Biomol Ther  
Carbon Monoxide Ameliorates 6-Hydroxydopamine-Induced Cell Death in C6 Glioma Cells
Hyewon Moon1, Jung-Hee Jang2, Tae Chang Jang3,* and Gyu Hwan Park1,*
1College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566,
2Department of Pharmacology, School of Medicine, Keimyung University, Daegu 42601,
3Department of Emergency Medicine, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea
E-mail: emzzang@cu.ac.kr (Jang TC), park014@knu.ac.kr (Park GH)
Tel: +82-53-650-4282 (Jang TC), +82-53-950-8576 (Park GH)
Fax: +82-53-650-4930 (Jang TC), +82-53-950-8557 (Park GH)
Received: January 18, 2018; Revised: January 19, 2018; Accepted: January 22, 2018; Published online: February 12, 2018.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Carbon monoxide (CO) is well-known as toxic gas and intrinsic signaling molecule such as neurotransmitter and blood vessel relaxant. Recently, it has been reported that low concentration of CO exerts therapeutic actions under various pathological conditions including liver failure, heart failure, gastric cancer, and cardiac arrest. However, little has been known about the effect of CO in neurodegenerative diseases like Parkinson’s disease (PD). To test whether CO could exert a beneficial action during oxidative cell death in PD, we examined the effects of CO on 6-hydroxydopamine (6-OHDA)-induced cell death in C6 glioma cells. Treatment of CO-releasing molecule-2 (CORM-2) significantly attenuated 6-OHDA-induced apoptotic cell death in a dose-dependent manner. CORM-2 treatment decreased Bax/Bcl2 ratio and caspase-3 activity, which had been increased by 6-OHDA. CORM-2 increased phosphorylation of NF-E2-related factor 2 (Nrf2) which is a transcription factor regulating antioxidant proteins. Subsequently, CORM-2 also increased the expression of heme oxygenase-1 and superoxide dismutases (CuZnSOD and MnSOD), which were antioxidant enzymes regulated by Nrf2. These results suggest that CO released by CORM-2 treatment may have protective effects against oxidative cell death in PD through the potentiation of cellular adaptive survival responses via activation of Nrf2 and upregulation of heme oxygenase-1, leading to increasing antioxidant defense capacity.
Keywords: CO, PD, Neuroprotection, Nrf2, HO-1, SOD


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