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Regulation of AKT/AMPK signaling, autophagy and mitigation of apoptosis in Rutin-pretreated SH-SY5Y cells exposed to MPP+

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Abstract

Accumulating evidence suggest that apoptosis, autophagy and dysregulation of signaling pathways are common mechanisms involved in Parkinson’s disease (PD) pathogenesis, and thus development of therapeutic agents targeting these mechanisms may be useful for the treatment of this disease. Although rutin (a bioflavonoid) is reported to have pharmacological benefits such as antioxidant, anti-inflammatory and antitumor activities, there are very few reports on the activity of this compound in 1-methyl-4-phenylpyridinium (MPP+)-induced PD models. Accordingly, we investigated the effects of rutin on apoptosis, autophagy and cell signaling markers (AKT/AMPK) in SH-SY5Y cells exposed to MPP+. Results show reduced changes in nuclear morphology and mitigation of caspase 3/7 and 9 activities in rutin pre-treated cells exposed to MPP+. Likewise, rutin regulated cell signaling pathways (AKT/AMPK) and significantly decreased protein expression levels of cleaved PARP, cytochrome c, LC3-II and p62. Also, rutin significantly increased protein expression levels of full-length caspase 3 in SH-SY5Y cells treated with MPP+. Transmission electron microscope (TEM) images demonstrated a reduction in autophagosomes in rutin-pretreated SH-SY5Y cells exposed to MPP+. These results provide experimental support for rutin’s neuroprotective activity against MPP+-induced toxicity in SH-SY5Y cells, which is as a promising therapeutic agent for clinical trials in humans.

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Abbreviations

6-OHDA:

6-hydroxydopamine

ADP:

Adenosine diphosphate

AKT:

Protein Kinase B

AMP:

Adenosine Monophosphate

AMPK:

5′ adenosine monophosphate-activated protein kinase

ATP:

Adenosine triphosphate

Ca2+ :

Calcium

DMEM:

Dulbecco’s modified Eagle medium

FBS:

Fetal bovine serum

LC3:

Light chain 3

MPP+ :

1-methyl-4-phenylpyridinium

MTT:

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

p62:

Ubiquitin-binding protein

PARP:

Poly (ADP-ribose) polymerase

PBS:

Phosphate buffered saline

PD:

Parkinson’s Disease

PI3K:

Phosphatidylinositol 3-kinase

SEM:

Standard error of the mean

SNpc:

Substantia Nigra pars compacta

TEM:

Transmission electron microscopy

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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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Authors and 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. Department of Anatomy, School of Basic Medical Sciences, University of Benin, Benin City, Edo State, Nigeria

    Adaze Bijou Enogieru

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

    William Haylett

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  1. Adaze Bijou Enogieru
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  2. William Haylett
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Contributions

ABE performed cell culture experiments and analyzed the data. WH assisted with the western blot experiments. DCH and OEE developed the concepts, designed, and supervised the project. All authors have read and approved the final manuscript.

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Correspondence to Okobi Eko Ekpo.

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Highlights

• Rutin inhibits cell toxicity in SH-SY5Y cells treated with MPP+

• Rutin protects against apoptosis in SH-SY5Y cells treated with MPP+

• Rutin rescues changes in nuclear morphology in SH-SY5Y cells treated with MPP+

• Rutin inhibits abnormal autophagy activation in SH-SY5Y cells treated with MPP+

• The protective effect of rutin against MPP+-induced toxicity involves the regulation of AKT/AMPK signaling

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Enogieru, A.B., Haylett, W., Hiss, D.C. et al. Regulation of AKT/AMPK signaling, autophagy and mitigation of apoptosis in Rutin-pretreated SH-SY5Y cells exposed to MPP+. Metab Brain Dis 36, 315–326 (2021). https://doi.org/10.1007/s11011-020-00641-z

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