scholarly journals Δ 9 -Tetrahydrocannabinol Promotes Functional Remyelination in the Mouse Brain

2021 ◽  
Author(s):  
Tania Aguado ◽  
Alba Huerga-Gómez ◽  
Aníbal Sánchez-De la Torre ◽  
Eva Resel ◽  
Juan Carlos Chara ◽  
...  
Keyword(s):  
Cannabis Sativa ◽  
Cannabinoid Receptor ◽  
Receptor Activation ◽  
Cell Cycle Exit ◽  
Active Constituent ◽  
Cb1 Cannabinoid Receptor ◽  
Function Recovery ◽  
Oligodendrocyte Precursor ◽  
Demyelinating Disorders ◽  
Cerebellar Cultures

Abstract Background: Research on demyelinating disorders aims to find novel molecules able to induce oligodendrocyte precursor cell differentiation to promote CNS remyelination and functional recovery. Δ9-Tetrahydrocannabinol (THC), the most prominent active constituent of the hemp plant Cannabis sativa, confers neuroprotection in animal models of demyelination. However, the possible effect of THC on myelin repair has never been studied. Methods: By using oligodendroglia-specific reporter mouse lines in combination with 2 models of toxin-induced demyelination, we analyzed the effect of THC on the processes of oligodendrocyte regeneration and functional remyelination. Results: We show that THC administration enhanced oligodendrocyte regeneration, white matter remyelination, and motor function recovery. THC also promoted axonal remyelination in organotypic cerebellar cultures. THC remyelinating action relied on the induction of oligodendrocyte precursor differentiation upon cell cycle exit and via CB1 cannabinoid receptor activation. Conclusions: Overall, our study identifies THC administration as a promising pharmacological strategy aimed to promote functional CNS remyelination in demyelinating disorders.

scholarly journals A2A Adenosine Receptor Antagonism Enhances Synaptic and Motor Effects of Cocaine via CB1 Cannabinoid Receptor Activation

PLoS ONE ◽  
2012 ◽  
Vol 7 (6) ◽  
pp. e38312 ◽  
Author(s):  
Alessandro Tozzi ◽  
Antonio de Iure ◽  
Valentina Marsili ◽  
Rosaria Romano ◽  
Michela Tantucci ◽  
...  
Keyword(s):  
Adenosine Receptor ◽  
Cannabinoid Receptor ◽  
Receptor Activation ◽  
A2a Adenosine Receptor ◽  
Receptor Antagonism ◽  
Cb1 Cannabinoid Receptor ◽  
Motor Effects

scholarly journals Energetic Metabolism and Human Sperm Motility: Impact of CB1 Receptor Activation

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5882-5892 ◽  
Author(s):  
A. Barbonetti ◽  
M. R. C. Vassallo ◽  
D. Fortunato ◽  
S. Francavilla ◽  
M. Maccarrone ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Sperm Motility ◽  
Cannabinoid Receptor ◽  
Human Sperm ◽  
Receptor Activation ◽  
Mitochondrial Activity ◽  
Energetic Metabolism ◽  
Cb1 Cannabinoid Receptor ◽  
High Doses

It has been reported that the endocannabinoid anandamide (AEA) exerts an adverse effect on human sperm motility, which has been ascribed to inhibition of mitochondrial activity. This seems to be at variance with evidence suggesting a major role of glycolysis in supplying ATP for sperm motility; furthermore, the role of AEA-binding receptors in mediating mitochondrial inhibition has not yet been explored. In this study, human sperm exposure to Met-AEA (methanandamide, nonhydrolyzable analog of AEA) in the micromolar range significantly decreased mitochondrial transmembrane potential (ΔΨm), similarly to rotenone, mitochondrial complex I inhibitor. The effect of Met-AEA (1 μm) was prevented by SR141716, CB1 cannabinoid receptor antagonist, but not by SR144528, CB2 antagonist, nor by iodoresiniferatoxin, vanilloid receptor antagonist. The effect of Met-AEA did not involve activation of caspase-9 or caspase-3 and was reverted by washing. In the presence of glucose, sperm exposure either to Met-AEA up to 1 μm or to rotenone for up to 18 h did not affect sperm motility. At higher doses Met-AEA produced a CB1-independent poisoning of spermatozoa, reducing their viability. Under glycolysis blockage, 1 μm Met-AEA, similarly to rotenone, dramatically abolished sperm motility, an effect that was prevented by SR1 and reverted by washing. In conclusion, CB1 activation induced a nonapoptotic decrease of ΔΨm, the detrimental reflection on sperm motility of which could be revealed only under glycolysis blockage, unless very high doses of Met-AEA, producing CB1-independent sperm toxicity, were used. The effects of CB1 activation reported here contribute to elucidate the relationship between energetic metabolism and human sperm motility.

scholarly journals CB1 Cannabinoid Receptor Signaling and Biased Signaling

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5413
Author(s):  
Luciana M. Leo ◽  
Mary E. Abood
Keyword(s):  
Adverse Effects ◽  
G Protein ◽  
Conformational Changes ◽  
Cannabinoid Receptor ◽  
Therapeutic Potential ◽  
Receptor Activation ◽  
Cb1 Receptor ◽  
Cb1 Cannabinoid Receptor ◽  
Biased Signaling ◽  
G Protein Coupled

The CB1 cannabinoid receptor is a G-protein coupled receptor highly expressed throughout the central nervous system that is a promising target for the treatment of various disorders, including anxiety, pain, and neurodegeneration. Despite the wide therapeutic potential of CB1, the development of drug candidates is hindered by adverse effects, rapid tolerance development, and abuse potential. Ligands that produce biased signaling—the preferential activation of a signaling transducer in detriment of another—have been proposed as a strategy to dissociate therapeutic and adverse effects for a variety of G-protein coupled receptors. However, biased signaling at the CB1 receptor is poorly understood due to a lack of strongly biased agonists. Here, we review studies that have investigated the biased signaling profile of classical cannabinoid agonists and allosteric ligands, searching for a potential therapeutic advantage of CB1 biased signaling in different pathological states. Agonist and antagonist bound structures of CB1 and proposed mechanisms of action of biased allosteric modulators are used to discuss a putative molecular mechanism for CB1 receptor activation and biased signaling. Current studies suggest that allosteric binding sites on CB1 can be explored to yield biased ligands that favor or hinder conformational changes important for biased signaling.

scholarly journals The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system

2013 ◽  
Vol 16 (6) ◽  
pp. 1407-1419 ◽  
Author(s):  
Alline C. Campos ◽  
Zaira Ortega ◽  
Javier Palazuelos ◽  
Manoela V. Fogaça ◽  
Daniele C. Aguiar ◽  
...  
Keyword(s):  
Thymidine Kinase ◽  
Progenitor Cells ◽  
Cannabis Sativa ◽  
Cannabinoid Receptor ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Anxiolytic Effect ◽  
Receptor Activation ◽  
Hippocampal Neurogenesis ◽  
Wild Type

Abstract Cannabidiol (CBD), the main non-psychotomimetic component of the plant Cannabis sativa, exerts therapeutically promising effects on human mental health such as inhibition of psychosis, anxiety and depression. However, the mechanistic bases of CBD action are unclear. Here we investigate the potential involvement of hippocampal neurogenesis in the anxiolytic effect of CBD in mice subjected to 14 d chronic unpredictable stress (CUS). Repeated administration of CBD (30 mg/kg i.p., 2 h after each daily stressor) increased hippocampal progenitor proliferation and neurogenesis in wild-type mice. Ganciclovir administration to GFAP-thymidine kinase (GFAP-TK) transgenic mice, which express thymidine kinase in adult neural progenitor cells, abrogated CBD-induced hippocampal neurogenesis. CBD administration prevented the anxiogenic effect of CUS in wild type but not in GFAP-TK mice as evidenced in the novelty suppressed feeding test and the elevated plus maze. This anxiolytic effect of CBD involved the participation of the CB1 cannabinoid receptor, as CBD administration increased hippocampal anandamide levels and administration of the CB1–selective antagonist AM251 prevented CBD actions. Studies conducted with hippocampal progenitor cells in culture showed that CBD promotes progenitor proliferation and cell cycle progression and mimics the proliferative effect of CB1 and CB2 cannabinoid receptor activation. Moreover, antagonists of these two receptors or endocannabinoid depletion by fatty acid amide hydrolase overexpression prevented CBD-induced cell proliferation. These findings support that the anxiolytic effect of chronic CBD administration in stressed mice depends on its proneurogenic action in the adult hippocampus by facilitating endocannabinoid-mediated signalling.

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