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Ketogenic diet decreases oxidative stress and improves mitochondrial respiratory complex activity
Open accessAbstract
Cerebral metabolism of ketones after traumatic brain injury (TBI) improves neuropathology and behavior in an age-dependent manner. Neuroprotection is attributed to improved cellular energetics, although other properties contribute to the beneficial effects. Oxidative stress is responsible for mitochondrial dysfunction after TBI. Ketones decrease oxidative stress, increase antioxidants and scavenge free radicals. It is hypothesized that ketogenic diet (KD) will decrease post-TBI oxidative stress and improve mitochondria. Postnatal day 35 (PND35) male rats were given sham or controlled cortical impact (CCI) injury and placed on standard (STD) or KD. Ipsilateral cortex homogenates and mitochondria were assayed for markers of oxidative stress, antioxidant expression and mitochondrial function. Oxidative stress was significantly increased at 6 and 24 h post-injury and attenuated by KD while inducing protein expression of antioxidants, NAD(P)H dehydrogenase quinone 1 (NQO1) and superoxide dismutase (SOD1/2). Complex I activity was inhibited in STD and KD groups at 6 h and normalized by 24 h. KD significantly improved Complex II–III activity that was reduced in STD at 6 h. Activity remained reduced at 24 h in STD and unchanged in KD animals. These results strongly suggest that ketones improve post-TBI cerebral metabolism by providing alternative substrates and through antioxidant properties, preventing oxidative stress-mediated mitochondrial dysfunction.
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“Moreover, a ketogenic diet mediates its neuroprotective function through the attenuation of oxidative stress and induction of protein expression of antioxidants (Greco et al., 2016), as well as the modulation of neurotransmitter levels such as GABA, monoamines and glutamate (Hartman et al., 2007;Yudkoff et al., 2008).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Greco et al., 2016
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“…reported that the ketogenic diet increases oxidative stress (Allen et al., 2013), in others it has been observed that ketones in the ketogenic diet prevent oxidative stress-mediated by mitochondrial dysfunction by providing alternative substrates and antioxidant properties (Greco et al., 2016).”
BackgroundPeran Diet Ketogenik dalam Tata Laksana Epilepsi
Saputra, D. H. (2022) · Cermin Dunia Kedokteran · doi:10.55175/cdk.v49i11.318 · Cited by 1
Andrianto, A., Ardiana, M., Wardhani, P., Triastuti, F., & Yurista, S. R. (2024) · Research Journal of Pharmacy and Technology · doi:10.52711/0974-360x.2024.00352 · Cited by 1
Ketogenic diet in epilepsy: an updated review
Dudzińska, M. (2018) · Journal of Epileptology · doi:10.21307/jepil-2018-004 · Cited by 1
“A rise in energy production in mitochondria and a drop in the number of free radicals contribute to the prevention of neuronal dysfunction, convulsions or even neurodegeneration (Bough et al., 2006; Greco et al., 2016).”
BackgroundThe Protective Role of Nutraceuticals in Critically Ill Patients with Traumatic Brain Injury
Rahimibashar, F., Fetrat, M. K., Gohari-Moghadam, K., Jamialahmadi, T., & Sahebkar, A. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-73234-9_16 · Cited by 1
Huang, C., Lei, H., Liu, C., & Wang, Y. (2022) · Toxicology · doi:10.1016/j.tox.2022.153367 · Cited by 1
Wang, L., Zhao, T., Shang, S., & Lu, X. (2024) · Research Square · doi:10.21203/rs.3.rs-4566991/v1 · Cited by 1
Dechandt, C. R. P. (2018) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.17.2018.tde-13092018-104230
Therapeutic ketosis for mild traumatic brain injury
Crownover, J. E. J., & Holland, A. M. (2019) · Translational Sports Medicine · doi:10.1002/tsm2.89
Neuroprotective Strategies Following Experimental Traumatic Brain Injury
Kulbe, J. R. (2019) · UKnowledge (University of Kentucky) · doi:10.13023/etd.2019.228
“Several approaches have been utilized to improve mitochondrial function following TBI, including mild uncoupling [125, 248], ketogenic diet [249], induction of endogenous antioxidant pathways [97, 113], and scavenging of lipid peroxyl radicals, peroxynitrite, and LP-derived aldehydes [58, 69, 71, 72, 109, 257, 310, 31…”
BackgroundMethodInfluentialThe ketogenic diet revisited - evaluation of the ketogenic diet in neurological disorders
Yıldız, D., & Scheurink, A. J. W. (2016)
Ketogenic Diet with Severe Altered States of Consciousness in Children
Hansen, G. (2021) · Novel Techniques in Nutrition & Food Science · doi:10.31031/ntnf.2021.06.000628
“In brain injury animal models, ketones have demonstrated significant neuroprotective effects through improved mitochondrial metabolic efficiency, decreased oxidative stress, preventing metabolic deficits, attenuating apoptosis, and reducing excitotoxicity [2-10].”
BackgroundKetogenic Diet and Ketones for Improving Neurologic Outcomes after Acute Neurotrauma
Seira, O., Kolehmainen, K., Plunet, W. T., Yarar‐Fisher, C., & Tetzlaff, W. (2022) · doi:10.1093/med/9780197501207.003.0018
Pyruvate dehydrogenase complex, metabolic enzymes, and energy derangement in traumatic brain injury
Lazzarino, G., O’Halloran, P., Pietro, V. D., Mangione, R., Tavazzi, B., Amorini, A. M., Lazzarino, G., & Signoretti, S. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-823036-7.00040-2
Research Progress on the Mechanism of Ketogenic Diet in Antiepilepsy
王, 贞. (2022) · Advances in Clinical Medicine · doi:10.12677/acm.2022.126846
The role of ketogenic therapy in developmental disorders
Taoulost, S., Rasgon, N., Ferretti, C. J., & Hollander, E. (2023) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2023.03.025
Brain trauma, ketogenic diets, and ketogenesis via enteral nutrition
White, H. T., & Heffernan, A. J. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-89834-8.00006-4
Exercise and sports performance
Zinn, C., Harvey, C., Noakes, T. D., Smith, J. A. H., Webster, C. C., & Sáenz, C. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-821617-0.00013-9
Cywes, R., Kajee, H., Wellington, N., Cucuzzella, M. T., Riley, K., Isaacs, D. M., Pataguana, N., Lake, I., Rauch, L., McKelvey, S., et al. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-821617-0.00010-3
Renck, A. C. (2023) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.5.2023.tde-13062023-142212
Ketogenic Diets Hold Therapeutic Potential Against Periodontal Inflammation
Karmakar, S., Shivaprasad, Arangaraju, R., Modak, B., & Shanmugasundaram, S. (2024) · Current Oral Health Reports · doi:10.1007/s40496-024-00376-1
“Overall, the KD has been shown to have a prolonged antioxidant and anti-inflammatory effect due to the activation of the Nrf2 pathway [63–65].”
Wingo, B. C., Ferguson, C. C., Roccati, E., Arora, N., Little, R. B., Pace, F., & Piccio, L. M. (2024) · Elsevier eBooks · doi:10.1016/b978-0-12-820480-1.00210-2
Ajagun, E. J., Asuku, A. O., Oyerinde, T. O., Sangodipe, H. A., Sanusi, W., Jayeoba, L. A., & Abdulsalam, T. A. (2024) · Nutritional neurosciences · doi:10.1007/978-981-97-6818-9_10
Liu, L., Zhou, T., Ming, L., Zhou, Q., Zhou, J., Liu, Z., Wu, D., & He, K. (2025) · Research Square · doi:10.21203/rs.3.rs-6172026/v1
Filipović, D., & Turck, C. W. (2025) · Reviews in the Neurosciences · doi:10.1515/revneuro-2025-0081
“Supporting this hypothesis, brain ketone metabolism has been shown to improve cellular energetics, increase glutathione peroxidase activity (Greco et al. 2015), and exert anti-in fl ammatory and antioxidant e ff ects both in vitro and in vivo (Haces et al. 2008; Maalouf et al. 2009; Veech et al.…”
Ford, B. J., Banerjee, A., Ding, S., Caton, A. A., Grothaus, A., Burke, S. N., & Hernandez, A. R. (2025) · Translational Medicine of Aging · doi:10.1016/j.tma.2025.11.001
The Application of Lifestyle Medicine in Traumatic Brain Injury
Smeding, S., Colussi-Pelaez, E., Sherzai, D., ZAFONTE, R. D., & Tran, D. T. (2025) · American Journal of Lifestyle Medicine · doi:10.1177/15598276251395671 · Cited by 1
Choi, A. H., Delgado, M., Chen, K. Y., Chung, S. T., Courville, A. B., Turner, S. A., Yang, S., Airaghi, K. J., Dustin, I. M., McGurrin, P. M., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26699942
Gao, W., Ma, R., Gu, H. C., Zhang, X., Liu, H., Xiao, M., Li, Z., Wang, Y., Sun, Y., & Xiao, X. (2026) · Food Science & Nutrition · doi:10.1002/fsn3.71462
“LCD has been shown to upregulate various antioxidant proteins such as NADPH, NQO1, and SOD (Greco et al. 2016; Roberts et al. 2017) and improve impaired mitochondrial function and biogenesis in diabetes by activating PGC-1α and SIRT1 signaling pathways (Roberts et al. 2017), thereby counteracting…”
de Souza, J. G., Gurgel, G. G., Rodrigues, F. M., Braga, R. A. M., Soares, R. A. M., Lage, L. A. D. P. C., Soares, I. C., Levy, D., & Damasceno, N. R. T. (2026) · Inflammation · doi:10.1007/s10753-025-02367-5
“KD promotes the disruption of lipid metabolism, stimulating metabolic and molecular mechanisms related to MASLD, including dyslipidemia [14], insulin resistance [15 ], inflammation [ 16, 17], and oxidation [18].”
Neurovascular unit changes after juvenile traumatic brain injury
Ichkova, A. (2019) · theses.fr (ABES) · doi:10.70675/7dacb9e2z3b14z4c14zbdafzbdcfad78c341
Efficacy of Treating Post-Traumatic Epilepsy in Children With Ketogenic Diet
Choi, H. W., Bhalla, S., Holt, P. J., & Johnson, M. (2026) · Journal of Child Neurology · doi:10.1177/08830738261439221
Quddus, D., Aydin, S., Waheed, A. A., Zeeshan, Q., Hamilton, D. K., Agarwal, N., & Maroon, J. C. (2026) · Frontiers in Nutrition · doi:10.3389/fnut.2026.1848682 · Cited by 1
Ali, A., Hussain, M. S., Ahmed, M. E., Giri, S., & Ahmad, A. S. (2026) · Journal of Neurotrauma · doi:10.1177/08977151261452922
Muhammad, Y. A. (2026) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2026.1775109
Metadata
- Authors
- Greco, T., Glenn, T. C., Hovda, D. A., & Prins, M. L.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Greco, Tiffany
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2016-07-22
- Volume
- 36
- Issue
- 9
- Pages
- 1603-1613
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- PMC
- PMC5012517
- OpenAlex
- W2285042112
- Cited by
- 210
- References
- 43
- Citations by year
- 2026: 22 · 2025: 28 · 2024: 27 · 2023: 18 · 2022: 24 · 2021: 28 · 2020: 22 · 2019: 15 · 2018: 13 · 2017: 6 · 2016: 7
- FWCI
- 6.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NFL Charities
- Brain Injury Research Center
- Topics
- Health Sciences › Medicine › Physiology (medical) › Diet and metabolism studies
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- ketogenic diet, traumatic brain injury, oxidative stress, mitochondrial dysfunction, respiratory chain complexes, ketone body metabolism, neuroprotection, antioxidant enzymes, NQO1, superoxide dismutase, controlled cortical impact, brain metabolism
- MeSH terms
- Animals, Antioxidants, Brain Injuries, Free Radicals, Ketones, Male, Mitochondria, Time Factors, Electron Transport Complex III, Oxidative Stress, Electron Transport Complex II, Rats, Diet, Ketogenic
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