Regulation of synaptosomal 2-arachidonoylglycerol metabolism by tetrahydrocannabinol during aging

SABRINA SALAS; ANA CLARA PASCUAL; PABLO MILANO; FLORENCIA MUSSO; ANA PAULA MURRAY; SUSANA PASQUARÉ

Buenos Aires

Simposio; Frontiers in Bioscience 4; 2023

The endocannabinoid 2-arachidonoylglycerol (2-AG) is known for its neuroprotective role. During aging, 2-AG metabolism in ratcerebral cortex (CC) synaptosomes (Syn) is dysregulated, resulting in a decrease in its availability, which could lead to synapticdysfunction. On the other hand, 2-AG metabolism was shown to be modulated by ligands of its own receptors. Delta-9-tetrahydrocannabinol (THC) is a partial cannabinoid receptor agonist present in Cannabis sp. extract (CE), which is widely used inMedicinal Cannabis (MC). Our previous results indicated that THC-enriched CE (1 μM THC) restored 2-AG hydrolysis in aged CCSyn. The purpose of this study was to evaluate if THC could modulate 2-AG synthesis. To this end, THC-enriched CE wereobtained from Cannabis Y Griega female flowers, previously grinded and heated at 115 °C for 40 min. Extractions wereperformed by adding 5% (w/v) ethanol, vortexed, sonicated and agitated. The mixture was centrifuged and the supernatant wasevaporated under a stream of N2. THC, cannabidiol (CBD) and cannabinol (CBN) were quantified by HPLC. CC Syn from adult (4-6months) and aged (24-26 months) rats were isolated by differential centrifugation and purified in Ficoll gradients. 2-AGsynthesis, by lysophosphatidate phosphohydrolase (LPAase) and by diacylglycerol lipase (DAGL), was assessed by incubating Synwith THC-enriched CE (1 μM THC) or 1 μM pure THC, and the respective radiolabeled substrate, simultaneously. Results showedthat either CE or pure THC increased LPAase activity in adult Syn (p