atherosclerosis in mice. THC activates central cannabinoid-1 receptors (CB1) with subsequent psychoactive effects as well as peripheral cannabinoid-2 receptors (CB2). In order to dissect the underlying mechanisms, we performed experiments under selective CB2 stimulation as well as after genetic disruption of the CB2 receptor. Atherosclerosis prone apolipoprotein E-deficient mice were crossed with cannabinoid receptor-2 deficient mice to obtain ApoE -/- CB2 -/- double knockout mice. After 8weeks of a high-cholesterol diet, immunohistochemical stainings of the aortic root revealed that vascular leukocyte infiltration in atherosclerotic plaques was accelerated in ApoE -/- CB2 -/- mice compared with ApoE -/- mice. This was accompanied by increased release of reactive oxygen species as measured using L012-enhanced chemiluminescence, and by decreased endothelial function as assessed in isolated aortic rings in organ chamber experiments. ApoE -/- mice treated with the selective CB2 agonist JWH 133 during a high-cholesterol diet showed decreased atherosclerotic lesion formation, improved endothelial function and reduced levels of reactive oxygen species. To assess whether CB2 expression in circulating cells influences atherosclerosis, irradiated ApoE -/- mice were repopulated with bone marrow-derived cells from ApoE -/- and ApoE -/- CB2 -/- mice and were fed a high-cholesterol diet for 8weeks. CB2 deficiency in bone marrow-derived cells increased leukocyte infiltration into the vessel wall, but had no impact on plaque formation. Cell culture experiments revealed that CB2 activation diminishes ROS generation in vascular cells. Selective CB2 receptor stimulation modulates atherogenesis via impact on both circulating proinflammatory and vascular cells.

(I have tons of daily screens which I haven't gotten through. May not.)

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To: scaram(o)uche who wrote (304)9/14/2011 2:13:25 AM
From: tuck
   of 414
[NAPEs and GPR119]

Certainly NAPEs seem to be part of the pathway. I found a couple of other papers that said NAPEs synthesize OEA, which is a ligand of GPR119. This is one:

And said OEA is also a PPAR alpha agonist. The paper you cite mentions the possibility of NAPEs working through the central nervous system. You're probably aware that rodents have higher concentrations of GPR119 in the brain than humans, which complicates matters a bit. You s'pose that issue is what torpedoed the GPR119 program at Arena?

The references in this paper you cite indicate the authors were aware of these issues, so one wonders why ohnoo couldn't help with how they lower food intake if he was one of them. I mean, at least SOME parts of the mechanism/pathway seem to be elucidated in that regard.

FWIW, here's the catalog description of the active NAPE ohnoo talked of:

Cheers, Tuck

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To: tuck who wrote (307)9/15/2011 1:10:47 PM
From: scaram(o)uche
   of 414
Can't connect the 119 dots, sorry. I've tried on several occasions. This Drucker probably knows what is going on.....

Message 27358409

Find some deep pockets to back you, and hop on a few planes (carrying fine wines) to visit a few academics?

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From: scaram(o)uche10/4/2011 6:00:58 PM
   of 414
Pharmacol Biochem Behav. 2011 Nov;100(1):33-9. Epub 2011 Jul 23.

Acute blockade of CB1 receptor leads to reinstatement of MDMA-induced conditioned place preference.

Daza-Losada M, Miñarro J, Aguilar MA, Valverde O, Rodríguez-Arias M.

Unidad de Investigación Psicobiología de las Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universitat de Valencia, Spain.

Cannabis is one of the drugs most commonly consumed in combination with ecstasy (3,4-methylenedioxymethamphetamine, MDMA). Although numerous studies have attempted to further our understanding of the role of the cannabinoid system in drug abuse, few have focused on how it influences the rewarding effects of MDMA. The aim of the present study was to evaluate the role of the CB1 cannabinoid receptor in vulnerability to reinstatement of a MDMA-induced conditioned place preference (CPP). Mice were first conditioned with 5mg/kg of MDMA. Once the preference had been extinguished, a priming dose of MDMA, alone or plus the CB1 cannabinoid agonist WIN 55,212-2 (0.1 and 0.5mg/kg) or the CB1 cannabinoid antagonist SR 141716A (0.3mg/kg), was administered on alternate days. The CB1 receptor antagonist, alone or with any of the priming doses of MDMA, induced reinstatement of the preference. In contrast, WIN 55,212-2 had no effect on reinstatement of the MDMA-induced CPP when administered alone, but potentiated the effects of subthreshold priming doses of MDMA. These results highlight the important role of the CB1 receptor in vulnerability to reinstatement of drug-seeking behavior and point to the importance of the endocannabinoid system in the addictive potential of MDMA.

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From: tnsaf10/7/2011 12:43:32 AM
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Placebos Use Pot Receptor Some pain-relief placebos work in part by activating a cannabinoid receptor, stimulating the same pathway as marijuana.

By Tia Ghose | October 5, 2011

It’s well known that a placebo can relieve pain, but how such non-active ingredients can have such a positive effect has long stumped scientists. Now, new researchers suggests that placebos may help ease a patient’s pain by activating cannabinoid receptors, which are also targeted by marijuana, according to a study published October 2(Sunday) in Nature Medicine.

Researchers can give subjects an opioid prior to wrapping their arm with a painfully tight tourniquet. Thereafter, volunteers can tolerate pain longer when given a placebo instead of drugs on follow-up days, presumably because they’ve been primed to expect pain relief from the drug. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as iburprofen can also be used as a primer to induce this placebo-pain relief effect.

In the new study, researchers gave volunteers an NSAID prior to a painful stimulus, followed by rimbonant, which blocks the activation of a cannabinoid receptor, on subsequent days. Volunteers who received rimbonant on the placebo days experienced no pain relief, suggesting that part of the placebo effect was working via the cannabinoid pathway, and that blocking the pathway abolished the effect, Wired Science reported. When researchers combined rimbonant with an opioid, the placebo still quieted pain, suggesting that the opioid placebo effect works through a different mechanism.

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From: scaram(o)uche10/24/2011 5:11:24 PM
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PLoS One. 2011;6(10):e25856. Epub 2011 Oct 7.

Cannabinoid CB1 Receptor Activation Mediates the Opposing Effects of Amphetamine on Impulsive Action and Impulsive Choice.

Wiskerke J, Stoop N, Schetters D, Schoffelmeer AN, Pattij T.

Department of Anatomy and Neurosciences, VU University Medical Center, Amsterdam, The Netherlands.

It is well known that acute challenges with psychostimulants such as amphetamine affect impulsive behavior. We here studied the pharmacology underlying the effects of amphetamine in two rat models of impulsivity, the 5-choice serial reaction time task (5-CSRTT) and the delayed reward task (DRT), providing measures of inhibitory control, an aspect of impulsive action, and impulsive choice, respectively. We focused on the role of cannabinoid CB1 receptor activation in amphetamine-induced impulsivity as there is evidence that acute challenges with psychostimulants activate the endogenous cannabinoid system, and CB1 receptor activity modulates impulsivity in both rodents and humans. Results showed that pretreatment with either the CB1 receptor antagonist/inverse agonist SR141716A or the neutral CB1 receptor antagonist O-2050 dose-dependently improved baseline inhibitory control in the 5-CSRTT. Moreover, both compounds similarly attenuated amphetamine-induced inhibitory control deficits, suggesting that CB1 receptor activation by endogenously released cannabinoids mediates this aspect of impulsive action. Direct CB1 receptor activation by ?9-Tetrahydrocannabinol (?9-THC) did, however, not affect inhibitory control. Although neither SR141716A nor O-2050 affected baseline impulsive choice in the DRT, both ligands completely prevented amphetamine-induced reductions in impulsive decision making, indicating that CB1 receptor activity may decrease this form of impulsivity. Indeed, acute ?9-THC was found to reduce impulsive choice in a CB1 receptor-dependent way. Together, these results indicate an important, though complex role for cannabinoid CB1 receptor activity in the regulation of impulsive action and impulsive choice as well as the opposite effects amphetamine has on both forms of impulsive behavior.

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From: scaram(o)uche11/4/2011 9:13:30 PM
   of 414
Neuropsychopharmacology. 2011 Nov 2. doi: 10.1038/npp.2011.262. [Epub ahead of print]

Exogenous and Endogenous Cannabinoids Suppress Inhibitory Neurotransmission in the Human Neocortex.
Kovacs FE, Knop T, Urbanski MJ, Freiman I, Freiman TM, Feuerstein TJ, Zentner J, Szabo B.

Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität, Freiburg i. Br., Germany.

Activation of CB(1) receptors on axon terminals by exogenous cannabinoids (eg, ?(9)-tetrahydrocannabinol) and by endogenous cannabinoids (endocannabinoids) released by postsynaptic neurons leads to presynaptic inhibition of neurotransmission. The aim of this study was to characterize the effect of cannabinoids on GABAergic synaptic transmission in the human neocortex. Brain slices were prepared from neocortical tissues surgically removed to eliminate epileptogenic foci. Spontaneous GABAergic inhibitory postsynaptic currents (sIPSCs) were recorded in putative pyramidal neurons using patch-clamp techniques. To enhance the activity of cannabinoid-sensitive presynaptic axons, muscarinic receptors were continuously stimulated by carbachol. The synthetic cannabinoid receptor agonist WIN55212-2 decreased the cumulative amplitude of sIPSCs. The CB(1) antagonist rimonabant prevented this effect, verifying the involvement of CB(1) receptors. WIN55212-2 decreased the frequency of miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin, but did not change their amplitude, indicating that the neurotransmission was inhibited presynaptically. Depolarization of postsynaptic pyramidal neurons induced a suppression of sIPSCs. As rimonabant prevented this suppression, it is very likely that it was due to endocannabinods acting on CB(1) receptors. This is the first demonstration that an exogenous cannabinoid inhibits synaptic transmission in the human neocortex and that endocannabinoids released by postsynaptic neurons suppress synaptic transmission in the human brain. Interferences of cannabinoid agonists and antagonists with synaptic transmission in the cortex may explain the cognitive and memory deficits elicited by these drugs.

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From: scaram(o)uche11/9/2011 3:06:24 PM
   of 414
Welcome Dr. Kendall! From which planet are you arriving???

Pharmacol Biochem Behav. 2011 Oct 20. [Epub ahead of print]

The effects of chronic administration of tranylcypromine and rimonabant on behaviour and protein expression in brain regions of the rat.

Assareh N, Elbatsh MM, Marsden CA, Kendall DA.

Recent findings indicate that CB1 receptor blockade might be relevant to the action of antidepressant drugs as inhibition of endocannabinoid function can increase synaptic availability of neurotransmitters; an effect also seen with chronic antidepressant drug treatment. Chronic treatments with established antidepressants also lead to raised brain BDNF levels. The aim of this study was to compare the effects of rimonabant (an inverse agonist/antagonist of CB1 receptors) with those of the antidepressant tranylcypromine (TCP), on behaviour and expression of BDNF/CREB signalling pathways in rat brain. Daily (i.p.) injections of vehicle or TCP (10mg/kg) or rimonabant (2mg/kg) were given for 14days. Locomotor activity (LMA) and a conditional emotional response (CER) were measured in addition to levels of BDNF and CREB/phospho-CREB, using immunoblotting, in the frontal cortex, hippocampus, striatum and cerebellum. The velocity of movement was increased significantly on the 3rd, but not 9th, day of TCP treatment versus vehicle-treated rats (p<0.05) while rimonabant had no effect. There were no significant changes in grooming or freezing behaviours after rimonabant or TCP compared to vehicle-treated rats. Rearing was significantly reduced by TCP treatment on the 3rd, but not 9th, day of treatment (p<0.001) while rimonabant had no effect. BDNF levels were significantly increased in the frontal cortex after TCP (p<0.05) but not by rimonabant. Neither TCP nor rimonabant significantly affected CREB or p-CREB expression. In conclusion, chronic administration of TCP to rats increased BDNF expression in the frontal cortex but no similar effect was observed with rimonabant indicating that rimonabant does not show antidepressant drug-like responses after chronic treatment.

Lipids Health Dis. 2011 Oct 28;10(1):194. [Epub ahead of print]

Adipose tissue endocannabinoid system gene expression: depot differences and effects of diet and exercise.

You T, Disanzo BL, Wang X, Yang R, Gong D.

Alterations of endocannabinoid system in adipose tissue play an important role in lipid regulation and metabolic dysfunction associated with obesity. The purpose of this study was to determine whether gene expression levels of cannabinoid type 1 receptor (CB1) and fatty acid amide hydrolase (FAAH) are different in subcutaneous abdominal and gluteal adipose tissue, and whether hypocaloric diet and aerobic exercise influence subcutaneous adipose tissue CB1 and FAAH gene expression in obese women. Methods: Thirty overweight or obese, middle-aged women (BMI=34.3+/-0.8 kg/m2, age= 59+/-1 years) underwent one of three 20-week weight loss interventions: caloric restriction only (CR, N=9), caloric restriction plus moderate-intensity aerobic exercise (CRM, 45-50% HRR, N=13), or caloric restriction plus vigorous-intensity aerobic exercise (CRV, 70-75% HRR, N=8). Subcutaneous abdominal and gluteal adipose tissue samples were collected before and after the interventions to measure CB1 and FAAH gene expression. Results: At baseline, FAAH gene expression was higher in abdominal, compared to gluteal adipose tissue (2.08+/-0.11 vs. 1.78+/-0.10, expressed as target gene/-actin mRNA ratio x 10-3, P<0.05). Compared to pre-intervention, CR did not change abdominal, but decreased gluteal CB1 (Delta=-0.82+/-0.25, P<0.05) and FAAH (Delta=-0.49+/-0.14, P<0.05) gene expression. CRM or CRV alone did not change adipose tissue CB1 and FAAH gene expression. However, combined CRM and CRV (CRM+CRV) decreased abdominal adipose tissue FAAH gene expression (Delta=-0.37+/-0.18, P<0.05). The changes in gluteal CB1 and abdominal FAAH gene expression levels in the CR alone and the CRM+CRV group were different (P<0.05) or tended to be different (P=0.10). Conclusions: There are depot differences in subcutaneous adipose tissue endocannabinoid system gene expression in obese individuals. Aerobic exercise training may preferentially modulate abdominal adipose tissue endocannabinoid-related gene expression during dietary weight loss.

Eur J Neurosci. 2011 Nov;34(9):1369-1377. doi: 10.1111/j.1460-9568.2011.07876.x.

Loss of striatal cannabinoid CB1 receptor function in attention-deficit?/?hyperactivity disorder mice with point-mutation of the dopamine transporter.

Castelli M, Federici M, Rossi S, De Chiara V, Napolitano F, Studer V, Motta C, Sacchetti L, Romano R, Musella A, Bernardi G, Siracusano A, Gu HH, Mercuri NB, Usiello A, Centonze D.

Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Via Montpellier, Rome, Italy Fondazione Santa Lucia, Rome, Italy Behavioural Neuroscience Laboratory, CEINGE - Biotecnologie Avanzate, Naples, Italy Clinica Psichiatrica, Dipartimento di Neuroscienze, Università Tor Vergata, Rome, Italy Department of Pharmacology, Ohio State University, Columbus, OH, USA Dipartimento di Scienze Ambientali, Seconda Università di Napoli, Caserta, Italy.

Abnormal dopamine (DA) transmission in the striatum plays a pivotal role in attention-deficit/hyperactivity disorder (ADHD). As striatal DA signalling modulates the endocannabinoid system (ECS), the present study was aimed at investigating cannabinoid CB1 receptor (CB1R) function in a model of ADHD obtained by triple point-mutation in the dopamine transporter (DAT) gene in mice, making them insensitive to cocaine [DAT cocaine-insensitive (DAT-CI) mice]. DAT-CI mice had a marked hyperactive phenotype, and neurophysiological recordings revealed that the sensitivity of CB1Rs controlling GABA-mediated synaptic currents [CB1Rs((GABA)) ] in the striatum was completely lost. In contrast, CB1Rs modulating glutamate transmission [CB1Rs((Glu)) ], and GABA(B) receptors were not affected in this model of ADHD. In DAT-CI mice, the blockade of CB1R((GABA)) function was complete even after cocaine or environmental manipulations activating the endogenous DA-dependent reward system, which are known to sensitize these receptors in control animals. Conversely, the hedonic property of sucrose was intact in DAT-CI mice, indicating normal sweet perception in these animals. Our results point to CB1Rs as novel molecular players in ADHD, and suggest that therapeutic strategies aimed at interfering with the ECS might prove effective in this disorder.

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From: scaram(o)uche11/9/2011 9:58:04 PM
   of 414
Given information in this thread, I'd say that Rick Perry has been smoking pot, about eight years straight.

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