Attenuation of cue-induced reinstatement of nicotine seeking by URB597 through cannabinoid CB1 receptor in rats.

Posted on February 13, 2016 by David

“The endocannabinoid system is composed of endocannabinoids (such as anandamide), their target receptors (CB₁ and CB₂ receptors, CB₁Rs and CB₂Rs), the enzymes that degrade them (fatty-acid-amide-hydrolase (FAAH) for anandamide), and an endocannabinoid transporter. FAAH inhibition has been recently identified as having a critical involvement in behaviors related to nicotine addiction and has been shown to reduce the effect of nicotine on the mesolimbic dopaminergic system via CB₁R and peroxisome proliferator-activated receptor alpha (PPARα). Thus, inhibition of FAAH may represent a novel strategy for smoking cessation, but its mechanism of action on relapse to nicotine seeking is still unknown.

OBJECTIVE:

The study aims to explore the mechanism of action of the inhibitor of FAAH activity, URB597, on relapse to nicotine seeking by evaluating the effect of the CB₁R, CB₂R, and PPARα antagonists on the attenuating effect of URB597 on cue-induced reinstatement of nicotine seeking in rats.

RESULTS:

URB597 reduced cue-induced reinstatement of nicotine seeking, an effect that was reversed by the CB₁R antagonist rimonabant, but not by the CB₂R or PPARα antagonists AM630 and MK886, respectively.

CONCLUSIONS:

These results indicate that URB597 reduces cue-induced reinstatement in rats through a CB₁ receptor-dependent mechanism, and not via CB₂R or PPARα. Since FAAH inhibition represent a novel and promising strategy for tobacco smoking cessation, dissecting how it produces its action may lead to a better understanding of the neurobiological mechanisms underlying nicotine addiction.”

http://www.ncbi.nlm.nih.gov/pubmed/26864774

Therapeutic Potential of Cannabinoids in Psychosis.

Posted on February 8, 2016 by David

“Over recent years, the interest in the endocannabinoid system (ECS) as a new target for the treatment of schizophrenia has evolved.

The ECS represents one of the most relevant neurotransmitter systems in the brain and mainly fulfills a homeostatic role in terms of neurotransmission but also with respect to inflammatory processes.

Two main approaches to the modulation of endocannabinoid functioning have been chosen so far. First, the selective blockade or inverse agonism of the type 1 cannabinoid receptor has been tested for the improvement of acute psychotic symptoms, as well as for the improvement of cognitive functions in schizophrenia.

Second, the modulation of endocannabinoid levels by use of the phytocannabinoid cannabidiol and selective fatty acid amide hydrolase inhibitors has been proposed, and the antipsychotic properties of cannabidiol are currently being investigated in humans.

Unfortunately, for most of these trials that have focused on psychopathological and cognitive effects of cannabidiol, no published data are available. However, there is first evidence that cannabidiol may ameliorate psychotic symptoms with a superior side-effect profile compared with established antipsychotics.

In conclusion, several clinical trials targeting the ECS in acute schizophrenia have either been completed or are underway. Although publicly available results are currently limited, preliminary data indicate that selected compounds modulating the ECS may be effective in acute schizophrenia.

Nevertheless, so far, sample sizes of patients investigated are not sufficient to come to a final judgment, and no maintenance studies are available to ensure long-term efficacy and safety.”

http://www.ncbi.nlm.nih.gov/pubmed/26852073

http://www.thctotalhealthcare.com/category/schizophrenia/

Cannabinoid receptor type 1 mediates high-fat diet-induced insulin resistance by increasing forkhead box O1 activity in a mouse model of obesity.

Posted on February 8, 2016 by David

“Hepatic glucose production is promoted by forkhead box O1 (FoxO1) under conditions of insulin resistance.

The overactivity of cannabinoid receptor type 1 (CB1R) partly causes increased liver fat deposits and metabolic dysfunction in obese rodents by decreasing mitochondrial function.

The aim of the present study was to investigate the role of FoxO1 in CB1R-mediated insulin resistance through the dysregulation of mitochondrial function in the livers of mice with high-fat diet (HFD)-induced obesity.

Taken together, our findings suggest that the anti-insulin resistance effect of AM251, which leads to an improvement of mitochondrial function in hepatic steatosis, is mediated through FoxO1.”

http://www.ncbi.nlm.nih.gov/pubmed/26847930

Anti-Inflammatory and Osteoprotective Effects of Cannabinoid-2 Receptor Agonist Hu-308 in a Rat Model of Lipopolysaccharide-Induced Periodontitis.

Posted on February 8, 2016 by David

“Anti-inflammatory and immunological properties of cannabinoids have been reported in several tissues.

Also, cannabinoid receptors type 2 (CB2) were reported to be expressed in osteoblast and osteoclast, suggesting a key role in bone metabolism.

The aim of the present study was to assess the effect of the treatment with the cannabinoid-2 receptor agonist HU-308 in the oral health of rats subjected to lipopolysaccharide (LPS)-induced periodontitis.

This study demonstrates the anti-inflammatory, osteoprotective and pro-homeostatic effects of HU-308 in oral tissues of rats with LPS-induced periodontitis.”

http://www.ncbi.nlm.nih.gov/pubmed/26846967

Selective Cannabinoid Receptor-1 Agonists Regulate Mast Cell Activation in an Oxazolone-Induced Atopic Dermatitis Model.

Posted on February 8, 2016 by David

“Many inflammatory mediators, including various cytokines (e.g. interleukins and tumor necrosis factor [TNF]), inflammatory proteases, and histamine are released following mast cell activation.

Endogenous cannabinoids such as palmitoylethanolamide (PEA) and N-arachidonoylethanolamine (anandamide or AEA), were found in peripheral tissues and have been proposed to possess autacoid activity, implying that cannabinoids may downregulate mast cell activation and local inflammation.

Our results indicate that CB1R agonists down-regulate mast cell activation and may be used for relieving inflammatory symptoms mediated by mast cell activation, such as atopic dermatitis, psoriasis, and contact dermatitis.”

http://www.ncbi.nlm.nih.gov/pubmed/26848215

Cannabinoid receptor 2 augments eosinophil responsiveness and aggravates allergen-induced pulmonary inflammation in mice.

Posted on February 8, 2016 by David

“Accumulation of activated eosinophils in tissue is a hallmark of allergic inflammation.

The endocannabinoid 2-arachidonoylglycerol (2-AG) has been proposed to elicit eosinophil migration in a CB₂ receptor/G_i/o -dependent manner.

Here we explored the direct contribution of specific CB₂ receptor activation to human and mouse eosinophil effector function in vitro and in vivo.

Our data indicate that CB₂ may directly contribute to the pathogenesis of eosinophil-driven diseases. Moreover, we provide new insights into the molecular mechanisms underlying the CB₂ -mediated priming of eosinophils. Hence, antagonism of CB₂ receptors may represent a novel pharmacological approach for the treatment of allergic inflammation and other eosinophilic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26850094

A systematic review of plant-derived natural compounds for anxiety disorders.

Posted on February 5, 2016 by David

“Anxiety disorders are the most common mental illnesses affecting human beings. They range from panic to generalized anxiety disorders upsetting the well-being and psychosocial performance of patients. Several conventional anxiolytic drugs are being used which in turn result in several adverse effects. Therefore, studies to find suitable safe medicines from natural sources are being conducted by researchers.

The aim of the present study is to comprehensively review phytochemical compounds with well-established anxiolytic activities and their structure-activity relationships as well as neuropsychopharmacological aspects. Results showed that phytochemicals like; alkaloids, flavonoids, phenolic acids, lignans, cinnamates, terpenes and saponins possess anxiolytic effects in a wide range of animal models of anxiety.

The involved mechanisms include interaction with γ-aminobutyric acid (GABA)A receptors at benzodiazepine (BZD) and non-BZD sites with various affinity to different subunits, serotonergic 5-hydrodytryptamine (5-HT)1A and 5-HT2A/C receptors, noradrenergic and dopaminergic systems, glycine and glutamate receptors, and κ-opioid receptor as well as cannabinoid (CB)1 and CB2 receptors.

Phytochemicals also modulate the hypothalamo-pituitary-adrenal (HPA) axis, the levels of pro-inflammatory cytokines like interleukin (IL)-2, IL-6, IL-1β and tumor necrosis factor (TNF)-α, and improve brain derived neurotrophic factor (BDNF) levels. Transient receptor potential cation channel subfamily V (TRPV)3, nitric oxide cyclic guanosine monophosphate (NO-cGMP) pathway and monoamine oxidase enzymes are other targets of phytochemicals with anxiolytic activity.

Taking together, these phytochemicals may be considered as supplements to conventional anxiolytic therapies in order to improve efficacy and reduce adverse effects.

Further preclinical and clinical studies are still needed in order to recognize the structure-activity relationships, metabolism, absorption, and neuropsychopharmacological mechanisms of plant-derived natural agents.”

http://www.ncbi.nlm.nih.gov/pubmed/26845556

The Cannabinoid CB1/CB2 Agonist WIN55212.2 Promotes Oligodendrocyte Differentiation In Vitro and Neuroprotection During the Cuprizone-Induced Central Nervous System Demyelination.

Posted on February 5, 2016 by David

“Different types of insults to the CNS lead to axon demyelination. Remyelination occurs when the CNS attempts to recover from myelin loss and requires the activation of oligodendrocyte precursor cells.

With the rationale that CB1 receptor is expressed in oligodendrocytes and marijuana consumption alters CNS myelination, we study the effects of the cannabinoid agonist WIN55212.2 in (1) an in vitro model of oligodendrocyte differentiation and (2) the cuprizone model for demyelination.

The cannabinoid agonist WIN55212.2 promotes oligodendrocyte differentiation in vitro.

Moreover, 0.5 mg/kg of the drug confers neuroprotection during cuprizone-induced demyelination, while 1 mg/kg aggravates the demyelination process.”

http://www.ncbi.nlm.nih.gov/pubmed/26842941

JWH-133, a Selective Cannabinoid CB2 Receptor Agonist, Exerts Toxic Effects on Neuroblastoma SH-SY5Y Cells.

Posted on February 5, 2016 by David

“Endocannabinoid system plays an important role in the regulation of diverse physiological functions.

Although cannabinoid type 2 receptors (CB₂) are involved in the modulation of immune system in peripheral tissues, recent findings demonstrated that they are also expressed in the central nervous system and could constitute a new target for the treatment of neurodegenerative disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26842917

Simultaneous Activation of Induced Heterodimerization between CXCR4 Chemokine Receptor and Cannabinoid Receptor 2 (CB2) Reveal a Mechanism for Regulation of Tumor Progression.

Posted on February 5, 2016 by David

“The G-protein-coupled chemokine receptor, CXCR4, generates signals that lead to cell migration, cell proliferation, and other survival mechanisms which result in the metastatic spread of primary tumor cells to distal organs.

Numerous studies have demonstrated that CXCR4 can form homodimers, or can heterodimerize with other GPCRs to form receptor complexes that can amplify or decrease the signaling capacity of each individual receptor.

Using biophysical and biochemical approaches, we found that CXCR4 can form an induced heterodimer with cannabinoid receptor 2 (CB2) in human breast and prostate cancer cells.

Simultaneous, agonist-dependent activation of CXCR4 and CB2 resulted in reduced CXCR4-mediated expression of phosphorylated ERK1/2, and ultimately, reduced cancer cell functions such as calcium mobilization and cellular chemotaxis.

Given that treatment with cannabinoids has been shown to reduce invasiveness of cancer cells, as well as CXCR4-mediated migration of immune cells, it is therefore plausible that CXCR4 signaling can be silenced through a physical heterodimeric association with CB2, thereby inhibiting subsequent functions of CXCR4.

Taken together, the data illustrates a mechanism by which the cannabinoid system can negatively modulate CXCR4 receptor function, and perhaps, tumor progression.”

http://www.ncbi.nlm.nih.gov/pubmed/26841863