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

• Published in: Molecular neurobiology 2018-10, Vol.55 (10), p.8038-8050
• Main Authors: Niranjan, Rituraj, Mishra, Kaushal Prasad, Thakur, Ashwani Kumar
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; AKT protein; Amine oxidase (flavin-containing); Apoptosis; Autophagy; Autophagy - drug effects; Biomedical and Life Sciences; Biomedicine; Caspase; Caspase 3 - metabolism; Caspase-3; Cell Biology; Cell death; Cell Line, Tumor; Cell Survival - drug effects; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - pharmacology; Cyclooxygenase-2; Humans; Inflammation; Inhibition; Lipopolysaccharides; Movement disorders; MPTP; Nerve Tissue Proteins - metabolism; Neurobiology; Neuroblastoma; Neuroblastoma - metabolism; Neuroblastoma - pathology; Neuroblasts; Neurodegenerative diseases; Neurology; Neurosciences; Nimesulide; p53 Protein; Parkinson Disease - enzymology; Parkinson Disease - pathology; Parkinson's disease; Phagocytosis; Prostaglandin E2; Proteins; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Reactive Oxygen Species - metabolism; Selegiline; Selegiline - pharmacology; Sulfonamides - pharmacology
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-018-0950-y

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.