NeuroMolecular Medicine

, Volume 18, Issue 3, pp 347–363 | Cite as

Effects of Long-Term Rice Bran Extract Supplementation on Survival, Cognition and Brain Mitochondrial Function in Aged NMRI Mice

  • Stephanie Hagl
  • Heike Asseburg
  • Martina Heinrich
  • Nadine Sus
  • Eva-Maria Blumrich
  • Ralf Dringen
  • Jan Frank
  • Gunter P. EckertEmail author
Original Paper


Aging represents a major risk factor for the development of neurodegenerative diseases like Alzheimer’s disease (AD). As mitochondrial dysfunction plays an important role in brain aging and occurs early in the development of AD, the prevention of mitochondrial dysfunction might help to slow brain aging and the development of neurodegenerative diseases. Rice bran extract (RBE) contains high concentrations of vitamin E congeners and γ-oryzanol. We have previously shown that RBE increased mitochondrial function and protected from mitochondrial dysfunction in vitro and in short-term in vivo feeding studies. To mimic the use of RBE as food additive, we have now investigated the effects of a long-term (6 months) feeding of RBE on survival, behavior and brain mitochondrial function in aged NMRI mice. RBE administration significantly increased survival and performance of aged NMRI mice in the passive avoidance and Y-maze test. Brain mitochondrial dysfunction found in aged mice was ameliorated after RBE administration. Furthermore, data from mRNA and protein expression studies revealed an up-regulation of mitochondrial proteins in RBE-fed mice, suggesting an increase in mitochondrial content which is mediated by a peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)-dependent mechanism. Our findings suggest that a long-term treatment with a nutraceutical containing RBE could be useful for slowing down brain aging and thereby delaying or even preventing AD.


Mitochondria Brain aging Nutrition Rice bran extract NMRI mice PGC1α 



Alzheimer’s disease


AMP-activated protein kinase


Beta-2 microglobulin


Brain-derived neurotrophic factor


Complex I


Complex II


Complex III


Complex IV


Complex V


Cytochrome c oxidase


cAMP response element-binding protein


Citrate synthase


Dissociated brain cells


Dynamin-related protein


Electron transport system




Growth-associated protein


Glyceraldehyde 3-phosphate dehydrogenase


High-performance liquid chromatography




Mitochondrial respiration medium 05


Mitochondrial membrane potential


Naval Medical Research Institute


Nuclear respiratory factor


Optic atrophy


Oxidative phosphorylation


Parkinson’s disease


Peroxisome proliferator-activated receptor gamma coactivator 1-alpha


Phosphoglycerate kinase


Quantitative real-time polymerase chain reaction


Rice bran extract


Respiratory control ratio


Residual oxygen consumption




Sodium nitroprusside


Mitochondrial transcription factor A



This work was funded by the German Federal Ministry for Economic Affairs and Energy (Grant No. KF2118004CS3). Authors thank Dr. Amr Helal from IT&M SA (Giza, Egypt) and Dr. Hesham El-Askary (Faculty of Pharmacy, Cairo University) for providing and characterizing the rice bran extract.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Standard

The protocol for the animal feeding study and tissue collection was approved by the local authorities for animal welfare, and all experiments were carried out according to the European Communities Council Directive (86/609/EEC) by individuals with appropriate training.

Supplementary material

12017_2016_8420_MOESM1_ESM.doc (28 kb)
Supplementary material 1 (DOC 28 kb)
12017_2016_8420_MOESM2_ESM.eps (75 kb)
Supplementary Fig. 10. Body weight of young and aged NMRI mice (for more information about the treatment of mice see labeling of Figure 1) over the three (young control) respectively six month (aged control, aged + RBE) study period; mean without SEM (EPS 75 kb)


  1. Afshordel, S., Hagl, S., Werner, D., Rohner, N., Kogel, D., Bazan, N. G., et al. (2015). Omega-3 polyunsaturated fatty acids improve mitochondrial dysfunction in brain aging—Impact of Bcl-2 and NPD-1 like metabolites. Prostaglandins Leukotrienes and Essential Fatty Acids, 92C, 23–31.CrossRefGoogle Scholar
  2. Barnard, N. D., Bush, A. I., Ceccarelli, A., Cooper, J., de Jager, Celeste A, & Erickson, K. I., et al. (2014). Dietary and lifestyle guidelines for the prevention of Alzheimer’s disease. Neurobiology of Aging, 35S2, S74–S78.Google Scholar
  3. Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., et al. (2006). Resveratrol improves health and survival of mice on a high-calorie diet. Nature, 444(7117), 337–342.CrossRefPubMedGoogle Scholar
  4. Bayram, B., Nikolai, S., Huebbe, P., Ozcelik, B., Grimm, S., Grune, T., et al. (2013). Biomarkers of oxidative stress, antioxidant defence and inflammation are altered in the senescence-accelerated mouse prone 8. AGE, 35(4), 1205–1217.CrossRefPubMedGoogle Scholar
  5. Bhullar, K. S., & Hubbard, B. P. (2015). Lifespan and healthspan extension by resveratrol. Biochimica et Biophysica Acta, 1852(6), 1209–1218.CrossRefPubMedGoogle Scholar
  6. Canto, C., & Auwerx, J. (2009). PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Current Opinion in Lipidology, 20(2), 98–105.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chistiakov, D. A., Sobenin, I. A., Revin, V. V., Orekhov, A. N., & Bobryshev, Y. V. (2014). Mitochondrial aging and age-related dysfunction of mitochondria. BioMed Research International, 2014, 238463.PubMedPubMedCentralGoogle Scholar
  8. Dringen, R., Kussmaul, L., & Hamprecht, B. (1998). Detoxification of exogenous hydrogen peroxide and organic hydroperoxides by cultured astroglial cells assessed by microtiter plate assay. Brain Research Protocols, 2(3), 223–228.CrossRefPubMedGoogle Scholar
  9. Eckert, G. P., Renner, K., Eckert, S. H., Eckmann, J., Hagl, S., Abdel-Kader, R. M., et al. (2012). Mitochondrial dysfunction-a pharmacological target in Alzheimer’s disease. Molecular Neurobiology, 46(1), 136–150.CrossRefPubMedGoogle Scholar
  10. Fernandez-Marcos, P. J., & Auwerx, J. (2011). Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis. American Journal of Clinical Nutrition, 93(4), 884S–900S.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Frick, K. M., & Fernandez, S. M. (2003). Enrichment enhances spatial memory and increases synaptophysin levels in aged female mice. Neurobiology of Aging, 24(4), 615–626.CrossRefPubMedGoogle Scholar
  12. Grasselli, G., & Strata, P. (2013). Structural plasticity of climbing fibers and the growth-associated protein GAP-43. Frontiers in Neural Circuits, 7, 25.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Grebenstein, N., & Frank, J. (2012). Rapid baseline-separation of all eight tocopherols and tocotrienols by reversed-phase liquid-chromatography with a solid-core pentafluorophenyl column and their sensitive quantification in plasma and liver. Journal of Chromatography, 1243, 39–46.CrossRefPubMedGoogle Scholar
  14. Grimm, A., Friedland, K., & Eckert, A. (2015). Mitochondrial dysfunction: The missing link between aging and sporadic Alzheimer’s disease. Biogerontology,. doi: 10.1007/s10522-015-9618-4.PubMedGoogle Scholar
  15. Hagl, S., Berressem, D., Bruns, B., Sus, N., Frank, J., & Eckert, G. P. (2015) Beneficial effects of ethanolic and hexanic rice bran extract on mitochondrial function in PC12 cells and the search for bioactive components. Molecules (Basel, Switzerland) 20(9), 16524–16539Google Scholar
  16. Hagl, S., Berressem, D., Grewal, R., Sus, N., Frank, J., & Eckert, G. P. (2016). Rice bran extract improves mitochondrial dysfunction in brains of aged NMRI mice. Nutritional Neuroscience, 19(1), 1–10.CrossRefPubMedGoogle Scholar
  17. Hagl, S., Grewal, R., Ciobanu, I., Helal, A., Khayyal, M. T., Muller, W. E., et al. (2015b). Rice bran extract compensates mitochondrial dysfunction in a cellular model of early Alzheimer’s disease. Journal of Alzheimer’s Disease, 43(3), 927–938.PubMedGoogle Scholar
  18. Hagl, S., Kocher, A., Schiborr, C., Eckert, S. H., Ciobanu, I., Birringer, M., et al. (2013). Rice bran extract protects from mitochondrial dysfunction in guinea pig brains. Pharmacological Research: The Official Journal of the Italian Pharmacological Society, 76, 17–27.CrossRefGoogle Scholar
  19. Hohnholt, M. C., & Dringen, R. (2014). Short time exposure to hydrogen peroxide induces sustained glutathione export from cultured neurons. Free Radical Biology and Medicine, 70, 33–44.CrossRefPubMedGoogle Scholar
  20. Howes, M.-J. R., & Perry, E. (2011). The role of phytochemicals in the treatment and prevention of dementia. Drugs and Aging, 28(6), 439–468.CrossRefPubMedGoogle Scholar
  21. Kann, O. (2015). The interneuron energy hypothesis: Implications for brain disease. Neurobiology of Diseases,. doi: 10.1016/j.nbd.2015.08.005.Google Scholar
  22. Kann, O., Papageorgiou, I. E., & Draguhn, A. (2014). Highly energized inhibitory interneurons are a central element for information processing in cortical networks. Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 34(8), 1270–1282.CrossRefGoogle Scholar
  23. Kim, H. G., & Oh, M. S. (2012). Nutraceuticals and prevention of neurodegeneration herbal medicines for the prevention and treatment of Alzheimer’s disease. Current Pharmaceutical Design,. doi: 10.2174/138161212798919002.PubMedCentralGoogle Scholar
  24. Kitani, K., Osawa, T., & Yokozawa, T. (2007). The effects of tetrahydrocurcumin and green tea polyphenol on the survival of male C57BL/6 mice. Biogerontology, 8(5), 567–573.CrossRefPubMedGoogle Scholar
  25. Lagouge, M., & Larsson, N.-G. (2013). The role of mitochondrial DNA mutations and free radicals in disease and ageing. Journal of Internal Medicine, 273(6), 529–543.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Larsen, S., Nielsen, J., Hansen, C. N., Nielsen, L. B., Wibrand, F., Stride, N., et al. (2012). Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects. The Journal of Physiology, 590(14), 3349–3360.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Leal, G., Afonso, P. M., Salazar, I. L., & Duarte, C. B. (2015). Regulation of hippocampal synaptic plasticity by BDNF. Brain Research, 1621, 82–101.CrossRefPubMedGoogle Scholar
  28. Leuner, K., Hauptmann, S., Abdel-Kader, R., Scherping, I., Keil, U., Strosznajder, J. B., et al. (2007). Mitochondrial dysfunction: The first domino in brain aging and Alzheimer’s disease? Antioxidants & Redox Signaling, 9(10), 1659–1675.CrossRefGoogle Scholar
  29. Linard, A., Macaire, J.-P., & Christon, R. (2001). Phospholipid hydroperoxide glutathione peroxidase activity and vitamin E level in the liver microsomal membrane: Effects of age and dietary alpha-linolenic acid deficiency. The Journal of Nutritional Biochemistry, 12(8), 481–491.CrossRefPubMedGoogle Scholar
  30. Lowry, O. H., Rosebrough, N. J., Farr, A. L., & Randall, R. J. (1951). Protein measurement with the Folin phenol reagent. The Journal of biological chemistry, 193(1), 265–275.PubMedGoogle Scholar
  31. Mamiya, T., Asanuma, T., Kise, M., Ito, Y., Mizukuchi, A., Aoto, H., et al. (2004). Effects of pre-germinated brown rice on beta-amyloid protein-induced learning and memory deficits in mice. Biological & Pharmaceutical Bulletin, 27(7), 1041–1045.CrossRefGoogle Scholar
  32. Marlatt, M. W., Potter, M. C., Lucassen, P. J., & van Praag, H. (2012). Running throughout middle-age improves memory function, hippocampal neurogenesis, and BDNF levels in female C57BL/6J mice. Developmental Neurobiology, 72(6), 943–952.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Mattson, M. P., Gleichmann, M., & Cheng, A. (2008). Mitochondria in neuroplasticity and neurological disorders. Neuron, 60(5), 748–766.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Mattson, M. P., Maudsley, S., & Martin, B. (2004). BDNF and 5-HT: A dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends in Neurosciences, 27(10), 589–594.CrossRefPubMedGoogle Scholar
  35. Müller, W., Eckert, A., Kurz, C., Eckert, G., & Leuner, K. (2010). Mitochondrial dysfunction: Common final pathway in brain aging and alzheimer’s disease—therapeutic aspects. Molecular Neurobiology, 41, 159–171.CrossRefPubMedGoogle Scholar
  36. Navarro, A., Bandez, M. J., Lopez-Cepero, J. M., Gomez, C., & Boveris, A. (2011). High doses of vitamin E improve mitochondrial dysfunction in rat hippocampus and frontal cortex upon aging. AJP: Regulatory, Integrative and Comparative Physiology, 300(4), R827.Google Scholar
  37. Navarro, A., & Boveris, A. (2010). Brain mitochondrial dysfunction in aging, neurodegeneration, and Parkinson’s disease. Frontiers in Aging Neuroscience, 2. doi: 10.3389/fnagi.2010.00034.
  38. Navarro, A., Gomez, C., Sanchez-Pino, M.-J., Gonzalez, H., Bandez, M. J., Boveris, A. D., et al. (2005). Vitamin E at high doses improves survival, neurological performance, and brain mitochondrial function in aging male mice. American Journal of Physiology, 289(5), R1392–R1399.PubMedGoogle Scholar
  39. Navarro, A., Sanchez Del Pino, M. J., Gomez, C., Peralta, J. L., & Boveris, A. (2002). Behavioral dysfunction, brain oxidative stress, and impaired mitochondrial electron transfer in aging mice. American Journal of Physiology, 282(4), R985–R992.PubMedGoogle Scholar
  40. Pannangrong, W., Wattanathorn, J., Muchimapura, S., Tiamkao, S., & Tong-un, T. (2011). Purple rice berry is neuroprotective and enhances cognition in a rat model of alzheimer’s disease. Journal of Medicinal Food, 14(7–8), 688–694.CrossRefPubMedGoogle Scholar
  41. Park, S.-Y. (2010). Potential therapeutic agents against Alzheimer’s disease from natural sources. Archives of Pharmacal Research, 33(10), 1589–1609.CrossRefPubMedGoogle Scholar
  42. Patterson, S. L. (2015). Immune dysregulation and cognitive vulnerability in the aging brain: Interactions of microglia, IL-1beta, BDNF and synaptic plasticity. Neuropharmacology, 96(Pt A), 11–18Google Scholar
  43. Petters, C., & Dringen, R. (2014). Comparison of primary and secondary rat astrocyte cultures regarding glucose and glutathione metabolism and the accumulation of iron oxide nanoparticles. Neurochemical Research, 39(1), 46–58.CrossRefPubMedGoogle Scholar
  44. Picard, M., & McEwen, B. S. (2014). Mitochondria impact brain function and cognition. Proceedings of the National Academy of Sciences of the United States of America, 111(1), 7–8.CrossRefPubMedGoogle Scholar
  45. Rabøl, R., Larsen, S., Højberg, P. M. V., Almdal, T., Boushel, R., Haugaard, S. B., et al. (2010). Regional anatomic differences in skeletal muscle mitochondrial respiration in type 2 diabetes and obesity. Journal of Clinical Endocrinology and Metabolism, 95(2), 857–863.CrossRefPubMedGoogle Scholar
  46. Reagan-Shaw, S., Nihal, M., & Ahmad, N. (2008). Dose translation from animal to human studies revisited. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology, 22(3), 659–661.CrossRefGoogle Scholar
  47. Schaffer, S., Asseburg, H., Kuntz, S., Muller, W. E., & Eckert, G. P. (2012). Effects of polyphenols on brain ageing and Alzheimer’s disease: Focus on mitochondria. Molecular Neurobiology, 46(1), 161–178.CrossRefPubMedGoogle Scholar
  48. Schindowski, K., Leutner, S., Kressmann, S., Eckert, A., & Muller, W. E. (2001). Age-related increase of oxidative stress-induced apoptosis in mice prevention by Ginkgo biloba extract (EGb761). Journal of Neural Transmission (Vienna, Austria: 1996), 108(8–9), 969–978.Google Scholar
  49. Schmoll, H., Ramboiu, S., Platt, D., Herndon, J. G., Kessler, C., & Popa-Wagner, A. (2005). Age influences the expression of GAP-43 in the rat hippocampus following seizure. Gerontology, 51(4), 215–224.CrossRefPubMedGoogle Scholar
  50. Seo, A. Y., Joseph, A.-M., Dutta, D., Hwang, Judy C. Y., Aris, J. P., & Leeuwenburgh, C. (2010). New insights into the role of mitochondria in aging: Mitochondrial dynamics and more. Journal of Cell Science, 123(Pt 15), 2533–2542.CrossRefPubMedPubMedCentralGoogle Scholar
  51. Shiga, T., Nakamura, T. J., Komine, C., Goto, Y., Mizoguchi, Y., Yoshida, M., et al. (2016). A single neonatal injection of ethinyl estradiol impairs passive avoidance learning and reduces expression of estrogen receptor alpha in the hippocampus and cortex of adult female rats. PLoS ONE, 11(1), e0146136.CrossRefPubMedPubMedCentralGoogle Scholar
  52. Sunagawa, T., Shimizu, T., Kanda, T., Tagashira, M., Sami, M., & Shirasawa, T. (2011). Procyanidins from apples (Malus pumila Mill.) extend the lifespan of Caenorhabditis elegans. Planta Medica, 77(2), 122–127.CrossRefPubMedGoogle Scholar
  53. Tarsa, L., & Goda, Y. (2002). Synaptophysin regulates activity-dependent synapse formation in cultured hippocampal neurons. Proceedings of the National Academy of Sciences of the United States of America, 99(2), 1012–1016.CrossRefPubMedPubMedCentralGoogle Scholar
  54. Tulpule, K., Hohnholt, M., Hirrlingerm J., & Dringen, R. (2014) Primary cultures of astrocytes and neurons as model systems to study the metabolism and metabolite export from brain cells. In Hirrlinger, J., Waagepetersen, H. S. (Eds.), Brain energy metabolism, Vol. 90 (pp. 45–72). New York: Springer.Google Scholar
  55. Wilson, M. A., Shukitt-Hale, B., Kalt, W., Ingram, D. K., Joseph, J. A., & Wolkow, C. A. (2006). Blueberry polyphenols increase lifespan and thermotolerance in Caenorhabditis elegans. Aging Cell, 5(1), 59–68.CrossRefPubMedPubMedCentralGoogle Scholar
  56. Wolf, A., Bauer, B., Abner, E. L., Ashkenazy-Frolinger, T., Hartz, & Anika, M. S. (2016). A comprehensive behavioral test battery to assess learning and memory in 129S6/Tg2576 mice. PLoS ONE, 11(1), e0147733.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Stephanie Hagl
    • 1
  • Heike Asseburg
    • 1
  • Martina Heinrich
    • 1
  • Nadine Sus
    • 3
  • Eva-Maria Blumrich
    • 4
    • 5
  • Ralf Dringen
    • 4
    • 5
  • Jan Frank
    • 3
  • Gunter P. Eckert
    • 1
    • 2
    Email author
  1. 1.Department of PharmacologyGoethe-UniversityFrankfurtGermany
  2. 2.Institute of Nutritional SciencesUniversity of GiessenGiessenGermany
  3. 3.Institute of Biological Chemistry and NutritionUniversity of HohenheimStuttgartGermany
  4. 4.Centre for Biomolecular Interactions BremenUniversity of BremenBremenGermany
  5. 5.Centre for Environmental Research and Sustainable TechnologyUniversity of BremenBremenGermany

Personalised recommendations