Cited by 210Diet and metabolism studiesTraumatic Brain Injury and Neurovascular DisturbancesMitochondrial Function and Pathology

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Ketogenic diet decreases oxidative stress and improves mitochondrial respiratory complex activity

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Greco, Tiffany, Glenn, Thomas C, Hovda, David A, Prins, Mayumi L·2016·Journal of Cerebral Blood Flow & Metabolism

DOI 10.1177/0271678x15610584PMC PMC5012517

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Abstract

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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Choi, A. H., Delgado, M., Chen, K. Y., Chung, S. T., Courville, A. B., Turner, S. A., Yang, S. B., Airaghi, K. J., Dustin, I. M., McGurrin, P. M., et al. (2024) · BMC Neurology · doi:10.1186/s12883-024-03603-5 · Cited by 37
Metabolic perturbations after pediatric TBI: It's not just about glucose
Bowman, C. E., Scafidi, J., & Scafidi, S. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.03.018 · Cited by 32
“Postnatal day 35 rats fed a ketogenic diet after TBI (CCI) were protected from a decrease in Complex II and III activities measured at 24 h after TBI (Greco et al., 2016).”
Ketogenic diet increases mitochondria volume in the liver and skeletal muscle without altering oxidative stress markers in rats
Parry, H. A., Kephart, W. C., Mumford, P. W., Romero, M. A., Mobley, C. B., Zhang, Y., Roberts, M. D., & Kavazis, A. N. (2018) · Heliyon · doi:10.1016/j.heliyon.2018.e00975 · Cited by 32
“Previous studies have investigated the metabolic profile, oxidative stress, and possible longevity benefits of KD, but the results of these studies are equivocal [14, 19, 28, 29, 30].”
Result
Nutritional Ketosis in Parkinson's Disease — a Review of Remaining Questions and Insights
Choi, A. H., Hallett, M., & Ehrlich, D. J. (2021) · Neurotherapeutics · doi:10.1007/s13311-021-01067-w · Cited by 35
“Pre-clinical data of a ketogenic diet in rats in a traumatic brain injury model showed improved cortical neuronal respiratory capacity, where reduced mitochondrial complexes II–IV related to nitric oxide/superoxide radical production was ameliorated in the ketogenic diet group [32].”
Background
Ketogenic diet attenuates hepatopathy in mouse model of respiratory chain complex III deficiency caused by a Bcs1l mutation
Purhonen, J., Rajendran, J., Mörgelin, M., Uusi-Rauva, K., Katayama, S., Krjutškov, K., Einarsdóttir, E., Velagapudi, V., Kere, J., Jauhiainen, M., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-01109-4 · Cited by 31
Sleep, mood disorders, and the ketogenic diet: potential therapeutic targets for bipolar disorder and schizophrenia
Choi, J., Kang, J., Kim, T., & Nehs, C. J. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2024.1358578 · Cited by 37
“Meanwhile, ketones are neuroprotective including anticonvulsant properties in epilepsy (8 – 10), reduced oxidative stress and in ﬂ ammation (11 – 13), and epigenetic upregulation of neurotrophic factors which could mediate improved mood symptoms (14).”
Background
The evolution of Alzheimer’s disease: From mitochondria to microglia
Yang, F., Liang, Y., Wang, X., Wang, J.-T., Gao, W., Ye, Q.-Y., Li, X., Yu, Y., & Li, H. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102838 · Cited by 32
Role of the ketogenic diet in acute neurological diseases
Arora, N., & Mehta, T. (2020) · Clinical Neurology and Neurosurgery · doi:10.1016/j.clineuro.2020.105727 · Cited by 30
Ketogenic diet in combination with voluntary exercise impacts markers of hepatic metabolism and oxidative stress in male and female Wistar rats
Moore, M. P., Cunningham, R. P., Kelty, T. J., Boccardi, L., Nguyen, N., Booth, F. W., & Rector, R. S. (2019) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2019-0042 · Cited by 29
“The previously reported effects of KD on measures of oxidative stress and antioxidant benefits seem to be largely equivocal (Greco et al. 2016; Hyatt et al. 2016; Jarrett et al. 2008; Kephart et al. 2017; Sullivan et al. 2004).”
Background
The Ketogenic Diet in the Treatment of Post-concussion Syndrome—A Feasibility Study
Rippee, M. A., Chen, J., & Taylor, M. (2020) · Frontiers in Nutrition · doi:10.3389/fnut.2020.00160 · Cited by 29
Ketogenic diet in therapy of bipolar affective disorder - case report and literature review
Chmiel, I. (2021) · Psychiatria Polska · doi:10.12740/pp/onlinefirst/136356 · Cited by 29
“The antioxidant properties of the ketogenic diet have been demonstrated in a study by Greco et al. [61] on female rats with severe brain damage.”
Vascular impairment as a pathological mechanism underlying long-lasting cognitive dysfunction after pediatric traumatic brain injury
Ichkova, A., Rodriguez‐Grande, B., Bar, C., Villega, F., Konsman, J. P., & Badaut, J. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2017.03.022 · Cited by 29
Exercise factors as potential mediators of cognitive rehabilitation following traumatic brain injury
Stephan, J. S., & Sleiman, S. F. (2019) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000754 · Cited by 32
“Ketones prevent oxidative stress-mediated mitochondrial dysfunction post-TBI by increasing antioxidants and scavenging free radicals [67].”
Background
Dietary Antioxidants and Natural Compounds in Preventing Thrombosis and Cardiovascular Disease
Giurranna, E., Nencini, F., Bettiol, A., Borghi, S., Argento, F. R., Emmi, G., Silvestri, E., Taddei, N., Fiorillo, C., & Becatti, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252111457 · Cited by 30
Dietary Restriction and Oxidative Stress: Friends or Enemies?
Mladenović, A., Lončarević‐Vasiljković, N., & Gonos, E. S. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7959 · Cited by 28
“Ketone bodies decrease oxidative stress, increase antioxidants, and scavenge free radicals after TBI, and improve cerebral metabolism by providing alternative substrates, leading to the prevention of oxidative stress-mediated mitochondrial dysfunction (59).”
Continuous Infusion of Phenelzine, Cyclosporine A, or Their Combination: Evaluation of Mitochondrial Bioenergetics, Oxidative Damage, and Cytoskeletal Degradation following Severe Controlled Cortical Impact Traumatic Brain Injury in Rats
Kulbe, J. R., Singh, I. N., Wang, J. A., Cebak, J. E., & Hall, E. D. (2018) · Journal of Neurotrauma · doi:10.1089/neu.2017.5353 · Cited by 26
Application of ketogenic diets for pediatric neurocritical care
Lin, K., Lin, J.-J., & Wang, H.-S. (2020) · Biomedical Journal · doi:10.1016/j.bj.2020.02.002 · Cited by 26
A Novel Ketone-Supplemented Diet Improves Recognition Memory and Hippocampal Mitochondrial Efficiency in Healthy Adult Mice
Saito, E. R., Warren, C. E., Hanegan, C. M., Larsen, J. G., du Randt, J. D., Cannon, M. E., Saito, J. Y., Campbell, R. J., Kemberling, C. M., Miller, G., et al. (2022) · Metabolites · doi:10.3390/metabo12111019 · Cited by 24
Development of Obesity: The Driver and the Passenger
Kopp, W. (2020) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s280146 · Cited by 25
Ketogenic diets and the nervous system: a scoping review of neurological outcomes from nutritional ketosis in animal studies
Field, R., Field, T., Pourkazemi, F., & Rooney, K. B. (2021) · Nutrition Research Reviews · doi:10.1017/s0954422421000214 · Cited by 23
“Redox balance (reported in fifteen studies across eight disease models(63,71,78,86,92,120,180,181,186,190,192,195,196,203,210)).”
Dietary Macronutrient Management to Treat Mitochondrial Dysfunction in Parkinson’s Disease
Bajracharya, R., Youngson, N. A., & Ballard, J. W. O. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20081850 · Cited by 24
“Largely, these improvements have been attributed to ketone bodies being able to act as an “alternative fuel”, ultimately bypassing glycolysis and providing Acetyl-CoA to enter the citric acid cycle and facilitate ATP production [110].”
Background
Insights into the Cellular Interactions and Molecular Mechanisms of Ketogenic Diet for Comprehensive Management of Epilepsy
Singh, D., Kumar, A., & Kumari, S. (2022) · Current Neuropharmacology · doi:10.2174/1570159x20666220420130109 · Cited by 22
“The diet treatment reduced the oxidative stress induced by the cortical impact injury in rats, as evident by attenuated levels of antioxidants, NAD(P)H dehydrogenase quinone 1 and superoxide dismutase [85].”
Nutritional interventions to improve neurophysiological impairments following traumatic brain injury: A systematic review
McGeown, J. P., Hume, P. A., Theadom, A., Quarrie, K. L., & Borotkanics, R. (2020) · Journal of Neuroscience Research · doi:10.1002/jnr.24746 · Cited by 23
Intermittent fasting promotes anxiolytic-like effects unrelated to synaptic mitochondrial function and BDNF support
Carteri, R. B., Menegassi, L. N., Feldmann, M., Kopczynski, A., Rodolphi, M. S., Strogulski, N. R., Almeida, A. S., Marques, D. M., Porciúncula, L. O., & Portela, L. V. (2021) · Behavioural Brain Research · doi:10.1016/j.bbr.2021.113163 · Cited by 21
Microbiota-gut-brain axis: A novel potential target of ketogenic diet for epilepsy
Tang, Y. C., Wang, Q., & Liu, J. (2021) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2021.08.018 · Cited by 21
Phase I single center trial of ketogenic diet for adults with traumatic brain injury
Arora, N., Litofsky, N. S., Golzy, M., Aneja, R., Staudenmyer, D., Qualls, K., & Patil, S. (2021) · Clinical Nutrition ESPEN · doi:10.1016/j.clnesp.2021.11.015 · Cited by 21
Short-Term Ketogenic Diet Induces a Molecular Response That Is Distinct From Dietary Protein Restriction
Kalafut, K. C., Mitchell, S. J., MacArthur, M. R., & Mitchell, J. R. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.839341 · Cited by 22
Re-routing Metabolism by the Mitochondrial Pyruvate Carrier Inhibitor MSDC-0160 Attenuates Neurodegeneration in a Rat Model of Parkinson’s Disease
Mallet, D., Goutaudier, R., Barbier, E., Carnicella, S., Colca, J. R., Fauvelle, F., & Boulet, S. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02962-9 · Cited by 21
Linking Migraine to Gut Dysbiosis and Chronic Non-Communicable Diseases
Lauro, M. D., Guerriero, C., Cornali, K., Albanese, M., Costacurta, M., Mercuri, N. B., Daniele, N. D., & Noce, A. (2023) · Nutrients · doi:10.3390/nu15204327 · Cited by 24
“These studies have shown that, through different mechanisms, the KD is able to reduce systemic inﬂammation [157] and OS [158] at the level of the CNS, and to positively modulate the gut microbiota [159], reducing the symptoms of migraine [160–162].”
Background
A Potential Role for the Ketogenic Diet in Alzheimer’s Disease Treatment: Exploring Pre-Clinical and Clinical Evidence
Oliveira, T. P. D., Morais, A. L. B., dos Reis, P. L. B., Palotás, A., & Vieira, L. B. (2023) · Metabolites · doi:10.3390/metabo14010025 · Cited by 24
“Ketones antagonize inflammatory processes and oxidative stress [95,96], acting as signaling mediators [83].”
Background
The ketogenic diet has the potential to decrease all-cause mortality without a concomitant increase in cardiovascular-related mortality
Qu, X., Huang, L. H., & Rong, J. (2024) · Scientific Reports · doi:10.1038/s41598-024-73384-x · Cited by 20
“In addition, the KD has demonstrated efficacy in attenuating oxidative stress and enhancing mitochondrial function, both of which are pivotal determinants of aging and longevity 24 .”
Background
Ketogenic Diets and Depression and Anxiety
Janssen‐Aguilar, R., Vije, T., Peera, M., Al-Shamali, H. F., Meshkat, S., Lin, Q., Lou, W. Y. W., Laviada‐Molina, H., Phillips, M. L., & Bhat, V. (2025) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2025.3261 · Cited by 20
Effect of oxidative stress in rostral ventrolateral medulla on sympathetic hyperactivity after traumatic brain injury
Chen, J., Chen, W., Han, K., Qi, E., Chen, R., Yu, M., Hou, L., & Lv, L. (2019) · European Journal of Neuroscience · doi:10.1111/ejn.14374 · Cited by 20
A ketogenic diet impacts markers of mitochondrial mass in a tissue specific manner in aged mice
Zhou, Z., Hagopian, K., López-Domínguez, J. A., Kim, K., Jasoliya, M., Roberts, M. N., Cortopassi, G. A., Showalter, M. R., Roberts, B. S., González-Reyes, J. A., et al. (2021) · Aging · doi:10.18632/aging.202834 · Cited by 19
Emerging Nonpharmacologic Interventions to Treat Diabetic Peripheral Neuropathy
Enders, J. D., Elliott, D., & Wright, D. E. (2022) · Antioxidants and Redox Signaling · doi:10.1089/ars.2022.0158 · Cited by 23
“(Greco et al, 2016).”
Proton Magnetic Resonance Spectroscopy (H1-MRS) Study of the Ketogenic Diet on Repetitive Mild Traumatic Brain Injury in Adolescent Rats and Its Effect on Neurodegeneration
Zhang, F., Wu, H., Jin, Y., & Zhang, X. (2018) · World Neurosurgery · doi:10.1016/j.wneu.2018.09.037 · Cited by 19
Ketogenic regimens for acute neurotraumatic events
Yarar‐Fisher, C., Li, J., Womack, E. D., Alharbi, A., Seira, O., Kolehmainen, K., Plunet, W. T., Alaeiilkhchi, N., & Tetzlaff, W. (2021) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2020.12.009 · Cited by 18
A ketogenic diet reduces mechanical allodynia and improves epidermal innervation in diabetic mice
Enders, J. D., Swanson, M. T., Ryals, J. M., & Wright, D. E. (2021) · Pain · doi:10.1097/j.pain.0000000000002401 · Cited by 18
Genome-wide interrogation of transfer RNA-derived small RNAs in a mouse model of traumatic brain injury
Xu, X.-J., Yang, M.-S., Zhang, B., Ge, Q., Niu, F., Dong, J., Zhuang, Y., & Liu, B.-Y. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.314315 · Cited by 18
“Secondary injury occurs as a consequence of diverse pathological mechanisms, including excitotoxicity (Fujikawa, 2015; Tehse and Taghibiglou, 2019), oxidative stress (Cornelius et al., 2013; Greco et al., 2016; Chen et al., 2017), cerebral metabolic dysfunction (Glenn et al.”
Background
Scientific Evidences of Calorie Restriction and Intermittent Fasting for Neuroprotection in Traumatic Brain Injury Animal Models: A Review of the Literature
Xu, Y., Liu, Z., Xu, S., Li, C., Li, M., Cao, S., Sun, Y., Dai, H., Guo, Y., Chen, X., et al. (2022) · Nutrients · doi:10.3390/nu14071431 · Cited by 18
“KD was recently found to reduce oxidative stress following CCI, while inducing the levels of antioxidants, superoxide dismutase (SOD1/2), and NAD(P)H dehydrogenase, thereby improving mitochondrial respiratory complex activity [56].”
Background
Dietary therapy to halt the progression of diabetes to diabetic kidney disease
Hu, H., Ding, G., & Liang, W. (2025) · Food & Function · doi:10.1039/d4fo06011c · Cited by 17
Advances and challenges in experimental models of posttraumatic epilepsy for therapeutic interventions
Reddy, D. S., Golub, V. M., Ramakrishnan, S., Churn, S. B., Shapiro, L. A., Iannucci, J., Pitkänen, A., Galanopoulou, A. S., Maganti, R. K., & Boison, D. (2025) · Pharmacological Reviews · doi:10.1016/j.pharmr.2025.100080 · Cited by 18
The Effect of the Restrictive Ketogenic Diet on the Body Composition, Haematological and Biochemical Parameters, Oxidative Stress and Advanced Glycation End-Products in Young Wistar Rats with Diet-Induced Obesity
Drabińska, N., Juśkiewicz, J., & Wiczkowski, W. (2022) · Nutrients · doi:10.3390/nu14224805 · Cited by 16
“In addition, KD was found to attenuate oxidative stress after traumatic brain injury in an animal model [23].”
Background
Inflammation and oxidative stress in epileptic children: from molecular mechanisms to clinical application of ketogenic diet
Ildarabadi, A., Ali, S. N. M. M., Rahmani, F., Mosavari, N., Pourbakhtyaran, E., & Rezaei, N. (2024) · Reviews in the Neurosciences · doi:10.1515/revneuro-2023-0128 · Cited by 17
Nutrition in adult patients with selected lysosomal storage diseases
Carubbi, F., Barbato, A., Burlina, A., Francini, F., Mignani, R., Pegoraro, E., Landini, L., Danieli, G. D., Bruni, S., Strazzullo, P., et al. (2020) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2020.11.028 · Cited by 16
β-Hydroxybutyrate, One of the Three Main Ketone Bodies, Ameliorates Acute Pancreatitis in Rats by Suppressing the NLRP3 Inflammasome Pathway
Şahin, E., Aykanat, N. E. B., Kaçar, S., Bağcı, R., & Şahıntürk, V. (2021) · The Turkish Journal of Gastroenterology · doi:10.5152/tjg.2021.191062 · Cited by 16
Ketogenic Diet for Neonatal Hypoxic–Ischemic Encephalopathy
Zhou, Y., Sun, L., & Wang, H. (2022) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.2c00609 · Cited by 15

Authors: Greco, T., Glenn, T. C., Hovda, D. A., & Prins, M. L.
Affiliations: University of California, Los Angeles (US)
Corresponding author: Greco, Tiffany
ORCID: Greco, Tiffany
Glenn, Thomas C
Prins, Mayumi L
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
DOI: 10.1177/0271678x15610584
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
Licence: journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
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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Ketogenic diet decreases oxidative stress and improves mitochondrial respiratory complex activity

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