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Curcumin Attenuates Colistin-Induced Neurotoxicity in N2a Cells via Anti-inflammatory Activity, Suppression of Oxidative Stress, and Apoptosis

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Abstract

Neurotoxicity is an unwanted side-effect seen in patients receiving therapy with the “last-line” polymyxin antibiotics. This is the first study to show that colistin-induced neurotoxicity in neuroblastoma-2a (N2a) cells gives rise to an inflammatory response involving the IL-1β/p-IκB-α/NF-κB pathway. Pretreatment with curcumin at 5, 10, and 20 μM for 2 h prior to colistin (200 μM) exposure for 24 h, produced an anti-inflammatory effect by significantly down-regulating the expression of the pro-inflammatory mediators cyclooxygenase-2 (COX-2), phosphorylation of the inhibitor of nuclear factor-kappa B (NF-κB) (p-IκB)-α, and concomitantly NF-κB levels. Moreover, curcumin significantly decreased intracellular reactive oxygen species (ROS) production and increased the activities of the anti-ROS enzymes superoxide dismutase, catalase, and the intracellular levels of glutathione. Curcumin pretreatment also protected the cells from colistin-induced mitochondrial dysfunction, caspase activation, and subsequent apoptosis. Overall, our findings demonstrate for the first time, a potential role for curcumin for treating polymyxin-induced neurotoxicity through the modulation of NF-κB signaling and its potent anti-oxidative and anti-apoptotic effects.

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Acknowledgements

This study was supported by Key Projects in the National Science and Technology Pillar Program during the 12th Five-Year Plan Period (2015BAD11B03) and Chinese Universities Scientific Fund (award number 2015DY003). T. V. is supported by a research grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (R01 AI111965). T. V. is also supported by the Australian National Health and Medical Research Council (NHMRC).

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Authors and Affiliations

  1. College of Veterinary Medicine, China Agricultural University, 2 Yuanmingyuan West Road, Beijing, 100193, People’s Republic of China

    Chongshan Dai, Shusheng Tang, Daowen Li, Sanlei Xie & Xilong Xiao

  2. Department of Pathology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia

    Giuseppe D. Ciccotosto & Roberto Cappai

  3. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia

    Tony Velkov

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  1. Chongshan Dai
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  2. Giuseppe D. Ciccotosto
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Correspondence to Xilong Xiao or Tony Velkov.

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Dai, C., Ciccotosto, G.D., Cappai, R. et al. Curcumin Attenuates Colistin-Induced Neurotoxicity in N2a Cells via Anti-inflammatory Activity, Suppression of Oxidative Stress, and Apoptosis. Mol Neurobiol 55, 421–434 (2018). https://doi.org/10.1007/s12035-016-0276-6

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