Evaluation of the Cytotoxic Potential of Racemic 1,3-Dimethylamylamine in SH-SY5Y Cells

Resumo

Background: 1,3-Dimethylamylamine (1,3-DMAA) is a chiral sympathomimetic drug which was used as a nasal decongestant up to the 1980s (Venhuis & De Kaste, 2012). However, the compound was latter withdrawn due to adverse effects including headaches, nervousness, psychomotor stimulation and tremors. In 2005, 1,3-DMAA re-emerged on the market, with applications ranging from dietary supplement for obesity control, ergogenic aid for athletic performance to psychoactive recreational and appetite suppression uses (Rodrigues & Dinis-Oliveira, 2023). So, despite being banned, the presence of 1,3-DMAA in doping controls and dietary supplements continues to be of significant concern. Although toxicological effects are described, mechanistic profile is not yet fully understood regarding neurotoxicity (Small et al., 2023).

Objective: To preliminary examine the in vitro neurotoxic effects of racemic 1,3-DMAA using a human neuroblastoma cell line through the assessment of mitochondrial and lysosomal integrity.

Methods: SH-SY5Y cells were cultured under standard conditions and treated with 15 concentrations of 1,3-DMAA (from 1.3×10⁻⁴ to 1.5×10¹ mM) for 48 hours, in five independent experiments. Mitochondrial metabolic activity was assessed by the MTT assay and lysosomal integrity through the neutral red uptake assay. Data were analysed using the GraphPad Prism software and fitted to the Logit model to determine EC₅₀ values.

Results: The EC₅₀ values were 5.24 mM for MTT and 6.36 mM for NR, with significant toxicity only occurring at relatively high, non-biologically relevant concentrations.

Conclusions: Mitochondrial impairment precedes lysosomal dysfunction in cytotoxic effects elicited by racemic 1,3-DMAA in SH-SY5Y cells, after 48 h exposures. These results set the basis for future mechanistic and enantiospecific studies aiming at elucidating the mechanisms underlying 1,3-DMMA cytotoxic effects.