Category Archives: Endocannabinoid System

Cannabinoid receptors in microglia of the central nervous system: immune functional relevance.

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“Microglia, resident macrophages of the brain, function as immune effector and accessory cells. Paradoxically, they not only play a role in host defense and tissue repair but also have been implicated in a variety of neuropathological processes.

Microglia, in addition to exhibiting phenotypic markers for macrophages, express CB1 and CB2 cannabinoid receptors. Recent studies suggest the existence of a third, yet-to-be cloned, non-CB1, non-CB2 cannabinoid receptor.

These receptors appear to be functionally relevant within defined windows of microglial activation state and have been implicated as linked to cannabinoid modulation of chemokine and cytokine expression.

The recognition that microglia express cannabinoid receptors and that their activation results in modulation of select cellular activities suggests that they may be amenable to therapeutic manipulation for ablating untoward inflammatory responses in the central nervous system.”  http://www.ncbi.nlm.nih.gov/pubmed/16204639

http://www.jleukbio.org/content/78/6/1192.long

 

Role of CB1 and CB2 receptors in the inhibitory effects of cannabinoids on lipopolysaccharide-induced nitric oxide release in astrocyte cultures.

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“The purpose of this study was to investigate the role of the central cannabinoid receptor (CB(1)) in mediating the actions of the endogenous cannabinoid agonist anandamide and the synthetic cannabinoid CP-55940.

Activation of primary mouse astrocyte cultures by exposure to bacterial lipopolysaccharide (LPS) caused a marked (approximately tenfold) increase in nitric oxide (NO) release.

Coincubation with the cannabinoid agonists anandamide or CP-55940 markedly inhibited release of NO (-12% to -55%).

We also showed that endogenous or synthetic cannabinoids inhibit LPS-induced inducible NO synthase expression (mRNA and protein) in astrocyte cultures.

These results indicate that CB1 receptors may promote antiinflammatory responses in astrocytes.”

http://www.ncbi.nlm.nih.gov/pubmed/11891798

Cannabinoid-mediated inhibition of inducible nitric oxide production by rat microglial cells: evidence for CB1 receptor participation.

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“Activated brain microglial cells release inflammatory mediators such as nitric oxide (NO) that may play important roles in central nervous system antibacterial, antiviral, and antitumor activities. However, excessive release of these factors has been postulated to elicit immune-mediated neurodegenerative inflammatory processes and to cause brain injury.

Recent studies using the rat animal model indicate that select cannabinoids may modulate production of these inflammatory factors.

Collectively, these results indicate that the cannabinoid analog CP55940 selectively inhibits inducible NO production by microglial cells and that this inhibition is effected, at least in part, through the CB1 receptor.”

http://www.ncbi.nlm.nih.gov/pubmed/11727767

The central cannabinoid receptor (CB1) mediates inhibition of nitric oxide production by rat microglial cells.

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Journal of Pharmacology and Experimental Therapeutics

“Upon activation, brain microglial cells release proinflammatory mediators, such as nitric oxide (NO), which may play an important role in the central nervous system antibacterial, antiviral, and antitumor activities. However, excessive release of NO has been postulated to elicit immune-mediated neurodegenerative inflammatory processes and to cause brain injury.

In the present study, the effect of cannabinoids on the release of NO from endotoxin/cytokine-activated rat cortical microglial cells was evaluated.

Collectively, these results indicate a functional linkage between the CB1 receptor and cannabinoid-mediated inhibition of NO production by rat microglial cells.”

http://www.ncbi.nlm.nih.gov/pubmed/10027878

“In summary, this study reports on CB1 receptor expression in a primary immune cell type in the context of functional relevance. That is, the data support a linkage between the CB1 receptor as expressed in brain microglial cells and the inhibition of NO.
These results expand on our current knowledge concerning the role of cannabinoid receptors in the modulation of immune cell function as, to date, the CB2 receptor has been the only cannabinoid receptor subtype implicated in cannabinoid-mediated immune modulation.
These data suggest also that select cannabinoid agonists have the potential to ablate the elicitation of proinflammatory mediators especially under conditions of chronic neuropathological disease.”
http://jpet.aspetjournals.org/content/288/3/1357.long

Cannabinoids ablate release of TNFalpha in rat microglial cells stimulated with lypopolysaccharide.

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“Upon activation, brain microglial cells release proinflammatory mediators, such as TNFalpha, which may play an important role in eliciting neuroinflammatory processes causing brain damage.

As cannabinoids have been reported to exert anti-inflammatory and neuroprotective actions in the brain, we here examined the effect of both synthetic and endogenous cannabinoids on TNFalpha release elicited by bacterial endotoxin lypopolysaccharide (LPS) in cultured microglia.

In summary, our data indicate that both synthetic and endogenous cannabinoids inhibit LPS-induced release of TNFalpha from microglial cells.

By showing that such effect does not appear to be mediated by either CB receptor type 1 or 2, we provide evidence suggestive of the existence of yet unidentified cannabinoid receptor(s) in brain microglia.”

http://www.ncbi.nlm.nih.gov/pubmed/12509806

Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis

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“Liver fibrosis, a consequence of chronic liver injury and a way station to cirrhosis and hepatocellular carcinoma, lacks effective treatment.

Endocannabinoids acting via cannabinoid-1 receptors (CB1R) induce profibrotic gene expression and promote pathologies that predispose to liver fibrosis. CB1R antagonists produce opposite effects, but their therapeutic development was halted due to neuropsychiatric side effects.

Inducible nitric oxide synthase (iNOS) also promotes liver fibrosis and its underlying pathologies, but iNOS inhibitors tested to date showed limited therapeutic efficacy in inflammatory diseases.

Here, we introduce a peripherally restricted, orally bioavailable CB1R antagonist, which accumulates in liver to release an iNOS inhibitory leaving group.

Additionally, it was able to slow fibrosis progression and to attenuate established fibrosis. Thus, dual-target peripheral CB1R/iNOS antagonists have therapeutic potential in liver fibrosis.

Regarding the pharmacodynamics of the hybrid CB1R/iNOS inhibitor, two important principles have emerged from efforts to develop effective antifibrotic therapies. First, antifibrotic treatment strategies could aim to control the primary disease, to inhibit fibrogenic gene expression and signaling, to promote molecular mechanisms involved in fibrosis regression, or a combination of these. Second, with multiple molecular mechanisms and signaling pathways involved in fibrosis, targeting more than one could increase antifibrotic efficacy, and the hybrid CB1R/iNOS inhibitor embodies optimal characteristics on both accounts.

As to the first principle, both the endocannabinoid/CB1R system and iNOS are ideal targets, as they are known to be involved directly in the fibrotic process and also in the conditions predisposing to liver fibrosis, as detailed in the Introduction. An emerging major predisposing factor to liver fibrosis is nonalcoholic fatty liver disease, and CB1R blockade has proven effective in mitigating obesity-related hepatic steatosis in both rodent models and humans. The other two major predisposing factors, alcoholic fatty liver disease and viral hepatitis, also involve increased CB1R activity. Hepatic CB1R expression is induced either by chronic ethanol intake or the hepatitis C virus, and CB1R blockade mitigates alcohol-induced steatosis and inhibits hepatitis C virus production.

The dual targeting of peripheral CB1R and iNOS demonstrated here exemplifies the therapeutic gain obtained by simultaneously hitting more than one molecule, which could then engage distinct as well as convergent cellular pathways. The advantage of such an approach is highlighted by emerging experience with recently developed antifibrotic medications, which indicates that targeting a single pathway has limited effect on fibrotic diseases.

Thus, the approach illustrated by the present study has promise as an effective antifibrotic strategy.”

http://insight.jci.org/articles/view/87336

Cannabinoids, inflammation, and fibrosis.

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“Cannabinoids apparently act on inflammation through mechanisms different from those of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs).

As a class, the cannabinoids are generally free from the adverse effects associated with NSAIDs. Their clinical development thus provides a new approach to treatment of diseases characterized by acute and chronic inflammation and fibrosis.

A concise survey of the anti-inflammatory actions of the phytocannabinoids Δ9-tetrahydrocannabinol (THC), cannabidiol, cannabichromene, and cannabinol is presented.

Mention is also made of the noncannabinoid plant components and pyrolysis products, followed by a discussion of 3 synthetic preparations-Cesamet (nabilone; Meda Pharmaceuticals, Somerset, NJ, USA), Marinol (THC; AbbVie, Inc., North Chicago, IL, USA), and Sativex (Cannabis extract; GW Pharmaceuticals, Cambridge United Kingdom)-that have anti-inflammatory effects. A fourth synthetic cannabinoid, ajulemic acid (CT-3, AJA; Resunab; Corbus Pharmaceuticals, Norwood, MA, USA), is discussed in greater detail because it represents the most recent advance in this area and is currently undergoing 3 phase 2 clinical trials by Corbus Pharmaceuticals.

The endogenous cannabinoids, including the closely related lipoamino acids, are then discussed. The review concludes with a presentation of a possible mechanism for the anti-inflammatory and antifibrotic actions of these substances.

Thus, several cannabinoids may be considered candidates for development as anti-inflammatory and antifibrotic agents. Of special interest is their possible use for treatment of chronic inflammation, a major unmet medical need.”

http://www.ncbi.nlm.nih.gov/pubmed/27435265

Expression of the Endocannabinoid Receptor 1 in Human Stroke: An Autoptic Study.

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“Stroke is one of the leading causes of disability and death in the world.

The endocannabinoid (eCB) system is upregulated in several neurological diseases including stroke. A previous animal study demonstrated an increased expression of the endocannabinoid receptor 1 (CB1R) in the penumbra area surrounding the ischemic core, suggesting a crucial role in inflammation/reperfusion after stroke. Regarding the localization of CB1/CB2 receptors, animal studies showed that cortical neurons, activated microglia, and astroglia are involved. Our aim was to evaluate the cerebral expression of CB1R in the ischemic brain areas of 9 patients who died due to acute cerebral infarction in the middle cerebral artery territory.

METHODS:

The cerebral autoptic tissue was collected within 48 hours since death. Ischemic and contralateral normal-appearing areas were identified. After tissue preprocessing, 4-µm-thick cerebral sections were incubated with the primary CB1R antibodies (Cayman Chemical Company, Ann Arbor, MI). Thereafter, all cerebral sections were hematoxylin treated. In each section, the total cell number and CB1R-positive cells were counted and the CB1R-positive cell count ratio was calculated. For statistical analysis, Student’s t-test was used.

RESULTS:

In normal tissue, CB1R-positive neurons were the majority; a few non-neuronal cells expressed CB1R. In the ischemic areas, a few neurons were detectable. A significant increase in total CB1R staining was found in the ischemic regions compared to contralateral areas.

CONCLUSIONS:

We found an increase in CB1R expression in the ischemic region (neuronal and non-neuronal cell staining), suggesting the inflammatory reaction to the ischemic insult. Whether such response might mediate neuroprotective actions or excitotoxicity-related detrimental effects is still unclear.”

http://www.ncbi.nlm.nih.gov/pubmed/27425766

Endocannabinoid system as a regulator of tumor cell malignancy – biological pathways and clinical significance

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“The endocannabinoid system (ECS) comprises cannabinoid receptors (CBs), endogenous cannabinoids, and enzymes responsible for their synthesis, transport, and degradation of (endo)cannabinoids.

To date, two CBs, CB1 and CB2, have been characterized; however, orphan G-protein-coupled receptor GPR55 has been suggested to be the third putative CB.

Several different types of cancer present abnormal expression of CBs, as well as other components of ECS, and this has been shown to correlate with the clinical outcome.

Although most effects of (endo)cannabinoids are mediated through stimulation of classical CBs, they also interact with several molecules, either prosurvival or proapoptotic molecules.

It should be noted that the mode of action of exogenous cannabinoids differs significantly from that of endocannabinoid and results from the studies on their activity both in vivo and in vitro could not be easily compared.

This review highlights the main signaling pathways involved in the antitumor activity of cannabinoids and the influence of their activation on cancer cell biology.

We also discuss changes in the expression pattern of the ECS in various cancer types that have an impact on disease progression and patient survival.

A growing amount of experimental data imply possible exploitation of cannabinoids in cancer therapy.”

https://www.dovepress.com/endocannabinoid-system-as-a-regulator-of-tumor-cell-malignancy-ndash-b-peer-reviewed-article-OTT

Cannabinoid activation of PPARα; a novel neuroprotective mechanism

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“The cannabinoids are a structurally diverse family of compounds with a large number of different biological targets.

Although CB1 receptor activation evokes neuroprotection in response to cannabinoids, some cannabinoids have been reported to be peroxisome proliferator activated receptor (PPAR) ligands, offering an alternative protective mechanism.

We have, therefore, investigated the ability of a range of cannabinoids to activate PPARα and for N-oleoylethanolamine (OEA), an endogenous cannabinoid-like compound (ECL), to evoke neuroprotection.

These data demonstrate the potential for a range of cannabinoid compounds, of diverse structures, to activate PPARα and suggest that at least some of the neuroprotective properties of these agents could be mediated by nuclear receptor activation.

In summary, the data presented here provide strong evidence that selected cannabinoids are PPARα agonists, and suggest a novel means by which the multiple effects of cannabinoids, in both the CNS and periphery, could be brought about.

In addition to its well-recognized role in lipid metabolism, PPARα activation showed obvious beneficial effects in ischaemic brain damage, which is likely to be connected with its anti-inflammatory action through the NF–κB pathway.

These discoveries not only broaden the potential use of cannabinoids as therapeutic agents, but also support PPARα as a new target for neuroprotective treatment.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2190030/