Monthly Archives: June 2018

Endocannabinoid and Muscarinic Signaling Crosstalk in the 3xTg-AD Mouse Model of Alzheimer’s Disease.

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“The endocannabinoid system, which modulates emotional learning and memory through CB1 receptors, has been found to be deregulated in Alzheimer’s disease (AD).

AD is characterized by a progressive decline in memory associated with selective impairment of cholinergic neurotransmission. The functional interplay of endocannabinoid and muscarinic signaling was analyzed in seven-month-old 3xTg-AD mice following the evaluation of learning and memory of an aversive stimulus.

The subchronic (seven days) stimulation of the endocannabinoid system following repeated WIN55,212-2 (1 mg/kg) or JZL184 (8 mg/kg) administration induced a CB1 receptor downregulation and CB1-mediated signaling desensitization, normalizing acquisition latencies to control levels. However, the observed modulation of cholinergic neurotransmission in limbic areas did not modify learning and memory outcomes.

A CB1 receptor-mediated decrease of GABAergic tone in the basolateral amygdala may be controlling the limbic component of learning and memory in 3xTg-AD mice. CB1 receptor desensitization may be a plausible strategy to improve behavior alterations associated with genetic risk factors for developing AD.”

https://www.ncbi.nlm.nih.gov/pubmed/29865071

https://content.iospress.com/articles/journal-of-alzheimers-disease/jad180137

Localization of cannabinoid receptors CB1, CB2, GPR55, and PPARα in the canine gastrointestinal tract.

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Histochemistry and Cell Biology

“The endocannabinoid system (ECS) is composed of cannabinoid receptors, their endogenous ligands, and the enzymes involved in endocannabinoid turnover.

Modulating the activity of the ECS may influence a variety of physiological and pathophysiological processes.

A growing body of evidence indicates that activation of cannabinoid receptors by endogenous, plant-derived, or synthetic cannabinoids may exert beneficial effects on gastrointestinal inflammation and visceral pain.

The present ex vivo study aimed to investigate immunohistochemically the distribution of cannabinoid receptors CB1, CB2, G protein-coupled receptor 55 (GPR55), and peroxisome proliferation activation receptor alpha (PPARα) in the canine gastrointestinal tract.

Cannabinoid receptors showed a wide distribution in the gastrointestinal tract of the dog.

Since cannabinoid receptors have a protective role in inflammatory bowel disease, the present research provides an anatomical basis supporting the therapeutic use of cannabinoid receptor agonists in relieving motility disorders and visceral hypersensitivity in canine acute or chronic enteropathies.”

https://www.ncbi.nlm.nih.gov/pubmed/29882158

https://link.springer.com/article/10.1007%2Fs00418-018-1684-7

[Cannabinoids in pain medicine]

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Der Schmerz

“The endocannabinoid system (ECS) controls a large number of vital functions.

Suboptimal tone of the ECS in certain regions of the nervous system may be associated with disorders that are also associated with pain.

Pain and inflammation processes can be modulated by the exogenous supply of cannabinoids.

Low-to-moderate pain-relieving effects and in individual cases large pain-relieving effects were observed in randomized, controlled studies of various types of chronic pain. People with chronic neuropathic pain and stress symptoms seem to particularly benefit.

The therapeutic range of cannabinoids is small; often small doses are sufficient for clinically significant effects. The “Cannabis-als-Medizin-Gesetz” (cannabis as medicine law) allows the prescription of cannabis preparations under certain conditions.

Available data indicate good long-term efficacy and tolerability. However, there is little systematic long-term experience from clinical studies.”

https://www.ncbi.nlm.nih.gov/pubmed/29881935

https://link.springer.com/article/10.1007%2Fs00482-018-0299-1

The importance of 15-lipoxygenase inhibitors in cancer treatment.

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Cancer and Metastasis Reviews

“Cancer-targeted therapy is an expanding and successful approach in treatment of many types of cancers. One of the main categories of targeted therapy is use of small molecule inhibitors. 15-Lipoxygenase (15-LOX) is an enzyme which reacts with polyunsaturated fatty acids and produces metabolites that are implicated in many important human diseases, such as cancer.

Considering the role of 15-LOX (mainly 15-LOX-1) in the progression of some cancers, the discovery of 15-LOX inhibitors could potentially lead to development of novel cancer therapeutics and it can be claimed that 15-LOX inhibitors might be suitable as chemotherapy agents in the near future.

This article reviews relevant publications on 15-LOX inhibitors with focus on their anticancer activities in vitro and in vivo. Many 15-LOX inhibitors have been reported for which separate studies have shown their anticancer activities. This review paves the way to further explore the mechanism of their antiproliferative effects via 15-LOX inhibition.”

 https://www.ncbi.nlm.nih.gov/pubmed/29882120
https://link.springer.com/article/10.1007%2Fs10555-018-9738-9

“Cannabidiol-2′,6′-Dimethyl Ether, a Cannabidiol Derivative, Is a Highly Potent and Selective 15-Lipoxygenase Inhibitor”  http://dmd.aspetjournals.org/content/37/8/1733.long

“Δ9-tetrahydrocannabinol and its major metabolite Δ9-tetrahydrocannabinol-11-oic acid as 15-lipoxygenase inhibitors.”  https://www.ncbi.nlm.nih.gov/pubmed/20891010

Systemic Injections of Cannabidiol Enhance Acetylcholine Levels from Basal Forebrain in Rats.

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Neurochemical Research

“Cannabis sativa is a plant that contains more than 500 components, of which the most studied are Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Several studies have indicated that CBD displays neurobiological effects, including wake promotion.

Moreover, experimental evidence has shown that injections of CBD enhance wake-related compounds, such as monoamines (dopamine, serotonin, epinephrine, and norepinephrine). However, no clear evidence is available regarding the effects of CBD on additional wake-related neurochemicals such as acetylcholine (ACh).

Here, we demonstrate that systemic injections of CBD (0, 5, 10 or 30 mg/kg, i.p.) at the beginning of the lights-on period, increase the extracellular levels of ACh collected from the basal forebrain and measured by microdialysis and HPLC means. Moreover, the time course effects on the contents of ACh were present 5 h post-injection of CBD.

Altogether, these data demonstrate that CBD increases ACh levels in a brain region related to wake control. This study is the first to show the effects of ACh levels in CBD-treated rats and suggests that the basal forebrain might be a site of action of CBD for wakefulness modulation.”

https://www.ncbi.nlm.nih.gov/pubmed/29876791

https://link.springer.com/article/10.1007%2Fs11064-018-2565-0

Medicinal cannabis: presenting possible treatment modalities for the future

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“Cannabis is the most popular recreational drug used in the world. It is estimated that 178 million people aged 15–64 years used cannabis at least once in 2012.

Cannabis or cannabinoids used to manage medical conditions is referred to as medicinal cannabis. There are various formulations of cannabis available on the market.

Cannabis can be administered orally, sublingually, or topically; it can be smoked, inhaled, mixed with food, or made into tea. It can be taken in herbal form, extracted naturally from the plant, gained by isomerization of cannabidiol (CBD), or manufactured synthetically.

The commercially available prescribed cannabinoids include dronabinol capsules, nabilone capsules, and the oromucosal spray nabiximols.

Canada and the Netherlands have government-run programs in which dedicated companies supply quality-controlled herbal cannabis. In the United States, 23 states and Washington, DC (May 2015) have introduced laws permitting the medical use of cannabis; other countries have similar laws.”

https://www.ncbi.nlm.nih.gov/pubmed/29870436

https://insights.ovid.com/crossref?an=01787381-201806000-00001

Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex.

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Molecular Neurobiology

“Currently available antidepressants have a substantial time lag to induce therapeutic response and a relatively low efficacy. The development of drugs that addresses these limitations is critical to improving public health.

Cannabidiol (CBD), a non-psychotomimetic component of Cannabis sativa, is a promising compound since it shows large-spectrum therapeutic potential in preclinical models and humans.

However, its antidepressant properties have not been completely investigated. Therefore, the aims of this study were to investigate in male rodents (i) whether CBD could induce rapid and sustained antidepressant-like effects after a single administration and (ii) whether such effects could be related to changes in synaptic proteins/function.

These results indicate that CBD induces fast and sustained antidepressant-like effect in distinct animal models relevant for depression. These effects may be related to rapid changes in synaptic plasticity in the mPFC through activation of the BDNF-TrkB signaling pathway.

The data support a promising therapeutic profile for CBD as a new fast-acting antidepressant drug.”

https://www.ncbi.nlm.nih.gov/pubmed/29869197

https://link.springer.com/article/10.1007%2Fs12035-018-1143-4

Therapeutic Symptomatic Strategies in the Parasomnias.

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Current Treatment Options in Neurology

“The purpose of this review was to discuss the currently available pharmacologic and non-pharmacologic treatment options for parasomnias.

Cannabinoids proved to be effective in some of parasomnias, as in many other neurological disorders.

Prazosin and cannabinoids are effective in nightmare disorder.”

https://www.ncbi.nlm.nih.gov/pubmed/29869076
https://link.springer.com/article/10.1007%2Fs11940-018-0508-3
“Parasomnias are a category of sleep disorders that involve abnormal movements, behaviors, emotions, perceptions, and dreams that occur while falling asleep, sleeping, between sleep stages, or during arousal from sleep.”  https://en.wikipedia.org/wiki/Parasomnia

Cannabidiol as a Promising Strategy to Treat and Prevent Movement Disorders?

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“Movement disorders such as Parkinson’s disease and dyskinesia are highly debilitating conditions linked to oxidative stress and neurodegeneration. When available, the pharmacological therapies for these disorders are still mainly symptomatic, do not benefit all patients and induce severe side effects. Cannabidiol is a non-psychotomimetic compound from Cannabis sativa that presents antipsychotic, anxiolytic, anti-inflammatory, and neuroprotective effects. Although the studies that investigate the effects of this compound on movement disorders are surprisingly few, cannabidiol emerges as a promising compound to treat and/or prevent them. Here, we review these clinical and pre-clinical studies and draw attention to the potential of cannabidiol in this field.”

https://www.ncbi.nlm.nih.gov/pubmed/29867488

https://www.frontiersin.org/articles/10.3389/fphar.2018.00482/full

Cannabinoid Receptor 2-Deficiency Ameliorates Disease Symptoms in a Mouse Model with Alzheimer’s Disease-Like Pathology.

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“It is widely accepted that the endocannabinoid system (ECS) is a modulator of neuroinflammation associated with neurodegenerative disorders, including Alzheimer’s disease (AD).

Thus, expression of the cannabinoid receptor 2 (CB2) is induced in plaque-associated microglia and astrocytes in brain tissues from AD patients and in genetic mouse models expressing pathogenic variants of the amyloid precursor protein (APP).

However, the exact mechanism of CB2 signaling in this mouse model remains elusive, because the genetic deletion of CB2 and the pharmacological activation of CB2 both reduced neuroinflammation.

Here, we demonstrate that CB2 deletion also improved cognitive and learning deficits in APP/PS1*CB2-/- mice. This was accompanied by reduced neuronal loss and decreased plaque levels and coincided with increased expression of Aβ degrading enzymes. Interestingly, plaque-associated microglia in APP/PS1*CB2-/- mice showed a less activated morphology, while plaques were smaller and more condensed than in APP/PS1 mice.

Taken together, these results indicate a beneficial effect of CB2-deficiency in APP transgenic mice. CB2 appears to be part of a protective system that may be detrimental when engaged continuously.”

https://www.ncbi.nlm.nih.gov/pubmed/29865078

https://content.iospress.com/articles/journal-of-alzheimers-disease/jad180230