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Inhibition of Cyclooxygenase-2 (COX-2) Initiates Autophagy and Potentiates MPTP-Induced Autophagic Cell Death of Human Neuroblastoma Cells, SH-SY5Y: an Inside in the Pathology of Parkinson’s Disease

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Abstract

Cyclooxygenase-2 or COX-2 has been known to be crucial for Parkinson’s disease (PD) pathogenesis; however, its exact role is still not known. We first time report that inhibition of COX-2 promotes 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP)-induced neuronal cell death via induction of autophagic mechanisms. We found that treatment with MPTP induced cell death of neuroblastoma cells SH-SY5Y in a dose dependent manner. Treatment of MPTP has also upregulated the expressions of autophagic proteins such as LC3, beclin, ATG-5, and p62. Interestingly, nimesulide, a preferential COX-2 inhibitor, further potentiated the MPTP-induced cell death of human neuroblastoma cells. Treatment of nimesulide with MPTP further potentiated expressions of p62, ATG-5, beclin-1, LC3 autophagic proteins. Furthermore, nimesulide with MPTP increased apoptotic protein cleaved caspase-3 and also induced expression of p53 gene. Interestingly, it was observed that Akt inhibitor significantly increased MPTP-induced cell death of neuroblastoma cells. However, (−) deprenyl, a monoamine oxidase B (MAO B) inhibitor, attenuated MPTP-induced autophagic response and protected cell death. The prior treatment with prostaglandin E2 protected against nimesulide induced-death of neuronal cells. This study confirms that neuroinflammation is associated to the autophagy and may be one of the main pathological mechanisms in Parkinson’s disease and other inflammation-associated disorders.

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Abbreviations

COX-2:

Cyclooxygenase-2

PD:

Parkinson’s disease

LPS:

Lipo-polysaccharide

ROS:

Reactive oxygen species

Akt:

Protein kinase B

MPTP:

1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine

PTGS:

Prostaglandin endoperoxide synthase

LC3:

Light chain 3

ATG-5:

Autophagy protein-5

ATG-12:

Autophagy protein 12

ATG-14:

Autophagy protein-14

ATG-7:

Autophagy protein-7

p62/SQSTM1:

Sequestosome 1

IL-1:

Interleukin-1

Nrf2:

Nuclear factor erythroid 2

MCP-1:

Monocyte chemotactic protein-1

IL-4:

Interleukin-4

IL-8:

Interleukin-8

TGF-β:

Transforming growth factor beta

IL-13:

Interleukin-13

SCF:

Stem cell factor

AMPK:

Adenosine monophosphate-activated protein kinase

eNOS:

Endothelial nitric oxide synthase

PGE-2:

Prostaglandin-E2

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Acknowledgements

The Senior Research Associateship (pool scientist) from council of scientific and industrial research (CSIR) Pool No. 8696A (IIT kanpur project No. CSIR/BSBE/2013399) to Dr. Rituraj Niranjan is gratefully acknowledged. The valuable suggestions provided by Dr. Purushothaman Jambulingam at Vector Control Research Center are also gratefully acknowledged.

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  1. Rituraj Niranjan

    Present address: Unit of Microbiology and Molecular Biology, ICMR-Vector Control Research Center, Puducherry, 605006, India

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  1. Lab # 6, Department of Biological Sciences and Bioengineering (BSBE), Indian Institute of Technology, Kanpur, Uttar Pradesh, 208016, India

    Rituraj Niranjan, Kaushal Prasad Mishra & Ashwani Kumar Thakur

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The entire work included in this manuscript was done at the department of Biological Sciences and Bio-engineering, Indian Institute of Technology, Kanpur, U.P. India. Some writing and analysis part of work was accomplished by Dr. Rituraj Niranjan at the ICMR-Vector Control Research Center, Puducherry, 605006.

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Niranjan, R., Mishra, K.P. & Thakur, A.K. Inhibition of Cyclooxygenase-2 (COX-2) Initiates Autophagy and Potentiates MPTP-Induced Autophagic Cell Death of Human Neuroblastoma Cells, SH-SY5Y: an Inside in the Pathology of Parkinson’s Disease. Mol Neurobiol 55, 8038–8050 (2018). https://doi.org/10.1007/s12035-018-0950-y

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