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

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Abstract

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.

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Abbreviations

AD:

Alzheimer’s disease

AMPK:

AMP-activated protein kinase

B2M:

Beta-2 microglobulin

BDNF:

Brain-derived neurotrophic factor

CI:

Complex I

CII:

Complex II

CIII:

Complex III

CIV:

Complex IV

CV:

Complex V

COX:

Cytochrome c oxidase

CREB:

cAMP response element-binding protein

CS:

Citrate synthase

DBC:

Dissociated brain cells

Drp:

Dynamin-related protein

ETS:

Electron transport system

fis:

Fission

GAP:

Growth-associated protein

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

HPLC:

High-performance liquid chromatography

Mfn:

Mitofusin

MIR05:

Mitochondrial respiration medium 05

MMP:

Mitochondrial membrane potential

NMRI:

Naval Medical Research Institute

Nrf:

Nuclear respiratory factor

Opa:

Optic atrophy

OXPHOS:

Oxidative phosphorylation

PD:

Parkinson’s disease

PGC1α:

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

PGK:

Phosphoglycerate kinase

qRT-PCR:

Quantitative real-time polymerase chain reaction

RBE:

Rice bran extract

RCR:

Respiratory control ratio

ROX:

Residual oxygen consumption

SIRT:

Sirtuin

SNP:

Sodium nitroprusside

Tfam:

Mitochondrial transcription factor A

References

  • 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.

    Article  Google Scholar 

  • 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.

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Bhullar, K. S., & Hubbard, B. P. (2015). Lifespan and healthspan extension by resveratrol. Biochimica et Biophysica Acta, 1852(6), 1209–1218.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Grasselli, G., & Strata, P. (2013). Structural plasticity of climbing fibers and the growth-associated protein GAP-43. Frontiers in Neural Circuits, 7, 25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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), 16524–16539

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Kann, O. (2015). The interneuron energy hypothesis: Implications for brain disease. Neurobiology of Diseases,. doi:10.1016/j.nbd.2015.08.005.

    Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leal, G., Afonso, P. M., Salazar, I. L., & Duarte, C. B. (2015). Regulation of hippocampal synaptic plasticity by BDNF. Brain Research, 1621, 82–101.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mattson, M. P., Gleichmann, M., & Cheng, A. (2008). Mitochondria in neuroplasticity and neurological disorders. Neuron, 60(5), 748–766.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Park, S.-Y. (2010). Potential therapeutic agents against Alzheimer’s disease from natural sources. Archives of Pharmacal Research, 33(10), 1589–1609.

    Article  CAS  PubMed  Google Scholar 

  • 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), 11–18

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

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.

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Authors and Affiliations

  1. Department of Pharmacology, Goethe-University, Biozentrum Niederursel, Max-von-Laue-Straße 9, 60438, Frankfurt, Germany

    Stephanie Hagl, Heike Asseburg, Martina Heinrich & Gunter P. Eckert

  2. Institute of Nutritional Sciences, University of Giessen, Wilhelmstrasse 20, 35392, Giessen, Germany

    Gunter P. Eckert

  3. Institute of Biological Chemistry and Nutrition, University of Hohenheim, Garbenstraße 28, 70599, Stuttgart, Germany

    Nadine Sus & Jan Frank

  4. Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany

    Eva-Maria Blumrich & Ralf Dringen

  5. Centre for Environmental Research and Sustainable Technology, University of Bremen, Bremen, Germany

    Eva-Maria Blumrich & Ralf Dringen

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  1. Stephanie Hagl
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  2. Heike Asseburg
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  3. Martina Heinrich
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  4. Nadine Sus
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  5. Eva-Maria Blumrich
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  7. Jan Frank
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  8. Gunter P. Eckert
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Correspondence to Gunter P. Eckert.

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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.

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12017_2016_8420_MOESM2_ESM.eps

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)

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Hagl, S., Asseburg, H., Heinrich, M. et al. Effects of Long-Term Rice Bran Extract Supplementation on Survival, Cognition and Brain Mitochondrial Function in Aged NMRI Mice. Neuromol Med 18, 347–363 (2016). https://doi.org/10.1007/s12017-016-8420-z

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