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

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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Correspondence to Okobi Eko Ekpo.

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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