The synthetic cannabinoids ADB-FUBINACA and AMB-FUBINACA enhance in vitro neurodifferentiation of NG108-15 cells, along with PGC-1α dysregulation and mitochondrial dysfunction.

There is growing concern regarding the use of Synthetic Cannabinoids (SCs) by young adults (including pregnant and breastfeeding women, and women of childbearing age), due to their potential to cause neurodevelopmental disorders. Here, we first-hand assessed the in vitro impact of two indazole-derived SCs, ADB-FUBINACA and AMB-FUBINACA, on the neurodifferentiation of NG108-15 cells, especially focusing on their modulation of mitochondrial function during such process. Both SCs tested enhanced neurite outgrowth in NG108-15 cells at biologically-relevant concentrations (< 1 μM), a process that was blocked by SR141716A and hemopressin (antagonists of cell membrane and intracelular CB1 receptors, respectively). Moreover, this effect was accompanied by a CB1 receptor-independent reduction in mitochondrial membrane potential. Interestingly, ADB-FUBINACA, but not AMB-FUBINACA, decreased intracellular ATP levels through CB1 activation. Notably, voltage-dependent anion channel (VDAC) expression, an indirect marker of mitochondrial mass, remained unchanged during exposure to both SCs. ADB-FUBINACA increased the expression of the key energy regulator PGC-1α in the cytosol (1pM-1µM), while decreasing it in the mitochondrial fraction (1 nM and 1 µM), without affecting its nuclear translocation, supporting its role in mitochondrial turnover. Other mitogenesis markers, like NFR-1 and TFAM, remain unchanged. Additionaly, the Parkin-PINK1 mitophagy pathway was not activated at the concentrations tested. Our findings demonstrate that ADB-FUBINACA and AMB-FUBINACA enhance neuronal differentiation of NG108-15 cells via CB1 receptor activation, while concomitantly promoting mitochondrial dysfunction. Although further research is required to fully elucidate the mechanisms underlying these observations, our data already suggests that these SCs may impact proper neurodevelopment.