Cannabinoids in Parkinson’s Disease.

Posted on September 2, 2017 by David Worrell

Mary Ann Liebert, Inc. publishers

“The endocannabinoid system plays a regulatory role in a number of physiological processes and has been found altered in different pathological conditions, including movement disorders. The interactions between cannabinoids and dopamine in the basal ganglia are remarkably complex and involve both the modulation of other neurotransmitters (γ-aminobutyric acid, glutamate, opioids, peptides) and the activation of different receptors subtypes (cannabinoid receptor type 1 and 2).

In the last years, experimental studies contributed to enrich this scenario reporting interactions between cannabinoids and other receptor systems (transient receptor potential vanilloid type 1 cation channel, adenosine receptors, 5-hydroxytryptamine receptors). The improved knowledge, adding new interpretation on the biochemical interaction between cannabinoids and other signaling pathways, may contribute to develop new pharmacological strategies.

A number of preclinical studies in different experimental Parkinson’s disease (PD) models demonstrated that modulating the cannabinoid system may be useful to treat some motor symptoms. Despite new cannabinoid-based medicines have been proposed for motor and nonmotor symptoms of PD, so far, results from clinical studies are controversial and inconclusive. Further clinical studies involving larger samples of patients, appropriate molecular targets, and specific clinical outcome measures are needed to clarify the effectiveness of cannabinoid-based therapies.” https://www.ncbi.nlm.nih.gov/pubmed/28861502

“Cannabis is a psychoactive compound widely used along history for recreational and therapeutic purposes. Although many open questions remain, cannabis-based therapies have become increasingly common raising considerable interest in politics as well as in general public for legalization of medical cannabis.” http://online.liebertpub.com/doi/10.1089/can.2017.0002

The Use of Cannabis for Headache Disorders.

Posted on September 2, 2017 by David Worrell

“Headache disorders are common, debilitating, and, in many cases, inadequately managed by existing treatments. Although clinical trials of cannabis for neuropathic pain have shown promising results, there has been limited research on its use, specifically for headache disorders. This review considers historical prescription practices, summarizes the existing reports on the use of cannabis for headache, and examines the preclinical literature exploring the role of exogenous and endogenous cannabinoids to alter headache pathophysiology. Currently, there is not enough evidence from well-designed clinical trials to support the use of cannabis for headache, but there are sufficient anecdotal and preliminary results, as well as plausible neurobiological mechanisms, to warrant properly designed clinical trials. Such trials are needed to determine short- and long-term efficacy for specific headache types, compatibility with existing treatments, optimal administration practices, as well as potential risks.” https://www.ncbi.nlm.nih.gov/pubmed/28861505 “Preclinical studies examining the role of the endocannabinoid system in migraine pathogenesis also suggest a potential therapeutic value for cannabis in the treatment of headache. It has been postulated that a general deficiency in endocannabinoid tone could underlie headache disorders.” http://online.liebertpub.com/doi/10.1089/can.2016.0033

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Cannabinoid Receptor 2 Modulates Neutrophil Recruitment in a Murine Model of Endotoxemia.

Posted on August 31, 2017 by David Worrell

“The endocannabinoid system consists of endogenous lipid mediators and cannabinoid receptors (CB) 1 and 2. It has previously been demonstrated that activation of the leukocyte-expressed CB₂ has anti-inflammatory effects in vivo. Here, we report its role under baseline conditions and in a model of low-dose endotoxemia by comparing CB₂ knockout to littermate control mice. CB₂-deficient mice displayed significantly more neutrophils and fewer monocytes in the bone marrow under steady state. In initial validation experiments, administration of 1 mg/kg LPS to male C57BL/6J mice was shown to transiently upregulate systemic proinflammatory mediators (peaked at 2 hours) and mobilise bone marrow neutrophils and monocytes into circulation. In CB₂ knockout mice, the level of the metalloproteinase MMP-9 was significantly elevated by 2 hours and we also observed augmented recruitment of neutrophils to the spleen in addition to increased levels of Ccl2, Ccl3, Cxcl10, and Il6. Collectively, our data show that the absence of CB₂ receptor increases the levels of innate immune cell populations in the bone marrow under steady state. Furthermore, during an acute systemic inflammatory insult, we observe a highly reproducible and site-specific increase in neutrophil recruitment and proinflammatory chemokine expression in the spleen of CB₂ knockout mice.” https://www.ncbi.nlm.nih.gov/pubmed/28852269 “In summary, we found that the lack of this GPCR leads to enhanced retention of neutrophils and increased release of monocytes in the bone marrow under steady state. We highlight a critical role for CB₂ in regulating neutrophil infiltration to the spleen during acute systemic inflammation. A potential mechanism for this effect is the increased secretion of MMP-9 and Ccl3/Cxcl10 expression in the spleens of CB₂ knockout mice. Taken together, we propose a novel role for CB₂ in suppressing neutrophil migration to lymphoid organs under inflammatory conditions which we believe warrants further investigation.” https://www.hindawi.com/journals/mi/2017/4315412/]]>

Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer's disease and levodopa-induced dyskinesia.

Posted on August 29, 2017 by David Worrell

“Endocannabinoids are important regulators of neurotransmission and, acting on activated microglia, they are postulated as neuroprotective agents. Endocannabinoid action is mediated by CB₁ and CB₂ receptors, which may form heteromeric complexes (CB₁-CB₂Hets) with unknown function in microglia. We aimed at establishing the expression and signaling properties of cannabinoidreceptors in resting and LPS/IFN-γ-activated microglia. Unlike CB₁, CB₂ receptors and CB₁-CB₂Hets were upregulated in activated microglia. Resting cell refractory CB₂ receptors became robustly coupled to G_i in activated cells, in which CB₁-CB₂Hets mediated a positive cross-talk. Resting cells were refractory while activated cells were highly responsive to cannabinoids. Interestingly, similar results were obtained in cultures treated with ß-amyloid (Aß_1-42). Activation microglial markers were detected in the striatum of a Parkinson’s disease (PD) model and, remarkably, in primary microglia cultures from the hippocampus of mutant β-amyloid precursor protein (APP_Sw,Ind) mice, a transgenic Alzheimer’s disease (AD) model. Also of note was the similar cannabinoid receptor signaling found in primary cultures of microglia from APP_Sw,Ind and in cells from control animals activated using LPS plus IFN- γ. Expression of CB₁-CB₂Hets was increased in the striatum from rats rendered dyskinetic by chronic levodopa treatment. In summary, our results showed sensitivity of activated microglial cells to cannabinoids, increased CB₁-CB₂Het expression in activated microglia and in microglia from the hippocampus of an AD model, and a correlation between levodopa-induced dyskinesia and striatal microglial activation in a PD model. Cannabinoid receptors and the CB₁-CB₂ heteroreceptor complex in activated microglia have potential as targets in the treatment of neurodegenerative diseases.” https://www.ncbi.nlm.nih.gov/pubmed/28843453 http://www.sciencedirect.com/science/article/pii/S0889159117304038]]>

Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer’s disease and levodopa-induced dyskinesia.

Posted on August 29, 2017 by David Worrell

Cover image

We aimed at establishing the expression and signaling properties of cannabinoidreceptors in resting and LPS/IFN-γ-activated microglia. Unlike CB₁, CB₂ receptors and CB₁-CB₂Hets were upregulated in activated microglia. Resting cell refractory CB₂ receptors became robustly coupled to G_i in activated cells, in which CB₁-CB₂Hets mediated a positive cross-talk. Resting cells were refractory while activated cells were highly responsive to cannabinoids. Interestingly, similar results were obtained in cultures treated with ß-amyloid (Aß_1-42). Activation microglial markers were detected in the striatum of a Parkinson’s disease (PD) model and, remarkably, in primary microglia cultures from the hippocampus of mutant β-amyloid precursor protein (APP_Sw,Ind) mice, a transgenic Alzheimer’s disease (AD) model. Also of note was the similar cannabinoid receptor signaling found in primary cultures of microglia from APP_Sw,Ind and in cells from control animals activated using LPS plus IFN- γ. Expression of CB₁-CB₂Hets was increased in the striatum from rats rendered dyskinetic by chronic levodopa treatment.

In summary, our results showed sensitivity of activated microglial cells to cannabinoids, increased CB₁-CB₂Het expression in activated microglia and in microglia from the hippocampus of an AD model, and a correlation between levodopa-induced dyskinesia and striatal microglial activation in a PD model. Cannabinoid receptors and the CB₁-CB₂ heteroreceptor complex in activated microglia have potential as targets in the treatment of neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/28843453

http://www.sciencedirect.com/science/article/pii/S0889159117304038

The potential role of cannabinoids in epilepsy treatment.

Posted on August 29, 2017 by David Worrell

“Epilepsy is one of the world’s oldest recognized and prevalent neurological diseases. It has a great negative impact on patients’ quality of life (QOL) as a consequence of treatment resistant seizures in about 30% of patients together with drugs’ side effects and comorbidities. Therefore, new drugs are needed and cannabinoids, above all cannabidiol, have recently gathered attention. This review summarizes the scientific data from human and animal studies on the major cannabinoids which have been of interest in the treatment of epilepsy, including drugs acting on the endocannabinoid system. Despite the fact that cannabis has been used for many purposes over 4 millennia, the development of drugs based on cannabinoids has been very slow. Only recently, research has focused on their potential effects and CBD is the first treatment of this group with clinical evidence of efficacy in children with Dravet syndrome; moreover, other studies are currently ongoing to confirm its effectiveness in patients with epilepsy. On the other hand, it will be of interest to understand whether drugs acting on the endocannabinoid system will be able to reach the market and prove their known preclinical efficacy also in patients with epilepsy.” https://www.ncbi.nlm.nih.gov/pubmed/28845714 http://www.tandfonline.com/doi/abs/10.1080/14737175.2017.1373019

“The role of cannabinoids and endocannabinoid system in the treatment of epilepsy. Cannabis has been used for thousands of years in the treatment of various diseases. Cannabinoids have been shown in preliminary animal model studies and in studies of patients with epilepsy to have antiepileptic activity. ” https://www.degruyter.com/view/j/joepi.ahead-of-print/joepi-2015-0034/joepi-2015-0034.xml

“Phytocannabinoids produce anticonvulsant effects through the endocannabinoid system, with few adverse effects.”

http://www.ncbi.nlm.nih.gov/pubmed/25475762

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Cannabinoids as Anticancer Drugs.

Posted on August 23, 2017 by David Worrell

“The endocannabinoid system encompassing cannabinoid receptors, endogenous receptor ligands (endocannabinoids), as well as enzymes conferring the synthesis and degradation of endocannabinoids has emerged as a considerable target for pharmacotherapeutical approaches of numerous diseases. Besides palliative effects of cannabinoids used in cancer treatment, phytocannabinoids, synthetic agonists, as well as substances that increase endogenous endocannabinoid levels have gained interest as potential agents for systemic cancer treatment. Accordingly, cannabinoid compounds have been reported to inhibit tumor growth and spreading in numerous rodent models. The underlying mechanisms include induction of apoptosis, autophagy, and cell cycle arrest in tumor cells as well as inhibition of tumor cell invasion and angiogenic features of endothelial cells. In addition, cannabinoids have been shown to suppress epithelial-to-mesenchymal transition, to enhance tumor immune surveillance, and to support chemotherapeutics’ effects on drug-resistant cancer cells. However, unwanted side effects include psychoactivity and possibly pathogenic effects on liver health. Other cannabinoids such as the nonpsychoactive cannabidiol exert a comparatively good safety profile while exhibiting considerable anticancer properties. So far experience with anticarcinogenic effects of cannabinoids is confined to in vitro studies and animal models. Although a bench-to-bedside conversion remains to be established, the current knowledge suggests cannabinoid compounds to serve as a group of drugs that may offer significant advantages for patients suffering from cancer diseases. The present review summarizes the role of the endocannabinoid system and cannabinoid compounds in tumor progression.” https://www.ncbi.nlm.nih.gov/pubmed/28826542 http://www.sciencedirect.com/science/article/pii/S105435891730039X?via%3Dihub]]>

Cannabinoids and Pain: Sites and Mechanisms of Action.

Posted on August 23, 2017 by David Worrell

“The endocannabinoid system, consisting of the cannabinoid₁ receptor (CB₁R) and cannabinoid₂ receptor (CB₂R), endogenous cannabinoid ligands (endocannabinoids), and metabolizing enzymes, is present throughout the pain pathways. Endocannabinoids, phytocannabinoids, and synthetic cannabinoid receptor agonists have antinociceptive effects in animal models of acute, inflammatory, and neuropathic pain. CB₁R and CB₂R located at peripheral, spinal, or supraspinal sites are important targets mediating these antinociceptive effects. The mechanisms underlying the analgesic effects of cannabinoids likely include inhibition of presynaptic neurotransmitter and neuropeptide release, modulation of postsynaptic neuronal excitability, activation of the descending inhibitory pain pathway, and reductions in neuroinflammatory signaling. Strategies to dissociate the psychoactive effects of cannabinoids from their analgesic effects have focused on peripherally restricted CB₁R agonists, CB₂R agonists, inhibitors of endocannabinoid catabolism or uptake, and modulation of other non-CB₁R/non-CB₂R targets of cannabinoids including TRPV1, GPR55, and PPARs. The large body of preclinical evidence in support of cannabinoids as potential analgesic agents is supported by clinical studies demonstrating their efficacy across a variety of pain disorders.” https://www.ncbi.nlm.nih.gov/pubmed/28826543 http://www.sciencedirect.com/science/article/pii/S1054358917300443?via%3Dihub]]>

Cannabinoids in the Cardiovascular System.

Posted on August 23, 2017 by David Worrell

“Cannabinoids are known to modulate cardiovascular functions including heart rate, vascular tone, and blood pressure in humans and animal models. Essential components of the endocannabinoid system, namely, the production, degradation, and signaling pathways of endocannabinoids have been described not only in the central and peripheral nervous system but also in myocardium, vasculature, platelets, and immune cells. The mechanisms of cardiovascular responses to endocannabinoids are often complex and may involve cannabinoid CB₁ and CB₂ receptors or non-CB_1/2 receptor targets. Preclinical and some clinical studies have suggested that targeting the endocannabinoid system can improve cardiovascular functions in a number of pathophysiological conditions, including hypertension, metabolic syndrome, sepsis, and atherosclerosis. In this chapter, we summarize the local and systemic cardiovascular effects of cannabinoids and highlight our current knowledge regarding the therapeutic potential of endocannabinoid signaling and modulation.” https://www.ncbi.nlm.nih.gov/pubmed/28826540 http://www.sciencedirect.com/science/article/pii/S1054358917300431?via%3Dihub]]>

Cannabinoid Receptor-Related Orphan G Protein-Coupled Receptors.

Posted on August 23, 2017 by David Worrell

“Of the druggable group of G protein-coupled receptors in the human genome, a number remain which have yet to be paired with an endogenous ligand-orphan GPCRs. Among these 100 or so entities, 3 have been linked to the cannabinoid system. GPR18, GPR55, and GPR119 exhibit limited sequence homology with the established CB₁ and CB₂ cannabinoid receptors. However, the pharmacology of these orphan receptors displays overlap with CB₁ and CB₂ receptors, particularly for GPR18 and GPR55. The linking of GPR119 to the cannabinoid receptors is less convincing and emanates from structural similarities of endogenous ligands active at these GPCRs, but which do not cross-react. This review describes the evidence for describing these orphan GPCRs as cannabinoid receptor-like receptors.” https://www.ncbi.nlm.nih.gov/pubmed/28826536 http://www.sciencedirect.com/science/article/pii/S1054358917300418?via%3Dihub]]>

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Tag Archives: endocannabinoid system

Cannabinoids in Parkinson’s Disease.

The Use of Cannabis for Headache Disorders.

Cannabinoid Receptor 2 Modulates Neutrophil Recruitment in a Murine Model of Endotoxemia.

Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer's disease and levodopa-induced dyskinesia.

Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer’s disease and levodopa-induced dyskinesia.

The potential role of cannabinoids in epilepsy treatment.

Cannabinoids as Anticancer Drugs.

Cannabinoids and Pain: Sites and Mechanisms of Action.

Cannabinoids in the Cardiovascular System.

Cannabinoid Receptor-Related Orphan G Protein-Coupled Receptors.