Systematic review of the potential role of cannabinoids as antiproliferative agents for urological cancers.

“The palliative effects of cannabis sativa (marijuana), which include appetite stimulation, attenuation of nausea and emesis, and pain relief, are well known.

The active components of cannabis sativa (cannabinoids) and their derivatives have received growing interest due to their diverse pharmacological activities, such as cell growth inhibition and tumour regression.

The aim of this review is to look at the current evidence on the antiproliferative effects of cannabinoids in urological malignancies, including renal, prostate, bladder, and testicular cancers.

The search yielded a total of 93 studies from Medline and PubMed, of which 23 studies were included in the final analysis. To date, there are various in vitro studies elucidating the potential mechanism of action of cannabinoids for urological cancers, along with population-based studies specifically for testicular malignancies. To date, no clinical trials have been conducted for urological cancer patients.

These results demonstrate that the role of endocannabinoids for urological malignancies is an area of active research. Further research is required not only to evaluate the crosstalk between cancer signaling pathways and cannabinoids, but also large randomized clinical studies with urological patients need to be conducted before cannabinoids can be introduced as potential therapeutic options for urological neoplasms.”

https://www.ncbi.nlm.nih.gov/pubmed/28515817

http://www.cuaj.ca/index.php/journal/article/view/4371

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Neuroprotection in oxidative stress-related neurodegenerative diseases: role of endocannabinoid system modulation.

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“Redox imbalance may lead to overproduction of reactive oxygen and nitrogen species (ROS/RNS) and subsequent oxidative tissue damage which is a critical event in the course of neurodegenerative diseases. It is still not fully elucidated, however, whether oxidative stress is the primary trigger or a consequence in process of neurodegeneration.

Recent Advances: Increasing evidence suggests that oxidative stress is involved in the propagation of neuronal injury and consequent inflammatory response, which in concert promote development of pathological alterations characteristic of most common neurodegenerative diseases.

Critical Issue: Accumulating recent evidence also suggests that there is an important interplay between the lipid endocannabinoid system (ECS; comprising of the main cannabinoid 1 and 2 receptors (CB1 and CB2), endocannabinoids and their synthetic and metabolizing enzymes) and various key inflammatory and redox-dependent processes.

FUTURE DIRECTIONS:

Targeting the ECS in order to modulate redox state-dependent cell death, and to decrease consequent or preceding inflammatory response holds therapeutic potential in multitude of oxidative stress-related acute or chronic neurodegenerative disorders from stroke and traumatic brain injury to Alzheimer`s and Parkinson`s diseases, and multiple sclerosis, just to name a few, which will be discussed in this overview.”

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A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice

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“The balance between detrimental, pro-aging, often stochastic processes and counteracting homeostatic mechanisms largely determines the progression of aging. There is substantial evidence suggesting that the endocannabinoid system (ECS) is part of the latter system because it modulates the physiological processes underlying aging.

The activity of the ECS declines during aging, as CB1 receptor expression and coupling to G proteins are reduced in the brain tissues of older animals and the levels of the major endocannabinoid 2-arachidonoylglycerol (2-AG) are lower. However, a direct link between endocannabinoid tone and aging symptoms has not been demonstrated.

Here we show that a low dose of Δ9-tetrahydrocannabinol (THC) reversed the age-related decline in cognitive performance of mice aged 12 and 18 months. This behavioral effect was accompanied by enhanced expression of synaptic marker proteins and increased hippocampal spine density.

THC treatment restored hippocampal gene transcription patterns such that the expression profiles of THC-treated mice aged 12 months closely resembled those of THC-free animals aged 2 months. The transcriptional effects of THC were critically dependent on glutamatergic CB1 receptors and histone acetylation, as their inhibition blocked the beneficial effects of THC.

Thus, restoration of CB1 signaling in old individuals could be an effective strategy to treat age-related cognitive impairments.”

https://www.nature.com/nm/journal/vaop/ncurrent/full/nm.4311.html

“CAN MARIJUANA RESTORE MEMORY? NEW STUDY SHOWS CANNABIS CAN REVERSE COGNITIVE DECLINE IN MICE” http://www.newsweek.com/cannabis-marijuana-restores-memory-learning-cognitive-decline-596160

“A little cannabis every day might keep brain ageing at bay” https://www.newscientist.com/article/2130257-a-little-cannabis-every-day-might-keep-brain-ageing-at-bay/

“Low-dose cannabinoid THC restores memory and learning in old mice”  http://www.medicalnewstoday.com/articles/317342.php

“Daily Dose Of Cannabis May Protect And Heal The Brain From Effects Of Aging”  https://www.forbes.com/sites/janetwburns/2017/05/08/daily-dose-of-cannabis-may-protect-and-heal-the-brain-from-effects-of-aging/#70ef658f2e44

“Cannabis reverses aging processes in the brain”  https://medicalxpress.com/news/2017-05-cannabis-reverses-aging-brain.html

“Future dementia cure – Chemical in cannabis could REVERSE the ageing process” http://www.express.co.uk/life-style/health/801827/dementia-cure-cannabis-THC-chemical-memory

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Endocannabinoid system acts as a regulator of immune homeostasis in the gut

PNAS, Proceedings of the National Academy of Sciences

“Exogenous cannabinoids such as marijuana exert their influence through cannabinoid receptors. Endogenous cannabinoids such as anandamide (AEA) function through the same receptors, and their physiological roles are a subject of intense study. Here, we show that AEA plays a pivotal role in maintaining immunological health in the gut. The immune system in the gut actively tolerates the foreign antigens present in the gut through mechanisms that are only partially understood. We show that AEA contributes to this critical process by promoting the presence of CX3CR1hi macrophages, which are immunosuppressive. These results uncover a major conversation between the immune and nervous systems. In addition, with the increasing prevalence of ingestion of exogenous marijuana, our study has significant implications for public health.”  http://www.pnas.org/content/early/2017/04/18/1612177114.full

“Our study unveils a role for the endocannabinoid system in maintaining immune homeostasis in the gut/pancreas and reveals a conversation between the nervous and immune systems using distinct receptors.”  https://www.ncbi.nlm.nih.gov/pubmed/28439004

“Active ingredients in both hot peppers and cannabis calm the gut’s immune system” https://medicalxpress.com/news/2017-04-ingredients-hot-peppers-cannabis-calm.html

 

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CB1 cannabinoid receptor drives oocyte maturation and embryo development via PI3K/Akt and MAPK pathways.

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“Endocannabinoids have been recognized as mediators of practically all reproductive events in mammals. However, little is known about the role of this system in oocyte maturation.

In a mouse model, we observed that activation of the cannabinoid receptor (CB)1during in vitro oocyte maturation modulated the phosphorylation status of Akt and ERK1/2 and enhanced the subsequent embryo production. In the absence of the CB1 receptor, in vivo oocyte maturation was impaired and embryo development delayed. The CB2receptor was unable to rescue these effects. Finally, we confirmed abnormal oocyte maturation rather than impaired embryonic transport through the oviduct in CB1 knockouts.

Our data suggest that cannabinoid agonists may be useful in vitro maturation supplements. For in vitro fertilization patients intolerant to gonadotropins, this could be a promising and only option.”

https://www.ncbi.nlm.nih.gov/pubmed/28428264

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Cannabinoids as Modulators of Cell Death: Clinical Applications and Future Directions.

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“Endocannabinoids are bioactive lipids that modulate various physiological processes through G-protein-coupled receptors (CB1 and CB2) and other putative targets. By sharing the activation of the same receptors, some phytocannabinoids and a multitude of synthetic cannabinoids mimic the effects of endocannabinoids.

In recent years, a growing interest has been dedicated to the study of cannabinoids properties for their analgesic, antioxidant, anti-inflammatory and neuroprotective effects. In addition to these well-recognized effects, various studies suggest that cannabinoids may affect cell survival, cell proliferation or cell death. These observations indicate that cannabinoids may play an important role in the regulation of cellular homeostasis and, thus, may contribute to tissue remodelling and cancer treatment.

For a long time, the study of cannabinoid receptor signalling has been focused on the classical adenylyl cyclase/cyclic AMP/protein kinase A (PKA) pathway. However, this pathway does not totally explain the wide array of biological responses to cannabinoids. In addition, the diversity of receptors and signalling pathways that endocannabinoids modulate offers an interesting opportunity for the development of specific molecules to disturb selectively the endogenous system.

Moreover, emerging evidences suggest that cannabinoids ability to limit cell proliferation and to induce tumour-selective cell death may offer a novel strategy in cancer treatment.

This review describes the main properties of cannabinoids in cell death and attempts to clarify the different pathways triggered by these compounds that may help to understand the complexity of respective molecular mechanisms and explore the potential clinical benefit of cannabinoids use in cancer therapies.”

https://www.ncbi.nlm.nih.gov/pubmed/28425013

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Anandamide and 2-AG Are Endogenously Present within the Laterodorsal Tegmental Nucleus: Functional Implications for a role of eCBs in arousal.

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“Previously, we presented electrophysiological evidence for presence in mice brain slices of functional cannabinoid type I receptors (CB1Rs) within the laterodorsal tegmentum (LDT), a brain stem nucleus critical in control of arousal and rapid eye movement (REM) sleep. Further, using pharmacological agents, we provided data suggestive of the endogenous presence of cannabinoids (CBs) acting at LDT CB1Rs. However, in those studies, we were unable to identify the type(s) of CB ligands endogenously present in the LDT, and this information has not been provided elsewhere. Accordingly, we used the highly-sensitive liquid chromatography/mass spectrometry (LC-MS) method to determine whether N-arachidonoylethanolamide (Anandamide or AEA) and 2-arachidonyl glycerol (2-AG), which are both endogenous CB ligands acting at CB1Rs, are present in the LDT. Mice brain tissue samples of the LDT were assayed using ion trap LC-MS in selected ion monitoring mode. Chromatographic analysis and product-ion MS scans identified presence of the CBs, AEA and 2-AG, from LDT mouse tissue. Data using the LC-MS method show that AEA and 2-AG are endogenously present within the LDT and when coupled with our electrophysiological findings, lead to the suggestion that AEA and 2-AG act at electropharmacologically-demonstrated CB1Rs in this nucleus. Accordingly, AEA and 2-AG likely play a role in processes governed by the LDT, including control of states of cortical gamma band activity seen in alert, aroused states, as well as cortical and motor activity characteristic of REM sleep.”

https://www.ncbi.nlm.nih.gov/pubmed/28404451

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Enhancement of Anandamide-Mediated Endocannabinoid Signaling Corrects Autism-Related Social Impairment

Mary Ann Liebert, Inc. publishers

We recently uncovered a signaling mechanism by which the endocannabinoid anandamide mediates the action of oxytocin, a neuropeptide that is crucial for social behavior, to control social reward. Oxytocin signaling has been implicated in autism spectrum disorder (ASD), and social reward is a key aspect of social functioning that is thought to be disrupted in ASD. Therefore, as a proof of principle for the core component of ASD—social impairment—we tested an endocannabinoid-enhancing compound on two widely studied mouse models of ASD, the BTBR and fmr1−/− (model of Fragile X Syndrome).

Remarkably, we found that FAAH blockade completely reversed the social impairment in both mouse models. CB1 receptor blockade prevented the prosocial action of FAAH inhibition in BTBR mice.

The results suggest that increasing anandamide activity at CB1 receptors improves ASD-related social impairment and identify FAAH as a novel therapeutic target for ASD.

In conclusion, the present study provides new insights into the role of endocannabinoid signaling in social behavior and validates FAAH as a novel therapeutic target for the social impairment of ASD.”
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Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome

“Fragile X syndrome, the most commonly known genetic cause of autism, is due to loss of the fragile X mental retardation protein, which regulates signal transduction at metabotropic glutamate receptor-5 in the brain.

The results identify the endocannabinoid signalosome as a molecular substrate for fragile X syndrome, which might be targeted by therapy.”  http://www.nature.com/articles/ncomms2045

“Cannabis-like chemical combats chief genetic cause of autism” http://www.belfasttelegraph.co.uk/news/health/cannabislike-chemical-combats-chief-genetic-cause-of-autism-28867862.html#ixzz2DRLsbjJO

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Monoglyceride lipase deficiency affects hepatic cholesterol metabolism and lipid-dependent gut transit in ApoE-/- mice.

 Image result for Oncotarget“Monoglyceride lipase (MGL) hydrolyzes monoglycerides (MGs) to glycerol and fatty acids. Among various MG species MGL also degrades 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid and potent activator of cannabinoid receptors (CBR) 1 and 2. MGL-knockout (-/-) mice exhibit pronounced 2-AG accumulation, but lack central cannabimimetic effects due to CB1R desensitization. We have previously shown that MGL affects plaque stability in apolipoprotein E (ApoE)-/- mice, an established animal model for dyslipidemia and atherosclerosis. In the current study, we investigated functional consequences of MGL deficiency on lipid and energy metabolism in ApoE/MGL double knockout (DKO) mice. MGL deficiency affected hepatic cholesterol metabolism by causing increased cholesterol elimination via the biliary pathway. Moreover, DKO mice exhibit lipid-triggered delay in gastric emptying without major effects on overall triglyceride and cholesterol absorption. The observed phenotype of DKO mice is likely not a consequence of potentiated CB1R signaling but rather dependent on the activation of alternative signaling pathways. We conclude that MGL deficiency causes complex metabolic changes including cholesterol metabolism and regulation of gut transit independent of the endocannabinoid system.”

https://www.ncbi.nlm.nih.gov/pubmed/28380440

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