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Attenuation of Endoplasmic Reticulum Stress, Impaired Calcium Homeostasis, and Altered Bioenergetic Functions in MPP+-Exposed SH-SY5Y Cells Pretreated with Rutin

Neurotoxicity Research volume 36, pages 764–776 (2019)Cite this article

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder that affects approximately 1% of the population over the age of 65 years. While treatment options for PD are limited, reports show that plant-derived bioactive compounds such as rutin possess numerous pharmacological benefits, including antioxidant and antiapoptotic activities. This study aimed to investigate the potential role of rutin in MPP+-treated SH-SY5Y neuroblastoma cells, an established cell model of PD. Our findings reveal increased concentrations of Ca2+ and endoplasmic reticulum (ER) stress as well as impaired mitochondrial membrane potential and bioenergetic status in SH-SY5Y cells treated with MPP+ only. This is demonstrated by a significant reduction in the expression levels of BiP, significantly reduced basal respiration, maximal respiration, and spare respiratory capacity as well as a significant increase in the expression levels of CHOP; however, these effects were significantly attenuated following pretreatment with rutin. Also, rutin significantly improved basal and compensatory glycolysis as a response to an impaired oxidative phosphorylation system triggered by MPP+, characterized by deficient ATP production. In conclusion, our findings provide the first evidence on the ability of rutin to maintain Ca2+ homeostasis, inhibit ER stress, and protect the mitochondria in MPP+-treated SH-SY5Y cells.

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Abbreviations

6-OHDA:

6-Hydroxydopamine

ATP:

Adenosine triphosphate

BiP:

Binding immunoglobulin protein

Ca2+ :

Calcium

CHOP:

CCAAT-enhancer-binding protein homologous protein

DMEM:

Dulbecco’s modified Eagle medium

ER:

Endoplasmic reticulum

FBS:

Fetal bovine serum

JC-1:

5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethylbenzimidazolocarbo-cyanine iodide

MMP:

Mitochondrial membrane potential

MPP+ :

1-Methyl-4-phenylpyridinium

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

OXPHOS:

Oxidative phosphorylation

PBS:

Phosphate-buffered saline

PD:

Parkinson’s disease

SEM:

Standard error of the mean

SNpc:

Substantia nigra pars compacta

UPR:

Unfolded protein response

UPS:

Ubiquitin proteasome system

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Acknowledgements

We are grateful to the Parkinson’s Disease Research Group, Division of Molecular Biology and Human Genetics, Stellenbosch University, for providing some laboratory materials and workspace needed for this study.

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Affiliations

  1. Department of Medical Biosciences, University of the Western Cape, Robert Sobukwe Road, Private Bag X17, Bellville, 7535, South Africa

    Adaze Bijou Enogieru, Donavon Charles Hiss & Okobi Eko Ekpo

  2. Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

    William Lloyd Haylett

  3. Division of Endocrinology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

    William Lloyd Haylett

  4. Focus Area for Human Metabolomics, Faculty of Natural Sciences, North-West University, Potchefstroom, South Africa

    Hayley Christy Miller & Francois Hendrikus van der Westhuizen

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  1. Adaze Bijou Enogieru
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Highlights

• Rutin protects against dysregulated Ca2+ homeostasis in SH-SY5Y cells treated with MPP+.

• Rutin maintains mitochondrial membrane potential in SH-SY5Y cells treated with MPP+.

• The protective effect of rutin against MPP+-induced toxicity involves the inhibition of ER stress.

• Rutin mitigates impaired oxidative phosphorylation in SH-SY5Y cells treated with MPP+.

• Rutin improves glycolysis in SH-SY5Y cells treated with MPP+.

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Enogieru, A.B., Haylett, W.L., Miller, H.C. et al. Attenuation of Endoplasmic Reticulum Stress, Impaired Calcium Homeostasis, and Altered Bioenergetic Functions in MPP+-Exposed SH-SY5Y Cells Pretreated with Rutin. Neurotox Res 36, 764–776 (2019). https://doi.org/10.1007/s12640-019-00048-4

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Keywords

  • Parkinson’s disease
  • Rutin
  • ER stress
  • Oxidative phosphorylation
  • Glycolysis