Cannabinoid 2 Receptors and Rheumatoid Arthritis

“A major raisond’etre for CB2 receptors (CB2R) are as immunomodulators (whereas CB1R has more of neuromodulatory reputation). Part of its life as an immune modulator regulating inflammation, an important and unfortunate component of many disease processes. CB2 activation decreases expression of pro-inflammatory cytokines, which in turn decreases bone destruction in joints affected by rheumatoid arthritis. In short, more and more evidence points to working with CB2 receptors as a means to decrease the destructive effects of inflammation.”

- Dr. David Hepburn

Abstract:

Cannabinoid receptor 2 (CB2) has been implicated as an important clinical regulator of inflammation and malignant osteolysis.

Here, its observed that CB2 expression was markedly higher in collagen-induced arthritis (CIA) mice synovium and bone tissues than in the non-inflamed synovium and bone tissues. The CB2 selective agonist (JWH133) but not an antagonist (SR144528) suppressed CIA in mice without toxic effects, as demonstrated by the decreased synovial hyperplasia, inflammatory responses, cartilage damage, and periarticular and systemic bone destruction.

Read full article here:

https://www.ncbi.nlm.nih.gov/pubmed/30508319

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Dr. David Hepburn website: https://doctordavidhepburn.com

The CB2 receptor plays a significant role in heart function in people with pulmonary hypertension

"The role the endocannabinoid system (ECS) plays in cardiovascular pathology continues to point to a path for possible therapeutic targets. This study shows how the ECS works to prevent death of cardiac cells in pulmonary hypertension, which, if it sounds like a good thing....it is."  -Dr. Dave Hepburn

Article Recommended by Dr. David Hepburn:

CB2-deficiency is associated with a stronger hypertrophy and remodeling of the right ventricle in a murine model of left pulmonary artery occlusion.

Abstract

AIMS:

Pulmonary hypertension (PH) leads to right ventricular (RV) adaptation and remodeling and has deleterious long-term effects on RV function. The endocannabinoid receptor CB2 has been associated with protective effects in adaptation and remodeling of the left ventricle after ischemia. Therefore, we investigated the role of CB2 receptor in RV adaptation after occlusion of the left pulmonary artery (LPA) in a murine model.

MAIN METHODS:

C57/Bl6 (WT)- and CB2 receptor-deficient (Cnr2-/-)-mice underwent paramedian sternotomy and LPA was occluded using a metal clip. Right heart hemodynamic study (Millar®) preceded organ harvesting for immunohistochemistry and mRNA analysis 7 and 21 days (d) post-occlusion.

KEY FINDINGS:

LPA occlusion led to higher RV systolic pressure in Cnr2-/--hearts, while hemodynamics were comparable with WT-hearts after 21d. Cnr2-/--hearts showed higher macrophage infiltration and lower interleukin-10 expression after 7 d, but otherwise a comparable inflammatory mediator expression profile. 

Cardiomyocyte-hypertrophy was stronger in Cnr2-/--mice, presenting with higher tenascin-C expression than WT-hearts. Planimetry revealed higher collagen area in Cnr2-/--hearts and small areas of cardiomyocyte-loss. Surrounding cardiomyocytes were cleaved caspase-3- and TUNEL positive in Cnr2-/--hearts. This was associated by maladaptation of myosin heavy-chain isoforms and lower reactive oxygen scavenger enzymes induction in Cnr2-/--hearts. We found comparable morphological changes in both lungs between the two genotypes.

SIGNIFICANCE:

LPA occlusion led to increased systolic pressure and adaptation of RV in CB2-deficient mice. CB2 receptor seems to modulate RV adaptation through expression of contractile elements, reactive oxygen scavenger enzymes, and inflammatory response in order to prevent cardiomyocyte apoptosis.

To read the full article please visit:

https://www.ncbi.nlm.nih.gov/pubmed/30403990 

Dr. Dave Hepburn website:https://doctordavidhepburn.com

Cannabinoid Receptor Protects Against Hearing Loss Caused by Chemotherapy - Dr. David Hepburn

Article recommend by Dr. David Hepburn:

The Endocannabinoid/Cannabinoid Receptor 2 System Protects Against Cisplatin-Induced Hearing Loss

Abstract

Previous studies have demonstrated the presence of cannabinoid 2 receptor (CB2R) in the rat cochlea which was induced by cisplatin. In an organ of Corti-derived cell culture model, it was also shown that an agonist of the CB2R protected these cells against cisplatin-induced apoptosis. In the current study, we determined the distribution of CB2R in the mouse and rat cochleae and examined whether these receptors provide protection against cisplatin-induced hearing loss. In a knock-in mouse model expressing the CB2R tagged with green fluorescent protein, we show distribution of CB2R in the organ of Corti, stria vascularis, spiral ligament and spiral ganglion cells. A similar distribution of CB2R was observed in the rat cochlea using a polyclonal antibody against CB2R. Trans-tympanic administration of (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone (JWH015), a selective agonist of the CB2R, protected against cisplatin-induced hearing loss which was reversed by blockade of this receptor with 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone (AM630), an antagonist of CB2R. JWH015 also reduced the loss of outer hair cells (OHCs) in the organ of Corti, loss of inner hair cell (IHC) ribbon synapses and loss of Na+/K+-ATPase immunoreactivity in the stria vascularis. Administration of AM630 alone produced significant hearing loss (measured by auditory brainstem responses) which was not associated with loss of OHCs, but led to reductions in the levels of IHC ribbon synapses and strial Na+/K+-ATPase immunoreactivity. Furthermore, knock-down of CB2R by trans-tympanic administration of siRNA sensitized the cochlea to cisplatin-induced hearing loss at the low and middle frequencies. Hearing loss induced by cisplatin and AM630 in the rat was associated with increased expression of genes for oxidative stress and inflammatory proteins in the rat cochlea. In vitro studies indicate that JWH015 did not alter cisplatin-induced killing of cancer cells suggesting this agent could be safely used during cisplatin chemotherapy. These data unmask a protective role of the cochlear endocannabinoid/CB2R system which appears tonically active under normal conditions to preserve normal hearing. However, an exogenous agonist is needed to boost the activity of endocannabinoid/CB2R system for protection against a more traumatic cochlear insult, as observed with cisplatin administration.

“One of the several possible nasty side effects of a common anticancer medication, is hearing loss. Activation of CB2R appears to prevent this, indicating an important role of the ECS (endocannabinoid system) in neuroprotection."

Dr. David Hepburn

To read the full article please visit:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110918/

Dr. David Hepburn website:
doctordavidhepburn.com