Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity.

Posted on May 23, 2015 by David

“Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited.

Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication…

In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity.”

http://www.ncbi.nlm.nih.gov/pubmed/25933444

http://www.thctotalhealthcare.com/category/addiction/

Cannabidiol Rescues Acute Hepatic Toxicity and Seizure Induced by Cocaine.

Posted on May 23, 2015 by David

“Cocaine is a commonly abused illicit drug that causes significant morbidity and mortality. The most severe and common complications are seizures, ischemic strokes, myocardial infarction, and acute liver injury. Here, we demonstrated that acute cocaine intoxication promoted seizure along with acute liver damage in mice, with intense inflammatory infiltrate.

Considering the protective role of the endocannabinoid system against cell toxicity, we hypothesized that treatment with an anandamide hydrolysis inhibitor, URB597, or with a phytocannabinoid, cannabidiol (CBD), protects against cocaine toxicity.

URB597 (1.0 mg/kg) abolished cocaine-induced seizure, yet it did not protect against acute liver injury.

Using confocal liver intravital microscopy, we observed that CBD reduced acute liver inflammation and damage induced by cocaine and prevented associated seizure.

Additionally, we showed that previous liver damage induced by another hepatotoxic drug (acetaminophen) increased seizure and lethality induced by cocaine intoxication, linking hepatotoxicity to seizure dynamics.

These findings suggest that activation of cannabinoid system may have protective actions on both liver and brain induced by cocaine, minimizing inflammatory injury promoted by cocaine, supporting its further clinical application in the treatment of cocaine abuse.”

http://www.ncbi.nlm.nih.gov/pubmed/25999668

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427116/

http://www.thctotalhealthcare.com/category/addiction/

Lipid nanoparticles as an emerging platform for cannabinoid delivery: physicochemical optimization and biocompatibility.

Posted on May 23, 2015 by David

“This work aims at developing and optimizing a valuable oral delivery carrier for the cannabinoid derivative CB13, which presents a high therapeutic potential in chronic pain states that respond poorly to conventional analgesics, but also shows highly unfavorable physicochemical properties.

CB13-loaded lipid nanoparticles (LNP) formulations were developed…

The LNP formulation proposed proved to be a promising carrier for the oral delivery of CB13, a cannabinoid with high therapeutic potential in chronic pain states that currently lack a valid oral treatment.”

http://www.ncbi.nlm.nih.gov/pubmed/25996463

Endocannabinoid-mediated improvement on a test of aversive memory in a mouse model of fragile X syndrome.

Posted on May 17, 2015 by David

“Silencing the gene FMR1 in fragile X syndrome (FXS) with consequent loss of its protein product, FMRP, results in intellectual disability, hyperactivity, anxiety, seizure disorders, and autism-like behavior. In a mouse model (Fmr1 knockout (KO)) of FXS, a deficit in performance on the passive avoidance test of learning and memory is a robust phenotype.

We report that drugs acting on the endocannabinoid (eCB) system can improve performance on this test.

Our results indicate that the eCB system is involved in FXS and suggest that the eCB system is a promising target for treatment of FXS.”

http://www.ncbi.nlm.nih.gov/pubmed/25979787

http://www.thctotalhealthcare.com/category/fragile-x-syndrome-fxs/

Neuroprotective effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite.

Posted on May 16, 2015 by David

“In glaucoma, the increased release of glutamate is the major cause of retinal ganglion cell death. Cannabinoids have been demonstrated to protect neuron cultures from glutamate-induced death.

In this study, we test the hypothesis that glutamate causes apoptosis of retinal neurons via the excessive formation of peroxynitrite, and that the neuroprotective effect of the psychotropic Delta9-tetrahydroxycannabinol (THC) or nonpsychotropic cannabidiol (CBD) is via the attenuation of this formation.

These results suggest the potential use of CBD as a novel topical therapy for the treatment of glaucoma.

“Cannabinoid components of marijuana, such as (−)Δ9-tetrahydrocannabinol (THC), or the synthetic cannabinoid WIN55,212-2, have been shown to prevent glutamate- or NMDA-induced neurotoxicity in isolated neurons or in the brain via activation of the cannabinoid receptor subtype CB1.

…the nonpsychotropic component of marijuana, cannabidiol (CBD), and the synthetic nonpsychotropic cannabinoid, HU-211, as well as THC have been demonstrated as potent antioxidants and/or NMDA receptor antagonists that protect neuron cultures from glutamate-induced death or from oxidative stress.

… we demonstrated that THC and CBD are neuroprotective against NMDA-induced retinal injury and that their protective actions are in part because of an effect in reducing formation of lipid peroxides, nitrite/nitrate, and nitrotyrosine.

In addition to possessing neuroprotective or retinal neuroprotective activity as demonstrated here and elsewhere, cannabinoids such as THC, WIN55,212-2, endogenous cannabinoid 2-arachidonoylglycerol, as well as nonpsychotropic HU-211 have been demonstrated to induce dose-related reductions in intraocular pressure in human and in animal models.

This suggests that cannabinoids may offer a multifaceted therapy for glaucoma.

In conclusion, our results indicate that lipid peroxidation and ONOO− formation play an important role in NMDA-induced retinal neurotoxicity and cell loss in the retina, and that THC and CBD, by reducing the formation of these compounds, are effective neuroprotectants.

The present studies could form the basis for the development of new topical therapies for the treatment of glaucoma.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1892413/

http://www.thctotalhealthcare.com/category/glaucoma-2/

Cannabinoid receptor 2 attenuates microglial accumulation and brain injury following germinal matrix hemorrhage via ERK dephosphorylation in vivo and in vitro.

Posted on May 13, 2015 by David

“Microglia accumulation plays detrimental roles in the pathology of germinal matrix hemorrhage (GMH) in the immature preterm brain.

Here, we investigated the effects of a cannabinoid receptor 2 (CB2R) agonist on microglia proliferation and the possible involvement of the mitogen-activated protein kinase (MAPK) family pathway in a collagenase-induced GMH rat model and in thrombin-induced rat microglia cells.

Overall, these findings suggest that activation of the endocannabinoid system might attenuate inflammation-induced secondary brain injury after GMH in rats by reducing microglia accumulation through a mechanism involving ERK dephosphorylation.

Enhancing CB2R activation is a potential treatment to slow down the course of GMH in preterm newborns.”

http://www.ncbi.nlm.nih.gov/pubmed/25963415

http://www.thctotalhealthcare.com/category/brain-trauma/

Id-1 is a key transcriptional regulator of glioblastoma aggressiveness and a novel therapeutic target.

Posted on May 12, 2015 by David

“Glioblastoma (GBM) is the most common form of primary adult brain tumors…

It is, therefore, essential to discover master regulators that control GBM invasiveness and target them therapeutically.

We demonstrate here that the transcriptional regulator Id-1 plays a critical role in modulating the invasiveness of GBM cell lines and primary GBM cells.

Furthermore, we show that a non-toxic compound, cannabidiol, significantly down-regulates Id-1 gene expression and associated glioma cell invasiveness…

Our results suggest that Id-1 regulates multiple tumor-promoting pathways in GBM, and that drugs targeting Id-1 represent a novel and promising strategy for improving the therapy and outcome of GBM patients.

We previously showed a strong correlation between Id-1 expression and the invasive and metastatic behavior of breast cancer cells.”

“Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells… CBD represents the first nontoxic exogenous agent that can significantly decrease Id-1 expression in metastatic breast cancer cells… Moreover, reducing Id-1 expression with cannabinoids could also provide a therapeutic strategy for the treatment of additional aggressive cancers because Id-1 expression was found to be up-regulated during the progression of almost all types…” http://mct.aacrjournals.org/content/6/11/2921.long

“In this report, we show that Id-1 is a key regulator of brain tumor cell invasiveness and neurosphere growth, and that Id-1 expression is specifically up-regulated in tissues from patients with high-grade gliomas. Importantly, we demonstrate that targeting Id-1 expression using either genetic approaches or the non-toxic cannabinoid, cannabidiol (CBD), leads to a significant reduction in the invasion of both GBM cell lines and patient-derived primary GBM cultures. CBD also significantly inhibits GBM dispersal ex vivo, and reduces tumor growth and Id-1 expression in vivo.

Consistent with the breast cancer study, we found that the non-psychoactive cannabinoid CBD significantly down-regulated Id-1 expression in serum-derived and primary GBM cells. As expected, we observed robust inhibition of glioma cell invasiveness.

In conclusion, our results establish Id-1 as a key regulator of both invasion and stemness in GBM cells and demonstrate that the non-toxic cannabinoid compound CBD down-regulates Id-1 expression and tumor aggressiveness in culture and in vivo.

The data also shed light on some of the key pathways that control GBM cell dispersal and progression. A greater understanding of these pathways may lead to more effective therapies for cancer patients including the additional refinement of cannabinoid analogs targeting Id-1.

We expect our efforts to ultimately translate to the development of future clinical trials with nontoxic compounds that target the expression of Id-1, a master regulator of GBM aggressiveness.

With its lack of systemic toxicity and psychoactivity, CBD is an ideal candidate agent in this regard and may prove useful in combination with front-line agents for the treatment of patients with aggressive and high-grade GBM tumors.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594064/

“McAllister Lab… Cannabidiol inhibits tumor (glioblastoma) progression in mouse models of brain cancer. Mice bearing human brain tumors derived from glioblastoma were treated with the naturally occurring cannabinoid, cannabidiol (CBD).” http://www.cpmcri-currents.org/our-people/discovery-investigators/mcallister-lab

“New Study Finds Cannabis Compound Could Have Even Greater Reach in Inhibiting Aggressive Cancer than Previously Thought. Researchers at California Pacific Medical Center Research Institute (CPMCRI, a Sutter Health affiliate) have found that a compound in cannabis previously shown to decrease metastatic breast cancer now shows promise in stopping aggressive brain cancer as well. The findings are particularly important given the safety of the cannabis compound and the fact that patients with advanced brain cancer have few options for treatment.” http://www.cpmc.org/about/press/news2012/cannabis-brain.html

http://www.thctotalhealthcare.com/category/brain-cancer/

Glioblastoma progression in mouse models of brain cancer, after treatment with CBD

Lipopolysaccharide-induced murine embryonic resorption involves changes in endocannabinoid profiling and alters progesterone secretion and inflammatory response by a CB1-mediated fashion.

Posted on May 11, 2015 by David

“Genital tract infections are a common complication of human pregnancy that can result in miscarriage. We have previously shown that a lipopolysaccharide (LPS) induces embryonic resorption in a murine model of inflammatory miscarriage. This is accompanied by a dramatic decrease in systemic progesterone levels associated with a robust pro-inflammatory response that results in embryo resoprtion.

Here, we tested the hypothesis that the endogenous cannabinoid system (eCS), through cannabinoid receptor 1 (CB1), plays a role in regulating progesterone levels and, therefore, the pro-inflammatory response.

We show that LPS treatment in pregnant mice causes significant changes in the eCS ligands, which are reversed by progesterone treatment. We further show the CB1-KO mice maintain higher plasma progesterone levels after LPS treatment, which is associated with a feebler uterine inflammatory response and a significant drop in embryo resorption.

These data suggest that manipulation of CB1 receptors and/or ligands is a potential therapeutic avenue to decrease infection-induced miscarriage.”

http://www.ncbi.nlm.nih.gov/pubmed/25958042

The cannabinoid CB₂ receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain.

Posted on May 10, 2015 by David

“The widespread plant volatile beta-caryophyllene (BCP) was recently identified as a natural selective agonist of the peripherally expressedcannabinoid receptor 2 (CB₂).

…the natural plant product BCP may be highly effective in the treatment of long lasting, debilitating pain states. Our results have important implications for the role of dietary factors in the development and modulation of chronic pain conditions.

Cannabis preparations, which have been used since thousands of years for the treatment of pain have recently come again into the focus as potential therapeutics for inflammatory and neuropathic pain conditions. Currently, cannabis extracts and synthetic preparations of the psychoactive cannabis compound Δ9-tetrahydrocannabinol (THC) have been approved in many countries for clinical pain management at doses and formulations that show on only minor central side effects…

A natural selective agonist for CB2 receptors is the plant volatile BCP, which represents a dietary phytocannabinoid. BCP is found in large amounts in the essential oils of many common spices and food plants… Several health effects have been attributed to BCP or medicinal plants containing BCP, including anti-inflammatory, local anesthetic, anti-carcinogenic, anti-fibrotic and anxiolytic-like activity.

In the present study, we investigated the analgesic effects of BCP in formalin-induced inflammation model and in a model of neuropathic pain, which involves the partial ligation of the sciatic nerve… BCP is the first natural CB2 receptor agonist, which could orally reduce inflammatory responses in different animal models of pain.

Thus, it is likely that BCP belongs to a group of common plant natural products with major potential impact on human health.

The oral intake of this dietary cannabinoid with vegetable food could be advantageous in the daily routine clinical practice over synthetic cannabinoid agonists.”

http://www.europeanneuropsychopharmacology.com/article/S0924-977X(13)00302-7/fulltext

http://www.thctotalhealthcare.com/category/neuropathic-pain/

The relationship between cannabidiol and psychosis: A review.

Posted on May 9, 2015 by David

“Cannabis sativa is the most widely used illicit drug in the world…

THC is considered responsible for the main psychotropic effects of the drug, while CBD seems to antagonize these effects, particularly those that induce psychosis.

The effects of Cannabis seem to depend on several variables related to the type of plant, its strength, usage patterns, and intersubjective variations.

CBD could be used to treat several conditions, including psychosis, when the current treatment is associated with significant side effects.

…further research involving the possible antipsychotic effect and other potential positive effects of Cannabis are needed.”

http://www.ncbi.nlm.nih.gov/pubmed/25954940

http://www.thctotalhealthcare.com/category/schizophrenia/