In vitro toxicity of the synthetic cannabinoids THJ-2201 and ADB-FUBINACA to human astrocytes
Synthetic cannabinoids (SCs) are a group of New Psychoactive Substances that mimic, with higher potency, the effects of Δ9-tetrahydrocannabidiol (Δ9-THC), the main psychoactive substance of cannabis. We recently showed that the SCs THJ-2201 and ADB-FUBINACA enhance neuronal differentiation of NG108-15 cells. Given the important role played by astrocytes to the neuronal network formation, we herein aimed to evaluate the toxicity of SCs to human astrocytes, as a first assessment of their effects on the regulation of astrocytic function.
To attain this objective, different toxicological parameters were evaluated in SVG p12 astrocytes, a human cell line, exposed to 24h to THJ-2201 or ADB-FUBINACA at 1pM, 1nM, 1µM and 10µM. A solvent control (0.2% DMSO) was also tested. Assayed parameters included metabolic activity (MTT reduction), lysosome integrity (neutral red inclusion), plasma membrane integrity [lactate dehydrogenase (LDH) release]; and changes in mitochondrial membrane potential (MMP; analyzed by TMRE labelling).
THJ-2201 and ADB-FUBINACA decreased metabolic activity of astrocytes in about 8.0% and 13.5%, respectively, relatively to the control, only at 10µM, a concentration 10x higher than the SC concentrations commonly as biologically relevant (< 1µM). None of the SCs tested significantly affected lysosomal or plasma membrane integrity up to 10µM, as no changes were observed in neutral red staining or LDH release, respectively, compared to the solvent control. Moreover, mitochondrial activity was also not affected by the SCs up to 10µM, as no changes in MMP were observed in SC-exposed cells.
Although structurally different, both THJ-2201 and ADB-FUBINACA demonstrated to be non-cytotoxic for human astrocytes at biologically relevant concentrations (< 1µM), previously shown to increase neurodifferentiation. Further research is thus needed to evaluate the putative modulation effects of SCs on astrocytic activity, at non-toxic concentrations.