Effects of new synthetic cannabinoid compounds on neuronal viability in schizophrenia subjects-derived olfactory neuroepithelial cell cultures

Background

Schizophrenia is a complex and heterogeneous psychiatric disorder characterized by neurodevelopmental alterations that affect neuronal survival, synaptic plasticity, and cellular resilience throughout life. Patient-derived olfactory neuroepithelial cells, accessible through minimally invasive nasal exfolation, provide a valuable in vitro model to investigate disease-associated cellular phenotypes while preserving individual-specific biological signatures and the genetic background of each donor. Cannabinoid-related compounds have emerged as potential modulators of neuronal function, but their effects on patient-derived neuronal systems remain insufficiently characterized, particularly in the context of major psychiatric disorders such as schizophrenia.

Objectives

The aim of this study was to evaluate the effects of three newly synthesized cannabinoid compounds on neuronal viability in neuronal enriched cultures derived from olfactory neuroepithelial cells of schizophrenia subjects and matched controls, in order to explore potential differential pharmacological responses linked to the disease.

Methods

Olfactory neuroepithelial cells were obtained non-invasively through nasal exfoliation from two schizophrenia subjects and two matched controls, and were subsequently differentiated into neuronal enriched cultures. Differentiated cells were treated with three synthetic cannabinoid pyrazoles at concentrations of 1 µM, 5 µM and 10 µM. Cell viability was quantitatively assessed using the methylthiazolyldiphenyl-tetrazolium bromide (MTT) colorimetric assay following the treatment period. Statistical analyses were performed using two-way analysis of variance with diagnosis and dose as independent factors, followed by post hoc multiple comparison tests to identify specific group differences.

Results

Compound 1 induced a marked dose-dependent increase in viability in schizophrenia-derived neurons (approximately 100 %, 180 %, and 220 % of control baseline at 1 µM, 5 µM and 10 µM, respectively), whereas control-derived cells showed a more moderate response (approximately 100 %, 130 %, and 100 %), with a statistically significant interaction between diagnosis and dose (p < 0.01). Compound 2 increased viability in both groups, but the effect was significantly greater in schizophrenia-derived cells at 10 µM (approximately 250 % versus 150 % in controls; p < 0.05). In contrast, compound 3 reduced cell viability at higher concentrations in schizophrenia-derived cultures (approximately 60 % of baseline), while control cells exhibited a less pronounced decrease (approximately 80 %), again resulting in a statistically significant interaction effect (p < 0.05).

Conclusions

These findings indicate that synthetic cannabinoids exert differential and dose-dependent effects on neuronal viability depending on disease status. Certain compounds enhance viability selectively in schizophrenia-derived neurons, suggesting a potential therapeutic relevance, whereas others may exert cytotoxic effects at higher concentrations, raising clinical safety considerations. Although limited by the small sample size and exploratory nature, this study supports the value of patient-derived cellular models for evaluating neuropsychopharmacological responses and highlights the need for further investigation, including studies with larger cohorts and mechanistic analyses, into the therapeutic potential and safety profile of cannabinoid-based compounds in schizophrenia.

References

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