Brain cannabinoid systems as targets for the therapy of neurological disorders.

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“Unprecedented developments in cannabinoid research within the past decade include discovery of a brain (CB1) and peripheral (CB2) receptor; endogenous ligands, anandamide, and 2-arachidonylglycerol; cannabinoid drug-induced partial and inverse agonism at CB1 receptors, antagonism of NMDA receptors and glutamate, and antioxidant activity; and preferential CB1 receptor localization in areas subserving spasticity, pain, abnormal involuntary movements, seizures, and amnesia. These endogenous structures and chemicals and mechanisms are potentially new pathophysiologic substrates, and targets for novel cannabinoid treatments, of several neurological disorders.” https://www.ncbi.nlm.nih.gov/pubmed/9974182 

“Endocannabinoid System in Neurological Disorders.” https://www.ncbi.nlm.nih.gov/pubmed/27364363
“Cannabinoids in the Treatment of Neurological Disorders” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604187/
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Activation of cannabinoid receptors elicits antidepressant-like effects in a mouse model of social isolation stress.

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“Social isolation stress (SIS) paradigm is a chronic stress procedure able to induce profound behavioral and neurochemical changes in rodents and evokes depressive and anxiety-like behaviors.

Recent studies demonstrated that the cannabinoid system plays a key role in behavioral abnormalities such as depression through different pathways; however, there is no evidence showing a relation between SIS and the cannabinoid system.

This study investigated the role of the cannabinoid system in depressive-like behavior and anxiety-like behavior of IC animals.

Our findings suggest that the cannabinoid system is involved in depressive-like behaviors induced by SIS.

We showed that activation of cannabinoid receptors (type 1 and 2) could mitigate depression-like behavior induced by SIS in a mouse model.”

https://www.ncbi.nlm.nih.gov/pubmed/28161196

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Antihyperalgesic effect of CB1 receptor activation involves the modulation of P2X3 receptor in the primary afferent neuron.

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“Cannabinoid system is a potential target for pain control.

Cannabinoid receptor 1 (CB1) activation play a role in the analgesic effect of cannabinoids once it is expressed in primary afferent neurons.

This study investigates whether the anti-hyperalgesic effect of CB1receptor activation involves P2×3 receptor in primary afferent neurons.

Our data suggest that the analgesic effect of CB1 receptor activation is mediated by a negative modulation of the P2×3 receptor in the primary afferent neurons.”

https://www.ncbi.nlm.nih.gov/pubmed/28131783

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Decreased CB receptor binding and cannabinoid signaling in three brain regions of a rat model of schizophrenia.

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“Schizophrenia is a serious mental health disorder characterized by several behavioral and biochemicel abnormalities.

In a previous study we have shown that mu-opioid (MOP) receptor signaling is impaired in specific brain regions of our three-hit animal model of schizophrenia. Since the cannabinoid system is significantly influenced in schizophrenic patients, in the present work we investigated cannabinoid (CB) receptor binding and G-protein activation in cortical, subcortical and cerebellar regions of control and ‘schizophrenic’ rats.

Taken together, in all three brain areas of model rats both cannabinoid receptor binding and cannabinoid agonist-mediated G-protein activation were regularly decreased.

Our results revealed that besides the opioids, the endocannabinoid – cannabis receptor system also shows impairment in our rat model, increasing its face validity and translational utility.”

https://www.ncbi.nlm.nih.gov/pubmed/27639959

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Cannabinoid receptors and TRPA1 on neuroprotection in a model of retinal ischemia.

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“Retinal ischemia is a pathological event present in several retinopathies such as diabetic retinopathy and glaucoma, leading to partial or full blindness with no effective treatment available.

Since synthetic and endogenous cannabinoids have been studied as modulators of ischemic events in the central nervous system (CNS), the present study aimed to investigate the involvement of cannabinoid system in the cell death induced by ischemia in an avascular (chick) retina.

We observed that chick retinal treatment with a combination of WIN 55212-2 and cannabinoid receptor antagonists (either AM251/O-2050 or AM630) decreased the release of lactate dehydrogenase (LDH) induced by retinal ischemia in an oxygen and glucose deprivation (OGD) model.

Further, the increased availability of endocannabinoids together with cannabinoid receptor antagonists also had a neuroprotective effect.

Surprisingly, retinal exposure to any of these drugs alone did not prevent the release of LDH stimulated by OGD.

Since cannabinoids may also activate transient receptor potential (TRP) channels, we investigated the involvement of TRPA1 receptors (TRPA1) in retinal cell death induced by ischemic events.

We demonstrated the presence of TRPA1 in the chick retina, and observed an increase in TRPA1 content after OGD, both by western blot and immunohistochemistry.

In addition, the selective activation of TRPA1 by mustard oil (MO) did not worsen retinal LDH release induced by OGD, whereas the blockage of TRPA1 completely prevented the extravasation of cellular LDH in ischemic condition.

Hence, these results show that during the ischemic event there is an augment of TRPA1, and activation of this receptor is important in cell death induction.

The data also indicate that metabotropic cannabinoid receptors, both type 1 and 2, are not involved with the cell death found in the early stages of ischemia. Therefore, the study points to a potential role of TRPA1 as a target for neuroprotective approaches in retinal ischemia.”

https://www.ncbi.nlm.nih.gov/pubmed/27876485

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High-resolution crystal structure of the human CB1 cannabinoid receptor.

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“The human cannabinoid G-protein-coupled receptors (GPCRs) CB1 and CB2 mediate the functional responses to the endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG), as well as the widely consumed plant (phyto)cannabinoid Δ9-tetrahydrocannabinol (THC)1. The cannabinoid receptors have been the targets of intensive drug discovery efforts owing to the therapeutic potential of modulators for controlling pain2, epilepsy3, obesity4, and other maladies. Although much progress has recently been made in understanding the biophysical properties of GPCRs, investigations of the molecular mechanisms of the cannabinoids and their receptors have lacked high-resolution structural data. We used GPCR engineering and lipidic cubic phase (LCP) crystallization to determine the structure of the human CB1 receptor bound to the inhibitor taranabant at 2.6 Å resolution. The extracellular surface of CB1, including the highly conserved membrane-proximal amino-terminal (N-terminal) region, is distinct from other lipid-activated GPCRs and forms a critical part of the ligand binding pocket. Docking studies further demonstrate how this same pocket may accommodate the cannabinoid agonist THC. Our CB1 structure provides an atomic framework for studying cannabinoid receptor function, and will aid the design and optimization of cannabinoid system modulators for therapeutic ends.”

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Tissue Engineering of Cartilage; Can Cannabinoids Help?

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“This review discusses the role of the cannabinoid system in cartilage tissue and endeavors to establish if targeting the cannabinoid system has potential in mesenchymal stem cell based tissue-engineered cartilage repair strategies.

The review discusses the potential of cannabinoids to protect against the degradation of cartilage in inflamed arthritic joints and the influence of cannabinoids on the chondrocyte precursors, mesenchymal stem cells (MSCs).

We provide experimental evidence to show that activation of the cannabinoid system enhances the survival, migration and chondrogenic differentiation of MSCs, which are three major tenets behind the success of a cell-based tissue-engineered cartilage repair strategy.

These findings highlight the potential for cannabinoids to provide a dual function by acting as anti-inflammatory agents as well as regulators of MSC biology in order to enhance tissue engineering strategies aimed at cartilage repair.”

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Dendritic Cell Regulation by Cannabinoid-Based Drugs.

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“Cannabinoid pharmacology has made important advances in recent years after the cannabinoid system was discovered.

Studies in experimental models and in humans have produced promising results using cannabinoid-based drugs for the treatment of obesity and cancer, as well as neuroinflammatory and chronic inflammatory diseases.

Moreover, as we discuss here, additional studies also indicates that these drugs have immunosuppressive and anti-inflammatory properties including modulation of immune cell function.

Thus, manipulation of the endocannabinoid system in vivo may provide novel therapeutic strategies against inflammatory disorders.

At least two types of cannabinoid receptors, cannabinoid 1 and cannabinoid 2 receptors are expressed on immune cells such as dendritic cells (DC). Dendritic cells are recognized for their critical role in initiating and maintaining immune responses.

Therefore, DC are potential targets for cannabinoid-mediated modulation.

Here, we review the effects of cannabinoids on DC and provide some perspective concerning the therapeutic potential of cannabinoids for the treatment of human diseases involving aberrant inflammatory processes.”

https://www.ncbi.nlm.nih.gov/pubmed/27713374

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Cannabinoids and Dementia: A Review of Clinical and Preclinical Data.

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“The endocannabinoid system has been shown to be associated with neurodegenerative diseases and dementia.

We review the preclinical and clinical data on cannabinoids and four neurodegenerative diseases: Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD) and vascular dementia (VD).

Numerous studies have demonstrated an involvement of the cannabinoid system in neurotransmission, neuropathology and neurobiology of dementias. In addition, several candidate compounds have demonstrated efficacy in vitro.

However, some of the substances produced inconclusive results in vivo. Therefore, only few trials have aimed to replicate the effects seen in animal studies in patients. Indeed, the literature on cannabinoid administration in patients is scarce.

While preclinical findings suggest causal treatment strategies involving cannabinoids, clinical trials have only assessed the suitability of cannabinoid receptor agonists, antagonists and cannabidiol for the symptomatic treatment of dementia.

Further research is needed, including in vivo models of dementia and human studies.”

https://www.ncbi.nlm.nih.gov/pubmed/27713372

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Cannabinoids and GI Disorders: Endogenous and Exogenous.

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“Despite the political and social controversy affiliated with it, the medical community must come to the realization that cannabinoids exist as a ubiquitous signaling system in many organ systems. Our understanding of cannabinoids and how they relate not only to homeostasis but also in disease states must be furthered through research, both clinically and in the laboratory. The identification of the cannabinoid receptors in the early 1990s have provided us with the perfect target of translational research. Already, much has been done with cannabinoids and the nervous system. Here, we explore the implications it has for the gastrointestinal tract. Most therapeutics currently on the market presently target only one aspect of the cannabinoid system. Our main purpose here is to highlight areas of research and potential avenues of discovery that the cannabinoid system has yet to reveal.”

https://www.ncbi.nlm.nih.gov/pubmed/27699625

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