Linalool Attenuates Oxidative Stress and Mitochondrial Dysfunction Mediated by Glutamate and NMDA Toxicity
Open accessAbstract
Mitochondrial dysfunction and inflammation contribute to the initiation and development of several brain pathological conditions, including Alzheimer's disease and cerebral ischemia. Linalool is an aromatic plant-derived monoterpene alcohol with reported anti-inflammatory, and anti-oxidant properties. We investigated the role of linalool on glutamate-induced mitochondrial oxidative stress in immortalized neuronal HT-22 cells. Glutamate induced oxidative stress in neuronal cells, as detected by real-time cell impedance measurements, MTT assay, and analysis of Annexin V/PI. Administration of linalool 100 μM reduced cell death mediated by glutamate. Staining of glutamate-stimulated mitochondria by MitoTracker revealed improved morphology in the presence of linalool. Furthermore, we demonstrated a potential neuroprotective effect of linalool in conditions of oxidative stress by a reduction of mitochondrial ROS and mitochondrial calcium levels, and by preserving mitochondrial membrane potential. Experiments using both high-resolution respirometry and Seahorse Extracellular flux analyzer showed that linalool was able to promote an increase in uncoupled respiration that could contribute to its neuroprotective capacity. Linalool protection was validated using organotypic hippocampal slices as ex vivo model with NMDA as a stimulus to induce excitotoxity cell damage. These results demonstrate that linalool is protective in an in vitro model of glutamate-induced oxidative stress and in an ex-vivo model for excitotoxity, proposing linalool as a potential therapeutic agent against neurodegenerative brain diseases where oxidative stress contributes to the pathology of the disease.
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Linalool significantly counteracts cell death and COX-2 increase in organotypic hippocampal slices exposed to NMDA.
“Moreover, linalool significantly counteracts cell death and COX-2 increase in organotypic hippocampal slices exposed to NMDA (Sabogal-Guáqueta et al., 2019).”
From Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes (2022) · cites this paper as Sabogal-Guáqueta et al., 2019
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Cites
Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death
Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.042 · Cited by 18,691 · see citing works
Neurodegenerative diseases and oxidative stress
Barnham, K. J., Masters, C. L., & Bush, A. I. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1330 · Cited by 3,683 · see citing works
Mitochondrial membrane permeabilization in cell death
Kroemer, G., Galluzzi, L., & Brenner, C. (2007) · Physiological Reviews · doi:10.1152/physrev.00013.2006 · Cited by 3,598 · see citing works
Chamorro, Á., Dirnagl, U., Urra, X., & Planas, A. M. (2016) · The Lancet Neurology · doi:10.1016/s1474-4422(16)00114-9 · Cited by 1,198 · see citing works
Murphy, T. H., Miyamoto, M., Sastre, A., Schnaar, R. L., & COYLE, J. T. (1989) · Neuron · doi:10.1016/0896-6273(89)90043-3 · Cited by 1,033 · see citing works
Oxidative stress in Alzheimer’s disease
Chen, Z., & Zhong, C. (2014) · Neuroscience Bulletin · doi:10.1007/s12264-013-1423-y · Cited by 797 · see citing works
Oxytosis: a novel form of programmed cell death
Shirlee Tan, B. S. P., David Schubert, B. S. P., & Pamela Maher, B. S. P. (2001) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026013394741 · Cited by 522 · see citing works
The effects of stress and aging on glutathione metabolism
Maher, P. A. (2005) · Ageing Research Reviews · doi:10.1016/j.arr.2005.02.005 · Cited by 426 · see citing works
BID links ferroptosis to mitochondrial cell death pathways
Neitemeier, S., Jelinek, A., Laino, V., Hoffmann, L., Eisenbach, I., Eying, R., Ganjam, G. K., Dolga, A. M., Oppermann, S., & Culmsee, C. (2017) · Redox Biology · doi:10.1016/j.redox.2017.03.007 · Cited by 366 · see citing works
Self-citationΚritis, A., Stamoula, Ε., Paniskaki, K., & Vavilis, T. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00091 · Cited by 359 · see citing works
Neuroprotective function for ramified microglia in hippocampal excitotoxicity
Vinet, J., van Weering, H. R., Heinrich, A., Kälin, R. E., Wegner, A., Brouwer, N., Heppner, F. L., van Rooijen, N., Boddeke, H. W., & Biber, K. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-27 · Cited by 274 · see citing works
Lewerenz, J., Ates, G., Methner, A., Conrad, M., & Maher, P. A. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00214 · Cited by 273 · see citing works
Effects of inhaled Linalool in anxiety, social interaction and aggressive behavior in mice
Linck, V. M., Silva, A. L. D., Figueiró, M., Caramão, E. B., Moreno, P. R. H., & Elisabetsky, E. (2009) · Phytomedicine · doi:10.1016/j.phymed.2009.10.002 · Cited by 268 · see citing works
Endophilin B1 is required for the maintenance of mitochondrial morphology
Karbowski, M., Jeong, S., & Youle, R. J. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200407046 · Cited by 264 · see citing works
Li, P., Stetler, R. A., Leak, R. K., Shi, Y., Li, Y., Yu, W., Bennett, M. V. L., & Chen, J. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.11.011 · Cited by 260 · see citing works
Ruijter, J. M., Pfaffl, M. W., Zhao, S., Spiess, A., Boggy, G. J., Blom, J., Rutledge, R. G., Sisti, D., Lievens, A., Preter, K. D., et al. (2012) · Methods · doi:10.1016/j.ymeth.2012.08.011 · Cited by 258 · see citing works
Mitochondria: isolation, structure and function
Picard, M. A., Taivassalo, T., Gouspillou, G., & Hepple, R. T. (2011) · The Journal of Physiology · doi:10.1113/jphysiol.2011.212712 · Cited by 251 · see citing works
Effects of linalool on glutamatergic system in the rat cerebral cortex
Elisabetsky, E., Marschner, J., & Souza, D. O. (1995) · Neurochemical Research · doi:10.1007/bf00973103 · Cited by 243 · see citing works
Doerrier, C., Garcia-Souza, L. F., Krumschnabel, G., Wohlfarter, Y., Mészáros, A., & Gnaiger, E. (2018) · Methods in molecular biology · doi:10.1007/978-1-4939-7831-1_3 · Cited by 238 · see citing works
Mitochondrial dysfunction in brain aging: Role of oxidative stress and cardiolipin
Paradies, G., Petrosillo, G., Paradies, V., & Ruggiero, F. M. (2011) · Neurochemistry International · doi:10.1016/j.neuint.2010.12.016 · Cited by 220 · see citing works
Linalool and β-pinene exert their antidepressant-like activity through the monoaminergic pathway
Guzmán‐Gutiérrez, S. L., Bonilla‐Jaime, H., Gómez‐Cansino, R., & Reyes‐Chilpa, R. (2015) · Life Sciences · doi:10.1016/j.lfs.2015.02.021 · Cited by 170 · see citing works
Peana, A. T., Marzocco, S., Popolo, A., & Pinto, A. (2006) · Life Sciences · doi:10.1016/j.lfs.2005.05.065 · Cited by 160 · see citing works
The role of mitochondrial respiration in physiological and evolutionary adaptation
Das, J. (2006) · BioEssays · doi:10.1002/bies.20463 · Cited by 154 · see citing works
Sabogal-Guáqueta, A. M., Osorio, E., & Cardona-Gómez, G. P. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.11.002 · Cited by 148 · see citing works
Self-citationBatista, P. A., Werner, M. F. D. P., Oliveira, E. C., Burgos, L., Pereira, P., Brum, L. F. D. S., Story, G. M., & Santos, A. R. S. (2010) · Journal of Pain · doi:10.1016/j.jpain.2010.02.022 · Cited by 143 · see citing works
Yang, S., & Li, W. (2016) · Brain Circulation · doi:10.4103/2394-8108.195279 · Cited by 143 · see citing works
A novel approach to screening for new neuroprotective compounds for the treatment of stroke
Maher, P. A., Salgado, K. F., Zivin, J. A., & Lapchak, P. A. (2007) · Brain Research · doi:10.1016/j.brainres.2007.07.061 · Cited by 132 · see citing works
Effects of Linalool on Glutamate Release and Uptake in Mouse Cortical Synaptosomes
Brum, L. F. S., Emanuelli, T., Souza, D. O., & Elisabetsky, E. (2001) · Neurochemical Research · doi:10.1023/a:1010904214482 · Cited by 131 · see citing works
Maher, P. A. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.11.015 · Cited by 102 · see citing works
Linalool as a neuroprotective agent against acrylamide-induced neurotoxicity in Wistar rats
Mehri, S., Meshki, M. A., & Hosseinzadeh, H. (2014) · Drug and Chemical Toxicology · doi:10.3109/01480545.2014.919585 · Cited by 101 · see citing works
Usta, J. A., Kreydiyyeh, S. I., Knio, K., Barnabe, P., Yolla, B., & Dagher, S. (2009) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2009.02.012 · Cited by 98 · see citing works
Dolga, A. M., Netter, M. F., Perocchi, F., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.453522 · Cited by 96 · see citing works
Self-citationÇeli̇k, S., & Özkaya, A. (2002) · BMB Reports · doi:10.5483/bmbrep.2002.35.6.547 · Cited by 95 · see citing works
Grohm, J., Plesnila, N., & Culmsee, C. (2009) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2009.11.015 · Cited by 90 · see citing works
Dowling, C. M., Herranz, C., & Kiely, P. A. (2014) · Bioscience Reports · doi:10.1042/bsr20140031 · Cited by 88 · see citing works
Beier, R. C., Byrd, J. A., Kubena, L. F., Hume, M. E., McReynolds, J. L., Anderson, R. C., & Nisbet, D. J. (2014) · Poultry Science · doi:10.3382/ps.2013-03254 · Cited by 86 · see citing works
Sil, S., & Ghosh, T. (2015) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2015.12.003 · Cited by 80 · see citing works
Singh, B. K., Tripathi, M., Chaudhari, B. P., Pandey, P. K., & Kakkar, P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034200 · Cited by 77 · see citing works
Xu, K., Qiu, J., Li, Q., Bell, K. A., Du, Y., Jung, D. W., Lee, J. Y., Hao, J., & Jiang, J. (2017) · Scientific Reports · doi:10.1038/s41598-017-09528-z · Cited by 69 · see citing works
Neuroprotective effects of (−)-linalool against oxygen-glucose deprivation-induced neuronal injury
Park, H. H., Seol, G. H., Ryu, S., & Choi, I.-Y. (2016) · Archives of Pharmacal Research · doi:10.1007/s12272-016-0714-z · Cited by 64 · see citing works
Cho, S., Jun, H., Lee, J. H., et al. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.09.012 · Cited by 62 · see citing works
Cardiovascular Effects Induced by Linalool in Normotensive and Hypertensive Rats
Anjos, P. J. C., Lima, A. O., Cunha, P. S., de Sousa, D. P., Onofre, A. S. C., Ribeiro, T. P., de Medeiros, I. A., Antoniolli, Â. R., Quintans‐Júnior, L. J., & Santos, M. R. V. (2013) · Zeitschrift für Naturforschung C · doi:10.1515/znc-2013-5-603 · Cited by 60 · see citing works
Wu, Q., Yu, L.-J., Qiu, J., Shen, B., Wang, D., Soromou, L. W., & Feng, H. (2014) · International Immunopharmacology · doi:10.1016/j.intimp.2014.05.030 · Cited by 59 · see citing works
Organotypic Hippocampal Slices as Models for Stroke and Traumatic Brain Injury
Li, Q., Han, X., & Wang, J. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9362-4 · Cited by 56 · see citing works
Li, J., Zhang, X., & Huang, H. (2014) · International Immunopharmacology · doi:10.1016/j.intimp.2014.10.001 · Cited by 55 · see citing works
SK2 channels regulate mitochondrial respiration and mitochondrial Ca2+ uptake
Honrath, B., Matschke, L. A., Meyer, T., Magerhans, L., Perocchi, F., Ganjam, G. K., Zischka, H., Krasel, C., Gerding, A., Bakker, B. M., et al. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.2 · Cited by 54 · see citing works
Self-citationInhibition of Insect Cytochromes P450 by Furanocoumarins
Neal, J. J., & Wu, D. (1994) · Pesticide Biochemistry and Physiology · doi:10.1006/pest.1994.1056 · Cited by 53 · see citing works
Li, D., Li, Y., Liu, Y., Bao, Y., Hu, B., & An, L. (2005) · Toxicon · doi:10.1016/j.toxicon.2004.09.007 · Cited by 48 · see citing works
Sabogal-Guáqueta, A. M., Posada‐Duque, R., Cortés, N., Arias-Londoño, J. D., & Cardona‐Gómez, G. P. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.04.015 · Cited by 48 · see citing works
Self-citationNeitemeier, S., Dolga, A. M., Honrath, B., Karuppagounder, S. S., Alim, I., Ratan, R. R., & Culmsee, C. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.107 · Cited by 47 · see citing works
Self-citationNeurobehavioral and genotoxic evaluation of (−)-linalool in mice
Coelho, V., Mazzardo‐Martins, L., Martins, D. F., Santos, A. R. S., Brum, L. F. D. S., Picada, J. N., & Pereira, P. (2013) · Journal of Natural Medicines · doi:10.1007/s11418-013-0751-6 · Cited by 38 · see citing works
Wang, X., Li, G., & Shen, W. (2017) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2017.5509 · Cited by 38 · see citing works
Kaka, G., Yaghoobi, K., Davoodi, S., Hosseini, S. R., Sadraie, S. H., & Mansouri, K. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00025 · Cited by 34 · see citing works
Alinejad, B., Ghorbani, A., & Sadeghnia, H. R. (2013) · PubMed · Cited by 30 · see citing works
Application of Monoterpenoids and their Derivatives for Treatment of Neurodegenerative Disorders
Volcho, K. P., Laev, S. S., Ashraf, G. M., et al. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867324666170112101837 · Cited by 23 · see citing works
Effects of β-pinene, a nonsubstituted monoterpene, on rat liver mitochondria
Uribe, S., Alvarez, R., & Peña, A. (1984) · Pesticide Biochemistry and Physiology · doi:10.1016/0048-3575(84)90008-7 · Cited by 18 · see citing works
Measurement of Proton Leak in Isolated Mitochondria
Affourtit, C., Wong, H. S., & Brand, M. D. (2018) · Methods in molecular biology · doi:10.1007/978-1-4939-7831-1_9 · Cited by 14 · see citing works
Molecular Mechanisms Underlying Oxytosis
Dolga, A., Oppermann, S., Richter, M., Honrath, B., Neitemeier, S., Jelinek, A., Ganjam, G., & Culmsee, C. (2018) · Apoptosis and Beyond · doi:10.1002/9781119432463.ch14 · Cited by 5 · see citing works
Self-citationEFFECTS OF THE APOTHECARIES' ACT.
Elliot, G. (1831) · The Lancet · doi:10.1016/s0140-6736(02)82141-9 · Cited by 1 · see citing works
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- V.M. Linck, A.L. Da Silva, M. Figueiró, E.B. Caramão, P.R.H. Moreno, E. Elisabetsky, Effects of inhaled Linalool in anxiety, social interaction and aggressive behavior in mice, Phytomedicine 17 (2010) 679-683, https://doi.org/10.1016/j.phymed.2009. 10.002. · DOI
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Piccialli, I., Tedeschi, V., Caputo, L., D’Errico, S., Ciccone, R., De Feo, V., Secondo, A., & Pannaccione, A. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.876614 · Cited by 73 · see citing works
- Authors
- Sabogal-Guáqueta, A. M., Hobbie, F., Keerthi, A., Oun, A., Kortholt, A., Boddeke, E., & Dolga, A.
- Affiliations
- University Medical Center Groningen (NL)
- University of Groningen (NL)
- Universidad de Antioquia (CO)
- Corresponding author
- Sabogal-Guáqueta, Angélica María
- Venue
- Biomedicine & Pharmacotherapy
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 118
- Pages
- 109295
- ISSN
- 0753-3322 (ISSN-L)
- OpenAlex
- W2972189281
- Cited by
- 154
- References
- 59
- Citations by year
- 2026: 12 · 2025: 26 · 2024: 23 · 2023: 22 · 2022: 28 · 2021: 24 · 2020: 18 · 2014: 1
- FWCI
- 5.79
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Biomedicine & Pharmacotherapy (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- Rijksuniversiteit Groningen
- Universitair Medisch Centrum Groningen
- European Commission
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plants and Neuroprotection
- Keywords
- linalool, monoterpenes, glutamate excitotoxicity, NMDA excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroprotection, mitochondrial reactive oxygen species, mitochondrial calcium, mitochondrial membrane potential, uncoupled respiration, HT22 cells, organotypic hippocampal slices, neurodegenerative diseases, Alzheimer's disease, cerebral ischemia
- MeSH terms
- Acyclic Monoterpenes, Animals, Brain, Mice, Inbred C57BL, Mitochondria, Lipid Peroxidation, N-Methylaspartate, Apoptosis, Oxidative Stress, Glutamic Acid, Cell Respiration, Protective Agents, Cyclooxygenase 2
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