Tag Archives: Cannabinoids

Cannabinoids Inhibit T-cells via Cannabinoid Receptor 2 in an in vitro Assay for Graft Rejection, the Mixed Lymphocyte Reaction

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“Cannabinoids are known to have anti-inflammatory and immunomodulatory properties.

Cannabinoid receptor 2 (CB2) is expressed mainly on leukocytes and is the receptor implicated in mediating many of the effects of cannabinoids on immune processes.

This study tested the capacity of Δ9-tetrahydrocannabinol (Δ9-THC) and of two CB2-selective agonists to inhibit the murine Mixed Lymphocyte Reaction (MLR), an in vitro correlate of graft rejection following skin and organ transplantation. Both CB2-selective agonists and Δ9-THC significantly suppressed the MLR in a dose dependent fashion…

Together, these data support the potential of this class of compounds as useful therapies to prolong graft survival in transplant patients.

Cannabinoids were reported to have effects on immune responses as early as the 1970s, but the basis for this activity was not understood until the cannabinoid receptors were cloned

Ideally, the anatomically disparate expression of CB1 and CB2 would allow for the use of compounds selective for CB2, and thus eliminate the unwanted psychoactive effects from CB1 activation, while maintaining the anti-inflammatory and immunosuppressive properties.

CB2-selective cannabinoids have been proposed as possible candidates to block graft rejection.

The results presented in this paper show that Δ9-THC, a mixed CB1/CB2 agonist, and two CB2-selective agonists can inhibit the Mixed Lymphocyte Reaction (MLR), an in vitro correlate of organ and skin graft rejection.”

 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864984/

Promising cannabinoid-based therapies for Parkinson’s disease: motor symptoms to neuroprotection.

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“Parkinson’s disease (PD) is a slow insidious neurological disorder characterized by a loss of dopaminergic neurons in the midbrain. Although several recent preclinical advances have proposed to treat PD, there is hardly any clinically proved new therapeutic for its cure.

Increasing evidence suggests a prominent modulatory function of the cannabinoid signaling system in the basal ganglia. Hence, use of cannabinoids as a new therapeutic target has been recommended as a promising therapy for PD.

The elements of the endocannabinoid system are highly expressed in the neural circuit of basal ganglia wherein they bidirectionally interact with dopaminergic, glutamatergic, and GABAergic signaling systems.

As the cannabinoid signaling system undergoes a biphasic pattern of change during progression of PD, it explains the motor inhibition typically observed in patients with PD.

Cannabinoid agonists such as WIN-55,212-2 have been demonstrated experimentally as neuroprotective agents in PD, with respect to their ability to suppress excitotoxicity, glial activation, and oxidative injury that causes degeneration of dopaminergic neurons.

Additional benefits provided by cannabinoid related compounds including CE-178253, oleoylethanolamide, nabilone and HU-210 have been reported to possess efficacy against bradykinesia and levodopa-induced dyskinesia in PD.

Despite promising preclinical studies for PD, use of cannabinoids has not been studied extensively at the clinical level. In this review, we reassess the existing evidence suggesting involvement of the endocannabinoid system in the cause, symptomatology, and treatment of PD. We will try to identify future threads of research that will help in the understanding of the potential therapeutic benefits of the cannabinoid system for treating PD.”

http://www.ncbi.nlm.nih.gov/pubmed/25888232

“To conclude, development of safe, effective cannabis-based medicines targeting different mechanisms may have a significant impact in PD therapy.”

Full-text: http://www.molecularneurodegeneration.com/content/10/1/17

http://www.thctotalhealthcare.com/category/parkinsons-disease/

Pure cannabidiol in the treatment of malignant migrating partial seizures in infancy: a case report.

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“Malignant migrating partial seizures in infancy is a devastating pharmacoresistent epileptic encephalopathy of unknown etiology characterized by onset in the first 6 months of life, continuous migrating focal seizures with corresponding multifocal electroencephalographic discharges, developmental deterioration, and early mortality.

Recent widespread interest in the nonpsychoactive component of the cannabis plant, cannabidiol, as a potential treatment for refractory devastating epilepsies has led to individual trials initiated by families or physicians in states that have legalized medical marijuana with anecdotal success.

We describe a now 10-month-old boy with malignant migrating partial seizures in infancy who made developmental gains and demonstrated sustained seizure reduction with the addition of cannabidiol to his antiepileptic regimen.

This report supports a role for cannabidiol in the treatment of malignant migrating partial seizures in infancy.”

http://www.ncbi.nlm.nih.gov/pubmed/25882081

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

CB 1Cannabinoid Receptor Agonist Inhibits Matrix Metalloproteinase Activity in Spinal Cord Injury: A Possible Mechanism of Improved Recovery.

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“Increased matrix metalloproteinase (MMP) activity contributes to glial scar formation that inhibits the repair path after spinal cord injury (SCI). We examined whether treatment with N-​(2-​chloroethyl)-​5Z,​8Z,​11Z,​14Z-​eicosatetraenamide (ACEA), a selective synthetic cannabinoid receptor (CB1R) agonist, inhibits MMP and improves functional and histological recovery in a mouse spinal cord compression injury model…

Collectively these data demonstrate that post-injury CB1R agonism can improve SCI outcome and also indicate marked attenuation of MMP-9 proteolytic enzyme activity as a biochemical mechanism.”

http://www.ncbi.nlm.nih.gov/pubmed/25881484

http://www.thctotalhealthcare.com/category/spinal-cord-injury/

The role of cannabinoids and leptin in neurological diseases.

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“Cannabinoids exert a neuroprotective influence on some neurological diseases, including Alzheimer’s, Parkinson’s, Huntington’s, multiple sclerosis and epilepsy.

Synthetic cannabinoid receptor agonists/antagonists or compounds can provide symptom relief or control the progression of neurological diseases. However, the molecular mechanism and the effectiveness of these agents in controlling the progression of most of these diseases remain unclear.

Cannabinoids may exert effects via a number of mechanisms and interactions with neurotransmitters, neurotropic factors and neuropeptides.

Leptin is a peptide hormone involved in the regulation of food intake and energy balance via its actions on specific hypothalamic nuclei. Leptin receptors are widely expressed throughout the brain, especially in the hippocampus, basal ganglia, cortex and cerebellum. Leptin has also shown neuroprotective properties in a number of neurological disorders, such as Parkinson’s and Alzheimer’s.

Therefore, cannabinoid and leptin hold therapeutic potential for neurological diseases.

Further elucidation of the molecular mechanisms underlying the effects on these agents may lead to the development of new therapeutic strategies for the treatment of neurological disorders.”

Regulation of inflammation by cannabinoids, the endocannabinoids 2-arachidonoyl-glycerol and arachidonoyl-ethanolamide, and their metabolites.

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“2-Arachidonoyl-glycerol (2-AG) and arachidonyl-ethanolamide (AEA) are endocannabinoids that have been implicated in many physiologic disorders, including obesity, metabolic syndromes, hepatic diseases, pain, neurologic disorders, and inflammation.

Their immunomodulatory effects are numerous and are not always mediated by cannabinoid receptors, reflecting the presence of an arachidonic acid (AA) molecule in their structure, the latter being the precursor of numerous bioactive lipids that are pro- or anti-inflammatory.

2-AG and AEA can thus serve as a source of AA but can also be metabolized by most eicosanoid biosynthetic enzymes, yielding additional lipids.

In this regard, enhancing endocannabinoid levels by using endocannabinoid hydrolysis inhibitors is likely to augment the levels of these lipids that could regulate inflammatory cell functions.

This review summarizes the metabolic pathways involved in the biosynthesis and metabolism of AEA and 2-AG, as well as the biologic effects of the 2-AG and AEA lipidomes in the regulation of inflammation.”

http://www.ncbi.nlm.nih.gov/pubmed/25877930

Effects of Cannabinoids on T-cell Function and Resistance to Infection.

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“This review examines the effects of cannabinoids on immune function, with a focus on effects on T-cells, as well as on resistance to infection. The paper considers the immune modulating capacity of marijuana, of ∆9-THC extracted from the marijuana plant, and synthetic cannabinoids…

The overall conclusion of the studies discussed in this review is that cannabinoids that bind to the CB2 receptor, including ∆9-THC and CB2 selective agonists are immunosuppressive.

The studies provide objective evidence for potentially beneficial effects of marijuana and ∆9-THC on the immune system in conditions where it is desirable to dampen immune responses.

An emerging area of investigation that is reviewed is evidence to support the conclusion that CB2 selective agonists are a new class of immunosuppressive and anti-inflammatory compounds that may have exceptional beneficial effects in a variety of conditions, such as autoimmune diseases and graft rejection, where it is desirable to dampen the immune response without psychoactive effects.”

http://www.ncbi.nlm.nih.gov/pubmed/25876735

http://www.thctotalhealthcare.com/category/autoimmune-disease/

WIN 55,212-2, Agonist of Cannabinoid Receptors, Prevents Amyloid β1-42 Effects on Astrocytes in Primary Culture.

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“Alzheimer´s disease (AD), a neurodegenerative illness involving synaptic dysfunction with extracellular accumulation of Aβ1-42 toxic peptide, glial activation, inflammatory response and oxidative stress, can lead to neuronal death.

Endogenous cannabinoid system is implicated in physiological and physiopathological events in central nervous system (CNS), and changes in this system are related to many human diseases, including AD…

In conclusion cannabinoid WIN 55,212-2 increases cell viability and anti-inflammatory response in cultured astrocytes. Moreover, WIN 55,212-2 increases expression of anti-oxidant Cu/Zn SOD and is able to prevent inflammation induced by Aβ1-42 in cultured astrocytes.

Further studies would be needed to assess the possible beneficial effects of cannabinoids in Alzheimer’s disease patients.”

http://www.ncbi.nlm.nih.gov/pubmed/25874692

http://www.thctotalhealthcare.com/category/alzheimers-disease-ad/

A role for GPR55 in human placental venous endothelial cells.

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“Endocannabinoids and their G protein-coupled receptors have been suggested to play a key role in human pregnancy, by regulating important aspects such as implantation, decidualization, placentation and labor.

G protein-coupled receptor 55 (GPR55) was previously postulated to be another cannabinoid receptor, since specific cannabinoids were shown to act independently of the classical cannabinoid receptors CB1 or CB2.

Current knowledge about GPR55 expression and function in human placenta is very limited and motivated us to evaluate human placental GPR55 expression in relation to other human peripheral tissues and to analyze spatiotemporal GPR55 expression in human placenta.

Gene expression analysis revealed low GPR55 levels in human placenta, when compared to spleen and lung, the organs showing highest GPR55 expression.

Moreover, expression analysis showed 5.8 fold increased placental GPR55 expression at term compared to first trimester. Immunohistochemistry located GPR55 solely at the fetal endothelium of first trimester and term placentas. qPCR and immunocytochemistry consistently confirmed GPR55 expression in isolated primary placental arterial and venous endothelial cells. Incubation with L-α-lysophosphatidylinositol (LPI), the specific and functional ligand for GPR55, at a concentration of 1 µM, significantly enhanced migration of venous, but not arterial endothelial cells.

LPI-enhanced migration was inhibited by the GPR55 antagonist O-1918, suggesting a role of the LPI-GPR55 axis in placental venous endothelium function.”

Negative Regulation of Leptin-induced ROS Formation by CB1 Receptor Activation in Hypothalamic Neurons.

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“The adipocyte-derived, anorectic hormone, leptin, was recently shown to owe part of its regulatory effects on appetite-regulating hypothalamic neuropeptides to the elevation of ROS levels in arcuate nucleus (ARC) neurons.

Leptin is also known to exert a negative regulation on hypothalamic endocannabinoid levels and hence on cannabinoid CB1 receptor activity.

Here we investigated the possibility of a negative regulation by CB1 receptor of leptin-mediated ROS formation in the ARC…

We conclude that CB1 activation reverses leptin-induced ROS formation, and hence possibly some of the ROS-mediated effects of the hormone, by preventing PPAR-γ inhibition by leptin, with subsequent increase of catalase activity.

This mechanism might underlie in part CB1 orexigenic actions under physiopathological conditions accompanied by elevated hypothalamic endocannabinoid levels.”