Monthly Archives: June 2016

β-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease.

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“Parkinson disease (PD) is a neurodegenerative disease characterized by progressive dopaminergic neurodegeneration in the substantia nigra pars compacta (SNc) area.

The present study was undertaken to evaluate the neuroprotective effect of β-caryophyllene (BCP) against rotenone-induced oxidative stress and neuroinflammation in a rat model of PD.

The findings demonstrate that BCP provides neuroprotection against rotenone-induced PD and the neuroprotective effects can be ascribed to its potent antioxidant and anti-inflammatory activities.”

http://www.ncbi.nlm.nih.gov/pubmed/27316720

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”  http://www.ncbi.nlm.nih.gov/pubmed/23138934

http://www.thctotalhealthcare.com/category/parkinsons-disease/

Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinsońs disease.

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“Elements of the endocannabinoid system are strongly expressed in the basal ganglia where they suffer profound rearrangements after dopamine depletion.

Modulation of the levels of the endocannabinoid 2-arachidonoyl glycerol by inhibiting monoacylglycerol lipase alters glial phenotypes and provides neuroprotection in a mouse model of Parkinsońs disease.

In this study, we assessed whether inhibiting fatty acid amide hydrolase could also provide beneficial effects on the time course of this disease.

Together, these results demonstrate an effect of fatty acid amide hydrolase inhibition on the motor symptoms of Parkinsońs disease in two distinct experimental models that is mediated by cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27318096

Cannabinoid receptor agonism suppresses tremor, cognition disturbances and anxiety-like behaviors in a rat model of essential tremor.

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“Cognitive and motor disturbances are serious consequences of tremor induced by motor disorders. Despite a lack of effective clinical treatment, some potential therapeutic agents have been used to alleviate the cognitive symptoms in the animal models of tremor.

In the current study, the effects of WIN55, 212-2 (WIN), a cannabinoid receptor (CBR) agonist, on harmaline-induced motor and cognitive impairments was studied.

The neuroprotective and anxiolytic effects of WIN demonstrated in the current study can be offered cannabinoid receptor (CBR) agonism as a potential neuroprotective agent in the treatment of patients with tremor that manifest mental dysfunctions.”

http://www.ncbi.nlm.nih.gov/pubmed/27317835

Upregulation of the cannabinoid CB2 receptor in environmental and viral inflammation-driven rat models of Parkinson’s disease.

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“In recent years, it has become evident that Parkinson’s disease is associated with a self-sustaining cycle of neuroinflammation and neurodegeneration, with dying neurons activating microglia, which, once activated, can release several factors that kill further neurons.

One emerging pharmacological target that has the potential to break this cycle is the microglial CB2 receptor which, when activated, can suppress microglial activity and reduce their neurotoxicity.

However, very little is known about CB2 receptor expression in animal models of Parkinson’s disease which is essential for valid preclinical assessment of the anti-Parkinsonian efficacy of drugs targeting the CB2 receptor.

Therefore, the aim of this study was to investigate and compare the changes that occur in CB2 receptor expression in environmental and inflammation-driven models of Parkinson’s disease.

Thus, this study has shown that CB2 receptor expression is dysregulated in animal models of Parkinson’s disease, and has also revealed significant differences in the level of dysregulation between the models themselves.

This study indicates that these models may be useful for further investigation of the CB2 receptor as a target for anti-inflammatory disease modification in Parkinson’s disease.”

http://www.ncbi.nlm.nih.gov/pubmed/27317300

Cannabinoids reverse the effects of early stress on neurocognitive performance in adulthood.

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“Early life stress (ES) significantly increases predisposition to psychopathologies. Cannabinoids may cause cognitive deficits and exacerbate the effects of ES.

Nevertheless, the endocannabinoid system has been suggested as a therapeutic target for the treatment of stress- and anxiety-related disorders.

Here we examined whether cannabinoids administered during “late adolescence” (extensive cannabis use in humans at the ages 18-25) could reverse the long-term adverse effects of ES on neurocognitive function in adulthood.

WIN administered during late adolescence prevented these stress-induced impairments and reduced anxiety levels.

There is a crucial role of the endocannabinoid system in the effects of early life stress on behavior at adulthood.”

http://www.ncbi.nlm.nih.gov/pubmed/27317195

Exercise as an adjunctive treatment for cannabis use disorder.

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“Despite cannabis being the most widely used illicit substance in the United States, individuals diagnosed with cannabis use disorder (CUD) have few well-researched, affordable treatment options available to them.

Although found to be effective for improving treatment outcomes in other drug populations, exercise is an affordable and highly accessible treatment approach that has not been routinely investigated in cannabis users. The aim of this paper is to inform the topic regarding exercise’s potential as an adjunctive treatment for individuals with CUD.

Given that exercise is a potent activator of the eCB system, it is mechanistically plausible that exercise could be an optimal method to supplement cessation efforts by reducing psychophysical withdrawal, managing stress, and attenuating drug cravings.”

http://www.ncbi.nlm.nih.gov/pubmed/27314543

“Exercise activates the endocannabinoid system.”  http://www.ncbi.nlm.nih.gov/pubmed/14625449

Chromenopyrazole, a Versatile Cannabinoid Scaffold with in Vivo Activity in a Model of Multiple Sclerosis.

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“A combination of molecular modeling and structure-activity relationship studies have been used to fine tune CB2 selectivity in the chromenopyrazole ring, a versatile CB1/CB2 cannabinoid scaffold. Thus, a series of 36 new derivatives covering a wide range of structural diversity have been synthesized and docking studies have been performed for some of them. Biological evaluation of the new compounds includes, among others, cannabinoid binding assays, functional studies and surface plasmon resonance measurements. The most promising compound [43 (PM226)], a selective and potent CB2 agonist isoxazole derivative, was tested in the acute phase of Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a well-established animal model of primary progressive multiple sclerosis. Compound 43 dampened neuroinflammation by reducing microglial activation in the TMEV.”

http://www.ncbi.nlm.nih.gov/pubmed/27309150

“CHROMENOPYRAZOLES: NON-PSYCHOACTIVE AND SELECTIVE CB1CANNABINOID AGONISTS WITH PERIPHERAL ANTINOCICEPTIVE PROPERTIES” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049093/

Cannabinoids in the Brain: New Vistas on an Old Dilemma

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“The use of cannabis as a therapeutic and recreational substance goes back to thousands of years throughout Asia, Middle East, Southern Africa, and South America.

The discovery of Δ-9-tetrahydrocannabinol (Δ9-THC) by Mechoulam and Gaoni in the midsixties as the major psychoactive constituent of cannabis sativa led to another important discovery, namely, its specific binding site that was isolated and cloned in 1990. This first cannabinoid receptor was coined CB1R and triggered a number of investigations on its expression, localization, and function within the body tissue including the brain, in various species. This was followed by the discovery in 1992 of the first endocannabinoid (eCB), anandamide, followed by another cannabinoid receptor CB2R and a second endocannabinoid called 2-arachidonoylglycerol (2-AG). Later on, some of the enzymes responsible for their synthesis (N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD); diacylglycerol lipase (DAGL)) and degradation (fatty acid amide hydrolase (FAAH); monoacylglycerol lipase (MAGL)) were identified.

Studies on the expression and localization of the cannabinoid receptors in the brain have burgeoned in the last decade and have furnished valuable data on their putative involvement in various sensory-motor and cognitive functions in diverse animal species, including Man. These studies have recently received substantial attention from pharmaceutical companies as a potential source for novel treatments. Additionally, the dilemma of legalizing the use of cannabis in some countries makes the investigation on cannabinoid systems more momentous. This special issue is therefore timely and brings historical and groundbreaking novel research on the role of these cannabinoid receptors in the mammalian central nervous system (CNS).

We hope that the collected papers in this special issue will contribute to the understanding of the various mechanisms involved in the functions of the endocannabinoid system and the development of new pharmaceutical tools to treat visual disorders.”

http://www.hindawi.com/journals/np/2016/9146713/

Inhibition of autophagy and enhancement of endoplasmic reticulum stress increase sensitivity of osteosarcoma Saos-2 cells to cannabinoid receptor agonist WIN55,212-2.

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“WIN55,212-2, a cannabinoid receptor agonist, can activate cannabinoid receptors, which has proven anti-tumour effects in several tumour types. Studies showed that WIN can inhibit tumour cell proliferation and induce apoptosis in diverse cancers.

However, the role and mechanism of WIN in osteosarcoma are still unclear. In this study, we examined the effect of WIN55,212-2 on osteosarcoma cell line Saos-2 in terms of cell viability and apoptosis. Meanwhile, we further explored the role of endoplasmic reticulum stress and autophagy in apoptosis induced by WIN55,212-2.

Our results showed that the cell proliferation of Saos-2 was inhibited by WIN55,212-2 in a dose-dependent and time-dependent manner. WIN55,212-2-induced Saos-2 apoptosis through mitochondrial apoptosis pathway. Meanwhile, WIN55,212-2 can induce endoplasmic reticulum stress and autophagy in Saos-2 cells. Inhibition of autophagy and enhancement of endoplasmic reticulum stress increased apoptosis induced by WIN55,212-2 in Saos-2 cells.

These findings indicated that WIN55,212-2 in combination with autophagic inhibitor or endoplasmic reticulum stress activator may shed new light on osteosarcoma treatment.”

http://www.ncbi.nlm.nih.gov/pubmed/27309350

Autophagy activation by novel inducers prevents BECN2-mediated drug tolerance to cannabinoids.

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“Cannabinoids and related drugs generate profound behavioral effects (such as analgesic effects) through activating CNR1 (cannabinoid receptor 1 [brain]). However, repeated cannabinoid administration triggers lysosomal degradation of the receptor and rapid development of drug tolerance, limiting the medical use of marijuana in chronic diseases.

Here we show that a protein involved in macroautophagy/autophagy (a conserved lysosomal degradation pathway), BECN2 (beclin 2), mediates cannabinoid tolerance by preventing CNR1 recycling and resensitization after prolonged agonist exposure, and deletion of Becn2 rescues CNR1 activity in mouse brain and conveys resistance to analgesic tolerance to chronic cannabinoids.

Overall, our findings demonstrate the functional link among autophagy, receptor signaling and animal behavior regulated by psychoactive drugs, and develop a new strategy to prevent tolerance and improve medical efficacy of cannabinoids by modulating the BECN2 interactome and autophagy activity.”

http://www.ncbi.nlm.nih.gov/pubmed/27305347