Abstract
Recreational use of synthetic cannabinoids (SCs) before and during pregnancy poses a major public health risk, due to the potential onset of neurodevelopmental disorders in the offspring. Herein, we report the assessment of the neurotoxic potential of two commonly abused SCs, THJ-2201 and 5F-PB22, particularly focusing on how they affect neuronal differentiation in vitro. Differentiation ratios, total neurite length, and neuronal marker expression were assessed in NG108-15 neuroblastoma x glioma cells exposed to the SCs at non-toxic, biologically relevant concentrations (≤1 μM), either in acute or repeated exposure settings. Both SCs enhanced differentiation ratios and total neurite length of NG108-15 cells near two-fold compared to vehicle-treated cells, in a CB1R activation-dependent way, as the CB1R blockade with a specific antagonist (SR141718) abrogated SC-induced effects. Interestingly, repeated 5F-PB22 exposure was required to reach effects similar to a single THJ-2201 dose. Cell viability and proliferation, mitochondrial membrane potential, and intracellular ATP levels were also determined. The tested SCs increased mitochondrial tetramethyl rhodamine ethyl ester (TMRE) accumulation after 24 h at biologically relevant concentrations but did not affect any of the other toxicological parameters. Overall, we report firsthand the CB1R-mediated enhancement of neurodifferentiation by 5F-PB22 and THJ-2201 at biologically relevant concentrations.
Highlights
Synthetic cannabinoids (SCs) comprise a chemically heterogenous group of new psychoactive substances, representing the largest group of new psychoactive substances monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), and accounting for 51% of total seizures of new psychoactive substances in the European Union [1]
This work comprises two main goals: (1) to evaluate the neurotoxicity of two commonly reported SCs—THJ-2201 and 5F-PB22—in a NG108-15 hybrid neuroblastoma x glioma cell line; (2) to assess the role played by these SCs on in vitro neuronal differentiation and proliferation of NG108-15 cells exposed at non-toxic, biologically relevant concentrations (
We found a clear modulation of in vitro neuronal differentiation following exposure of NG108-15 cells to THJ-2201 and 5F-PB22 at concentrations below 1 nM
Summary
Synthetic cannabinoids (SCs) comprise a chemically heterogenous group of new psychoactive substances, representing the largest group of new psychoactive substances monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), and accounting for 51% of total seizures of new psychoactive substances in the European Union [1]. To the best of our knowledge, the neurobiology underlying the impact of SCs’ use by pregnant women and women of childbearing age on their offspring remains virtually unexplored, with only a few studies correlating impaired cognition with perinatal SC exposure, as we previously reviewed [9] Of note, these data are often conflicting, varying among cell models or types of SCs used. The analysis of SCs neurotoxic potential assumes critical relevance to strengthen SC risk assessment, especially by contributing to elucidate the impact of these substances’ use by pregnant women and women of childbearing age In this sense, this work comprises two main goals: (1) to evaluate the neurotoxicity of two commonly reported SCs—THJ-2201 and 5F-PB22—in a NG108-15 hybrid neuroblastoma x glioma cell line; (2) to assess the role played by these SCs on in vitro neuronal differentiation and proliferation of NG108-15 cells exposed at non-toxic, biologically relevant concentrations (
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