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Cytotoxic Effects of Cannabidiol on Neonatal Rat Cortical Neurons and Astrocytes: Potential Danger to Brain
Damijana Mojca Jurič1, Klara Bulc Rozman2, Metoda Lipnik-Štangelj1
1Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia.
Abstract:
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 µM) concentrations attainable in humans. The effect of CBD was concentration- and time-dependent and cell-specific. In neurons, 0.1 µM CBD induced an early and transient change in mitochondrial membrane potential (ΔΨm), 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 µM CBD caused an immediate short-term dysregulation of ΔΨm, 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.
Insights
Cannabidiol (CBD) significantly impacts developing brain cells. This study reveals CBD triggers cell death in perinatal neurons and astrocytes, highlighting developmental neurotoxicity risks.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Cannabidiol (CBD) is a non-intoxicating compound with potential medical uses, including in vulnerable populations like pregnant women and children.
- The effects of CBD on developing brain cells, particularly during critical perinatal periods, remain poorly understood.
Purpose of the Study:
- To investigate the cellular and molecular responses of perinatal rat cortical neurons and astrocytes to varying concentrations of CBD.
- To determine the specific mechanisms and pathways involved in CBD-induced cellular changes in developing brain cells.
Main Methods:
- Exposure of primary rat cortical neurons and astrocytes to submicromolar concentrations of CBD (0.1–5 µM).
- Assessment of mitochondrial membrane potential (ΔΨm), ATP levels, and caspase activation (caspase-8, -9, -3/7) to evaluate cell viability and apoptosis.
- Utilized transient receptor potential vanilloid 1 (TRPV1) and cannabinoid receptor 1 (CB1) antagonists to explore protective mechanisms.
Main Results:
- CBD exhibited concentration- and time-dependent, cell-specific effects on neurons and astrocytes.
- In neurons, low-dose CBD induced apoptosis via mitochondrial pathways, characterized by dendritic changes and cell shrinkage, preventable by TRPV1 antagonists.
- In astrocytes, CBD triggered apoptosis and necroptosis, with both TRPV1 and CB1 receptor antagonists offering protection.
Conclusions:
- CBD exposure during critical developmental periods can induce significant neurotoxicity in perinatal cortical cells.
- The findings challenge the notion of CBD as universally non-toxic, particularly concerning its impact on the developing brain and endogenous cannabinoid system.
- These results underscore the need for caution regarding CBD use in pregnant women and children due to potential developmental risks.
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