Opposite effects of cannabinoid CB1 and CB2 receptors on antipsychotic clozapine-induced cardiotoxicity.

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“Clozapine is an atypical antipsychotic drug that is very efficacious in treating psychosis but the risk of severe cardiotoxicity limits its clinical use.

The present study investigated the myocardial injury effects of clozapine and assessed the involvement of cannabinoid receptors in clozapine cardiotoxicity.

Our data provided evidence that cannabinoid CB1 and CB2 receptors had opposite effects and selective antagonists of CB1R or agonists of CB2R might confer protective effects against clozapine.”

https://www.ncbi.nlm.nih.gov/pubmed/30707759

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14591

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Activation of the cannabinoid CB2 receptor increases renal perfusion.

Physiological Genomics 0 0 cover image

“Acute kidney injury (AKI) is an increasing problem clinically and is associated with chronic kidney disease progression.

Cannabinoid type 2 receptor activation has been shown to mitigate some of the deleterious tubular effects due to AKI, but its role on the renal vasculature has not been fully described.

In this study, we investigated the effects of our novel cannabinoid CB2 receptor agonist, SMM-295, on renal vasculature by assessing cortical perfusion using laser Doppler flowmetry and changes in luminal diameter using isolated afferent arterioles.

These data provide new insight into the potential benefit of SMM-295 by activating vascular and non-vascular CB2 receptors to promote renal vasodilation, and provide a new therapeutic target to treat renal injuries that impact renal blood flow dynamics.”

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Cannabinoids and Bone Regeneration.

 Publication Cover“Bone is a complex tissue of the with unique properties such as high strength and regeneration capabilities while carrying out multiple functions. Bone regeneration occurs both in physiological situations (bone turnover) and pathological situations (e.g. fractures), being performed by osteoblasts and osteoclasts. If this process is inadequate, fracture nonunion or aseptic loosening of implants occurs and requires a complex treatment.

Exogenous factors are currently used to increase bone regeneration process when needed, such as bisphosphonates and vitamin D, but limitations do exist. Cannabinoid system has been shown to have positive effects on bone metabolism. Cannabinoids at bone level mainly act on two receptors called CB-1 and CB-2, but GPR55, GPR119, TPRV1, TPRV4 receptors may also be involved. The CB-2 receptors are found in bone cells at higher levels compared to other receptors.

Endocannabinods represented by anandamide and 2-arachidonoylglycerol, can stimulate osteoblast formation, bone formation and osteoclast activity. CB-2 agonists including HU-308, HU-433, JWH133 and JWH015 can stimulate osteoblast proliferation and activity, while CB-2 antagonists such as AM630 and SR144528 can inhibit osteoclast differentiation and function. CB-1 antagonist AM251 has been shown to inhibit osteoclast differentiation and activity, while GPR55 antagonist cannabidiol increases osteoblast activity and decreases osteoclast function.

An optimal correlation of dose, duration, moment of action and affinity can lead to an increased bone regeneration capacity, with important benefits in many pathological situations which involve bone tissue. As adverse reactions of cannabinoids haven’t been described in patients under controlled medication, cannabinoids can represent future treatment for bone regeneration.”

https://www.ncbi.nlm.nih.gov/pubmed/30702341

https://www.tandfonline.com/doi/abs/10.1080/03602532.2019.1574303?journalCode=idmr20

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Diet-Induced Obesity in Cannabinoid-2 Receptor Knockout Mice and Cannabinoid Receptor 1/2 Double-Knockout Mice.

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“Evidence suggests that cannabinoid-1 receptor (CB1R) activation is associated with increased food intake and body weight gain. Human epidemiological studies, however, show decreased prevalence of obesity in cannabis users.

Given the overlapping and complementary functions of the cannabinoid receptors (CB1R and CB2R), mice lacking CB2R and mice lacking both CB1R and CB2R were studied.

These results indicate that lacking both CB1R and CB2R protected mice from diet-induced obesity, possibly through the prominent role of CB1R in obesity or through an interactive effect of both receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/30699233

https://onlinelibrary.wiley.com/doi/abs/10.1002/oby.22403

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[Endogenous Cannabinoid System of the Brain as the Target for Influences at Neurodegenerate Diseases]

“The review represents the analysis of works about role of endogenous cannabinoid (EC) system in the neuro- degenerate diseases (ND), in which the cellular death and disturbances of neuronal functions of the hippo- campus, neocortex and striatum are observed. Here, the diseases.ofAlzheimer, of Parkinson, of Hangtington, and the temporal lobe epilepsy are considered. In recent years the fundamental role of EC system in regu- lation of neuroexcitability, energy metabolism, inflammatory and many other processes has been opened in ND pathogenesis. It points to possibility of development of therapeutic approaches which use the prepara- tions for activation of EC system. In the review various mechanisms of cellular survival and their reparations provided to EC system during action of pathological factors are stated.”

https://www.ncbi.nlm.nih.gov/pubmed/30695519

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Targeting CB1 and GPR55 Endocannabinoid Receptors as a Potential Neuroprotective Approach for Parkinson’s Disease.

 “Cannabinoid CB1 receptors (CB1R) and the GPR55 receptor are expressed in striatum and are potential targets in the therapy of Parkinson’s disease (PD), one of the most prevalent neurodegenerative diseases in developed countries.

The aim of this paper was to address the potential of ligands acting on those receptors to prevent the action of a neurotoxic agent, MPP+, that specifically affects neurons of the substantia nigra due to uptake via the dopamine DAT transporter.

These results show that neurons expressing heteromers are more resistant to cell death but question the real usefulness of CB1R, GPR55, and their heteromers as targets to afford PD-related neuroprotection.”

https://www.ncbi.nlm.nih.gov/pubmed/30687889

https://link.springer.com/article/10.1007%2Fs12035-019-1495-4

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Cannabinoid type-1 receptor blockade restores neurological phenotypes in two models for Down syndrome.

Neurobiology of Disease

“Intellectual disability is the most limiting hallmark of Down syndrome, for which there is no gold-standard clinical treatment yet. The endocannabinoid system is a widespread neuromodulatory system involved in multiple functions including learning and memory processes. Our results identify CB1R as a novel druggable target potentially relevant for the improvement of cognitive deficits associated with Down syndrome.”

https://www.ncbi.nlm.nih.gov/pubmed/30685352

https://www.sciencedirect.com/science/article/pii/S0969996118306855?via%3Dihub

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Cannabinoids (Marijuana) A Stem Cell Stimulator!!

Institute of Regenerative Medicine®“Some time ago a wrote a blog about the use of certain components of the marijuana plant. It was a fairly short blog which I will include here. More and more states are proposing the legalization of marijuana. There are numerous health claims about hemp oil which is a derivative of Cannabis. There may be merit to these claims possibly by the action of the Cannabis on stem cells. Below is the blog and I will expand more on it:

“We use to think that marijuana was bad for one’s health. Now we are not so sure about it. We need to clarify things a bit.
Cannabinoids, the active components of cannabis (Cannabis sativa) extracts, have attracted the attention of human civilizations for centuries for a variety of uses. The use of Cannabis or Marijuana (scientific name is Cannabis sativa) came before we were able to discover the active portion or substrate. This substrate is called endocannabinoid system. The endocannabbinoid system has a number of components. The system consists of lipids, the receptors for the lipids and certain metabolic enzymes. The Cannabinoid signaling regulates cell proliferation, differentiation and it reduces cell aptosis or death. These receptors are found in the very early stages of life. The results of the Cannabinoid receptors depend upon molecular targets and cellular context involved. There are two main receptors which are called CB1 and CB2 receptors. These receptors seem to be involved in neural degeneration. They seem to be involved in all three germ layer formations. . CB1 and CB2 show opposite patterns of expression, the former increasing and the latter decreasing along neuronal differentiation. It is thought that the CB2 receptors may be most important. Recently, endocannabinoid (eCB) signaling has also been shown to regulate proliferation and differentiation of hematopoietic and mesenchymal stem cells, with a key role in determining the formation of several cell types in peripheral tissues, including blood cells, adipocytes, osteoblasts/osteoclasts and epithelial cells. The developmental regulation of cannabinoid receptor expression and cellular/sub-cellular localization, together with their role in progenitor/stem cell biology, may have important implications in human health and disease. Bone marrow and stem cells make endocannabinoids, these endocannabinoids interact with the cannabinoid receptors (Cannabinoid receptors have been found in nearly every cell in the human body). If cannabinoids can enhance stem cell migration and proliferation, this could be a powerful therapy. For instance, if you can increase the numbers and movement of stem cells to an injured tissue, you could vastly enhance the healing process. Lastly, the synthetic cannabinoid HU-210 is about 100-1000x times more potent than THC from Cannabis and this synthetic agent has been found to be neurogenic. Meaning that HU-210 can cause new neurons (brain cells) in the brain to form. However this study was done in rats…and humans are different from rats. Will I prescribe medical marijuana for my stem cell patients? At present I do not think I have enough information to make an intelligent decision about this. I suspect if some day I do prescribe this it will be some derivative of Cannabis. There are certainly some intriguing aspects of Cannabis but I feel the jury is still out. I suspect we will certainly hear more about this. Thanks Dr. P”

That was the blog I wrote some time ago. At this juncture I am getting closer to utilizing some component of Cannabis. I have further looked at the literature and there seems to be some very good science on the effect of Cannabis on stem cell workings. One of the intriguing aspects of the CB2 receptor is that it is found mostly in the immune system. At the University of South Carolina, a team discovered that THC could reduce the inflammation associated with autoimmune diseases by suppressing the activity of certain genes involved in the immune response. Its presence there interests scientists because the immune system triggers inflammation, and studies show marijuana can have an anti-inflammatory effect. When we start talking about the immune system we have a host of implications. We are aware that many diseases of aging may have some basis as an auto-immune disease. One of these that interests me is Osteoporosis. There may be both receptors at work. CB-2 works on the immune system while CB-1 is induced during osteogenic differentiation. As I have written in another blog, Very Small Embryonic Like Stem Cells may have a profound effect on the course of Osteoporosis. The next question is can we prime these cells additionally with Cannabis and take things to the next level. More to come I am sure. Dr. P.”

https://stemcellorthopedic.com/cannabinoids-marijuana-stem-cell-stimulator/?fbclid=IwAR1DDMIk0X8rJiWFPkNXWouQfdPNfG5iHEklW6oSxFqP5ELLt4lz3IM_O-k

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CB2R agonist prevents nicotine induced lung fibrosis.

 Publication Cover“Nicotine stimulates fibroblast proliferation while increasing inflammation and fibrosis of tissues.

The cannabinoid receptor 1 (CB1R) is mainly located in the CNS, while cannabinoid receptor 2 (CB2R) is located in the immune cells within the body. CB2R regulates inflammatory processes and fibroblast function.

Nicotine induces interstitial lung fibrosis that is enhanced by the CB2R antagonist and diminished by the CB2R agonist. Therefore, the CB2R agonist may offer a protection against fibrosis.”

https://www.ncbi.nlm.nih.gov/pubmed/30675824

https://www.tandfonline.com/doi/abs/10.1080/01902148.2018.1543368?journalCode=ielu20

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Some Prospective Alternatives for Treating Pain: The Endocannabinoid System and Its Putative Receptors GPR18 and GPR55.

Image result for frontiers in pharmacology“Marijuana extracts (cannabinoids) have been used for several millennia for pain treatment.

Regarding the site of action, cannabinoids are highly promiscuous molecules, but only two cannabinoid receptors (CB1 and CB2) have been deeply studied and classified.

Thus, therapeutic actions, side effects and pharmacological targets for cannabinoids have been explained based on the pharmacology of cannabinoid CB1/CB2 receptors. However, the accumulation of confusing and sometimes contradictory results suggests the existence of other cannabinoid receptors.

Different orphan proteins (e.g., GPR18, GPR55, GPR119, etc.) have been proposed as putative cannabinoid receptors.

According to their expression, GPR18 and GPR55 could be involved in sensory transmission and pain integration.

This work summarized novel data supporting that, besides cannabinoid CB1 and CB2receptors, GPR18 and GPR55 may be useful for pain treatment.

Conclusion: There is evidence to support an antinociceptive role for GPR18 and GPR55.”

https://www.ncbi.nlm.nih.gov/pubmed/30670965

https://www.frontiersin.org/articles/10.3389/fphar.2018.01496/full

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