Neurotoxicity of synthetic cannabinoid receptor agonist cumyl-PINACA : an in vitro study on rat cortical neurons and astrocytes

Jurič, Damijana Mojca (avtor), Bulc Rozman, Klara (avtor), Lipnik Štangelj, Metoda (avtor), Šuput, Dušan (avtor), Brvar, Miran (avtor)

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.

• Jezik: Angleški jezik
• Ključne besede: synthetic cannabinoid receptor agonists (SCRAs), cumyl-PINACA (SGT-24), neurons, astrocytes, neurotoxicity, receptors
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: MF - Medicinska fakulteta
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2026
• Št. strani: Str. 1-19
• Številčenje: Vol. 19, iss. 9, art. 1436
• PID: 20.500.12556/RUL-188846
• UDK: 616.8
• ISSN pri članku: 1424-8247
• DOI: 10.3390/ph19091436
• COBISS.SI-ID: 292411651
• Datum objave v RUL: 29.09.2026

Gradivo je del revije

• Naslov: Pharmaceuticals
• Skrajšan naslov: Pharmaceuticals
• Založnik: MDPI
• ISSN: 1424-8247
• COBISS.SI-ID: 517582617

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: sintetični agonisti kanabinoidnih receptorjev, kumil-PINACA (SGT-24), nevroni, astrociti, nevrotoksičnost, receptorji

Projekti

• Financer: ARIS - Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije
• Številka projekta: P3-0019
• Naslov: Aplikativna in bazična fiziologija in patofiziologija v medicini

• Financer: ARIS - Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije
• Številka projekta: P3-0067
• Naslov: Farmakologija in farmakogenomika