20.500.12556/RUL-188846 Neurotoxicity of synthetic cannabinoid receptor agonist cumyl-PINACA an in vitro study on rat cortical neurons and astrocytes Background/Objectives: Synthetic cannabinoid receptor agonists (SCRAs) are associated with severe neurotoxicity, but the cellular mechanisms underlying their effects remain poorly defined. We investigated the effects of Cumyl-PINACA (SGT-24), a carboxamide-type SCRA derived from cumylamine, on rat cortical neurons and astrocytes. Methods: Primary rat cortical neurons and astrocytes were exposed to 1–10,000 nM SGT-24. Metabolic activity, mitochondrial function, morphology, and cell death were evaluated. Selective antagonists of cannabinoid receptor type 1 (CB1), G protein-coupled receptor 55 (GPR55), peroxisome proliferator-activated receptor gamma (PPARγ), and transient receptor potential cation channel subfamily V member 1 (TRPV1) were used to probe the involvement of these receptor pathways. Results: SGT-24 decreased metabolic activity in both cell types in a concentration- and time-dependent manner, with greater potency in neurons (IC50 = 13.2 nM) than in astrocytes (IC50 = 39.8 nM). After 24 h, maximal effects were observed at 100 nM in neurons and 500 nM in astrocytes, reducing metabolic activity by 45.2% and 36.2%, respectively. At these concentrations, mitochondrial membrane potential decreased to 57.6% and 54.1% of control, while cellular ATP levels fell to 51.6% and 52.5%, respectively. Neurons predominantly exhibited early apoptosis (21.9% of cells vs. 3.1% in controls), whereas astrocytes showed mainly 7-aminoactinomycin D (7-AAD)-positive cell death (19.3% vs. 8.2% in controls). Pharmacological inhibition of CB1, TRPV1, and PPARγ attenuated SGT-24-induced metabolic impairment, mitochondrial dysfunction, and apoptosis in neurons, whereas inhibition of CB1 and PPARγ reduced astrocytic toxicity. Conclusions: SGT-24 exerts potent, cell-type-dependent neuroglial toxicity associated with mitochondrial dysfunction and distinct cell death patterns, suggesting the involvement of cannabinoid receptor-dependent and non-cannabinoid signalling mechanisms. The nanomolar potency of SGT-24 underscores the toxicological risk posed by high-potency SCRAs. synthetic cannabinoid receptor agonists (SCRAs) cumyl-PINACA (SGT-24) neurons astrocytes neurotoxicity receptors sintetični agonisti kanabinoidnih receptorjev kumil-PINACA (SGT-24) nevroni astrociti nevrotoksičnost receptorji true false true Angleški jezik Slovenski jezik Članek v reviji 2026-09-29 11:24:03 2026-09-29 11:24:08 2026-09-30 04:29:20 0000-00-00 00:00:00 2026 0 0 Str. 1-19 iss. 9, art. 1436 Vol. 19 2026 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616.8 1424-8247 10.3390/ph19091436 292411651 RAZ_Juric_Damijana_Mojca_2026.pdf RAZ_Juric_Damijana_Mojca_2026.pdf 1 9D939571285A5E0FD06AEA115A954399 99e9a0ff30ee1940eac31cd051f4e2c984a8a858600a84b2a9b6bfd6bd95d995 a0a16f28-bbe7-11f1-8bc5-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=249213 https://www.mdpi.com/1424-8247/19/9/1436 1 6ca2eeb1-bbe7-11f1-8bc5-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=249212 Medicinska fakulteta 0 0 0