Tag Archives: cannabinoid

Cannabinoid receptor type 1 modulates the effects of polyunsaturated fatty acids on memory of stressed rats.

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 Publication Cover“Memory and GABAergic activity in the hippocampus of stressed rats improve after n-3 polyunsaturated fatty acid (PUFA) supplementation.

On the other hand, cannabinoid receptor type 1 (CB1) strongly regulates inhibitory neurotransmission in the hippocampus. Speculation about a possible relation between stress, endocannabinoids, and PUFAs.

Here, we examined whether the effects of PUFAs on memory of chronically stressed rats depends on pharmacological manipulation of CB1 receptors.

Memory improved in the stressed rats that were treated with AM251 and/or n-3 PUFAs. Supplementation with n-6 PUFAs did not affect memory of stressed rats, but co-treatment with AM251 improved it, while co-treatment with WIN55,212-2 did not affect memory.

Our results demonstrate that activity of the CB1 receptors may modulate the effects of PUFAs on memory of stressed rats. This study suggests that endocannabinoids and PUFAs can both become a singular system by being self-regulated in limbic areas, so they control the effects of stress on the brain.”

https://www.ncbi.nlm.nih.gov/pubmed/31637966

https://www.tandfonline.com/doi/abs/10.1080/1028415X.2019.1659561?journalCode=ynns20

Cannabidiol As A Novel Therapeutic Strategy For Oral Inflammatory Diseases: A Review Of Current Knowledge And Future Perspectives.

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Image result for altern ther health med “The high frequency and painful profile of inflammatory oral lesions and the lack of an effective drug protocol for their management stimulate the search for pharmacological alternatives for the treatment of these conditions. Cannabidiol is the major non-psychotropic constituent of Cannabis sativa, receiving lately scientific interest because of its potential in the treatment of inflammatory disorders such as asthma, colitis and arthritis. There is little published in the current literature about the use of cannabidiol in oral health. Among its many protective functions, the ability to attenuate inflammation through the modulation of cytokines and its antiedema and analgesic effects may be important features in the treatment of oral lesions. In this review, we suggest that cannabidiol can be useful in the management of oral inflammatory disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/31634872

Ligands of the CB2 cannabinoid receptors augment activity of the conventional antidepressant drugs in the behavioural tests in mice.

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Behavioural Brain Research“Although a lot of information can be found on the specific dual role of the endocannabinoid system in the emotional-related responses, little is known whether stimulation or inhibition of the CB receptors may affect the activity of the frequently prescribed antidepressant drugs.

Our interests have been particularly focused on the potential influence of the CB2 receptors, as the ones whose central effects are relatively poorly documented when compared to the central effects of the CB1 receptors. Therefore, we evaluated the potential interaction between the CB2 receptor ligands (i.e., JWH133 – CB2 receptor agonist and AM630 – CB2 receptor inverse agonist) and several common antidepressant drugs that influence the monoaminergic system (i.e., imipramine, escitalopram, reboxetine).

Summarizing, the results of the present study revealed that both activation and inhibition of the CB2 receptor function have a potential to strengthen the antidepressant activity of drugs targeting the monoaminergic system. Most probably, the described interaction has a pharmacodynamic background.”

https://www.ncbi.nlm.nih.gov/pubmed/31626848

“Interplay between CB2 receptor ligands and antidepressants is pharmacodynamic in nature.”

https://www.sciencedirect.com/science/article/pii/S0166432819311891?via%3Dihub

Altered cannabinoid receptor expression in pancreatic islets in experimental model of uremia.

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Folia Morphologica “Uremia leads to a number of metabolic and hormonal disorders including defective carbohydrate metabolism.

Endocannabinoids exert their effect on insulin and glucagon secretion via activation of specific receptors named CB1 and CB2. For this reason and the absence of reports on location and immunoreactivity of CB1, CB2 receptors compared to immunoreactivity of insulin- and glucagon- secreting cells in experimental uremia, the author decided to investigate this issue.

The aim of the present study was the immunohistochemical localization and evaluation of cannabinoid receptors (CB1, CB2), insulin and glucagon in the pancreatic islets of uremic rats.

RESULTS:

It was revealed the decreased immunoreactivity of the CB1 receptor and higher intensity of the immunohistochemical reaction against CB2 receptor as compared to the value in the control animals. Significantly higher immunoreactivity of glucagon-positive cells and weaker immunoreactivity of insulin-positive cells were observed in pancreatic islets of uremic rats.

CONCLUSIONS:

The obtained results indicate the involvement of cannabinoid receptors in the pathomechanism of carbohydrate metabolism disorders, associated with abnormal secretion of hormones by the α and β cells in uremia.”

https://www.ncbi.nlm.nih.gov/pubmed/31625133

https://journals.viamedica.pl/folia_morphologica/article/view/64828

“Uremia is a clinical syndrome marked by elevated concentrations of urea in the blood and associated with fluid, electrolyte, and hormone imbalances and metabolic abnormalities, which develop in parallel with deterioration of renal function.  The term uremia, which literally means urine in the blood, was first used by Piorry to describe the clinical condition associated with renal failure”  https://emedicine.medscape.com/article/245296-overview

Neuropeptide Y and cannabinoids interaction in the amygdala after exposure to shock and reminders model of PTSD.

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Neuropharmacology“Modulation of cannabinoid and neuropeptide Y (NPY) receptors may offer therapeutic benefits for post-traumatic stress disorder (PTSD).

In this study, we aimed to investigate the functional interaction between these systems in the basolateral amygdala (BLA) in a rat model of PTSD.

The findings suggest that the functional interaction between the eCB and NPY1 systems is complex and provide a rationale for exploring novel therapeutic strategies that target the cannabinoid and NPY systems for stress-related diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/31622603

https://www.sciencedirect.com/science/article/pii/S0028390819303661?via%3Dihub

Systematic Affinity Purification Coupled to Mass Spectrometry Identified p62 as Part of the Cannabinoid Receptor CB2 Interactome.

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Image result for frontiers in molecular neuroscience“The endocannabinoid system (ECS) consists particularly of cannabinoid receptors 1 and 2 (CB1 and CB2), their endogenous ligands, and enzymes that synthesize and degrade their ligands. It acts in a variety of organs and disease states ranging from cancer progression over neuropathic pain to neurodegeneration. Protein components engaged in the signaling, trafficking, and homeostasis machinery of the G-protein coupled CB2, are however largely unknown. It is therefore important to identify further interaction partners to better understand CB2 receptor functions in physiology and pathophysiology. For this purpose, we used an affinity purification and mass spectrometry-based proteomics approach of Strep-HA-CB2 receptor in HEK293 cells. After subtraction of background interactions and protein frequency library assessment we could identify 83 proteins that were classified by the identification of minimally 2 unique peptides as highly probable interactors. A functional protein association network analysis obtained an interaction network with a significant enrichment of proteins functionally involved in protein metabolic process, in endoplasmic reticulum, response to stress but also in lipid metabolism and membrane organization. The network especially contains proteins involved in biosynthesis and trafficking like calnexin, Sec61A, tubulin chains TUBA1C and TUBB2B, TMED2, and TMED10. Six proteins that were only expressed in stable CB2 expressing cells were DHC24, DHRS7, GGT7, HECD3, KIAA2013, and PLS1. To exemplify the validity of our approach, we chose a candidate having a relatively low number of edges in the network to increase the likelihood of a direct protein interaction with CB2 and focused on the scaffold/phagosomal protein p62/SQSTM1. Indeed, we independently confirmed the interaction by co-immunoprecipitation and immunocytochemical colocalization studies. 3D reconstruction of confocal images furthermore showed CB2 localization in close proximity to p62 positive vesicles at the cell membrane. In summary, we provide a comprehensive repository of the CB2 interactome in HEK293 cells identified by a systematic unbiased approach, which can be used in future experiments to decipher the signaling and trafficking complex of this cannabinoid receptor. Future studies will have to analyze the exact mechanism of the p62-CB2 interaction as well as its putative role in disease pathophysiology.”

https://www.ncbi.nlm.nih.gov/pubmed/31616248

https://www.frontiersin.org/articles/10.3389/fnmol.2019.00224/full

Cannabinoid Receptor Interacting Protein 1a (CRIP1a): Function and Structure.

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molecules-logo“Cannabinoid receptor interacting protein 1a (CRIP1a) is an important CB1 cannabinoid receptor-associated protein, first identified from a yeast two-hybrid screen to modulate CB1-mediated N-type Ca2+ currents. In this paper we review studies of CRIP1a function and structure based upon in vitro experiments and computational chemistry, which elucidate the specific mechanisms for the interaction of CRIP1a with CB1 receptors. N18TG2 neuronal cells overexpressing or silencing CRIP1a highlighted the ability of CRIP1 to regulate cyclic adenosine 3′,5’monophosphate (cAMP) production and extracellular signal-regulated kinase (ERK1/2) phosphorylation. These studies indicated that CRIP1a attenuates the G protein signaling cascade through modulating which Gi/o subtypes interact with the CB1 receptor. CRIP1a also attenuates CB1 receptor internalization via β-arrestin, suggesting that CRIP1a competes for β-arrestin binding to the CB1 receptor. Predictions of CRIP1a secondary structure suggest that residues 34-110 are minimally necessary for association with key amino acids within the distal C-terminus of the CB1 receptor, as well as the mGlu8a metabotropic glutamate receptor. These interactions are disrupted through phosphorylation of serines and threonines in these regions. Through investigations of the function and structure of CRIP1a, new pharmacotherapies based upon the CRIP-CB1 receptor interaction can be designed to treat diseases such as epilepsy, motor dysfunctions and schizophrenia.”

https://www.ncbi.nlm.nih.gov/pubmed/31614728

https://www.mdpi.com/1420-3049/24/20/3672

The Endocannabinoid System as a Window Into Microglial Biology and Its Relationship to Autism.

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Image result for frontiers in cellular neuroscience“Microglia are the resident, innate immune cells of the central nervous system (CNS) and are critical in managing CNS injuries and infections. Microglia also maintain CNS homeostasis by influencing neuronal development, viability, and function. However, aberrant microglial activity and phenotypes are associated with CNS pathology, including autism spectrum disorder (ASD). Thus, improving our knowledge of microglial regulation could provide insights into the maintenance of CNS homeostasis as well as the prevention and treatment of ASD.

Control of microglial activity is in part overseen by small, lipid-derived molecules known as endogenous cannabinoids (endocannabinoids). Endocannabinoids are one component of the endocannabinoid system (ECS), which also includes the enzymes that metabolize these ligands, in addition to cannabinoid receptor 1 (CB1) and 2 (CB2).

Interestingly, increased ECS signaling leads to an anti-inflammatory, neuroprotective phenotype in microglia. Here, we review the literature and propose that ECS signaling represents a largely untapped area for understanding microglial biology and its relationship to ASD, with special attention paid to issues surrounding the use of recreational cannabis (marijuana). We also discuss major questions within the field and suggest directions for future research.”

https://www.ncbi.nlm.nih.gov/pubmed/31619967

“Microglial activity can be modulated by eCB signaling, which makes the ECS a potentially forceful tool in the prevention and management of CNS dysfunction.”

https://www.frontiersin.org/articles/10.3389/fncel.2019.00424/full

Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions.

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Epilepsia banner“Cannabidiol (CBD) has been approved by the US Food and Drug Administration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox-Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first-line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam.

RESULTS:

CBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N-CLB. Combination CBD-clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a+/- mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub-anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABAA receptor activation.

SIGNIFICANCE:

Our study highlights the involvement of both pharmacodynamic and pharmacokinetic interactions between CBD and clobazam that may contribute to its efficacy in Dravet syndrome.”

https://www.ncbi.nlm.nih.gov/pubmed/31625159

“Our results here suggest a novel benefit of CBD and clobazam combination therapy on premature death, a devastating aspect of the Dravet syndrome phenotype.”

https://onlinelibrary.wiley.com/doi/full/10.1111/epi.16355

Modulation of the Endocannabinoid and Oxytocinergic Systems as a Potential Treatment Approach for Social Anxiety Disorder.

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 “Social anxiety disorder (SAD), or social phobia, is one of the most common types of anxiety disorder, with a lifetime prevalence that can reach 15%.

Pharmacological treatments for SAD have moderate efficacy and are associated with significant adverse reactions. Therefore, recent studies have focused on searching for new treatments for this disorder.

Preclinical studies and preliminary evidence in humans suggest that the phytocannabinoid cannabidiol and the neuropeptide oxytocin have anxiolytic effects. In the present text, we review this evidence and its implications for pharmacological treatment.

We conclude that although current available studies show promising results regarding both the safety and efficacy of cannabidiol and oxytocin for the treatment of SAD, most studies were performed using single or few doses of these compounds, with small sample sizes.

Therefore, future studies should explore the anxiolytic potential of these compounds using long-term, placebo-controlled designs with larger samples to elucidate the possible use of these compounds in the treatment of SAD.”

https://www.ncbi.nlm.nih.gov/pubmed/31617149

https://link.springer.com/article/10.1007%2Fs40263-019-00669-5