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Neuroprotection of SAK3 on scopolamine-induced cholinergic dysfunction in human neuroblastoma SH-SY5Y cells

Abstract

Alzheimer’s disease (AD) is the most common type of senile dementia. A number of factors have been proposed regarding pathology of AD, such as presence of β-amyloid, and cholinergic and oxidative stress. SAK3 (ethyl 8′-methyl-2′,5-dioxo-2-piperidin-1-ylspiro[cyclopentene-3,3′-imidazo[1,2-a]pyridine]-1-carboxylate) reduces β-amyloid deposition and improves cognitive functions in amyloid precursor protein knock-in mice. Scopolamine is used to induce in cell lines a cholinergic deficit that mimics AD. In order to evaluate the possible neuroprotective properties of SAK3, human neuroblastoma SH-SY5Y cells were pretreated with the compound (25–100 nM) and further incubated in the presence of scopolamine (2 mM). SAK3 inhibited scopolamine-induced cellular apoptosis (morphologically and by determination of pro- and anti-apoptotic factor levels), increase in ROS levels, decrease in choline acetyltransferase level, phosphorylation of NF-κB, activation of Akt, JNK and p38 intracellular signaling pathways, and elevation of proinflammatory cytokines IL-1β and IL-6, but not enhanced level of β-site amyloid precursor protein cleaving enzyme 1 (BACE1). These results indicate SAK3 possessed protective properties against cholinergic deficit associated with anti-oxidant, anti-apoptotic and anti-inflammatory activities, suggesting that SAK3 might be a potential agent in the development of AD drug therapeutics.

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Acknowledgements

This research was partially supported by a joint Mahidol University and the Thailand Research Fund (TRF) Grant (IRG5780009). The authors are grateful to Prof. Prapon Wilairat, Mahidol University for critical reading of the manuscript.

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Correspondence to Wipawan Thangnipon.

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Suthprasertporn, N., Mingchinda, N., Fukunaga, K. et al. Neuroprotection of SAK3 on scopolamine-induced cholinergic dysfunction in human neuroblastoma SH-SY5Y cells. Cytotechnology (2020). https://doi.org/10.1007/s10616-019-00366-7

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Keywords

  • Alzheimer’s disease
  • Acetylcholine
  • Apoptosis
  • Neuroblastoma SH-SY5Y cell line
  • Oxidative stress
  • SAK3
  • Scopolamine