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

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

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.

• Language: English
• Keywords: synthetic cannabinoid receptor agonists (SCRAs), cumyl-PINACA (SGT-24), neurons, astrocytes, neurotoxicity, receptors
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2026
• Number of pages: Str. 1-19
• Numbering: Vol. 19, iss. 9, art. 1436
• PID: 20.500.12556/RUL-188846
• UDC: 616.8
• ISSN on article: 1424-8247
• DOI: 10.3390/ph19091436
• COBISS.SI-ID: 292411651
• Publication date in RUL: 29.09.2026

Record is a part of a journal

• Title: Pharmaceuticals
• Shortened title: Pharmaceuticals
• Publisher: MDPI
• ISSN: 1424-8247
• COBISS.SI-ID: 517582617

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: sintetični agonisti kanabinoidnih receptorjev, kumil-PINACA (SGT-24), nevroni, astrociti, nevrotoksičnost, receptorji

Projects

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: P3-0019
• Name: Aplikativna in bazična fiziologija in patofiziologija v medicini

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: P3-0067
• Name: Farmakologija in farmakogenomika