Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Cytotechnology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Alvarez-Jimenez R, Groeneveld GJ, van Gerven JM, Goulooze SC, Baakman AC, Hay JL, Stevens J (2016) Model-based exposure-response analysis to quantify age related differences in the response to scopolamine in healthy subjects. Br J Clin Pharmacol 82:1011–1021

    Article  CAS  Google Scholar 

  • Baban B, Liu JY, Mozaffari MS (2014) SGK-1 regulates inflammation and cell death in the ischemic-reperfused heart: pressure-related effects. Am J Hypertens 27:846–856

    Article  CAS  Google Scholar 

  • Budzynska B, Boguszewska-Czubara A, Kruk-Slomka M, Skalicka-Wozniak K, Michalak A, Musik I, Biala G (2014) Effects of imperatorin on scopolamine-induced cognitive impairment and oxidative stress in mice. Psychopharmacology 232:931–942

    Article  Google Scholar 

  • Chatila ZK, Kim E, Berle C, Bylykbashi E, Rompala A, Oram MK, Gupta D, Kwak SS, Kim YH, Kim DY, Choi SH, Tanzi RE (2018) BACE1 regulates proliferation and neuronal differentiation of newborn cells in the adult hippocampus in mice. eNeuro. https://doi.org/10.1523/ENEURO.0067-18.2018

    Article  PubMed  PubMed Central  Google Scholar 

  • Dokumaci AH, Yerer Aycan MB (2019) Vildagliptine Protects SH-SY5Y human neuron-like cells from Aβ 1-42 induced toxicity, in vitro. Cytotechnology 71:635–646

    Article  CAS  Google Scholar 

  • Du X, Wang X, Geng M (2018) Alzheimer’s disease hypothesis and related therapies. Transl Neurodegener 7:1–7

    Article  Google Scholar 

  • Izumi H, Shinoda Y, Saito T, Saido TC, Sato K, Yabuki Y, Matsumoto Y, Kanemitsu Y, Tomioka Y, Abolhassani N, Nakabeppu Y, Fukunaga K (2018) The Disease-modifying drug candidate, SAK3 improves cognitive impairment and inhibits amyloid β deposition in APP knock-in mice. Neuroscience 377:87–97

    Article  CAS  Google Scholar 

  • Kovalevich J, Langford D (2013) Considerations for the use of SH-SY5Y neuroblastoma cells in neurobiology. Methods Mol Biol 1078:9–21

    Article  CAS  Google Scholar 

  • Lim H, Kim B, Kim Y, Jeong S (2018) Phytochemical allylguaiacol exerts a neuroprotective effect on hippocampal cells and ameliorates scopolamine-induced memory impairment in mice. Behav Brain Res 339:261–268

    Article  CAS  Google Scholar 

  • Liu Q, Qiu J, Liang M, Golinski J, van Leyen K, Jung JE, You Z, Lo EH, Degterev A, Whalen MJ (2014) Akt and mTOR mediate programmed necrosis in neurons. Cell Death Dis 5:e1084

    Article  CAS  Google Scholar 

  • Liu T, Zhang L, Joo D, Sun SC (2017) NF-κB signaling in inflammation. Signal Transduct Target Ther 2:1–9

    CAS  Google Scholar 

  • Mamelak M, Delaney S, Yang K, O’Brien P (2010) Ketone bodies, sodium oxybate and Alzheimer’s disease: oxidative stress and neuroprotection. Alzheimer’s Dementia 6:S389

    Article  Google Scholar 

  • Moriguchi S, Shioda N, Yamamoto Y, Tagashira H, Fukunaga K (2012) The T-type voltage-gated calcium channel as a molecular target of the novel cognitive enhancer ST101: enhancement of long-term potentiation and CaMKII autophosphorylation in rat cortical slices. J Neurochem 121:44–53

    Article  CAS  Google Scholar 

  • Nunes-Tavares N, Santos LE, Stutz B, Brito-Moreira J, Klein WL, Ferreira ST, de Mello FG (2012) Inhibition of choline acetyltransferase as a mechanism for cholinergic dysfunction induced by amyloid-β peptide oligomers. J Biol Chem 287:19377–19385

    Article  CAS  Google Scholar 

  • Puangmalai N, Thangnipon W, Soi-ampornkul R, Suwanna N, Tuchinda P, Nobsathian S (2017) Neuroprotection of N-benzylcinnamide on scopolamine-induced cholinergic dysfunction in human SH-SY5Y neuroblastoma cells. Neural Regen Res 12:1492–1498

    Article  Google Scholar 

  • Pudlo M, Luzet V, Ismaïli L, Tomassoli I, Iutzeler A, Refouvelet B (2014) Quinolone–benzylpiperidine derivatives as novel acetylcholinesterase inhibitor and antioxidant hybrids for Alzheimer Disease. Bioorg Med Chem 22:2496–2507

    Article  CAS  Google Scholar 

  • Rinne J, Kaasinen V, Jarvenpaa T, Nagren K, Roivanen A, Yu M (2003) Brain acetylcholinesterase activity in mild cognitive impairment and early Alzheimer’s disease. Neurol Neurosurg Psychiatry 74:113–115

    Article  CAS  Google Scholar 

  • Rojsanga P, Boonyarat C, Utsintong M, Nemecz Á, Yamauchi J, Talley T, Olson AJ, Matsumoto K, Vajragupta O (2012) The effect of crebanine on memory and cognition impairment via the α-7 nicotinic acetylcholine receptor. Life Sci 91:107–114

    Article  CAS  Google Scholar 

  • Selkoe D, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8:595–608

    Article  CAS  Google Scholar 

  • Suthprasertporn N, Suwanna N, Thangnipon W (2019) Protective effects of diarylpropionitrile against hydrogen peroxide-induced damage in human neuroblastoma SH-SY5Y cells. Drug Chem Toxicol. https://doi.org/10.1080/01480545.2019.1658768

    Article  PubMed  Google Scholar 

  • Tao L, Xie J, Wang Y, Wang S, Wu S, Wang Q, Ding H (2014) Protective effects of aloe-emodin on scopolamine-induced memory impairment in mice and H2O2-induced cytotoxicity in PC12 cells. Bioorg Med Chem Lett 24:5385–5389

    Article  CAS  Google Scholar 

  • Thangnipon W, Suwanna N, Kitiyanant N, Soi-ampornkul R, Tuchinda P, Munyoo B, Nobsathian S (2012) Protective role of N-trans-feruloyltyramine against β-amyloid peptide-induced neurotoxicity in rat cultured cortical neurons. Neurosci Lett 513:229–232

    Article  CAS  Google Scholar 

  • Thangnipon W, Puangmalai N, Chinchalongporn V, Jantrachotechatchawan C, Kitiyanant N, Soi-Ampornkul R, Tuchinda P, Nobsathian S (2013) N-benzylcinnamide protects rat cultured cortical neurons from β-amyloid peptide-induced neurotoxicity. Neurosci Lett 556:20–25

    Article  CAS  Google Scholar 

  • Tiong CX, Lu M, Bian JS (2010) Protective effect of hydrogen sulphide against 6-OHDA-induced cell injury in SH-SY5Y cells involves PKC/PI3K/Akt pathway. Br J Pharmacol 161:467–480

    Article  CAS  Google Scholar 

  • Venkatesan R, Subedi L, Yeo EJ, Kim SY (2016) Lactucopicrin ameliorates oxidative stress mediated by scopolamine-induced neurotoxicity through activation of the NRF2 pathway. Neurochem Int 99:133–146

    Article  CAS  Google Scholar 

  • Voleti B, Navarria A, Liu RJ, Banasr M, Li N, Terwilliger R, Sanacora G, Eid T, Aghajanian G, Duman RS (2013) Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. Biol Psychiatry 74:742–749

    Article  CAS  Google Scholar 

  • Wang H, Xu Y, Yan J, Zhao X, Sun X, Zhang Y, Guo J, Zhu C (2009) Acteoside protects human neuroblastoma SH-SY5Y cells against β-amyloid-induced cell injury. Brain Res 1283:139–147

    Article  CAS  Google Scholar 

  • Wang X, Wang W, Li L, Perry G, Lee H, Zhu X (2014) Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta 1842:1240–1247

    Article  CAS  Google Scholar 

  • Yabuki Y, Jing X, Fukunaga K (2017a) The T-type calcium channel enhancer SAK3 inhibits neuronal death following transient brain ischemia via nicotinic acetylcholine receptor stimulation. Neurochem Int 108:272–281

    Article  CAS  Google Scholar 

  • Yabuki Y, Matsuo K, Izumi H, Haga H, Yoshida T, Wakamori M, Kakei A, Sakimura K, Fukuda T, Fukunaga K (2017b) Pharmacological properties of SAK3, a novel T-type voltage-gated Ca2+ channel enhancer. Neuropharmacology 117:1–13

    Article  CAS  Google Scholar 

  • Zhang H, Wu L, Pchitskaya E, Zakharova O, Saito T, Saido T, Bezprozvanny I (2015) Neuronal store-operated calcium entry and mushroom spine loss in amyloid precursor protein knock-in mouse model of Alzheimer’s disease. J Neurosci 35:13275–13286

    Article  CAS  Google Scholar 

  • Zhou H, Gao S, Duan X, Liang S, Scott DA, Lamont RJ, Wang H (2015) Inhibition of serum- and glucocorticoid-inducible kinase 1 enhances TLR-mediated inflammation and promotes endotoxin-driven organ failure. FASEB J. 29:3737–3749

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhonpathom, 73170, Thailand

    Nopparat Suthprasertporn, Nopparada Mingchinda & Wipawan Thangnipon

  2. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan

    Kohji Fukunaga

Authors
  1. Nopparat Suthprasertporn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nopparada Mingchinda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kohji Fukunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wipawan Thangnipon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wipawan Thangnipon.

Ethics declarations

conflict of interest

The authors declare no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Suthprasertporn, N., Mingchinda, N., Fukunaga, K. et al. Neuroprotection of SAK3 on scopolamine-induced cholinergic dysfunction in human neuroblastoma SH-SY5Y cells. Cytotechnology 72, 155–164 (2020). https://doi.org/10.1007/s10616-019-00366-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10616-019-00366-7

Keywords

Search

Navigation