{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:05:33Z","timestamp":1789574733992,"version":"build-2803163510"},"reference-count":66,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,21]],"date-time":"2022-10-21T00:00:00Z","timestamp":1666310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Slovenian Research Agency","award":["P3-0019"],"award-info":[{"award-number":["P3-0019"]}]},{"name":"Slovenian Research Agency","award":["P3-0067"],"award-info":[{"award-number":["P3-0067"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>The influence of cannabidiol (CBD) on brain development is inadequately understood. Since CBD is considered a non-intoxicating drug, it has attracted great interest concerning its potential medical applicability, including in pregnant women and children. Here, we elucidated the response of perinatal rat cortical neurons and astrocytes to CBD at submicromolar (0.1, 0.5, 1, 5 \u00b5M) concentrations attainable in humans. The effect of CBD was concentration- and time-dependent and cell-specific. In neurons, 0.1 \u00b5M CBD induced an early and transient change in mitochondrial membrane potential (\u0394\u03a8m), ATP depletion, and caspase-8 activation, followed by rapid ATP recovery and progressive activation of caspase-9 and caspase-3\/7, resulting in early apoptotic cell death with reduction and shortening of dendrites, cell shrinkage, and chromatin condensation. The decrease in neuronal viability, ATP depletion, and caspase activation due to CBD exposure was prevented by transient receptor potential vanilloid 1 (TRPV1) antagonist. In astrocytes, 0.5 \u00b5M CBD caused an immediate short-term dysregulation of \u0394\u03a8m, followed by ATP depletion with transient activation of caspase-8 and progressive activation of caspase-9 and caspase-3\/7, leading to early apoptosis and subsequent necroptosis. In astrocytes, both TRPV1 and cannabinoid receptor 1 (CB1) antagonists protected viability and prevented apoptosis. Given that CBD is a non-intoxicating drug, our results clearly show that this is not the case during critical periods of brain development when it can significantly interfere with the endogenous cannabinoid system.<\/jats:p>","DOI":"10.3390\/toxins14100720","type":"journal-article","created":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T11:53:55Z","timestamp":1666612435000},"page":"720","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Cytotoxic Effects of Cannabidiol on Neonatal Rat Cortical Neurons and Astrocytes: Potential Danger to Brain Development"],"prefix":"10.3390","volume":"14","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"}]},{"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":"Centre for Clinical Physiology, 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 Physiology, Faculty of Medicine, University of Ljubljana, Zalo\u0161ka Cesta 4, 1000 Ljubljana, Slovenia"},{"name":"Centre for Clinical Toxicology and Pharmacology, University Medical Centre Ljubljana, Zalo\u0161ka Cesta 7, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1016\/j.neuron.2019.07.009","article-title":"Development and Arealization of the Cerebral Cortex","volume":"103","author":"Cadwell","year":"2019","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1126\/science.291.5504.657","article-title":"Control of synapse number by glia","volume":"291","author":"Ullian","year":"2001","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1126\/science.aat0473","article-title":"Glia as architects of central nervous system formation and function","volume":"362","author":"Allen","year":"2018","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13064-018-0104-y","article-title":"Astrocytes, neurons, synapses: A tripartite view on cortical circuit development","volume":"13","author":"Allen","year":"2018","journal-title":"Neural. 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