Cannabidiol Exposure During Neuronal Differentiation Sensitizes Cells Against Redox-Active Neurotoxins

Abstract

Cannabidiol (CBD), one of the most abundant Cannabis sativa-derived compounds, has been implicated with neuroprotective effect in several human pathologies. Until now, no undesired side effects have been associated with CBD. In this study, we evaluated CBD's neuroprotective effect in terminal differentiation (mature) and during neuronal differentiation (neuronal developmental toxicity model) of the human neuroblastoma SH-SY5Y cell line. A dose-response curve was performed to establish a sublethal dose of CBD with antioxidant activity (2.5 μM). In terminally differentiated SH-SY5Y cells, incubation with 2.5 μM CBD was unable to protect cells against the neurotoxic effect of glycolaldehyde, methylglyoxal, 6-hydroxydopamine, and hydrogen peroxide (H2O2). Moreover, no difference in antioxidant potential and neurite density was observed. When SH-SY5Y cells undergoing neuronal differentiation were exposed to CBD, no differences in antioxidant potential and neurite density were observed. However, CBD potentiated the neurotoxicity induced by all redox-active drugs tested. Our data indicate that 2.5 μM of CBD, the higher dose tolerated by differentiated SH-SY5Y neuronal cells, does not provide neuroprotection for terminally differentiated cells and shows, for the first time, that exposure of CBD during neuronal differentiation could sensitize immature cells to future challenges with neurotoxins.

Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders

“…The deleterious consequences in brain development and psychiatric implications in the adulthood induced by psychoactive THC exposure have been widely studied (Tortoriello et al, 2014; Alpár et al, 2015; de Salas-Quiroga et al, 2015). Recent evidence indicates that while CBD in the adult brain is safe and lacks undesired side effects, in the differentiating neurons it may increase their sensitivity to future oxidative insults (Schönhofen et al, 2015). Clearly, research on CBD safety during brain development is essential.…”

Reduced Neurite Density in Neuronal Cell Cultures Exposed to Serum of Patients with Bipolar Disorder

“…Randomly selected images were captured using an EVOS Floid Cell Imaging Station (Thermo Fisher Scientific Inc.) and analyzed with Nikon Imaging Software (NIS), the NIS- elements. The neurite density was assessed using the AutoQuant Neurite software (implemented in R program) and expressed as arbitrary units (AU) as described previously (Schonhofen et al, 2015). …”

“…The differentiated human neuroblastoma cell line, SH-SY5Y, has been used as an experimental model to assess molecular and biochemical pathways involved in the pathophysiology of brain disorders (Lopes et al, 2010) and for neurotoxicological experiments in developmental and mature neurons (Schonhofen et al, 2015). This model has the advantage of being derived of human cells, displaying neuronal morphology, and neuronal markers (as high neurite density, tyrosine hydroxylase, dopamine transporter) during RA-differentiation (Lopes et al, 2010).…”

RA Differentiation Enhances Dopaminergic Features, Changes Redox Parameters, and Increases Dopamine Transporter Dependency in 6-Hydroxydopamine-Induced Neurotoxicity in SH-SY5Y Cells

“…Cell cycle and cellular growth DNA composition was measured using propidium iodide (PI) (Thermo (Schönhofen et al 2015). (Korecka et al 2013).…”