engleski

The effects of vitamin B3-based compounds on neuronal and muscle cells

Compounds based on vitamin B3 active form nicotinamide, have been associated with many targets due to their antitumoral, antibacterial, anti-inflammatory, and various other biological activities. Our previous work has characterized these compounds as inhibitors of human cholinesterases which makes them possible drugs for cholinergic neurotransmission-linked pathologies. Our aim was to assess in more detail the safety of these compounds on target cells. In the present study we evaluated the effects of these nicotinamides on neuronal (SH-SY5Y) and muscle cells, as types of cells involved in neuromuscular junction. Possible cytotoxic effect in both cell types was evaluated by MTS assay and the involvement of several nicotinamide-associated signalling pathways in the mechanism behind observed cellular effects was further analysed using flow cytometry. Results showed that out of nine tested compounds, four have displayed time- dependent cytotoxicity in treated cells. Cytotoxicity profiling revealed that compounds in doses of 100 μM could induce events possibly leading to cell death. These responses likely arise from modulation of nicotinamide-linked pathways such as MAPK-, AMPK-, Akt- and mTOR signalling that have an important role in multiple cellular functions. Nevertheless, the concentration affecting the cells, especially for the potent ChE- inhibitor 1-(4'-phenylphenacyl)-3- carbamoylpyridinium bromide, was far greater than predicted to be used in therapy according to the determined inhibition potency or in the general aspect of drug administration. However, the observed effects on cells should not be neglected in any future detailed studies of nicotinamide derivatives as new drug scaffolds. This research was supported by the Croatian Science Foundation grant UIP-2017-05-7260, Croatian- Slovenian Bilateral project BI-HR/20-21 and Slovenian Research Agency grant P3-0043 in J7-8276.

nicotinamide ; neuronal cells ; muscle cells ; cytotoxicity ; PI3K ; MAPK

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