Cannabidiol Modulates the Expression of Alzheimer’s Disease-Related Genes in Mesenchymal Stem Cells.

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“Mesenchymal stem cells (MSCs) have emerged as a promising tool for the treatment of several neurodegenerative disorders, including Alzheimer’s disease (AD). The main neuropathological hallmarks of AD are senile plaques, composed of amyloid beta (Aβ), and neurofibrillary tangles, formed by hyperphosphorylated tau. However, current therapies for AD have shown limited efficacy.

In this study, we evaluated whether pre-treatment with cannabidiol (CBD), at 5 μM concentration, modulated the transcriptional profile of MSCs derived from gingiva (GMSCs) in order to improve their therapeutic potential, by performing a transcriptomic analysis by the next-generation sequencing (NGS) platform.

By comparing the expression profiles between GMSCs treated with CBD (CBD-GMSCs) and control GMSCs (CTR-GMSCs), we found that CBD led to the downregulation of genes linked to AD, including genes coding for the kinases responsible of tau phosphorylation and for the secretases involved in Aβ generation. In parallel, immunocytochemistry analysis has shown that CBD inhibited the expression of GSK3β, a central player in AD pathogenesis, by promoting PI3K/Akt signalling.

In order to understand through which receptor CBD exerted these effects, we have performed pre-treatments with receptor antagonists for the cannabinoid receptors (SR141716A and AM630) or for the vanilloid receptor 1 (TRPVI). Here, we have proved that TRPV1 was able to mediate the modulatory effect of CBD on the PI3K/Akt/GSK3β axis.

In conclusion, we have found that pre-treatment with CBD prevented the expression of proteins potentially involved in tau phosphorylation and Aβ production in GMSCs. Therefore, we suggested that GMSCs preconditioned with CBD possess a molecular profile that might be more beneficial for the treatment of AD.”

https://www.ncbi.nlm.nih.gov/pubmed/28025562

Identification of an endocannabinoid system in the rat pars tuberalis-a possible interface in the hypothalamic-pituitary-adrenal system?

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“Endocannabinoids (ECs) are ubiquitous endogenous lipid derivatives and play an important role in intercellular communication either in an autocrine/paracrine or in an endocrine fashion. Recently, an intrinsic EC system has been discovered in the hypophysial pars tuberalis (PT) of hamsters and humans. In hamsters, this EC system is under photoperiodic control and appears to influence the secretion of hormones such as prolactin from the adenohypophysis. We investigate the EC system in the PT of the rat, a frequently used species in endocrine research.

By means of immunocytochemistry, enzymes involved in EC biosynthesis, e.g., N-arachidonoyl-phosphatidylethanolamine-phospholipase D (NAPE-PLD) and diacylglycerol lipase α (DAGLα) and enzymes involved in EC degradation, e.g., fatty acid amide hydrolase (FAAH) and cyclooxygenase-2 (COX-2), were demonstrated in PT cells of the rat. Immunoreactions (IR) for FAAH and for the cannabinoid receptor CB1 were observed in corticotrope cells of the rat adenohypophysis; these cells were identified by antibodies against proopiomelanocortin (POMC) or adrenocorticotrophic hormone (ACTH). In the outer zone of the median eminence, numerous nerve fibers and terminals displayed CB1 IR. The majority of these were also immunolabeled by an antibody against corticotropin-releasing factor (CRF).

These results suggest that the EC system at the hypothalamo-hypophysial interface affects both the CRF-containing nerve fibers and the corticotrope cells in the adenohypophysis. Our data give rise to the hypothesis that, in addition to its well-known role in the reproductive axis, the PT might influence adrenal functions and, thus, the stress response and immune system.”

https://www.ncbi.nlm.nih.gov/pubmed/27999963

Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists.

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“The misuse of prescription opiates is on the rise with combination therapies (e.g. acetaminophen or NSAIDs) resulting in severe liver and kidney damage. In recent years, cannabinoid receptors have been identified as potential modulators of pain and rewarding behaviors associated with cocaine, nicotine and ethanol in preclinical models. Yet, few studies have identified whether mu opioid agonists and CB2 agonists act synergistically to inhibit chronic pain while reducing unwanted side effects including reward liability.

We determined if analgesic synergy exists between the mu-opioid agonist morphine and the selective CB2 agonist, JWH015, in rodent models of acute and chronic inflammatory, post-operative, and neuropathic pain using isobolographic analysis. We also investigated if the MOR-CB2 agonist combination decreased morphine-induced conditioned place preference (CPP) and slowing of gastrointestinal transit. Co-administration of morphine with JWH015 synergistically inhibited preclinical inflammatory, post-operative and neuropathic-pain in a dose- and time-dependent manner; no synergy was observed for nociceptive pain. Opioid-induced side effects of impaired gastrointestinal transit and CPP were significantly reduced in the presence of JWH015.

Here we show that MOR + CB2 agonism results in a significant synergistic inhibition of preclinical pain while significantly reducing opioid-induced unwanted side effects.

The opioid sparing effect of CB2 receptor agonism strongly supports the advancement of a MOR-CB2 agonist combinatorial pain therapy for clinical trials.”

https://www.ncbi.nlm.nih.gov/pubmed/28007501

Cannabinoid receptors on peripheral leukocytes from patients with schizophrenia: Evidence for defective immunomodulatory mechanisms.

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“These results suggest a defective endocannabinoid system-mediated immunomodulation in patients with schizophrenia.”

https://www.ncbi.nlm.nih.gov/pubmed/28011441

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

Cannabidiol reduces brain damage and improves functional recovery in a neonatal rat model of arterial ischemic stroke.

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Neuropharmacology

“Currently there is no effective treatment for neonatal arterial ischemic stroke (AIS).

Cannabidiol (CBD) is neuroprotective in models of newborn hypoxic-ischemic brain damage and adult stroke.

The purpose of this work was to study the protective effect of CBD in a neonatal rat model of AIS.

RESULTS:

CBD administration improved neurobehavioral function regarding strength, hemiparesis, coordination and sensorimotor performance as assessed at P15 and P38. MRI indicated that CBD did not reduce the volume of infarct but reduced the volume of perilesional gliosis. H+-MRS indicated that CBD reduced metabolic derangement and excitotoxicty, and protected astrocyte function. Histologic studies indicated that CBD reduced neuronal loss and apoptosis, and modulated astrogliosis and microglial proliferation and activation.

CONCLUSIONS:

CBD administration after Middle Cerebral Artery Occlusion (MCAO) led to long-term functional recovery, reducing neuronal loss and astrogliosis, and modulating apoptosis, metabolic derangement, excitotoxicity and neuro-inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/28012949

“Post-stroke administration of Cannabidiol (CBD) is neuroprotective in neonatal rats. CBD neuroprotection is sustained in the long term. CBD treatment led to functional recovery in both motor and sensorimotor domains. CBD modulated excitotoxicity, astrocyte dysfunction and microglial activation.”

https://www.sciencedirect.com/science/article/pii/S0028390816305810

Marijuana use and inpatient outcomes among hospitalized patients: analysis of the nationwide inpatient sample database

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Cancer Medicine

“The purpose of this paper is to examine the relationship between marijuana use and health outcomes among hospitalized patients, including those hospitalized with a diagnosis of cancer.

A total of 387,608 current marijuana users were identified based on ICD-9 codes for marijuana use among hospitalized patients in the Nationwide Inpatient Sample database between 2007 and 2011. Logistic regression analysis was performed to determine the association between marijuana use and heart failure, cardiac disease, stroke, and in-hospital mortality. All models were adjusted for age, gender, race, residential income, insurance, residential region, pain, and number of comorbidities.

Among hospitalized patients, marijuana use was associated with a 60% increased odds of stroke (OR: 1.60, 95% CI: 1.44–1.77) compared with non-users, but significantly reduced odds of heart failure (OR: 0.78, 95% CI: 0.75–0.82), cardiac disease (OR: 0.86, 95% CI: 0.82–0.91), or in-hospital mortality (OR: 0.41, 95% CI: 0.38–0.44).

Among cancer patients, odds of in-hospital mortality was significantly reduced among marijuana users compared with non-users (OR: 0.44, 95% CI: 0.35–0.55).

Hospitalized marijuana users were more likely to experience a stroke compared with non-users, but less likely to experience in-hospital mortality.”

http://onlinelibrary.wiley.com/doi/10.1002/cam4.968/full

Cannabis and epilepsy: An ancient treatment returns to the fore.

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“Cannabis has been associated with the treatment of epilepsy throughout history, and if ancient Assyrian sources referring to “hand of ghost” are considered credible, this relationship may span four millennia.

A tradition of usage continued in Arabic medicine and Ayurvedic practice in India, which led, in turn, to early experiments in Europe and North America with “Indian hemp.”

Lack of standardization, bioavailability issues, and ultimately prohibition were all factors in cannabis-based medicines failing to maintain mainstream usage in seizure treatment, but investigation was resumed in the 1970s with interesting signals noted in both laboratory and clinical settings.

Early case studies showed promise, but lacked sufficient rigor. Resumption of research coupled with mass experimentation by families of epilepsy patients has led to intense interest in cannabis-based medicines for its treatment once more, with greatest focus on cannabidiol, but additional investigation of tetrahydrocannabinol, tetrahydrocannabinolic acid, and other phytocannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/27989385

CB2 receptors regulate natural killer cells that limit allergic airway inflammation in a murine model of asthma.

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“Allergic asthma is a chronic airway inflammatory disease involving the complementary actions of innate and adaptive immune responses.

Endogenously generated cannabinoids, acting via CB2 receptors play important roles in both homeostatic and inflammatory processes. However, the contribution of CB2-acting eicosanoids to the innate events preceding sensitization to the common house dust mite (HDM) allergen, remain to be elucidated. We investigated the role of CB2 activation during allergen-induced pulmonary inflammation and NK cell effector function.

CONCLUSIONS:

Collectively, these results reveal that CB2 activation is crucial in regulating pulmonary NK cell function, and suggest that NK cells serve to limit ILC2 activation and subsequent allergic airway inflammation. CB2 inhibition may present an important target to modulate NK cell response during pulmonary inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/27992060

Expression of Cannabinoid Type 1 Receptors in Human Odontoblast Cells.

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“The aim of this study was to investigate the functional expression of cannabinoid type 1 (CB1) receptors in human odontoblasts (HODs) and the possible internal mechanism.

In the present study, we examined the molecular and functional expression of the CB1 receptors in cultured HOD-like cells and native HODs obtained from healthy wisdom teeth.

We conclude that HODs can express functional CB1 receptors that may play an important role in mediating the physiological function in tooth pulp.”

https://www.ncbi.nlm.nih.gov/pubmed/27989582

“Involvement of the endocannabinoid system in periodontal healing.”  https://www.ncbi.nlm.nih.gov/pubmed/20233580

Bidirectional Effects of Cannabidiol on Contextual Fear Memory Extinction

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“Cannabidiol (CBD) is the major non-psychotropic constituent of the Cannabis plant and has anxiolytic therapeutic potential.

Cannabidiol (CBD) has been established to have both acute and long-lasting effects to reduce fear memory expression.

We showed that under conditions of strong fear conditioning, CBD reduced contextual fear memory expression both acutely during the extinction session as well as later at a fear retention test.

This pattern of results is consistent with CBD enhancing contextual fear memory extinction when the initial conditioning is strong, but impairing extinction when conditioning is weak. This bidirectional effect of CBD may be related to stress levels induced by conditioning and evoked at retrieval during extinction, rather than the strength of the memory per se.

 In summary, CBD had bidirectional effects on the extinction of contextual fear conditioning, depending on the nature of the initial fear conditioning. Nevertheless, in the more translationally-relevant stronger conditioning setting, CBD both acutely inhibited fear expression and enhanced extinction to produce longer lasting reductions in fear.
These observations provide further support for the potential translational use of CBD in conditions such as posttraumatic stress disorder and specific phobias.”

http://journal.frontiersin.org/article/10.3389/fphar.2016.00493/full?utm_source=S-TWT&utm_medium=SNET&utm_campaign=ECO_FPHAR_XXXXXXXX_auto-dlvrit%0A