The role of cannabinoid signaling in acute and chronic kidney diseases.

 Image result for Kidney Int. “The endogenous cannabinoids anandamide and 2-arachidonoylglycerol bind to the cannabinoid receptors of type 1 and 2. These receptors are also the binding sites for exogenous, both natural and synthetic, cannabinoids that are used for recreation purposes.

Until recently, cannabinoids and cannabinoid receptors have attracted little interest among nephrologists; however, a full endocannabinoid system (ECS) is present in the kidney and it has recently emerged as an important player in the pathogenesis of diabetic nephropathy, drug nephrotoxicity, and progressive chronic kidney disease.

This newly established role of the ECS in the kidney might have therapeutic relevance, as pharmacological modulation of the ECS has renoprotective effects in experimental animals, raising hope for future potential applications in humans.

In addition, over the last years, there has been a number of reported cases of acute kidney injury (AKI) associated with the use of synthetic cannabinoids that appear to have higher potency and rate of toxicity than natural Cannabis. This poorly recognized cause of renal injury should be considered in the differential diagnosis of AKI, particularly in young people.

In this review we provide an overview of preclinical evidence indicating a role of the ECS in renal disease and discuss potential future therapeutic applications.”

https://www.ncbi.nlm.nih.gov/pubmed/29706358

[The impact of cannabinoids on the endocrine system].

 

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“Cannabinoids are naturally occurring compounds, derivatives of Indian hemp, in which tetrahydrocannabinol (THC) is the most important. Marijuana, hashish and hash oil are among those most commonly used in the group.

Cannabinoids (marjhuana and hashish) have been used throughout recorded history as effective drugs in treating various diseases and conditions such as: malaria, hypertension, constipation, bronchial asthma, rheumatic pains, and as natural pain relief in labour and joint pains.

Marijuana acts through cannabinoid receptors CB 1 and CB2. Both receptors inhibit cAMP accummulation (through Gi/o proteins) and stimulate mitrogen- activated protein kinase. CB1 rceptors are located in CNS and in adipose tissue, digestive tract, muscles, heart, lungs, liver, kidneys, gonads, prostate gland and other peripheral tissues. CB2 cannabinoid receptors are located in the peripheral nervous system (at the ends of peripheral nerves), and on the surfaces of the cells of the immunological system.

The discovery of endogenous cannabinoids has contributed to a better understanding of their role in the regulation of the intake of food, energetic homeostasis and their significant influence on the endocrine system.”

Cannabidiol inhibits endocannabinoid signaling in autaptic hippocampal neurons.

Molecular Pharmacology

“Δ9-THC and cannabidiol (CBD) are two main cannabinoid constituents of marijuana and hashish. The pharmacology of Δ9-THC has been extensively studied, while our understanding of the pharmacology of CBD has remained limited, despite excitement in CBD’s potential role in treating certain pediatric epilepsies and its reputation for attenuating some Δ9-THC-induced effects.

It was established early on that CBD binds poorly to the orthosteric site of CB1 or CB2 cannabinoid receptors and its actions were commonly attributed to other non-cannabinoid receptor mechanisms. However, recent evidence suggests that CBD does indeed act at cannabinoid CB1 receptors as a negative allosteric modulator (NAM) of CB1 signaling. By altering the orthosteric signaling of a GPCR, allosteric modulators greatly increase the richness of GPCR pharmacology.

We have recently surveyed candidate CB1 NAMs in autaptic hippocampal neurons, a well-characterized neuronal model of endogenous cannabinoid signaling, and have now tested CBD in this model. We find that while CBD has no direct effect on excitatory transmission it does inhibit two forms of endogenous cannabinoid-mediated retrograde synaptic plasticity: depolarization-induced suppression of excitation (DSE) and metabotropic suppression of excitation (MSE), while not affecting signaling via GABA-B receptors.

These results are consistent with the recently described NAM activity of CBD and suggest interesting possible mechanisms for CBD’s therapeutic actions.”

The use of cannabis in supportive care and treatment of brain tumor

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“Anticancer Effects of Cannabinoids may be able to Prolong Life.

Cannabinoids are multitarget substances. Currently available are dronabinol (synthetic delta-9-tetrahydrocannabinol, THC), synthetic cannabidiol (CBD) the respective substances isolated and purified from cannabis, a refined extract, nabiximols (THC:CBD = 1.08:1.00); and nabilone, which is also synthetic and has properties that are very similar to those of THC.

Cannabinoids have a role in the treatment of cancer as palliative interventions against nausea, vomiting, pain, anxiety, and sleep disturbances. THC and nabilone are also used for anorexia and weight loss, whereas CBD has no orexigenic effect. The psychotropic effects of THC and nabilone, although often undesirable, can improve mood when administered in low doses. CBD has no psychotropic effects; it is anxiolytic and antidepressive.

Of particular interest are glioma studies in animals where relatively high doses of CBD and THC demonstrated significant regression of tumor volumes (approximately 50% to 95% and even complete eradication in rare cases). Concomitant treatment with X-rays or temozolomide enhanced activity further. Similarly, a combination of THC with CBD showed synergistic effects. Although many questions, such as on optimized treatment schedules, are still unresolved, today’s scientific results suggest that cannabinoids could play an important role in palliative care of brain tumor patients.

THC, a partial CB1, CB2 agonist, has the stigma of psychotropic effects that are mediated by CB1 stimulation. However, CB1 stimulation is necessary for improving mood and appetite and many other effects. At present, it is hard to imagine a better approach than adjusting THC doses individually to balance wanted versus unwanted effects. Generally, higher doses are needed to achieve analgesic and antiemetic effects. Even much higher, supraphysiologic oral doses would be needed to combat tumors.

Combinations were synergistic under many circumstances such as in pain and antitumor studies. Cannabinoids differ in their antitumor activities and probably in their mechanisms and targets, which is a rationale for combinations. However, for many pharmacological effects (except against tumors) roughly 10-times higher daily doses are needed for CBD compared to THC.

In summary, the endocannabinoid system is likely playing a crucial role in palliative care. The future will show whether an optimized treatment strategy with cannabinoids can also prolong life of brain tumor patients by their virtue to combat cancer cells.”

https://academic.oup.com/nop/article/4/3/151/2918616

“Cannabinoid Drug Prolongs the Life of Brain Tumor Patients in Phase II Trials”  https://labiotech.eu/gw-pharmaceuticals-brain-tumor/

Therapeutic cannabinoids in multiple sclerosis: immunomodulation revisited.

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Cannabinoids are compounds with pleiotropic properties that act on the cannabinoid receptors, CB1 and CB2, and are divided into endocannabinoids, the endogenous ligands of these receptors, synthetic cannabinoids and phytocannabinoids.

The latter are derived from the plant Cannabis sativa. The therapeutic and psychoactive properties of this plant have been observed and used for centuries.

Of the over 60 compounds that are unique to Cannabis sativa, the substances that have been attributed the greatest therapeutic potential are Δ9 – tetrahydrocannabinol (THC) and cannabidiol (CBD), both of which, used alone or combined with each other, have become approved drugs.”

https://www.ncbi.nlm.nih.gov/pubmed/29633480

https://onlinelibrary.wiley.com/doi/abs/10.1111/ene.13658

Cannabinoids in health and disease: pharmacological potential in metabolic syndrome and neuroinflammation.

 

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“The use of different natural and/or synthetic preparations of Cannabis sativa is associated with therapeutic strategies for many diseases. Indeed, thanks to the widespread diffusion of the cannabinoidergic system in the brain and in the peripheral districts, its stimulation, or inhibition, regulates many pathophysiological phenomena.

In particular, central activation of the cannabinoidergic system modulates the limbic and mesolimbic response which leads to food craving.

Moreover, cannabinoid agonists are able to reduce inflammatory response.

In this review a brief history of cannabinoids and the protagonists of the endocannabinoidergic system, i.e. synthesis and degradation enzymes and main receptors, will be described. Furthermore, the pharmacological effects of cannabinoids will be outlined. An overview of the involvement of the endocannabinoidergic system in neuroinflammatory and metabolic pathologies will be made.

Finally, particular attention will also be given to the new pharmacological entities acting on the two main receptors, cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2), with particular focus on the neuroinflammatory and metabolic mechanisms involved.”

Cannabidiol Reverses Deficits in Hippocampal LTP in a Model of Alzheimer’s Disease.

Neurochemical Research

“Here we demonstrate for the first time that cannabidiol (CBD) acts to protect synaptic plasticity in an in vitro model of Alzheimer’s disease (AD).

The non-psycho active component of Cannabis sativa, CBD has previously been shown to protect against the neurotoxic effects of beta amyloid peptide (Aβ) in cell culture and cognitive behavioural models of neurodegeneration. Hippocampal long-term potentiation (LTP) is an activity dependent increase in synaptic efficacy often used to study cellular mechanisms related to memory.

Here we show that acute application of soluble oligomeric beta amyloid peptide (Aβ1-42) associated with AD, attenuates LTP in the CA1 region of hippocampal slices from C57Bl/6 mice. Application of CBD alone did not alter LTP, however pre-treatment of slices with CBD rescued the Aβ1-42 mediated deficit in LTP.

We found that the neuroprotective effects of CBD were not reversed by WAY100635, ZM241385 or AM251, demonstrating a lack of involvement of 5HT1A, adenosine (A2A) or Cannabinoid type 1 (CB1) receptors respectively. However in the presence of the PPARγ antagonist GW9662 the neuroprotective effect of CBD was prevented.

Our data suggests that this major component of Cannabis sativa, which lacks psychoactivity may have therapeutic potential for the treatment of AD”

https://www.ncbi.nlm.nih.gov/pubmed/29574668

https://link.springer.com/article/10.1007%2Fs11064-018-2513-z

Glial expression of cannabinoid CB(2) receptors and fatty acid amide hydrolase are beta amyloid-linked events in Down’s syndrome.

Neuroscience

“Recent data suggest that the endocannabinoid system (ECS) may be involved in the glial response in different types of brain injury. Both acute and chronic insults seem to trigger a shift in the pattern of expression of some elements of this system from neuronal to glial. Specifically, data obtained in human brain tissue sections from Alzheimer’s disease patients showed that the expression of cannabinoid receptors of the CB(2) type is induced in activated microglial cells while fatty acid amide hydrolase (FAAH) expression is increased in reactive astrocytes. The present study was designed to determine the time-course of the shift from neuronal to glial induction in the expression of these proteins in Down‘s syndrome, sometimes referred to as a human model of Alzheimer-like beta-amyloid (Abeta) deposition. Here we present immunohistochemical evidence that both CB(2) receptors and FAAH enzyme are induced in Abeta plaque-associated microglia and astroglia, respectively, in Down‘s syndrome. These results suggest that the induction of these elements of the ECS contributes to, or is a result of, amyloid deposition and subsequent plaque formation. In addition, they confirm a striking differential pattern of distribution of FAAH and CB(2) receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/18068305

https://www.sciencedirect.com/science/article/abs/pii/S0306452207012924

Anti-invasion Effects of Cannabinoids Agonist and Antagonist on Human Breast Cancer Stem Cells.

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“Studies show that cancer cell invasion or metastasis is the primary cause of death in malignancies including breast cancer.

The existence of cancer stem cells (CSCs) in breast cancer may account for tumor initiation, progression, and metastasis.

Recent studies have reported different effects of cannabinoids on cancer cells via CB1 and CB2 cannabinoid receptors.

In the present study, the effects of ACEA (a selective CB1 receptor agonist) and AM251 (a selective CB1 antagonist) on CSCs and their parental cells were investigated.

It was observed that ACEA decreased CD44+/CD24-/low/ESA+ cancer stem cell invasiveness.

Since one of the main cancer recurrence factors is anti-cancer drugs fail to inhibit CSC population, this observation would be useful for cancer treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/29552056

“Our results indicate that cannabinoids may interfere with invasive cancer stem cells in benefit of cancer eradication. In summary, our results clarified that cannabinoid receptor agonist possesses anti-invasion potential in both main population and breast cancer stem cells. Considering that most anti-cancer drugs do not eradicate stem cells and only target main population cells, the results disclosed here can be used for prevention of cancer recurrence.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843309/

Cannabinoid Receptors, Mental Pain and Suicidal Behavior: a Systematic Review.

Current Psychiatry Reports

“The current serotonin-based biological model of suicidal behavior (SB) may be too simplistic. There is emerging evidence that other biomarkers and biological systems may be involved in SB pathophysiology. The literature on the endocannabinoid (EC) systems and SB is limited. The objective of the present article is to review all available information on the relationship between cannabinoid receptors (CB1 and CB2 receptors), and SB and/or psychological pain.

RECENT FINDINGS:

Our review is limited by the small number and heterogeneity of studies identified: (1) an autopsy study describing elevated levels of CB1 receptor activity in the prefrontal cortex and suicide in both depression and alcoholism and (2) studies supporting the involvement of both CB1 and CB2 receptors in the regulation of neuropathic pain and stress-induced analgesia. We conclude that cannabinoid receptors, particularly CB1 receptors, may become promising targets for the development of novel therapeutic tools for the treatment of SB.”

https://www.ncbi.nlm.nih.gov/pubmed/29546501

https://link.springer.com/article/10.1007%2Fs11920-018-0880-4