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Dietary Energy Restriction Ameliorates Cognitive Impairment in a Mouse Model of Traumatic Brain Injury

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Abstract

Traumatic brain injury (TBI) is one of the most common causes of neurological damage in young people. It was previously reported that dietary restriction, by either intermittent fasting (IF) or daily caloric restriction (CR), could protect neurons against dysfunction and degeneration in animal models of stroke and Parkinson’s disease. Recently, several studies have shown that the protein Sirtuin 1 (SIRT1) plays a significant role in the induced neuroprotection following dietary restriction. In the present study, we found a significant reduction of SIRT1 levels in the cortex and hippocampus in a mouse model of mild weight-drop closed head TBI. This reduction was prevented in mice maintained on IF (alternate day fasting) and CR initiated after the head trauma. Hippocampus-dependent learning and memory (measured using a novel object recognition test) was impaired 30 days post-injury in mice fed ad libitum, but not in mice in the IF and CR groups. These results suggest a clinical potential for IF and/or CR as an intervention to reduce brain damage and improve functional outcome in TBI patients.

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References

  • Agarwal S, Sharma S, Agrawal V, Roy N (2005) Caloric restriction augments ROS defense in S. cerevisiae, by a Sir2p independent mechanism. Free Radic Res 39:55–62

    Article  CAS  PubMed  Google Scholar 

  • Anton SD, Moehl K, Donahoo WT, Marosi K, Lee SA, Mainous AG III, Leeuwenburgh C, Mattson MP (2018) Flipping the metabolic switch: understanding and applying the health benefits of fasting. Obesity (Silver Spring) 26:254–268

    Article  Google Scholar 

  • Arumugam TV, Phillips TM, Cheng A, Morrell CH, Mattson MP, Wan R (2010) Age and energy intake interact to modify cell stress pathways and stroke outcome. Ann Neurol 67:41–52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bele MS, Gajare KA, Deshmukh AA (2015) Caloric restriction mimetic 2-deoxyglucose maintains cytoarchitecture and reduces tau phosphorylation in primary culture of mouse hippocampal pyramidal neurons. In Vitro Cell Dev Biol Anim 51:546–555

    Article  CAS  PubMed  Google Scholar 

  • Bogdanova Y, Verfaellie M (2012) Cognitive sequelae of blast-induced traumatic brain injury: recovery and rehabilitation. Neuropsychol Rev 22:4–20

    Article  PubMed  PubMed Central  Google Scholar 

  • Brownlow ML, Joly-Amado A, Azam S, Elza M, Selenica ML, Pappas C, Small B, Engelman R, Gordon MN, Morgan D (2014) Partial rescue of memory deficits induced by calorie restriction in a mouse model of tau deposition. Behav Brain Res 271:79–88

    Article  CAS  PubMed  Google Scholar 

  • Bruce-Keller AJ, Umberger G, McFall R, Mattson MP (1999) Food restriction reduces brain damage and improves behavioral outcome following excitotoxic and metabolic insults. Ann Neurol 45:8–15

    Article  CAS  PubMed  Google Scholar 

  • Chang HC, Guarente L (2013) SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 153:1448–1460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cohen DE, Supinski AM, Bonkowski MS, Donmez G, Guarente LP (2009) Neuronal SIRT1 regulates endocrine and behavioral responses to calorie restriction. Genes Dev 23:2812–2817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Kruijk JR, Twijnstra A, Leffers P (2001) Diagnostic criteria and differential diagnosis of mild traumatic brain injury. Brain Inj 15:99–106

    Article  PubMed  Google Scholar 

  • Dhurandhar EJ, Allison DB, van Groen T, Kadish I (2013) Hunger in the absence of caloric restriction improves cognition and attenuates Alzheimer’s disease pathology in a mouse model. PLoS One 8:e60437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Donmez G (2012) The effects of SIRT1 on Alzheimer’s disease models. Int J Alzheimers Dis 2012:509529. https://doi.org/10.1155/2012/509529

  • Donmez G, Arun A, Chung CY, McLean PJ, Lindquist S, Guarente L (2012) SIRT1 protects against alpha-synuclein aggregation by activating molecular chaperones. J Neurosci 32:124–132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fann DY, Santro T, Manzanero S, Widiapradja A, Cheng YL, Lee SY, Chunduri P, Jo DG, Stranahan AM, Mattson MP, Arumugam TV (2014) Intermittent fasting attenuates inflammasome activity in ischemic stroke. Exp Neurol 257:114–119

    Article  CAS  PubMed  Google Scholar 

  • Gao Y, Nikulina E, Mellado W, Filbin MT (2003) Neurotrophins elevate cAMP to reach a threshold required to overcome inhibition by MAG through extracellular signal-regulated kinase-dependent inhibition of phosphodiesterase. J Neurosci 23:11770–11777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greve MW, Zink BJ (2009) Pathophysiology of traumatic brain injury. Mt Sinai J Med 76:97–104

    Article  PubMed  Google Scholar 

  • Guarente L (2013) Calorie restriction and sirtuins revisited. Genes Dev 27:2072–2085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haan MN (2006) Therapy insight: type 2 diabetes mellitus and the risk of late-onset Alzheimer’s disease. Nat Clin Pract Neurol 2:159–166

    Article  CAS  PubMed  Google Scholar 

  • Hadem IKH, Majaw T, Kharbuli B, Sharma R (2019) Beneficial effects of dietary restriction in aging brain. J Chem Neuroanat 95:123–133. https://doi.org/10.1016/j.jchemneu.2017.10.001

  • Halagappa VK, Guo Z, Pearson M, Matsuoka Y, Cutler RG, Laferla FM, Mattson MP (2007) Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer’s disease. Neurobiol Dis 26:212–220

    Article  CAS  PubMed  Google Scholar 

  • Heim LR, Bader M, Edut S, Rachmany L, Baratz-Goldstein R, Lin R, Elpaz A, Qubty D, Bikovski L, Rubovitch V, Schreiber S, Pick CG (2017) The invisibility of mild traumatic brain injury: impaired cognitive performance as a silent symptom. J Neurotrauma 34:2518–2528

    Article  PubMed  Google Scholar 

  • Holm L, Cassidy JD, Carroll LJ, Borg J, Neurotrauma Task Force on Mild Traumatic Brain Injury of the, W.H.O.C.C (2005) Summary of the WHO collaborating centre for neurotrauma task force on mild traumatic brain injury. J Rehabil Med 37:137–141

    Article  PubMed  Google Scholar 

  • Hunt ND, Hyun DH, Allard JS, Minor RK, Mattson MP, Ingram DK, de Cabo R (2006) Bioenergetics of aging and calorie restriction. Ageing Res Rev 5:125–143

    Article  CAS  PubMed  Google Scholar 

  • Ingram DK, Young J, Mattison JA (2007) Calorie restriction in nonhuman primates: assessing effects on brain and behavioral aging. Neuroscience 145:1359–1364

    Article  CAS  PubMed  Google Scholar 

  • Lambert AJ, Merry BJ (2004) Effect of caloric restriction on mitochondrial reactive oxygen species production and bioenergetics: reversal by insulin. Am J Physiol Regul Integr Comp Physiol 286:R71–R79

    Article  CAS  PubMed  Google Scholar 

  • Li XH, Chen C, Tu Y, Sun HT, Zhao ML, Cheng SX, Qu Y, Zhang S (2013) Sirt1 promotes axonogenesis by deacetylation of Akt and inactivation of GSK3. Mol Neurobiol 48:490–499

    Article  CAS  PubMed  Google Scholar 

  • Loncarevic-Vasiljkovic N, Pesic V, Todorovic S, Popic J, Smiljanic K, Milanovic D, Ruzdijic S, Kanazir S (2012) Caloric restriction suppresses microglial activation and prevents neuroapoptosis following cortical injury in rats. PLoS One 7:e37215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Loncarevic-Vasiljkovic N, Milanovic D, Pesic V, Tesic V, Brkic M, Lazic D, Avramovic V, Kanazir S (2016) Dietary restriction suppresses apoptotic cell death, promotes Bcl-2 and Bcl-xl mRNA expression and increases the Bcl-2/Bax protein ratio in the rat cortex after cortical injury. Neurochem Int 96:69–76

    Article  CAS  PubMed  Google Scholar 

  • Longo VD, Mattson MP (2014) Fasting: molecular mechanisms and clinical applications. Cell Metab 19:181–192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maalouf M, Rho JM, Mattson MP (2009) The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev 59:293–315

    Article  CAS  PubMed  Google Scholar 

  • Manley G, Gardner AJ, Schneider KJ, Guskiewicz KM, Bailes J, Cantu RC, Castellani RJ, Turner M, Jordan BD, Randolph C, Dvorak J, Hayden KA, Tator CH, McCrory P, Iverson GL (2017) A systematic review of potential long-term effects of sport-related concussion. Br J Sports Med 51:969–977

    Article  PubMed  Google Scholar 

  • Martin A, Tegla CA, Cudrici CD, Kruszewski AM, Azimzadeh P, Boodhoo D, Mekala AP, Rus V, Rus H (2015) Role of SIRT1 in autoimmune demyelination and neurodegeneration. Immunol Res 61:187–197

    Article  CAS  PubMed  Google Scholar 

  • Mattson MP (2012) Energy intake and exercise as determinants of brain health and vulnerability to injury and disease. Cell Metab 16:706–722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mattson MP, Duan W, Guo Z (2003) Meal size and frequency affect neuronal plasticity and vulnerability to disease: cellular and molecular mechanisms. J Neurochem 84:417–431

    Article  CAS  PubMed  Google Scholar 

  • Mattson MP, Longo VD, Harvie M (2017) Impact of intermittent fasting on health and disease processes. Ageing Res Rev 39:46–58

    Article  PubMed  Google Scholar 

  • Mattson MP, Moehl K, Ghena N, Schmaedick M, Cheng A (2018) Intermittent metabolic switching, neuroplasticity and brain health. Nat Rev Neurosci 19:63–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McAllister TW (2011) Neurobiological consequences of traumatic brain injury. Dialogues Clin Neurosci 13:287–300

    PubMed  PubMed Central  Google Scholar 

  • Milman A, Rosenberg A, Weizman R, Pick CG (2005) Mild traumatic brain injury induces persistent cognitive deficits and behavioral disturbances in mice. J Neurotrauma 22:1003–1010

    Article  CAS  PubMed  Google Scholar 

  • Mychasiuk R, Hehar H, Ma I, Esser MJ (2015) Dietary intake alters behavioral recovery and gene expression profiles in the brain of juvenile rats that have experienced a concussion. Front Behav Neurosci 9:17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nogueiras R, Habegger KM, Chaudhary N, Finan B, Banks AS, Dietrich MO, Horvath TL, Sinclair DA, Pfluger PT, Tschop MH (2012) Sirtuin 1 and sirtuin 3: physiological modulators of metabolism. Physiol Rev 92:1479–1514

    Article  CAS  PubMed  Google Scholar 

  • Pasinetti GM, Wang J, Ho L, Zhao W, Dubner L (2015) Roles of resveratrol and other grape-derived polyphenols in Alzheimer’s disease prevention and treatment. Biochim Biophys Acta 1852:1202–1208

    Article  CAS  PubMed  Google Scholar 

  • Prozorovski T, Schulze-Topphoff U, Glumm R, Baumgart J, Schroter F, Ninnemann O, Siegert E, Bendix I, Brustle O, Nitsch R, Zipp F, Aktas O (2008) Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat Cell Biol 10:385–394

    Article  CAS  PubMed  Google Scholar 

  • Rachmany L, Tweedie D, Rubovitch V, Yu QS, Li Y, Wang JY, Pick CG, Greig NH (2013) Cognitive impairments accompanying rodent mild traumatic brain injury involve p53-dependent neuronal cell death and are ameliorated by the tetrahydrobenzothiazole PFT-alpha. PLoS One 8:e79837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rafalski VA, Ho PP, Brett JO, Ucar D, Dugas JC, Pollina EA, Chow LM, Ibrahim A, Baker SJ, Barres BA, Steinman L, Brunet A (2013) Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain. Nat Cell Biol 15:614–624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramadori G, Fujikawa T, Anderson J, Berglund ED, Frazao R, Michan S, Vianna CR, Sinclair DA, Elias CF, Coppari R (2011) SIRT1 deacetylase in SF1 neurons protects against metabolic imbalance. Cell Metab 14:301–312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ran M, Li Z, Yang L, Tong L, Zhang L, Dong H (2015) Calorie restriction attenuates cerebral ischemic injury via increasing SIRT1 synthesis in the rat. Brain Res 1610:61–68

    Article  CAS  PubMed  Google Scholar 

  • Rankin JW, Shute M, Heffron SP, Saker KE (2006) Energy restriction but not protein source affects antioxidant capacity in athletes. Free Radic Biol Med 41:1001–1009

    Article  CAS  PubMed  Google Scholar 

  • Rich NJ, Van Landingham JW, Figueiroa S, Seth R, Corniola RS, Levenson CW (2010) Chronic caloric restriction reduces tissue damage and improves spatial memory in a rat model of traumatic brain injury. J Neurosci Res 88:2933–2939

    CAS  PubMed  Google Scholar 

  • Rubovitch V, Ten-Bosch M, Zohar O, Harrison CR, Tempel-Brami C, Stein E, Hoffer BJ, Balaban CD, Schreiber S, Chiu WT, Pick CG (2011) A mouse model of blast-induced mild traumatic brain injury. Exp Neurol 232:280–289

    Article  PubMed  PubMed Central  Google Scholar 

  • Sasaki T, Kim HJ, Kobayashi M, Kitamura YI, Yokota-Hashimoto H, Shiuchi T, Minokoshi Y, Kitamura T (2010) Induction of hypothalamic Sirt1 leads to cessation of feeding via agouti-related peptide. Endocrinology 151:2556–2566

    Article  CAS  PubMed  Google Scholar 

  • Slemmer JE, Zhu C, Landshamer S, Trabold R, Grohm J, Ardeshiri A, Wagner E, Sweeney MI, Blomgren K, Culmsee C, Weber JT, Plesnila N (2008) Causal role of apoptosis-inducing factor for neuronal cell death following traumatic brain injury. Am J Pathol 173:1795–1805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Solari N, Hangya B (2018) Cholinergic modulation of spatial learning, memory and navigation. Eur J Neurosci 48:2199–2230

    Article  PubMed  PubMed Central  Google Scholar 

  • Speakman JR, Mitchell SE (2011) Caloric restriction. Mol Asp Med 32:159–221

    Article  CAS  Google Scholar 

  • Stamatovic SM, Martinez-Revollar G, Hu A, Choi J, Keep RF, Andjelkovic AV (2018) Decline in Sirtuin-1 expression and activity plays a critical role in blood-brain barrier permeability in aging. Neurobiol Dis. https://doi.org/10.1016/j.nbd.2018.09.006

  • Tashlykov V, Katz Y, Gazit V, Zohar O, Schreiber S, Pick CG (2007) Apoptotic changes in the cortex and hippocampus following minimal brain trauma in mice. Brain Res 1130:197–205

    Article  CAS  PubMed  Google Scholar 

  • Tashlykov V, Katz Y, Volkov A, Gazit V, Schreiber S, Zohar O, Pick CG (2009) Minimal traumatic brain injury induce apoptotic cell death in mice. J Mol Neurosci 37:16–24

    Article  CAS  PubMed  Google Scholar 

  • Thrasivoulou C, Soubeyre V, Ridha H, Giuliani D, Giaroni C, Michael GJ, Saffrey MJ, Cowen T (2006) Reactive oxygen species, dietary restriction and neurotrophic factors in age-related loss of myenteric neurons. Aging Cell 5:247–257

    Article  CAS  PubMed  Google Scholar 

  • Ugochukwu NH, Figgers CL (2007) Caloric restriction inhibits up-regulation of inflammatory cytokines and TNF-alpha, and activates IL-10 and haptoglobin in the plasma of streptozotocin-induced diabetic rats. J Nutr Biochem 18:120–126

    Article  CAS  PubMed  Google Scholar 

  • Vos BC, Nieuwenhuijsen K, Sluiter JK (2018) Consequences of traumatic brain injury in professional American football players: a systematic review of the literature. Clin J Sport Med 28:91–99

    Article  PubMed  Google Scholar 

  • Zohar O, Schreiber S, Getslev V, Schwartz JP, Mullins PG, Pick CG (2003) Closed-head minimal traumatic brain injury produces long-term cognitive deficits in mice. Neuroscience 118:949–955

    Article  CAS  PubMed  Google Scholar 

  • Zohar O, Rubovitch V, Milman A, Schreiber S, Pick CG (2011) Behavioral consequences of minimal traumatic brain injury in mice. Acta Neurobiol Exp 71:36–45

    Google Scholar 

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Acknowledgments

This research was supported in part by the Ari and Regine Aprijaskis Fund, at Tel-Aviv University and by the Intramural Research Program of the National Institute on Aging, NIH.

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Authors and Affiliations

  1. Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    V. Rubovitch, A. Pharayra, M. Har-Even, O. Dvir & C. G. Pick

  2. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA

    M. P. Mattson

  3. Sagol School of Neuroscience, Tel-Aviv University, 69978, Tel-Aviv, Israel

    C. G. Pick

  4. The Dr. Miriam and Sheldon G. Adelson Chair and Center for the Biology of Addictive Diseases, Tel-Aviv University, 69978, Tel-Aviv, Israel

    C. G. Pick

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  1. V. Rubovitch
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Correspondence to V. Rubovitch.

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All applicable international, national, and/or, institutional guidelines for the care and use of animals were followed. If applicable (where such a committee exists), all procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Rubovitch, V., Pharayra, A., Har-Even, M. et al. Dietary Energy Restriction Ameliorates Cognitive Impairment in a Mouse Model of Traumatic Brain Injury. J Mol Neurosci 67, 613–621 (2019). https://doi.org/10.1007/s12031-019-01271-6

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