Microglial Cannabinoid Type 1 Receptor Regulates Brain Inflammation in a Sex-Specific Manner

A molecular docking approach was employed to evaluate the binding affinity of six triterpenes, namely epifriedelanol, friedelin, α-amyrin, α-amyrin acetate, β-amyrin acetate, and bauerenyl acetate, towards the cannabinoid type 1 receptor (CB1). Molecular docking studies showed that friedelin, α-amyrin, and epifriedelanol had the strongest binding affinity towards CB1. Molecular dynamics simulation studies revealed that friedelin and α-amyrin engaged in stable non-bonding interactions by binding to a pocket close to the active site on the surface of the CB1 target protein. The studied triterpenes showed a good capacity to penetrate the blood–brain barrier. These results help to provide some evidence to justify, at least in part, the previously reported antinociceptive and sedative properties of Vernonia patula.

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Cannabinoid Type 1 Receptor Antagonists Modulate Transport Activity of Multidrug Resistance-Associated Proteins MRP1, MRP2, MRP3, and MRP4

Drug Metabolism and Disposition ◽

10.1124/dmd.110.037812 ◽

2011 ◽

Vol 39 (7) ◽

pp. 1294-1302 ◽

Cited By ~ 30

Author(s):

Hanneke G. M. Wittgen ◽

Jeroen J. M. W. van den Heuvel ◽

Petra H. H. van den Broek ◽

Heike Dinter-Heidorn ◽

Jan B. Koenderink ◽

...

Keyword(s):

Multidrug Resistance ◽

Transport Activity ◽

Receptor Antagonists ◽

Cannabinoid Type 1 Receptor ◽

Associated Proteins

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Contrasting Roles of Ang II and ACEA in the Regulation of IL10 and IL1β Gene Expression in Primary SHR Astroglial Cultures

Molecules ◽

10.3390/molecules26103012 ◽

2021 ◽

Vol 26 (10) ◽

pp. 3012

Author(s):

Dhanush Haspula ◽

Michelle A. Clark

Keyword(s):

Gene Expression ◽

Wistar Rats ◽

Gene Signature ◽

Brain Regions ◽

Inhibitory Effect ◽

Ang Ii ◽

Cannabinoid Type 1 Receptor ◽

Il10 Gene ◽

Cerebellar Astrocytes

Angiotensin (Ang) II is well-known to have potent pro-oxidant and pro-inflammatory effects in the brain. Extensive crosstalk between the primary Ang II receptor, Ang type 1 receptor (AT1R), and the cannabinoid type 1 receptor (CB1R) has been demonstrated by various groups in the last decade. Since activation of glial CB1R has been demonstrated to play a key role in the resolution of inflammatory states, we investigated the role of Ang II (100 nM) and/or ACEA (10 nM), a potent CB1R-specific agonist in the regulation of inflammatory markers in astrocytes from spontaneously hypertensive rats (SHR) and Wistar rats. Astrocytes were cultured from brainstems and cerebellums of SHR and Wistar rats and assayed for IL1β and IL10 gene expression and secreted fraction, in treated and non-treated cells, by employing qPCR and ELISA, respectively. mRNA expression of both IL10 and IL1β were significantly elevated in untreated brainstem and cerebellar astrocytes isolated from SHR when compared to Wistar astrocytes. No changes were observed in the secreted fraction. While ACEA-treatment resulted in a significant increase in IL10 gene expression in Wistar brainstem astrocytes (Log2FC ≥ 1, p < 0.05), its effect in SHR brainstem astrocytes was diminished. Ang II treatment resulted in a strong inhibitory effect on IL10 gene expression in astrocytes from both brain regions of SHR and Wistar rats (Log2FC ≤ −1, p < 0.05), and an increase in IL1β gene expression in brainstem astrocytes from both strains (Log2FC ≥ 1, p < 0.05). Co-treatment of Ang II and ACEA resulted in neutralization of Ang II-mediated effect in Wistar brainstem and cerebellar astrocytes, but not SHR astrocytes. Neither Ang II nor ACEA resulted in any significant changes in IL10 or IL1β secreted proteins. These data suggest that Ang II and ACEA have opposing roles in the regulation of inflammatory gene signature in astrocytes isolated from SHR and Wistar rats. This however does not translate into changes in their secreted fractions.

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Discovery of 1-[9-(4-Chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4-ethylaminopiperidine-4-carboxylic Acid Amide Hydrochloride (CP-945,598), a Novel, Potent, and Selective Cannabinoid Type 1 Receptor Antagonist

Journal of Medicinal Chemistry ◽

10.1021/jm8012932 ◽

2009 ◽

Vol 52 (2) ◽

pp. 234-237 ◽

Cited By ~ 51

Author(s):

David A. Griffith ◽

John R. Hadcock ◽

Shawn C. Black ◽

Philip A. Iredale ◽

Philip A. Carpino ◽

...

Keyword(s):

Carboxylic Acid ◽

Receptor Antagonist ◽

Acid Amide ◽

Carboxylic Acid Amide ◽

Cannabinoid Type 1 Receptor

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Methamphetamine Administration Increases Proceptive Behavior by Activating Src Kinase and Upregulating Progesterone Receptor in the Medial Amygdala

10.1101/475616 ◽

2018 ◽

Cited By ~ 1

Author(s):

Katrina M Williams ◽

Sarah A Rudzinskas ◽

Jessica A Mong

Keyword(s):

Progesterone Receptor ◽

Phosphorylation Site ◽

Progesterone Receptors ◽

Receptor Expression ◽

Medial Amygdala ◽

Specific Manner ◽

Receptor Action ◽

Necessary And Sufficient ◽

Motivated Behaviors

Methamphetamine, a psychostimulant drug of abuse, increases sexual motivation both in humans and in rodent models. The activation of dopamine type-1 receptors (D1Rs) within the medial amygdala, in the presence of ovarian hormones (EB+P), are both necessary and sufficient for increases in proceptive, or sexually motivated, behaviors. Here, we demonstrate that methamphetamine increases progesterone receptor expression in the medial amygdala independently of D1R activation, and that lentiviral overexpression of the progesterone receptor was able to recapitulate the methamphetamine-induced enhancement of proceptive behaviors. Furthermore, we found that within the medial amygdala, these progesterone receptors show an increase in phosphorylation of serine 294 of the progesterone receptor in a region-specific manner. The involvement of this phosphorylation site suggests a role for cytosolic kinases, which may be responsible for enhanced progesterone receptor action. The phosphorylation of serine 294 is blocked by D1R antagonists, and by inhibiting cSrc and ERK1/2, downstream of D1R signaling, we identified that Src and ERK1/2 are required for enhanced proceptive behavior. Taken together, we propose that within the medial amygdala, methamphetamine enhances progesterone receptors sensitivity to its cognate ligand via interaction with cSrc kinase and ERK1/2, as well as an increase total progesterone receptors, thus leading to enhanced proceptive behaviors in the rat.

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Long-term decreased cannabinoid type-1 receptor activity restores specific neurological phenotypes in the Ts65Dn mouse model of Down syndrome

10.1101/2021.11.22.469296 ◽

2021 ◽

Author(s):

Anna Vazquez-Oliver ◽

Silvia Perez-Garcia ◽

Nieves Pizarro ◽

Laura Molina-Porcel ◽

Rafael de la Torre ◽

...

Keyword(s):

Down Syndrome ◽

Side Effects ◽

Mouse Model ◽

Neurological Deficits ◽

Wild Type ◽

Male And Female ◽

Cannabinoid Type 1 Receptor ◽

Cognitive Improvement

Intellectual disability is the most prevalent and limiting hallmark of Down syndrome (DS), without any pharmacological treatment available. Neurodegeneration and neuroinflammation are relevant neurological features of DS reaching to early development of Alzheimer s disease. Preclinical evidence suggests that the endocannabinoid system, an important neuromodulator on cognition and neuroinflammation, could act as beneficial target in DS. Indeed, cannabinoid type-1 receptor (CB1R) activity was enhanced in the hippocampus of young-adult trisomic Ts65Dn mice, a well-characterized surrogate model of DS. In previous studies, inhibition of CB1R, was able to restore key neurological deficits in this mouse model. To determine the possible clinical relevance of this target, it is mandatory to evaluate the long-term consequences of attenuated CB1R activity and to minimize the possible side-effects associated to this mechanism. We found that CB1R expression was significantly enhanced in the hippocampus brains of aged DS subjects. Similarly, middle-aged trisomic mice showed enhanced CB1R expression. Long-term oral administration of a low dose of the CB1R specific antagonist rimonabant was administered to male and female Ts65Dn trisomic and wild-type mice from the time of weaning to 10 months, an age when signs of neurodegeneration have been described in the model. CB1R inhibition resulted in significant cognitive improvement in novel object-recognition memory in trisomic male and female mice, reaching a similar performance to that of wild-type littermates. Interestingly, this long-term rimonabant treatment modify locomotor activity, anxiety-like behavior, body weight or survival rates. Brain analysis at 10 months of age revealed noradrenergic and cholinergic neurodegeneration signs in trisomic mice that were not modified by the treatment, although the alterations in hippocampal microglia morphology shown by vehicle-treated trisomic mice was normalized in trisomic mice exposed to rimonabant. Altogether, our results demonstrate a sustained pro-cognitive effect of CB1R inhibition at doses that do not produce major side effects that could be associated to an anti-inflammatory action, suggesting a potential interest in this target of to preserve cognitive functionality in DS.

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