Pretreatment with a ketogenic diet inhibits mitochondrial damage in rat models of spinal cord injury via the PGC-1α/Sirt1/Nrf1 pathway

Document Type : Original Article

Authors

1 Department of Spinal Surgery, Affiliated Longyan First Hospital of Fujian Medical University, Longyan, 364000, Fujian, China

2 Department of Radiology, Affiliated Longyan First Hospital of Fujian Medical University, Longyan, 364000, Fujian, China

10.22038/ijbms.2025.82683.18565

Abstract

Objective(s): Spinal cord injury (SCI) often results in poor recovery prospects and a high disability rate. Although the ketogenic diet (KD) was suggested as a neuroprotective agent after SCI, its underlying mechanism remains unclear. 
Materials and Methods: Rats were divided into three groups: sham-operated controls, SCI with standard diet (SD), and SCI with KD. Following a 2-week dietary pretreatment, the SD and KD groups underwent a cervical level 5 hemi-contusion injury, and their neuromotor functions were monitored for 28 days. The expression levels of PGC-1α, Sirt1, Nrf1, and TOMM20 in the spinal cord tissues were measured using qPCR and immunofluorescence staining.
Results: Compared with the SD group, KD pretreatment significantly improved neuromotor recovery and reduced neuronal apoptosis. The expression levels of PGC-1, Sirt1, and Nrf1 in the spinal cord tissues of rats in the KD group were significantly up-regulated. Additionally, KD was found to alleviate neuronal mitochondrial dysfunction by regulating TOMM20 expression.
Conclusion: KD pretreatment enhances SCI recovery by modulating the PGC-1α/Sirt1/Nrf1 pathway, improving mitochondrial function, and reducing neuronal death. The study provides new insights into the mechanisms of KD.

Keywords

Main Subjects

References

1. Ahuja CS, Wilson JR, Nori S, Kotter MRN, Druschel C, Curt A, et al. Traumatic spinal cord injury. Nat Rev Primer 2017; 27: 17018.
2. Shultz RB, Zhong Y. Minocycline targets multiple secondary injury mechanisms in traumatic spinal cord injury. Neural Regen Res 2017; 12: 702-713.
3. Slater PG, Domínguez-Romero ME, Villarreal M, Eisner V, Larraín J. Mitochondrial function in spinal cord injury and regeneration. Cell Mol Life Sci 2022; 79: 239-263.
4. Kang J, Wang Y, Guo X, He X, Liu W, Chen H, et al. N-acetylserotonin protects PC12 cells from hydrogen peroxide induced damage through ROS mediated PI3K / AKT pathway. Cell Cycle 2022; 21: 2268-2282.
5. Crowe CS, Liu YK, Curtin CM, Hentz VR, Kozin SH, Fox IK, et al. Surgical strategies for functional upper extremity reconstruction after spinal cord injury. Muscle Nerve 2025; 71: 802-815.
6. Sherrod BA, Porche K, Condie CK, Dailey AT. Pharmacologic therapy for spinal cord injury. Clin Spine Surg 2024; 37: 433-439.
7. Streijger F, Plunet WT, Lee JH, Liu J, Lam CK, Park S, et al. Ketogenic diet improves forelimb motor function after spinal cord injury in rodents. PLoS One 2013; 8: e78765-78784.
8. Maalouf M, Rho JM, Mattson MP. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev 2009; 59: 293-315.
9. Martin-McGill KJ, Jackson CF, Bresnahan R, Levy RG, Cooper PN. Ketogenic diets for drug-resistant epilepsy. Cochrane Database Syst Rev 2018; 11: Cd001903-1945.
10. Fu SP, Wang JF, Xue WJ, Liu HM, Liu BR, Zeng YL, et al. Anti-inflammatory effects of BHBA in both in vivo and in vitro Parkinson’s disease models are mediated by GPR109A-dependent mechanisms. J Neuroinflamm 2015; 12: 9-23.
11. Van der Auwera I, Wera S, Van Leuven F, Henderson ST. A ketogenic diet reduces amyloid beta 40 and 42 in a mouse model of Alzheimer’s disease. Nutr Metab 2005; 2: 28-36.
12. Stafstrom CE, Rho JM. The ketogenic diet as a treatment paradigm for diverse neurological disorders. Front Pharmacol 2012; 3: 59-67.
13. Koh S, Dupuis N, Auvin S. Ketogenic diet and Neuroinflammation. Epilepsy Res 2020; 167: 106454.
14. Jeong MA, Plunet W, Streijger F, Lee JH, Plemel JR, Park S, et al. Intermittent fasting improves functional recovery after rat thoracic contusion spinal cord injury. J Neurotrauma 2011; 28: 479-492.
15. Plunet WT, Lam CK, Lee JH, Liu J, Tetzlaf W. Prophylactic dietary restriction may promote functional recovery and increase lifespan after spinal cord injury. Ann N Y Acad Sci 2010; 1198: E1-E11.
16. Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 2013; 339: 211-214.
17. Newman JC, Verdin E. Ketone bodies as signaling metabolites. Trends Endocrinol Metab 2014; 25: 42-52.
18. Newman JC and Verdin E. Beta-hydroxybutyrate: Much more than a metabolite. Diabetes Res Clin Pract 2014; 106: 173-181.
19. Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab 2017; 25: 262-284.
20. Puchowicz MA, Zechel JL, Valerio J, Emancipator DS, Xu K, Pundik S, et al. Neuroprotection in diet induced ketotic rat brain after focal ischemia. J Cereb Blood Flow Metab 2008; 28: 1907-1916.
21. Tieu K, Perier C, Caspersen C, Teismann P, Wu DC, Yan SD, et al. D-β-Hydroxybutyrate rescues mitochondrial respira tion and mitigates features of Parkinson disease. J Clin Invest 2003; 112: 892-901.
22. Lehto A, Koch K, Barnstorf-Brandes J, Viel C, Fuchs M, Klein J. ß-Hydroxybutyrate Improves Mitochondrial Function After Transient Ischemia in the Mouse. Neurochem Res 2022; 47: 3241-3249. 
23. Huang Z, Li R, Liu J, Huang Z, Hu Y, Wu X, et al. Longitudinal electrophysiological changes after cervical hemi-contusion spinal cord injury in rats. Neurosci Lett 2018; 664: 116-122.
24. Lee JH, Streijger F, Tigchelaar S, Maloon M, Liu J, Tetzlaf W, et al. A contusive model of unilateral cervical spinal cord injury using the infnite horizon impactor. J Vis Exp 2012; 65: 3313-3320.
25. Lu Y, Wang R, Dong Y, Tucker D, Zhao N, Ahmed ME. Lowlevel laser therapy for beta amyloid toxicity in rat hippocampus. Neurobiol Aging 2017; 49: 165-182. 
26. Bradke F, Fawcett JW, Spira ME. Assembly of a new growth cone after axotomy: The precursor to axon regeneration. Nat Rev Neurosci 2012; 13: 183-193.
27. Greco T, Glenn TC, Hovda DA, Prins ML. Ketogenic diet decreases oxidative stress and improves mitochondrial respiratory complex activity. J Cereb Blood Flow Metab 2016; 36: 1603-1613.
28. Cantó C, Auwerx J. PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol 2009; 20: 98-105.
29. Zhou Y, Wang S, Li Y, Yu S, Zhao Y. SIRT1/PGC-1α signaling promotes mitochondrial functional recovery and reduces apoptosis after intracerebral hemorrhage in rats. Front Mol Neurosci 2017; 10: 443-457.
30. Gao K, Niu J, Dang X. Neuroprotection of melatonin on spinal cord injury by activating autophagy and inhibiting apoptosis via SIRT1/AMPK signaling pathway. Biotechnol Lett 2020; 42: 2059-2069.
31. Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, Moraes CT. Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proc Natl Acad Sci U S A 2009; 106: 20405-20410.
32. Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, et al. Transcriptional co-activator PGC-1alpha drives the formation of slow-twitch muscle fibers. Nature 2002; 418: 797-801.
33. Arany Z, He H, Lin J, Hoyer K, Handschin C, Toka O, et al. Transcriptional coactivator PGC-1alpha controls the energy state and contractile function of cardiac muscle. Cell Metab 2005; 1: 259-271.
34. Handschin C, Choi CS, Chin S, Kim S, Kawamori D, Kurpad AJ, et al. Abnormal glucose homeostasis in skeletal muscle-specific PGC-1alpha knockout mice reveals skeletal muscle-pancreatic beta cell crosstalk. J Clin Invest 2007; 117: 3463-3474.
35. Jayanthy G, Roshana Devi V, Ilango K, Subramanian SP. Rosmarinic acid mediates mitochondrial biogenesis in insulin resistant skeletal muscle through activation of AMPK. J Cell Biochem 2017; 118: 1839-1848.
36. Jeong EA, Jeon BT, Shin HJ, Kim N, Lee DH, Kim HJ, et al. Ketogenic diet-induced peroxisome proliferator-activated receptor-g activation decreases neuroinflammation in the mouse hippocampus after kainic acid-induced seizures. Exp Neurol 2011; 232: 195-202.
37. Yang Q, Guo M, Wang X, Zhao Y, Zhao Q, Ding H, et al. Ischemic preconditioning with a ketogenic diet improves brain ischemic tolerance through increased extracellular adenosine levels and hypoxia-inducible factors. Brain Res 2017; 1667: 11-18.
38. Cahill GF Jr. Fuel metabolism in starvation. Annu Rev Nutr 2006; 26: 1-22.
39. Prins ML. Cerebral ketone metabolism during development and injury. Epilepsy Res 2012; 100: 218-223.
40. McDougall A, Bayley M and Munce SE. The ketogenic diet as a treatment for traumatic brain injury: A scoping review. Brain In 2018; 32: 416-422.
41. Lu Y, Yang YY, Zhou MW, Liu N, Xing HY, Liu XX, et al. Ketogenic diet attenuates oxidative stress and inflammation after spinal diet cord injury by activating Nrf2 and suppressing the NF-kappaB signaling pathways. Neurosci Lett 2018; 683: 13-18
42. Qian J, Zhu W, Lu M, Ni B, Yang J. D-beta-hydroxybutyrate promotes functional recovery and relieves pain hypersensitivity in mice with spinal cord injury. Br J Pharmacol 2017; 174: 1961-1971
43. Yarar-Fisher C, Kulkarni A, Li J, Farley P, Renfro C, Aslam H, et al. Evaluation of a ketogenic diet for improvement of neurological recovery in individuals with acute spinal cord injury: A pilot, randomized safety and feasibility trial. Spinal Cord Ser Cases 2018; 4: 88-96.
Iranian Journal of Basic Medical Sciences
Volume 28, Issue 11
November 2025
Pages 1516-1522

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