Tag Archives: CB2

Activation of Cortical Type 2 Cannabinoid Receptors Ameliorates Ischemic Brain Injury, Study Suggests

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“A new study published in the March issue of The American Journal of Pathology suggests that cortical type 2 cannabinoid (CB2) receptors might serve as potential therapeutic targets for cerebral ischemia.

Researchers found that the cannabinoid trans-caryophyllene (TC) protected brain cells from the effects of ischemia in both in vivo and in vitro animal models. In rats, post-ischemic treatment with TC decreased cerebral infarct size and edema. In cell cultures composed of rat cortical neurons and glia exposed to oxygen-glucose deprivation and reoxygenation (OGD/R), TC decreased neuronal injury and mitochondrial depolarization, specifically through type 2 cannabinoid receptor (CB2R) pathways.

“To our knowledge, novel data presented in this study provide evidence for the first time supporting a previously unappreciated role of cortical CB2R, especially neuronal CB2Rs, in ischemia,” says lead investigator Won-Ki Kim, PhD, of the Department of Neuroscience, College of Medicine, Korea University in Seoul. “This study suggests that further investigation is warranted to establish the clinical usefulness of TC as a preventative and therapeutic agent for treatment of stroke.””

More: http://www.sciencedaily.com/releases/2013/02/130221141140.htm

Marijuana Derivative May Offer Hope in Cocaine Addiction – TIME

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“A new study in mice has found that activating a receptor affected by marijuana can dramatically reduce cocaine consumption. The research suggests that new anti-addiction drugs might be developed using synthetic versions of cannabidiol (CBD), the marijuana component that activates the receptor—or even by using the purified natural compound itself.

Researchers formerly believed that the receptor, known as CB2, was not found in the brain and that therefore CBD had no psychoactive effects. But a growing body of research suggests otherwise. After THC, CBD is the second most prevalent active compound in marijuana.”

More: http://healthland.time.com/2011/07/26/marijuana-derivative-may-offer-hope-in-cocaine-addiction/

[From cannabis to selective CB2R agonists: molecules with numerous therapeutical virtues].

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“Originally used in Asia for the treatment of pain, spasms, nausea and insomnia, marijuana is the most consumed psychotropic drug worldwide. The interest of medical cannabis has been reconsidered recently, leading to many scientific researches and commercialization of these drugs.

Natural and synthetic cannabinoids display beneficial antiemetic, anti-inflammatory and analgesic effects in numerous diseases, however accompanied with undesirable effects due to the CB1 receptor. Present researches focus on the design of therapeutical molecules targeting the CB2 receptors, and thus avoiding central side effects and therefore psychotropic effects caused by the CB1 receptor.”

http://www.ncbi.nlm.nih.gov/pubmed/23732102

Synthetic and Patented Cannabinoids

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“Historically, laboratory synthesis of cannabinoids were often based on the structure of herbal cannabinoids, and a large number of analogs have been produced and tested, especially in a group led by Roger Adams as early as 1941 and later in a group led by Raphael Mechoulam.

Newer compounds are no longer related to natural cannabinoids or are based on the structure of the endogenous cannabinoids.

Synthetic cannabinoids are particularly useful in experiments to determine the relationship between the structure and activity of cannabinoid compounds, by making systematic, incremental modifications of cannabinoid molecules.

Medications containing natural or synthetic cannabinoids or cannabinoid analogs:

  • Dronabinol (Marinol), is Δ9-tetrahydrocannabinol (THC), used as an appetite stimulant, anti-emetic, and analgesic
  • Nabilone (Cesamet), a synthetic cannabinoid and an analog of Marinol. It is Schedule II unlike Marinol, which is Schedule III
  • Sativex, a cannabinoid extract oral spray containing THC, CBD, and other cannabinoids used for neuropathic pain and spasticity in Canada and Spain. Sativex develops whole-plant cannabinoid medicines
  • Rimonabant (SR141716), a selective cannabinoid (CB1) receptor antagonist used as an anti-obesity drug under the proprietary name Acomplia. It is also used for smoking cessation

Other notable synthetic cannabinoids include:

  • CP-55940, produced in 1974, this synthetic cannabinoid receptor agonist is many times more potent than THC
  • Dimethylheptylpyran
  • HU-210, about 100 times as potent as THC
  • HU-331 a potential anti-cancer drug derived from cannabidiol that specifically inhibits topoisomerase II.
  • SR144528, a CB2 receptor antagonists
  • WIN 55, a potent cannabinoid receptor agonist
  • JWH-133, a potent selective CB2 receptor agonist
  • Levonantradol (Nantrodolum), an anti-emetic and analgesic but not currently in use in medicine”

http://www.news-medical.net/health/Synthetic-and-Patented-Cannabinoids.aspx

Cannabinoid Receptors

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“Before the 1980s, it was often speculated that cannabinoids produced their physiological and behavioral effects via nonspecific interaction with cell membranes, instead of interacting with specific membrane-bound receptors.

The discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate.

These receptors are common in animals, and have been found in mammals, birds, fish, and reptiles.

At present, there are two known types of cannabinoid receptors, termed CB1 and CB2, with mounting evidence of more.

Cannabinoid receptor type 1

CB1 receptors are found primarily in the brain, to be specific in the basal ganglia and in the limbic system, including the hippocampus.

They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are absent in the medulla oblongata, the part of the brain stem responsible for respiratory and cardiovascular functions. Thus, there is not a risk of respiratory or cardiovascular failure as there is with many other drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.

Cannabinoid receptor type 2

CB2 receptors are almost exclusively found in the immune system, with the greatest density in the spleen.

While found only in the peripheral nervous system, a report does indicate that CB2 is expressed by a subpopulation of microglia in the human cerebellum.

CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.”

http://www.news-medical.net/health/Cannabinoid-Receptors.aspx

Dysregulation of Cannabinoid CB1 Receptor and Associated Signaling Networks in Brains of Cocaine Addicts and Cocaine-Treated Rodents.

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The endocannabinoid system is implicated in the neurobiology of cocaine addiction. This study evaluated the status of cannabinoid CB1 and CB2 receptors, the endocytic cycle of CB1 receptors, receptor regulatory kinases (GRK), and associated signaling (mTOR and p70S6K) in brain cortex of drug abusers and cocaine- and cannabinoid-treated rodents…

 In long-term cocaine addicts, mTOR and p70S6K activations were not altered when compared with controls, indicating that CB1 receptor signaling was dampened. The dysregulation of CB1 receptor, GRK2/3/5, and mTOR/p70S6K signaling by cocaine may contribute to alterations of neuroplasticity and/or neurotoxicity in brains of cocaine addicts.”

More: http://www.ncbi.nlm.nih.gov/pubmed/23727505

Anti-inflammatory cannabinoids in diet: Towards a better understanding of CB(2) receptor action?

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“The endocannabinoid system is an ancient lipid signaling network which in mammals modulates neuronal functions, inflammatory processes, and is involved in the aetiology of certain human lifestyle diseases, such as Crohn’s disease, atherosclerosis and osteoarthritis.

The system is able to downregulate stress-related signals that lead to chronic inflammation and certain types of pain, but it is also involved in causing inflammation-associated symptoms, depending on the physiological context.

The cannabinoid type-2 (CB2) receptor, which unlike the CB1 receptor does not induce central side effects, has been shown to be a promising therapeutic target. While CB1 receptor antagonists/inverse agonists are of therapeutic value, also CB2 receptor ligands including agonists are of pharmacological interest.

 Although the endocannabinoid system is known to be involved in the regulation of energy homoeostasis and metabolism (mainly via CB1 receptors) there was hitherto no direct link between food intake and cannabinoid receptor activation. Our recent finding that beta-caryophyllene, a ubiquitous lipohilic plant natural product, selectively binds to the CB2 receptor and acts as a full agonist is unexpected…

In the case of the dietary natural product beta-caryophyllene, a full CB2 receptor-selective agonist in vitro, potent anti-inflammatory cannabimimetic effects are observed. Intriguingly, the lowest oral dose tested (5 mg/Kg) of this widespread and apparently non-toxic compound, which is also an FDA-approve food additive, was the most effective. Maybe this strengthens the hypothesis that beta-caryophyllene is indeed a dietary cannabinoid, thus inferring that by eating this compound the endocannabinoid system may be modulated in a beneficial way…”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2633791/

Cannabinoid Receptor 2-Mediated Attenuation of CXCR4-Tropic HIV Infection in Primary CD4+ T Cells

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“Agents that activate cannabinoid receptor pathways have been tested as treatments for cachexia, nausea or neuropathic pain in HIV-1/AIDS patients… Cannabinoid agonists activate the CB1R and CB2R cannabinoid receptors…

Cannabinoid agonists are currently under investigation for the treatment of AIDS-associated cachexia, nausea, and neuropathic pain. One such drug, dronabinol (Δ9-THC; Marinol®), has won Food and Drug Administration (FDA) approval for treatment of HIV-associated anorexia. Additionally, the prescription of smoked or ingested cannabis (marijuana) for treatment of AIDS-related symptoms has been approved…. Despite the use of cannabinoids by HIV/AIDS patients, few studies have investigated the impact of such drugs in regard to viral pathogenesis or immune regulation…

….Indeed, both smoked marijuana and dronabinol were reported to increase total CD4+ T cell number and naïve T cell number over a 21-day period. A decrease in viral load was also observed in these patients. Similarly, in SIV infected rhesus macaques, Δ9-THC exposure reduced viral load and CD4+ T cell depletion, significantly increasing animal survival over an 11 month period.

. Our findings suggest that CB2R activation in CD4+ T cells can inhibit actin reorganization and impair productive infection following cell-free or cell-associated viral acquisition of CXCR4-tropic HIV-1 in resting cells.

Therefore, the clinical use of CB2R agonists in the treatment of AIDS symptoms may also exert beneficial adjunctive antiviral effects against CXCR4-tropic viruses in late stages of HIV-1 infection.

Further study of cannabinoids and other neuroendocrine regulators that selectively modulate immune function may result in the discovery of new anti-viral drugs that can also mitigate AIDS-associated symptoms.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309010/

Cannabinoid Inhibition of Macrophage Migration to the Trans-Activating (Tat) Protein of HIV-1 Is Linked to the CB2 Cannabinoid Receptor

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“Macrophage-like cells are primary targets for infection by HIV-1…  In the present study, the exogenous cannabinoids δ-9-tetrahydrocannabinol (THC) and (−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP55940) were shown to significantly inhibit migration of human U937 macrophage-like cells to the Tat protein in a concentration-related manner….

Collectively, the pharmacological and biochemical knockdown data indicate that cannabinoid-mediated modulation of macrophage migration to the HIV-1 Tat protein is linked to the CB2 cannabinoid receptor. Furthermore, these results suggest that the CB2 cannabinoid receptor has potential to serve as a therapeutic target for ablation of HIV-1-associated untoward inflammatory response…

,,, the CB2 receptor has the potential to serve as a molecular target for ablating hyperinflammatory responses of macrophage-like cells while avoiding untoward psychotropic effects caused by activation of the CB1 receptor.

 In conclusion, the immunosuppressive and anti-inflammatory properties of select cannabinoids may have profound therapeutic potential in moderating HIV-associated immunopathology, including microglial activation, chemokine/cytokine dysregulation, and monocyte infiltration in the CNS.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846023/

Attenuation of HIV-1 replication in macrophages by cannabinoid receptor 2 agonists.

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“Previous studies showed that activation of the CB2 can attenuate inflammatory responses and affect HIV-1 infectivity in T cells and microglia. Here, we report that CB2 agonists can also act as immunomodulators on HIV-1-infected macrophages.

   We speculate that these findings indicate that prevention of viral entry is not a central mechanism for CB2-mediated suppression in viral replication.

However, CB2 may affect the HIV-1 replication machinery.

Results from a single-round infection with the pseudotyped virus revealed a marked decrease in HIV-1 LTR activation by the CB2 ligands.

Together, these results indicate that CB2 may offer a means to limit HIV-1 infection in macrophages.”

http://www.ncbi.nlm.nih.gov/pubmed/23463725