Regulation of synaptosomal 2-arachidonoylglycerol metabolism by Tetrahydroccananinol during aging

SALAS ROSICLER S; PASCUAL A.C.; PASQUARÉ S.J.; MILANO P.G.

Mar del Plata

Congreso; LXVII Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2022

SAIC

The endocannabinoid 2-arachidonoylglycerol (2-AG) is known for its neuroprotective role. During aging, 2-AG metabolism in rat cerebral cortex (CC) synaptosomes (Syn) is dysregulated, resulting in a decrease in its availability, which could lead to synaptic dysfunction. 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 in Medicinal Cannabis (MC). Our previous results indicated that THC-enriched CE (1 μM THC) restored 2-AG hydrolysis in aged CC Syn. The purpose of this study was to evaluate if THC could modulate 2-AG synthesis. To this end, THC-enriched CE were obtained from Cannabis Y Griega female flowers, previously grinded and heated at 115 °C for 40 min. Extractions were performed by adding 5% (w/v) ethanol, vortexed, sonicated and agitated. The mixture was centrifuged and the supernatant was evaporated under a stream of N2. THC, cannabidiol (CBD) and cannabinol (CBN) were quantified by HPLC. CC Syn from adult (4-6 months) and aged (24-26 months) rats were isolated by differential centrifugation and purified in Ficoll gradients. 2-AG synthesis, by lysophospholipid phosphohydrolase (LPAase) and by diacylglycerol lipase (DAGL), was assessed by incubating Syn with THC-enriched CE (1 μM THC) or 1 μM pure THC, and the respective radiolabeled substrate, simultaneously. Results showed that either CE or pure THC increased LPAase activity in adult Syn (p<0.05). However, pure THC caused a slight decrease in the activity only in aged Syn (p<0.05). On the other hand, DAGL activity was not modified by THC either in adult or in aged Syn (p>0.05). In conclusion, THC-enriched CE could attenuate aged synaptosomal 2-AG deficit, while pure THC could potentiate this loss. These findings highlight the importance of using the whole-plant CE in the success of MC therapy.