The Synthetic Cannabinoids THJ-2201 and 5F-PB22 Enhance In Vitro CB₁ Receptor-Mediated Neuronal Differentiation at...

Area of Science:

• Neuroscience
• Toxicology
• Pharmacology

Background:

• Recreational synthetic cannabinoid (SC) use during pregnancy is a public health concern due to potential neurodevelopmental risks in offspring.
• Understanding the specific neurotoxic effects of commonly abused SCs, such as THJ-2201 and 5F-PB22, is crucial.

Purpose of the Study:

• To assess the neurotoxic potential of THJ-2201 and 5F-PB22 on neuronal differentiation in vitro.
• To investigate the role of CB1 receptor (CB1R) activation in SC-induced effects on neurodifferentiation.

Main Methods:

• NG108-15 neuroblastoma x glioma cells were exposed to THJ-2201 and 5F-PB22 at non-toxic, biologically relevant concentrations (≤1 μM).
• Assessed differentiation ratios, total neurite length, and neuronal marker expression.
• Evaluated cell viability, proliferation, mitochondrial membrane potential, and intracellular ATP levels; CB1R blockade was used to determine receptor dependency.

Main Results:

• Both THJ-2201 and 5F-PB22 significantly enhanced neuronal differentiation and neurite outgrowth, approximately doubling effects compared to controls.
• These effects were dependent on CB1R activation, as demonstrated by the abrogation of SC-induced effects with a specific CB1R antagonist (SR141718).
• Repeated exposure to 5F-PB22 was needed to match the effects of a single THJ-2201 dose; SCs increased mitochondrial TMRE accumulation but did not impact other toxicological parameters.

Conclusions:

• THJ-2201 and 5F-PB22 promote neuronal differentiation and neurite elongation via CB1R-mediated mechanisms at biologically relevant concentrations.
• This study provides novel insights into the CB1R-dependent enhancement of neurodifferentiation by specific synthetic cannabinoids.