Abstract
(−)-Linalool, a major component of many essential oils, is widely used in cosmetics and flavoring ingredients as well as in traditional medicines. Although various in vitro and in vivo studies have shown that (−)-linalool has anti-convulsant, anti-nociceptive, anti-inflammatory and anti-oxidative properties, its anti-ischemic/hypoxic effects have yet to be determined. This study assessed the neuroprotective effects of (−)-linalool against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced cortical neuronal injury, an in vitro model of ischemic stroke. (−)-Linalool significantly attenuated OGD/R-evoked cortical neuronal injury/death, although it did not inhibit N-methyl-d-aspartate (NMDA)-induced excitotoxicity. (−)-Linalool significantly reduced intracellular oxidative stress during OGD/R-induced injury, as well as scavenging peroxyl radicals (Trolox equivalents or TE = 3.8). This anti-oxidant effect was found to correlate with the restoration of OGD/R-induced decreases in the activities of SOD and catalase. In addition, (−)-linalool inhibited microglial migration induced by monocyte-chemoattractant protein-1 (MCP-1), a chemokine released by OGD/R. These findings show that (−)-linalool has neuroprotective effects against OGD/R-induced neuronal injury, which may be due to its anti-oxidant and anti-inflammatory activities. Detailed examination of the anti-ischemic mechanisms of (−)-linalool may indicate strategies for the development of drugs to treat cerebral ischemic injury.
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Abramov AY, Scorziello A, Duchen MR (2007) Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci 27:1129–1138
Allen CL, Bayraktutan U (2009) Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int J Stroke 4:461–470
Almeida A, Delgado-Esteban M, Bolanos JP, Medina JM (2002) Oxygen and glucose deprivation induces mitochondrial dysfunction and oxidative stress in neurones but not in astrocytes in primary culture. J Neurochem 81:207–217
Batista PA, Werner MF, Oliveira EC, Burgos L, Pereira P, Brum LF, Story GM, Santos AR (2010) The antinociceptive effect of (−)-linalool in models of chronic inflammatory and neuropathic hypersensitivity in mice. J Pain 11:1222–1229
Berliocchi L, Russo R, Levato A, Fratto V, Bagetta G, Sakurada S, Sakurada T, Mercuri NB, Corasaniti MT (2009) (−)-Linalool attenuates allodynia in neuropathic pain induced by spinal nerve ligation in c57/bl6 mice. Int Rev Neurobiol 85:221–235
Bindokas VP, Jordan J, Lee CC, Miller RJ (1996) Superoxide production in rat hippocampal neurons: selective imaging with hydroethidine. J Neurosci 16:1324–1336
Brum LFs, Emanuelli T, Souza DO, Elisabetsky E (2001) Effects of linalool on glutamate release and uptake in mouse cortical synaptosomes. Neurochem Res 26:191–194
Celik S, Ozkaya A (2002) Effects of intraperitoneally administered lipoic acid, vitamin E, and linalool on the level of total lipid and fatty acids in guinea pig brain with oxidative stress induced by H2O2. J Biochem Mol Biol 35:547–552
Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22:391–397
Dringen R (2000) Metabolism and functions of glutathione in brain. Prog Neurobiol 62:649–671
Elisabetsky E, Marschner J, Souza DO (1995) Effects of Linalool on glutamatergic system in the rat cerebral cortex. Neurochem Res 20:461–465
Elisabetsky E, Brum LF, Souza DO (1999) Anticonvulsant properties of linalool in glutamate-related seizure models. Phytomedicine 6:107–113
Facchinetti F, Dawson VL, Dawson TM (1998) Free radicals as mediators of neuronal injury. Cell Mol Neurobiol 18:667–682
Guzman-Gutierrez SL, Gomez-Cansino R, Garcia-Zebadua JC, Jimenez-Perez NC, Reyes-Chilpa R (2012) Antidepressant activity of Litsea glaucescens essential oil: identification of beta-pinene and linalool as active principles. J Ethnopharmacol 143:673–679
Halliwell B (1992) Reactive oxygen species and the central nervous system. J Neurochem 59:1609–1623
Huang D, Ou B, Prior RL (2005) The chemistry behind antioxidant capacity assays. J Agric Food Chem 53:1841–1856
Huo M, Cui X, Xue J, Chi G, Gao R, Deng X, Guan S, Wei J, Soromou LW, Feng H, Wang D (2013) Anti-inflammatory effects of linalool in RAW 264.7 macrophages and lipopolysaccharide-induced lung injury model. J Surg Res 180:e47–54
Iadecola C, Alexander M (2001) Cerebral ischemia and inflammation. Curr Opin Neurol 14:89–94
Jin R, Yang G, Li G (2010) Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 87:779–789
Johnson I, Spence MTZ (2010) The molecular probes® handbook: a guide to fluorescent probes and labeling technologies, 11th edn. Life Technologies Corporation, California, p 805
Kalyanaraman B (2013) Teaching the basics of redox biology to medical and graduate students: oxidants, antioxidants and disease mechanisms. Redox Biol 1:244–257
Lai TW, Zhang S, Wang YT (2013) Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol 115:157–188
Letizia CS, Cocchiara J, Lalko J, Api AM (2003) Fragrance material review on linalool. Food Chem Toxicol 41:943–964
Lim JH, Lee JC, Lee YH, Choi IY, Oh YK, Kim HS, Park JS, Kim WK (2006) Simvastatin prevents oxygen and glucose deprivation/reoxygenation-induced death of cortical neurons by reducing the production and toxicity of 4-hydroxy-2E-nonenal. J Neurochem 97:140–150
Mimica-Dukic N, Bugarin D, Grbovic S, Mitic-Culafic D, Vukovic-Gacic B, Orcic D, Jovin E, Couladis M (2010) Essential oil of Myrtus communis L. as a potential antioxidant and antimutagenic agents. Molecules 15:2759–2770
Moskowitz MA, Lo EH, Iadecola C (2010) The science of stroke: mechanisms in search of treatments. Neuron 67:181–198
Naderi GA, Asgary S, Ani M, Sarraf-Zadegan N, Safari MR (2004) Effect of some volatile oils on the affinity of intact and oxidized low-density lipoproteins for adrenal cell surface receptors. Mol Cell Biochem 267:59–66
Nantes IL, Rodrigues T, Yokomizo CH, Araújo-Chaves JC, Pessoto FS, Kisaki KM, Moraes VWR (2012) Antioxidant action of mobile electron carriers of the respiratory chain. In: Clark K (ed) Bioenergetics. InTech, Rijeka, pp 3–28
Paramo B, Hernandez-Fonseca K, Estrada-Sanchez AM, Jimenez N, Hernandez-Cruz A, Massieu L (2010) Pathways involved in the generation of reactive oxygen and nitrogen species during glucose deprivation and its role on the death of cultured hippocampal neurons. Neuroscience 167:1057–1069
Peana AT, D’Aquila PS, Panin F, Serra G, Pippia P, Moretti MD (2002) Anti-inflammatory activity of linalool and linalyl acetate constituents of essential oils. Phytomedicine 9:721–726
Porter NA (1984) Chemistry of lipid peroxidation. Methods Enzymol 105:273–282
Ray PD, Huang BW, Tsuji Y (2012) Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal 24:981–990
Rota C, Chignell CF, Mason RP (1999) Evidence for free radical formation during the oxidation of 2’-7’-dichlorofluorescin to the fluorescent dye 2’-7’-dichlorofluorescein by horseradish peroxidase: possible implications for oxidative stress measurements. Free Radic Biol Med 27:873–881
Teixeira HD, Schumacher RI, Meneghini R (1998) Lower intracellular hydrogen peroxide levels in cells overexpressing CuZn-superoxide dismutase. Proc Natl Acad Sci U S A 95:7872–7875
Trachootham D, Lu W, Ogasawara MA, Nilsa RD, Huang P (2008) Redox regulation of cell survival. Antioxid Redox Signal 10:1343–1374
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This research was supported by grants from the National Research Foundation of Korea (NRF) funded by the Korean government (MEST) (No. 2012R1A2A2A02007145) and a Korea University Grant (2015).
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Hyeon Park and Geun Hee Seol have contributed equally to this work.
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Park, H., Seol, G.H., Ryu, S. et al. Neuroprotective effects of (−)-linalool against oxygen-glucose deprivation-induced neuronal injury. Arch. Pharm. Res. 39, 555–564 (2016). https://doi.org/10.1007/s12272-016-0714-z
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DOI: https://doi.org/10.1007/s12272-016-0714-z