{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T05:02:46Z","timestamp":1789534966014,"version":"build-2803163510"},"reference-count":60,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004329","name":"The Slovenian Research and Innovation Agency","doi-asserted-by":"publisher","award":["P3-0019"],"award-info":[{"award-number":["P3-0019"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004329","name":"The Slovenian Research and Innovation Agency","doi-asserted-by":"publisher","award":["P3-0067"],"award-info":[{"award-number":["P3-0067"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"award":["P3-0019"],"award-info":[{"award-number":["P3-0019"]}],"id":[{"id":"https:\/\/ror.org\/059bp8k51","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P3-0067"],"award-info":[{"award-number":["P3-0067"]}],"id":[{"id":"https:\/\/ror.org\/059bp8k51","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>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\u201310,000 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 (PPAR\u03b3), 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 PPAR\u03b3 attenuated SGT-24-induced metabolic impairment, mitochondrial dysfunction, and apoptosis in neurons, whereas inhibition of CB1 and PPAR\u03b3 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.<\/jats:p>","DOI":"10.3390\/ph19091436","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T15:54:19Z","timestamp":1789055659000},"page":"1436","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neurotoxicity of Synthetic Cannabinoid Receptor Agonist Cumyl-PINACA: An In Vitro Study on Rat Cortical Neurons and Astrocytes"],"prefix":"10.3390","volume":"19","author":[{"given":"Damijana Mojca","family":"Juri\u010d","sequence":"first","affiliation":[{"name":"Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3302-3738","authenticated-orcid":false,"given":"Klara","family":"Bulc Rozman","sequence":"additional","affiliation":[{"name":"Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zalo\u0161ka cesta 4, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Metoda","family":"Lipnik-\u0160tangelj","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4031-7267","authenticated-orcid":false,"given":"Du\u0161an","family":"\u0160uput","sequence":"additional","affiliation":[{"name":"Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zalo\u0161ka cesta 4, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8493-3638","authenticated-orcid":false,"given":"Miran","family":"Brvar","sequence":"additional","affiliation":[{"name":"Centre for Clinical Toxicology and Pharmacology, University Medical Centre Ljubljana, Zalo\u0161ka cesta 7, 1000 Ljubljana, Slovenia"},{"name":"Centre for Clinical Physiology, Faculty of Medicine, University of Ljubljana, Zalo\u0161ka cesta 4, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1124\/mi.11.1.6","article-title":"Marijuana-based drugs: Innovative therapeutics or designer drugs of abuse?","volume":"11","author":"Seely","year":"2011","journal-title":"Mol. 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