Cannabidiol (CBD), a non-psychotomimetic constituent of Cannabis sativa, has been recently approved for epileptic syndromes often associated with Autism spectrum disorder (ASD). However, the putative efficacy and mechanism of action of CBD in patients suffering from ASD and related comorbidities remain debated, especially because of the complex pharmacology of CBD. We used pharmacological, immunohistochemical and biochemical approaches to investigate the effects and mechanisms of action of CBD in the recently validated Fmr1-Δexon 8 rat model of ASD, that is also a model of Fragile X Syndrome (FXS), the leading monogenic cause of autism. CBD rescued the cognitive deficits displayed by juvenile Fmr1-Δexon 8 animals, without inducing tolerance after repeated administration. Blockade of CA1 hippocampal GPR55 receptors prevented the beneficial effect of both CBD and the fatty acid amide hydrolase (FAAH) inhibitor URB597 in the short-term recognition memory deficits displayed by Fmr1-Δexon 8 rats. Thus, CBD may exert its beneficial effects through CA1 hippocampal GPR55 receptors. Docking analysis further confirmed that the mechanism of action of CBD might involve competition for brain fatty acid binding proteins (FABPs) that deliver anandamide and related bioactive lipids to their catabolic enzyme FAAH. These findings demonstrate that CBD reduced cognitive deficits in a rat model of FXS and provide initial mechanistic insights into its therapeutic potential in neurodevelopmental disorders.

• Klíčová slova
• Cannabidiol, Cognitive performance, Fatty acid amide hydrolase, Fragile X syndrome, GPR55 receptors,
• MeSH
• hipokampální oblast CA1 účinky léků   metabolismus   MeSH
• hipokampus * účinky léků   metabolismus   MeSH
• kanabidiol * farmakologie   terapeutické užití   MeSH
• krysa rodu Rattus MeSH
• modely nemocí na zvířatech * MeSH
• paměť účinky léků   MeSH
• protein FMRP metabolismus   genetika   MeSH
• receptory kanabinoidní * metabolismus   MeSH
• receptory spřažené s G-proteiny metabolismus   MeSH
• rozpoznávání (psychologie) * účinky léků   MeSH
• simulace molekulového dockingu MeSH
• syndrom fragilního X * farmakoterapie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Fmr1 protein, rat MeSH Prohlížeč
• GPR55 protein, rat MeSH Prohlížeč
• kanabidiol * MeSH
• protein FMRP MeSH
• receptory kanabinoidní * MeSH
• receptory spřažené s G-proteiny MeSH

Circadian clocks coordinate physiological and behavioral rhythms that allow the organism to anticipate and adapt to daily changes in environment. The clock-driven cellular oscillations are highly tissue specific to efficiently fine-tune local signaling, manage energy use and segregate incompatible processes. In most peripheral tissues, food acts as the main cue that entrains the oscillations to external time. Food intake and energy balance are under control of endocannabinoid (EC) signaling. Despite this obvious link between the circadian and EC systems, evidence for their interaction started to emerge only recently. We used targeted lipidomics to analyze circadian variations in EC tone in rat plasma, liver and adrenal tissue. The results provide the evidence that ECs, monoacylglycerols, N-acylethanolamines and their precursors oscillate with a tissue-specific circadian phase in plasma and liver. We then identified a set of rhythmically expressed genes likely responsible for the variations in EC tissue tone. In contrast to the liver, EC levels did not oscillate in the adrenal glands. Instead, we revealed that local EC receptor genes are under circadian regulation. To explore the impact of metabolic signals on expression of these genes, we used daytime-restricted feeding schedule. We subsequently showed that daytime feeding strongly suppressed liver-expressed fatty acid binding protein 5 (Fabp5) and adrenal-expressed non-canonical endocannabinoid receptors Gpr55 and Trpv1, whereas it upregulated liver-expressed Trpv1 and glycerophosphodiester phosphodiesterase 1 (Gde1). Our results reveal tissue-specific mechanisms involved in interaction between endocannabinoid signaling, circadian system and metabolism.

• Klíčová slova
• Adrenal gland, Cannabinoid receptors, Circadian clock, Endocannabinoids, Rat liver, Restricted feeding,
• MeSH
• cirkadiánní hodiny MeSH
• cirkadiánní rytmus * MeSH
• endokanabinoidy krev   metabolismus   MeSH
• energetický metabolismus MeSH
• fotoperioda MeSH
• játra metabolismus   MeSH
• krysa rodu Rattus MeSH
• nadledviny metabolismus   MeSH
• potkani Wistar MeSH
• regulace chuti k jídlu MeSH
• stravovací zvyklosti MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• endokanabinoidy MeSH

The lipid molecule, lysophosphatidylinositol (LPI), is hypothesised to form part of a novel lipid signalling system that involves the G protein-coupled receptor GPR55 and distinct intracellular signalling cascades in endothelial cells. This work aimed to study the possible mechanisms involved in LPI-evoked cytosolic Ca(2+) mobilization in human brain microvascular endothelial cells. Changes in intracellular Ca(2+) concentrations were measured using cell population Ca(2+) assay. LPI evoked biphasic elevation of intracellular calcium concentration, a rapid phase and a sustained phase. The rapid phase was attenuated by the inhibitor of PLC (U 73122), inhibitor of IP(3) receptors, 2-APB and the depletor of endoplasmic reticulum Ca(2+) store, thapsigargin. The sustained phase, on the other hand, was enhanced by U 73122 and abolished by the RhoA kinase inhibitor, Y-27632. In conclusion, the Ca(2+) signal evoked by LPI is characterised by a rapid phase of Ca(2+) release from the endoplasmic reticulum, and requires activation of the PLC-IP(3) signalling pathway. The sustained phase mainly depends on RhoA kinase activation. LPI acts as novel lipid signalling molecule in endothelial cells, and elevation of cytosolic Ca(2+) triggered by it may present an important intracellular message required in gene expression and controlling of vascular tone.

• MeSH
• cytosol účinky léků   metabolismus   MeSH
• endoteliální buňky účinky léků   metabolismus   MeSH
• lidé MeSH
• lysofosfolipidy farmakologie   MeSH
• mikrocévy účinky léků   metabolismus   MeSH
• transformované buněčné linie MeSH
• vápníková signalizace účinky léků   fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• lysofosfolipidy MeSH
• lysophosphatidylinositol MeSH Prohlížeč