Dietary restriction (DR) increases the lifespan of rodents and increases their resistance to several different age-related diseases including cancer and diabetes. Beneficial effects of DR on brain plasticity and neuronal vulnerability to injury have recently been reported, but the underlying mechanisms are unknown. We report that levels of brain-derived neurotrophic factor (BDNF) are significantly increased in the hippocampus, cerebral cortex, and striatum of rats maintained on a DR regimen compared to animals fed ad libitum (AL). Seizure-induced damage to hippocampal neurons was significantly reduced in rats maintained on DR, and this beneficial effect was attenuated by intraventricular administration of a BDNF-blocking antibody. These findings provide the first evidence that diet can effect expression of a neurotrophic factor, demonstrate that BDNF signaling plays a central role in the neuroprotective effect of DR, and proffer DR as an approach for reducing neuronal damage in neurodegenerative disorders.
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Ballarin M., Ernfors P., Lindefors N., and Persson H. (1991) Hippocampal damage and kainic acid injection induce a rapid increase in mRNA for BDNF and NGF in the rat brain. Exp. Neurol. 114, 35–43.
Bemelmans A. P., Horellou P., Pradier L., Brunet I., Colin P., and Mallet, J. (1999) Brain-derived neurotrophic factor-mediated protection of striatal neurons in an excitotoxic rat model of Huntington’s disease, as demonstrated by adenoviral gene transfer. Hum. Gene Ther. 10, 2987–2997.
Bramham C. R., Southard T., Sarvey J. M., Herkenham M., and Brady L. S. (1992) Unilateral LTP triggers bilateral increases in hippocampal neurotrophin and trk receptor mRNA expression in behaving rats: evidence for interhemispheric communication J. Comp. Neurol. 368, 371–382.
Bruce-Keller A. J., Umberger G., McFall R., and Mattson M. P. (1999) Food restriction reduces brain damage and improves behavioral outcome following excitotoxic and metabolic insults. Ann. Neurol. 45, 8–15.
Castren E., Zafra F., Thoenen H., and Lindholm D. (1992) Light regulates expression of brain-derived neurotrophic factor mRNA in rat visual cortex. Proc. Natl. Acad. Sci. USA 89, 9444–9448.
Cheng B. and Mattson M. P. (1994) NT-3 and BDNF protect CNS neurons against metabolic/excitotoxic insults. Brain Res 640, 56–67.
Datta S. R., Dudek H., Tao X., Masters S., Fu H., Gotoh Y., and Greenberg M. E. (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231–241.
Duan W. and Mattson M. P. (1999) Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson’s disease. J. Neurosci. Res. 57, 195–206.
Dubey A., Forster M. J., Lal H., and Sohal R. S. (1996) Effect of age and caloric intake on protein oxidation in different brain regions and on behavioral functions of mouse. Arch. Biochem. Biophys. 333, 189–197.
Ehrenfried J. A., Evers B. M., Chu K. U., Townsend C. M., and Thompson J. C. (1996) Caloric restriction increases the expression of heat shock protein in the gut. Ann. Surg. 223, 592–597.
Endres M., Fan G., Hirt L., Fujii M., Matsushita K., Liu X., Jaenisch R., and Moskowitz M. A. (2000) Ischemic brain damage in mice after selectively modifying BDNF or NT4 gene expression. J. Cereb. Blood Flow Metab. 20, 139–144.
Ghosh A., Carnahan J., and Greenberg M. E. (1994) Requirement for BDNF in activity-dependent survival of cortical neurons. Science 263, 1618–1623.
Goodrick C. L., Ingram D. K., Reynolds M. A., Freeman J. R., and Cider N. L. (1983) Differential effects of intermittent feeding and voluntary exercise on body weight and lifespan in adult rats. J. Gerontol. 38, 36–45.
Guo Q., Sebastian L., Sopher B. L., Miller M. W., Glazner G. W., Ware C. B., et al. (1999) Neurotrophic factors [activity-dependent neurotrophic factor (ADNF) and basic fibroblast growth factor (bFGF)] interrupt excitotoxic neurodegenerative cascades promoted by a presenilin-1 mutation. Proc. Natl. Acad. Sci. USA 96, 4125–4130.
Hetman M., Kanning K., Cavanaugh J. E., and Xia Z. (1999) Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. J. Biol. Chem. 274, 22,569–22,580.
Heydari A. R., You S., Takahashi R., Gutsmann A., Sarge K. D., and Richardson A. (1996) Effect of caloric restriction on the expression of heat shock protein 70 and the activation of heat shock transcription factor 1. Dev. Genet. 18, 114–124.
Hicks R. R., Numan S., Dhillon H. S., Prasad M. R., and Seroogy K. B. (1997) Alterations in BDNF and NT-3 mRNAs in rat hippocampus after experimental brain trauma. Mol. Brain Res. 48, 401–406.
Idrobo F., Nandy K., Mostofsky D. I., Blatt L., and Nandy L. (1987) Dietary restriction: effects on radial maze learning and lipofuscin pigment deposition in the hippocampus and frontal cortex. Arch. Gerontol. Geriatr. 6, 355–362.
Ingram D. K., Weindruch R., Spangler E. L., Freeman J. R., and Walford R. L. (1987) Dietary restriction benefits learning and motor performance of aged mice. J. Gerontol. 42, 78–81.
Johnston A. N., Clements M. P., and Rose S. P. (1999) Role of brain-derived neurotrophic factor and presynaptic proteins in passive avoidance learning in day-old domestic chicks. Neuroscience 88, 1033–1042.
Korte M., Kang H., Bonhoeffer T., and Schuman E. (1998) A role for BDNF in the late-phase of hippocampal long-term potentiation. Neuropharmacology 37, 553–559.
Kritchevsky D. and Klurfeld D. M. (1986) Influence of caloric intake on experimental carcinogenesis: a review. Adv. Exp. Med. Biol. 206, 55–68.
Larsson E., Nanobashvili A., Kokaia Z., and Lindvall O. (1999) Evidence for neuroprotective effects of endogenous brain-derived neurotrophic factor after global forebrain ischemia in rats. J. Cereb. Blood Flow Metab. 19, 1220–1228.
Lee S., Williamson J., Lothman E. W., Szele F. G., Chesselet M. F., Von Hagen S., et al. (1997) Early induction of mRNA for calbindin-D28k and BDNF but not NT-3 in rat hippocampus after kainic acid treatment. Mol. Brain Res. 47, 183–194.
Lee J., Bruce-Keller A. J., Kruman I., Chan S., and Mattson M. P. (1999) 2-deoxy-D-glucose protects hippocampal neurons against excitotoxic and oxidative injury: involvement of stress proteins. J. Neurosci. Res. 57, 48–61.
Levine E. S., Dreyfus C. F., Black I. B., and Plummer M. R. (1995) Brain-derived neurotrophic factor rapidly enhances synaptic transmission in hippocampal neurons via postsynaptic tyrosine kinase receptors. Proc. Natl. Acad. Sci. USA 92, 8074–8077.
Lindvall O., Ernfors P., Bengzon J., Kokaia Z., Smith M. L., Siesjo B. K., and Persson H. (1992) Differential regulation of mRNAs for nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 in the adult rat brain following cerebral ischemia and hypoglycemic coma. Proc. Natl. Acad. Sci. USA 89, 648–652.
Mattson M. P. and Furukawa K. (1996) Programmed cell life: anti-apoptotic signaling and therapeutic strategies for neurodegenerative disorders. Restorative Neurol. Neurosci. 9, 191–205.
Mattson M. P., Lovell M. A., Furukawa K., and Markesbery W. R. (1995) Neurotrophic factors attenuate glutamate-induced accumulation of peroxides, elevation of intracellular Ca2+ concentration, and neurotoxicity and increase antioxidant enzyme activities in hippocampal neurons. J. Neurochem. 65, 1740–1751.
Morgan T. E., Rozovsky I., Goldsmith S. K., Stone D. J., Yoshida T., and Finch C. E. (1997) Increased transcription of the astrocyte gene GFAP during middle age is attenuated by food restriction: implications for the role of oxidative stress. Free Rad. Biol. Med. 23, 524–528.
Mu J. S., Li W. F., Yao Z. H., and Zhou X. F. (1999) Deprivation of endogenous brain-derived neurotrophic factor results in impairment of spatial learning and memory in adult rats. Brain Res. 835, 259–265.
Neeper S. A., Gomez-Pinilla F., Choi J., and Cotman C. (1995) Exercise and brain neurotrophins. Nature 373, 109.
Neeper S. A., Gomez-Pinilla F., Choi J., and Cotman C. W (1996) Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain. Brain Res. 726, 49–56.
Patterson S. L., Grover L. M., Schwartzkroin P. A., and Bothwell M. (1992) Neurotrophin expression in rat hippocampal slices: a stimulus paradigm inducing LTP in CA1 evokes increases in BDNF and NT-3 mRNAs. Neuron 9, 1081–1088.
Ren J. M. and Finklestein S.P. (1997) Time window of infarct reduction by intravenous basic fibroblast growth factor in focal cerebral ischemia. Eur. J Pharmacol. 327, 11–16.
Rudge J. S., Mather P. E., Pasnikowski E. M., Cai N., Corcoran T., Acheson A., et al. (1998) Endogenous BDNF protein is increased in adult rat hippocampus after a kainic acid induced excitotoxic insult but exogenous BDNF is not neuroprotective. Exp. Neurol. 149, 398–410.
Sanna M. G., Duckett C. S., Richter B. W., Thompson C. B., and Ulevitch R. J. (1998) Selective activation of JNK1 is necessary for the anti-apoptotic activity of hILP. Proc. Natl. Acad. Sci. USA 95, 6015–6020.
Seroogy K. B. and Herman J. P. (1997) In situ hybridization approaches to the study of the nervous system, in Neurochemistry: a Practical Approach, 2nd ed. (Turner A. J., Bachelard H. S., eds.), Oxford University Press., Oxford, UK, pp. 121–150.
Skaper S. D., Floreani M., Negro A., Facci L., and Giusti P. (1998) Neurotrophins rescue cerebellar granule neurons from oxidative stress-mediated apoptotic death: selective involvement of phosphatidylinositol 3-kinase and the mitogen-activated protein kinase pathway. J. Neurochem. 70, 1859–1868.
Smith-Swintosky V. L., et al. (1996) Bacterial alkaloids mitigate seizure-induced hippocampal damage and spatial memory deficits. Exp. Neurol. 141, 287–296.
Sohal R. S. and Weindruch R. (1996) Oxidative stress, caloric restriction, and aging. Science 273, 59–63.
Sohal R. S., Ku H. H., Aagarwal S., Forster M. J., and Lal H. (1994) Oxidative damage, mitochondrial oxidant generation and antioxidant defenses during aging and in response to food restriction in the mouse. Mech. Aging Dev. 74, 121–133.
Stewart J., Mitchell J., and Kalant N. (1989) The effects of life-long food restriction on spatial memory in young and aged Fischer 344 rats measured in the eight-arm radial and the Morris water mazes. Neurobiol. Aging 10, 669–675.
Talan M. I. and Ingram D. K. (1985) Effect of intermittent feeding on thermoregulatory abilities of young and aged C57BL/6J mice. Arch. Gerontol. Geriatr. 4, 251–259.
Tran J., Rak J., Sheehan C., Saibil S. D., LaCasse E., Korneluk R. G., and Kerbel R. S. (1999) Marked induction of the IAP family antiapoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells. Biochem. Biophys. Res. Commun. 264, 781–788.
Tsukahara T., Takeda M., Shimohama S., Ohara O., and Hashimoto N. (1995) Effects of brain-derived neurotrophic factor on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in monkeys. Neurosurgery 37, 733–739.
Wachsman J. T. (1996) The beneficial effects of dietary restriction: reduced oxidative damage and enhanced apoptosis. Mutat. Res. 350, 25–34.
Wang X., Martindale J. L., Liu Y., and Holbrook N. J. (1998) The cellular response to oxidative stress: influences of mitogen-activated protein kinase signalling pathways on cell survival. Biochem. J. 333, 291–300.
Young D., Lawlor P. A., Leone P., Dragunow M., and During M. J. (1999) Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nature Med. 5, 448–453.
Yu Z. F. and Mattson M. P. (1999) Dietary restriction and 2-deoxyglucose administration reduce focal ischemic brain damage and improve behavioral outcome: evidence for a preconditioning mechanism. J. Neurosci. Res. 57, 830–839.
Zhu H., Guo Q., and Mattson M. P. (1999) Dietary restriction protects hippocampal neurons against the death-promoting action of a presenilin-1 mutation. Brain Res. 842, 224–229.
These authors contributed equally to this work.
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Duan, W., Lee, J., Guo, Z. et al. Dietary restriction stimulates BDNF production in the brain and thereby protects neurons against excitotoxic injury. J Mol Neurosci 16, 1–12 (2001). https://doi.org/10.1385/JMN:16:1:1
- caloric restriction
- cerebral cortex
- epileptic seizures