Microglia activation states and cannabinoid system: Therapeutic implications.

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“Microglial cells are recognized as the brain’s intrinsic immune cells, mediating actions that range from the protection against harmful conditions that modify CNS homeostasis, to the control of proliferation and differentiation of neurons and their synaptic pruning. To perform these functions, microglia adopts different activation states, the so-called phenotypes that depending on the local environment involve them in neuroinflammation, tissue repair and even the resolution of the inflammatory process.

There is accumulating evidence indicating that cannabinoids (CBs) might serve as a promising tool to modify the outcome of inflammation, especially by influencing microglial activity.

Microglia has a functional endocannabinoid (eCB) signaling system, composed of cannabinoid receptors and the complete machinery for the synthesis and degradation of eCBs.

The expression of cannabinoid receptors – mainly CB2 – and the production of eCBs have been related to the activation profile of these cells and therefore, the microglial phenotype, emerging as one of the mechanisms by which microglia becomes alternatively activated.

Here, we will discuss recent studies that provide new insights into the role of CBs and their endogenous counterparts in defining the profile of microglia activation.

These actions make CBs a promising therapeutic tool to avoid the detrimental effects of inflammation and possibly paving the way to target microglia in order to generate a reparative milieu in neurodegenerative diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/27373505

The bright side of psychoactive substances: cannabinoid-based drugs in motor diseases.

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“Psychoactive substances are associated with the idea of drugs with high addictive liability, affecting mental states, cognition, emotion and motor behavior. However these substances can modify synaptic transmission and help to disclose some mechanisms underlying alterations in brain processing and pathophysiology of motor disease. Hence, the “bright side” of cannabinoid-based drugs must be thoroughly examined to be identified within the latter framework.

We will analyze the preclinical and clinical evidence of cannabinoid-based drugs, discussing their therapeutic value in basal ganglia motor disorders such as Parkinson’s disease and Huntington disease.

Expert commentary: despite the knowledge acquired in the last years, the therapeutic potential of cannabinoid-based drugs should be further tested by novel routes of investigation. This should be focused on the role of cannabinoid signaling system in mitochondrial function as well as on the physical and functional interaction with other key receptorial targets belonging to this network.”

http://www.ncbi.nlm.nih.gov/pubmed/27373318

Researcher explores effects of cannabinoids on blood pressure

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Andrei Derbenev, associate professor of physiology, Tulane School of Medicine

“Hypertension — or high blood pressure — is a long-term, high-risk condition for millions of people worldwide.

At the moment, synthetic beta-blockers are one of the most common drugs prescribed to treat hypertension.

But what if a natural drug, marijuana, which has been known for 5,000 years, could be used in the treatment of high blood pressure?

Andrei Derbenev, associate professor of physiology in the Tulane University School of Medicine, recently received a four-year, $1.5 million research grant from the National Institutes of Health to study how cannabinoids — the compounds of cannabis (another name for marijuana) — affect a brain stem area involved in blood pressure control.

His research may have important clinical applications for the treatment of hypertension.

He is identifying the cells in the sympathetic nervous system linked to the kidneys, a key organ in hypertension. (The sympathetic nervous system is the part of the autonomic nervous system that stimulates the body’s “fight or flight” response. Overactivity of the sympathetic nervous system is a cause of high blood pressure.)

He and his research team are studying the effect of exogenous cannabinoids — from the marijuana plant — and endogenous cannabinoids —those naturally produced within the body.

Cannabis “has lots of different chemicals inside. Some of them are painkillers. Some of them, we don’t know what they are doing.”

People ask Derbenev all the time: Is marijuana good? Is it bad? But the debate, he says, should be, instead, “Which works? Which does not work?”

About a decade ago, Derbenev led a study about the effect of cannabinoids on the parasympathetic nervous system, the part of the autonomic nervous system that stimulates the body to “rest and digest.” In that investigation, his team showed the mechanism by which cannabis can reduce digestive spasms and thus decrease vomiting. It’s a finding of great interest to cancer patients experiencing nausea while undergoing chemotherapy.”

https://news.tulane.edu/news/researcher-explores-effects-cannabinoids-blood-pressure

Medical Marijuana for Epilepsy?

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“Treatment-refractory epilepsy remains an important clinical problem. There is considerable recent interest by the public and physicians in using medical marijuana or its derivatives to treat seizures. The endocannabinoid system has a role in neuronal balance and ictal control. There is clinical evidence of success in diminishing seizure frequencies with cannabis derivatives, but also documentation about exacerbating epilepsy or of no discernible effect. There are lay indications and anecdotal reports of success in attenuating the severity of epilepsy, but without solid investigational corroboration. Marijuana remains largely illegal, and may induce adverse consequences. Clinical applications are not approved, thus are restricted and only recommended in selected treatment unresponsive cases, with appropriate monitoring.”

http://www.ncbi.nlm.nih.gov/pubmed/27354925

Delta-9-tetrahydrocannabinol protects against MPP+ toxicity in SH-SY5Y cells by restoring proteins involved in mitochondrial biogenesis.

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“Proliferator-activated receptor γ (PPARγ) activation can result in transcription of proteins involved in oxidative stress defence and mitochondrial biogenesis which could rescue mitochondrial dysfunction in Parkinson’s disease (PD). The PPARγ agonist pioglitazone is protective in models of PD; however side effects have limited its clinical use.

The cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) may have PPARγ dependent anti-oxidant properties. Here we investigate the effects of Δ9-THC and pioglitazone on mitochondrial biogenesis and oxidative stress.

We found that only Δ9-THC was able to restore mitochondrial content in MPP+ treated SH-SY5Y cells in a PPARγ dependent manner by increasing expression of the PPARγ co-activator 1α (PGC-1α), the mitochondrial transcription factor (TFAM) as well as mitochondrial DNA content.

… unlike pioglitazone, Δ9-THC resulted in a PPARγ dependent reduction of MPP+ induced oxidative stress.

We therefore suggest that, in contrast to pioglitazone, Δ9-THC mediates neuroprotection via PPARγ-dependent restoration of mitochondrial content which may be beneficial for PD treatment.”

http://www.ncbi.nlm.nih.gov/pubmed/27366949

http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=10314&path[]=32486

Cannabinoid receptors in the kidney.

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“The endocannabinoid system modulates cell signaling targets that are essential for energy homeostasis. Endocannabinoids bind to G protein-coupled receptors in the central nervous system and periphery, including the kidney. Modulation of cannabinoid receptor 1 (CB1) and CB2 activity in the kidney in diabetes and obesity has been identified as potential therapeutic target to reduce albuminuria and renal fibrosis.

CB1 and CB2 have been reported to play key roles in renal function and dysfunction. Recent studies have determined that antagonism of CB1 and agonism of CB2 in diabetic nephropathy and obesity associated kidney disease can reduce albuminuria, potentially by acting on both the glomeruli and tubules. Emerging studies have also identified a role for CB1 in renal diseases associated with fibrosis, with CB1 upregulated in multiple models of human nephropathies.

Emerging studies using isolated cells, rodent models, and human studies have identified a critical role for the endocannabinoid system in renal function and disease. Thus, therapeutics that modulate the activity of CB1 and CB2 in renal disease could become clinically relevant.”

http://www.ncbi.nlm.nih.gov/pubmed/27367912

 

Endocannabionoid System in Neurological Disorders.

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“Several studies support the evidence that the endocannabinoid system and cannabimimetic drugs might have therapeutic potential in numerous pathologies. These pathologies range from neurological disorders, atherosclerosis, stroke, cancer to obesity/metabolic syndrome and others.

In this paper we review the endocannabinoid system signaling and its alteration in neurodegenerative disorders like multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease and discuss the main findings about the use of cannabinoids in the therapy of these pathologies.

Despite different etiologies, neurodegenerative disorders exhibit similar mechanisms like neuro-inflammation, excitotoxicity, deregulation of intercellular communication, mitochondrial dysfunction and disruption of brain tissue homeostasis.

Current treatments ameliorate the symptoms but are not curative.

Interfering with the endocannabinoid signaling might be a valid therapeutic option in neuro-degeneration.

To this aim, pharmacological intervention to modulate the endocannabinoid system and the use of natural and synthetic cannabimimetic drugs have been assessed. CB1 and CB2 receptor signaling contributes to the control of Ca2+ homeostasis, trophic support, mitochondrial activity, and inflammatory conditions.

Several studies and patents suggest that the endocannabinoid system has neuro-protective properties and might be a target in neurodegenerative diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/27364363

Marijuana fights Alzheimer’s disease, Salk Institute scientists discover

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Cannabinoids remove plaque-forming Alzheimer's proteins from brain cells

“Salk Institute scientists have discovered that a main compound found in marijuana can fight a toxic protein associated with Alzheimer’s disease. According to the scientists, at this time, there are no drugs that significantly inhibit cell death associated with Alzheimer’s disease (AD), Parkinson’s or Huntington’s diseases. However, the most recent data about Alzheimer’s and marijuana suggests that there is a therapeutic potential of cannabinoids (the chemical compounds secreted by cannabis flowers) for the treatment of AD. Cannabinoids are able to remove plaque-forming Alzheimer’s proteins from brain cells, reports the Medical Express on June 29.”  http://www.examiner.com/article/marijuana-fights-alzheimer-s-disease-salk-institute-scientists-discover

“Cannabinoids remove plaque-forming Alzheimer’s proteins from brain cells”  http://medicalxpress.com/news/2016-06-cannabinoids-plaque-forming-alzheimer-proteins-brain.html

“Cannabinoids remove toxic proteins associated with Alzheimer’s disease from the brain” http://www.irishexaminer.com/examviral/science-world/cannabinoids-remove-toxic-proteins-associated-with-alzheimers-disease-from-the-brain-407788.html

“Marijuana Compound Helps Remove Alzheimer’s Disease Protein From Brain” -brain.” http://www.scienceworldreport.com/articles/42990/20160630/marijuana-compound-helps-remove-alzheimers-disease-protein-from-brain.htm

“Marijuana compound removes toxic Alzheimer’s protein from the brain”  http://www.sciencealert.com/marijuana-compound-removes-toxic-alzheimer-s-protein-from-the-brain

“Cannabinoids remove plaque-forming Alzheimer’s proteins from brain cells”  https://www.sciencedaily.com/releases/2016/06/160629095609.htm

“Cannabinoids Remove Plaque-forming Alzheimer’s Proteins from Brain Cells”  https://www.laboratoryequipment.com/news/2016/06/cannabinoids-remove-plaque-forming-alzheimers-proteins-brain-cells

“MARIJUANA COMPOUND REMOVES ALZHEIMER’S PLAQUE FROM BRAIN CELLS, STUDY FINDS” http://www.popsci.com/marijuana-compound-removes-alzheimers-plaque-from-brain-cells-study

“Cannabinoids remove plaque-forming Alzheimer’s proteins from brain cells. Preliminary lab studies at the Salk Institute find THC reduces beta amyloid proteins in human neurons.” http://www.salk.edu/news-release/cannabinoids-remove-plaque-forming-alzheimers-proteins-from-brain-cells/

 

Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids

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“The beta amyloid (Aβ) and other aggregating proteins in the brain increase with age and are frequently found within neurons. The mechanistic relationship between intracellular amyloid, aging and neurodegeneration is not, however, well understood.

We use a proteotoxicity model based upon the inducible expression of Aβ in a human central nervous system nerve cell line to characterize a distinct form of nerve cell death caused by intracellular Aβ.

It is shown that intracellular Aβ initiates a toxic inflammatory response leading to the cell’s demise. Aβ induces the expression of multiple proinflammatory genes and an increase in both arachidonic acid and eicosanoids, including prostaglandins that are neuroprotective and leukotrienes that potentiate death.

Cannabinoids such as tetrahydrocannabinol stimulate the removal of intraneuronal Aβ, block the inflammatory response, and are protective.

Altogether these data show that there is a complex and likely autocatalytic inflammatory response within nerve cells caused by the accumulation of intracellular Aβ, and that this early form of proteotoxicity can be blocked by the activation of cannabinoid receptors.”

http://www.nature.com/articles/npjamd201612

“Cannabinoids remove plaque-forming Alzheimer’s proteins from brain cells. Preliminary lab studies at the Salk Institute find THC reduces beta amyloid proteins in human neurons.” http://www.salk.edu/news-release/cannabinoids-remove-plaque-forming-alzheimers-proteins-from-brain-cells/

Expression of the endocannabinoid receptors in human fascial tissue.

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“Cannabinoid receptors have been localized in the central and peripheral nervous system as well as on cells of the immune system, but recent studies on animal tissue gave evidence for the presence of cannabinoid receptors in different types of tissues.

Their presence was supposed also in myofascial tissue, suggesting that the endocannabinoid system may help resolve myofascial trigger points and relieve symptoms of fibromyalgia.

However, until now the expression of CB1 (cannabinoid receptor 1) and CB2 (cannabinoid receptor 2) in fasciae has not yet been established.

Small samples of fascia were collected from volunteers patients during orthopedic surgery. For each sample were done a cell isolation, immunohistochemical investigation (CB1 and CB2 antibodies) and real time RT-PCR to detect the expression of CB1 and CB2.

Both cannabinoid receptors are expressed in human fascia and in human fascial fibroblasts culture cells, although to a lesser extent than the control gene. We can assume that the expression of mRNA and protein of CB1 and CB2 receptors in fascial tissue are concentrated into the fibroblasts.

This is the first demonstration that the fibroblasts of the muscular fasciae express CB1 and CB2. The presence of these receptors could help to provide a description of cannabinoid receptors distribution and to better explain the role of fasciae as pain generator and the efficacy of some fascial treatments.

Indeed the endocannabinoid receptors of fascial fibroblasts can contribute to modulate the fascial fibrosis and inflammation.”

http://www.ncbi.nlm.nih.gov/pubmed/27349320