Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 17, Pages -Publisher
MDPI
DOI: 10.3390/ijms23179695
Keywords
downregulation; heteromers; hypoxia; ischemia; phytocannabinoids; serotonin
Funding
- Spanish MCIN/AEI [PID2020-113430RB-I00]
- European Union
- European Union Next Generation EU/PRTR
- ERDF A way of making Europe
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The study found that CBD acts on CB2-5HT(1A)-Hets and reduces the abnormal expression of the receptor-receptor complex under hypoxic and ischemic conditions, thereby exerting a therapeutic effect on neonatal hypoxia.
Background: Cannabidiol (CBD) is a phytocannabinoid with potential in one of the most prevalent syndromes occurring at birth, the hypoxia of the neonate. CBD targets a variety of proteins, cannabinoid CB2 and serotonin 5HT(1A) receptors included. These two receptors may interact to form heteromers (CB2-5HT(1A)-Hets) that are also a target of CBD. Aims: We aimed to assess whether the expression and function of CB2-5HT(1A)-Hets is affected by CBD in animal models of hypoxia of the neonate and in glucose- and oxygen-deprived neurons. Methods: We developed a quantitation of signal transduction events in a heterologous system and in glucose/oxygen-deprived neurons. The expression of receptors was assessed by immuno-cyto and -histochemistry and, also, by using the only existing technique to visualize CB2-5HT(1A)-Hets fixed cultured cells and tissue sections (in situ proximity ligation PLA assay). Results: CBD and cannabigerol, which were used for comparative purposes, affected the structure of the heteromer, but in a qualitatively different way; CBD but not CBG increased the affinity of the CB2 and 5HT(1A) receptor-receptor interaction. Both cannabinoids regulated the effects of CB2 and 5HT(1A) receptor agonists. CBD was able to revert the upregulation of heteromers occurring when neurons were deprived of oxygen and glucose. CBD significantly reduced the increased expression of the CB2-5HT(1A)-Het in glucose/oxygen-deprived neurons. Importantly, in brain sections of a hypoxia/ischemia animal model, administration of CBD led to a significant reduction in the expression of CB2-5HT(1A)-Hets. Conclusions: Benefits of CBD in the hypoxia of the neonate are mediated by acting on CB2-5HT(1A)-Hets and by reducing the aberrant expression of the receptor-receptor complex in hypoxic-ischemic conditions. These results reinforce the potential of CBD for the therapy of the hypoxia of the neonate.
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