Monthly Archives: March 2016

Encapsulation of cannabinoid drugs in nanostructured lipid carriers.

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“This study describes the development and optimization of a method to encapsulate the potent and expensive cannabinoids drugs in nanostructured lipid carriers; namely, URB597, AM251 and rimonabant have been considered. NLC production by melt and ultrasonication protocol has been specifically designed to optimize nanoparticle recovery and drug encapsulation efficiency. Special care has been devoted to the modality of oil and water phase emulsification and the entire production has been studied and discussed. NLC recovery, morphology, dimensional distribution and encapsulation efficiency are presented.”

http://www.ncbi.nlm.nih.gov/pubmed/26952905

PnPP-19, a spider toxin analogue, induces peripheral antinociception through opioid and cannabinoid receptors and inhibition of Neutral endopeptidase.

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“The synthetic peptide PnPP-19 has been studied as a new drug candidate to treat erectile dysfunction. However, PnTx2-6, the spider toxin from which the peptide was designed, induces hyperalgesia. Therefore, we intended to investigate the role of PnPP-19 in the nociceptive pathway.

Antinociception induced by PnPP-19 might involve the inhibition of NEP and activation of CB1 , μ- and δ-opioid receptors. Our data provide a comprehension of the antinociceptive effect induced by PnPP-19 and it should be useful as a new antinociceptive drug candidate.”

http://www.ncbi.nlm.nih.gov/pubmed/26947933

Dynamic of expression and localization of cannabinoid-degrading enzymes FAAH and MGLL in relation to CB1 during meiotic maturation of human oocytes.

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“The endogenous cannabinoid system has been characterized in some female reproductive organs but little is known about the expression and localization pattern of cannabinoid-degrading enzymes in relation to the CB1 cannabinoid receptor in human oocytes. In this study, we focus on the investigation of the presence and differential distribution of fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGLL) in relation to CB1 during the maturation of human oocytes. We used a total of 290 human oocytes not suitable for in vitro fertilization/intracytoplasmic sperm injection (ICSI): germinal-vesicle (GV) and metaphase-I (MI) stages and metaphase-II (MII) oocytes that had not developed into an embryo after ICSI.Cannabinoid-degrading enzymes and the cannabinoid CB1 receptor were present in human oocytes. Specifically, FAAH was detected in the periphery of the oocyte from the GV to MI stage and co-localized with CB1. Later, by the MII stage, FAAH was spread within the oocyte, whereas MGLL immunostaining was homogeneous across the oocyte at all stages of maturation and only overlapped with CB1 at the GV stage. This coordinated redistribution of cannabinoid system proteins suggests a role for this system in the maturation of the female gamete.”

http://www.ncbi.nlm.nih.gov/pubmed/26948343

Cannabinoid receptors are involved in the protective effect of a novel curcumin derivative C66 against CCl4-induced liver fibrosis.

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“Liver fibrosis is one of the major causes of morbidity and mortality worldwide and lacks efficient therapy. Recent studies suggest the curcumin protects liver from fibrosis. However, curcumin itself is in low bioavailable concentration when administered orally, and the protective mechanism remains poorly understood. The current study aimed to investigate whether a more stable derivative of curcumin, C66, protects against CCl4-inudced liver fibrosis and examine the underlying mechanism involving cannabinoid receptor (CB receptor). At a dose lower than curcumin itself, C66 displayed a superior anti-fibrotic effect. C66 significantly reduced collagen deposition, pro-inflammatory cytokine expression, and liver enzyme activities. Mechanistic study revealed that C66 treatment decreased CCl4-induced cannabinoid receptor 1 (CB1 receptor) expression and increased cannabinoidreceptor 2 (CB2 receptor) expression, along with an inhibition of JNK/NF-κB-mediated inflammatory signaling. In conclusion, this curcumin derivative attenuates liver fibrosis likely involving a CB/JNK/NF-κB-mediated pathway.”

http://www.ncbi.nlm.nih.gov/pubmed/26945822

Nutritional n-3 PUFA Deficiency Abolishes Endocannabinoid Gating of Hippocampal Long-Term Potentiation.

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“Maternal n-3 polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid, is critical during perinatal brain development. How early postnatal n-3 PUFA deficiency impacts on hippocampal synaptic plasticity is mostly unknown. Here we compared activity-dependent plasticity at excitatory and inhibitory synapses in the CA1 region of the hippocampus in weaned pups whose mothers were fed with an n-3 PUFA-balanced or n-3 PUFA-deficient diet. Normally, endogenous cannabinoids (eCB) produced by the post-synapse dually control network activity by mediating the long-term depression of inhibitory inputs (iLTD) and positively gating NMDAR-dependent long-term potentiation (LTP) of excitatory inputs. We found that both iLTD and LTP were impaired in n-3 PUFA-deficient mice. Pharmacological dissection of the underlying mechanism revealed that impairment of NMDAR-dependent LTP was causally linked to and attributable to the ablation of eCB-mediated iLTD and associated to disinhibitory gating of excitatory synapses. The data shed new light on how n-3 PUFAs shape synaptic activity in the hippocampus and provide a new synaptic substrate to the cognitive impairments associated with perinatal n-3 deficiency.”

http://www.ncbi.nlm.nih.gov/pubmed/26946127

An Increase in the Omega-6/Omega-3 Fatty Acid Ratio Increases the Risk for Obesity.

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“In the past three decades, total fat and saturated fat intake as a percentage of total calories has continuously decreased in Western diets, while the intake of omega-6 fatty acid increased and the omega-3 fatty acid decreased, resulting in a large increase in the omega-6/omega-3 ratio from 1:1 during evolution to 20:1 today or even higher.

This change in the composition of fatty acids parallels a significant increase in the prevalence of overweight and obesity.

Experimental studies have suggested that omega-6 and omega-3 fatty acids elicit divergent effects on body fat gain through mechanisms of adipogenesis, browning of adipose tissue, lipid homeostasis, brain-gut-adipose tissue axis, and most importantly systemic inflammation.

Prospective studies clearly show an increase in the risk of obesity as the level of omega-6 fatty acids and the omega-6/omega-3 ratio increase in red blood cell (RBC) membrane phospholipids, whereas high omega-3 RBC membrane phospholipids decrease the risk of obesity.

Recent studies in humans show that in addition to absolute amounts of omega-6 and omega-3 fatty acid intake, the omega-6/omega-3 ratio plays an important role in increasing the development of obesity via both AA eicosanoid metabolites and hyperactivity of the cannabinoid system, which can be reversed with increased intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

A balanced omega-6/omega-3 ratio is important for health and in the prevention and management of obesity.”

http://www.ncbi.nlm.nih.gov/pubmed/26950145

Effects of fixed or self-titrated dosages of Sativex on cannabis withdrawal and cravings.

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“There is currently no pharmacological treatment approved for cannabis dependence. In this proof of concept study, we assessed the feasibility/effects of fixed and self-titrated dosages of Sativex (1:1, Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD)) on craving and withdrawal from cannabis among nine community-recruited cannabis-dependent subjects.

The results found in this proof of concept study warrant further systematic exploration of Sativex as a treatment option for cannabis withdrawal and dependence.”

http://www.ncbi.nlm.nih.gov/pubmed/26925704

Effects of cannabinoid receptor activation by CP55,940 on normal bladder function and irritation-induced bladder overactivity in non-awake anaesthetised rats.

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“CP55,940 is a synthetic analogue of tetrahydrocannabidiol, which is a psychoactive ingredient of the Cannabis plant.

This study was designed to evaluate the effects of CP55,940 on normal bladder function in vivo and examine whether it suppresses urinary frequency induced by nociceptive stimuli in the bladder.

CP55,940 decreases bladder activity and urinary frequency induced by nociceptive stimuli, probably by suppression of bladder afferent activity. Effects of CP55,940 were abolished by both CBR antagonists. This data implicates a role for the endocannabinoid system in bladder mechanoafferent function in rats. In addition, our results show that CP55,940 reverses urinary frequency exemplified in an overactive bladder model, suggesting it could be an effective treatment for patients with lower urinary tract symptoms.”

http://www.ncbi.nlm.nih.gov/pubmed/26942594

Longitudinal examination of the intestinal lamina propria cellular compartment of SIV-infected rhesus macaques provides broader and deeper insights into the link between aberrant microRNA expression and persistent immune activation.

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“Persistent gastrointestinal tract (GI) disease/inflammation is a cardinal feature of HIV/SIV infection. Increasing evidence points to a critical role for microRNAs (miRNAs) in controlling several aspects of the immune/inflammatory response. Here, we show significant dysregulation of miRNA expression exclusively in the intestinal lamina propria cellular compartment through the course of SIV infection. Specifically, the study identified miRNA signatures associated with key pathogenic events such as viral replication, T-cell activation and microbial translocation. The T-cell enriched miR-150 showed significant downregulation throughout SIV infection and was confirmed to target IRAK1 (Interleukin-1 receptor 1 kinase), a critical signal-transducing component of the IL-1 receptor and TLR signaling pathways. Reduced miR-150 expression was associated with markedly elevated IRAK1 expression in the intestines of chronically SIV-infected macaques. Finally, delta-9 -tetrahydrocannabinol mediated blockade of CD8+ T cell activation in vitro significantly inhibited miR-150 downregulation and IRAK1 upregulation suggesting its potential for targeted immune modulation in HIV infection.”

http://www.ncbi.nlm.nih.gov/pubmed/26937033

Combined treatment with morphine and Δ9-tetrahydrocannibinol (THC) in rhesus monkeys: antinociceptive tolerance and withdrawal.

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“Opioid receptor agonists are effective for treating pain; however, tolerance and dependence can develop with repeated treatment. Combining opioids with cannabinoids can enhance their analgesic potency…

These results demonstrate that antinociceptive tolerance is greater during treatment with the mixture, and although treatment conditions were sufficient for dependence to development on morphine, withdrawal was not markedly altered by concurrent treatment with THC.

Thus, THC can enhance some (antinociception, tolerance) but not all (dependence) effects of morphine.”

http://www.ncbi.nlm.nih.gov/pubmed/26937020