Cellular and Molecular Neurobiology

, Volume 31, Issue 1, pp 83–91 | Cite as

Beneficial Effects of Folic Acid on Enhancement of Memory and Antioxidant Status in Aged Rat Brain

  • Rashmi Singh
  • Shalinder S. Kanwar
  • Pooja K. Sood
  • Bimla Nehru
Original Research

Abstract

As our population ages, diseases affecting memory and daily functioning will affect an increasing number of individuals, their families and the healthcare system. Therefore, there is a need to study and evaluate effects of certain conditions for anti-aging of the brain. Nutrient supplementation can modify the brain function. The chemistry and function of both the developing and the mature brain are influenced by diet (Fernstrom, Am J Clinical Nutrition 71:1669S–1673S, 2000). Clinical, biochemical, and pathological aspects have shown a correlation between mental symptoms, especially depression and cognitive decline, with high incidence of folate deficiency (Bottiglieri et al., J Neurol Neurosurg Psychiatry 69:562, 2000). In the present study, consequences of folic acid supplementation on brain dysfunction as a result of aging were studied in cerebral cortex, mid brain, and cerebellar regions of rat brain. This study was carried out on 6-, 11-, and 16-month-old rats, which received folic acid at a dose of 5 mg/kg body weight/day for a period of 8 weeks. Respective control groups of the same age groups were also taken. At the end of the treatment duration, behavioral studies were performed and later the animals were killed for various biochemical and histological investigations. Results indicated significant improvement in memory as assessed by active avoidance, passive avoidance, and plus maze tests in the folic acid supplemented aged animals. Significant improvement was also seen in the cellular protective mechanisms where by the activity of superoxide dismutase and catalase enzymes increased in folic acid supplemented group and so was the glutathione content. Increased lipid peroxidation content, a marker of aging, was also found to be decreased during folic acid supplementation in all the three regions of brain in our study. Thus, it can be concluded that folic acid helps in improving the memory status by reducing oxidative stress and maintaining the integrity of neurons during aging.

Keywords

Aging Folic acid Free radicals Cognitive function 

Notes

Acknowledgments

We are grateful to all our colleagues and members of the Pharmacology Division, UIPS, Panjab University Chandigarh for providing the facilities for performing behavioral tests. Authors are also thankful to Ms Pooja Khanna, Mr. Saurav Pathria, Ms. Neera Singh for giving valuable suggestions.

References

  1. Barber DA, Harris SR (1994) Oxygen free radicals and antioxidants: a review. Am Pharm 34:26–35Google Scholar
  2. Blundell G, Jones BG, Rose FA, Tudball N (1996) Homocysteine mediated endothelial cell toxicity and its amelioration. Atherosclerosis 122:163–172CrossRefPubMedGoogle Scholar
  3. Botez MI, Reynolds EH (1979) Folic acid in neurology, psychiatry and internal medicine. Raven Press, New YorkGoogle Scholar
  4. Bottiglieri T, Reynolds EH, Laundy M (2000) Folate in CSF and age. J Neurol Neurosurg Psychiatry 69:562CrossRefPubMedGoogle Scholar
  5. Brattstrom L (1996) Vitamins as homocysteine lowering agents. J Nutr 126:1276S–1280SPubMedGoogle Scholar
  6. Chauveau P, Chadefaux B, Coude M, Aupetit J, Kamoun P, Jungers P (1996) Long-term folic acid (but not pyridoxine) supplementation lowers elevated plasma homocysteine level in chronic renal failure. Miner Electrolyte Metab 22:106–109PubMedGoogle Scholar
  7. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM (1998) Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 55:1449–1455CrossRefPubMedGoogle Scholar
  8. Cotron RS, Kumar V, Collins T (1999) Robbin’s pathological basis of disease, 6th edn. Thompson Press Ltd, Noida, pp 1–31Google Scholar
  9. Dierkes J, Domrose U, Ambrosch A, Schneede J, Guttormsen AB, Neumann KH, Luley C (1999) Supplementation with vitamin B12 decreases homocysteine and methylmalonic acid but also serum folate in patients with end-stage renal disease. Metabolism 48:631–635CrossRefPubMedGoogle Scholar
  10. Durand P, Fortin LJ, Lussier Cacan S, Davignon J, Blache D (1996) Hyperhomocysteinamia induced by folic acid deficiency and methionine load. Clin Chim Acta 252:83–93CrossRefPubMedGoogle Scholar
  11. Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77CrossRefPubMedGoogle Scholar
  12. Fernstrom JD (2000) Can nutrient supplements modify brain function. Am J Clin Nutr 71:1669S–1673SPubMedGoogle Scholar
  13. Fridovich I (1983) Superoxide radical as an endogenous toxicant. Ann Rev Pharmacol Toxicol 23:239–257CrossRefGoogle Scholar
  14. Halliwell B (1994) Free radicals and antioxidants: a personal view. Nutr Rev 52:253–265CrossRefPubMedGoogle Scholar
  15. Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300PubMedGoogle Scholar
  16. Haug H (1985) Are neurons of the human cerebral cortex really lost during ageing? A morphometric examination. In: Tarber J, Gispen WH (eds) Senile dementia of Alzheimer type. Springer, Berlin, pp 150–163Google Scholar
  17. Hazelton GA, Lang CA (1980) Glutathione contents of tissues in the aging mouse. Biochem J 188(1):25–30PubMedGoogle Scholar
  18. Hof PR, Morrison JH (2004) The aging brain: morphomolecular senescence of cortical circuits. Trends Neurosci 27:607–613CrossRefPubMedGoogle Scholar
  19. Huang RF, Hsu YC, Lin HL, Yang FL (2001) Folate depletion and elevated plasma homocysteine promote oxidative stress in rat livers. J Nutr 131:33–38PubMedGoogle Scholar
  20. Hultberg B, Andersson A, Isaksson A (1997) The cell-damaging effects of low amounts of homocysteine and copper ions in human cell line cultures are caused by oxidative stress. Toxicology 123:33–40CrossRefPubMedGoogle Scholar
  21. Humanson GL (1961) In: Basic Procedures-Animal Tissue Technique. 1:130–132.Google Scholar
  22. Jacob RA, Gretz DM, Taylor PC, James SJ, Pogribny IP, Miller BJ, Henning SM, Swendseid ME (1998) Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women. J Nutr 128:1204–1212PubMedGoogle Scholar
  23. Jenner P (1998) Oxidative mechanisms in nigral cell death in Parkinson’s disease. Mov Discord 13:24–34Google Scholar
  24. Jones BG, Rose FA, Tudball N (1994) Lipid peroxidation and homocysteine induced toxicity. Atherosclerosis 105:165–170CrossRefPubMedGoogle Scholar
  25. Joshi R, Adhikari S, Patro BS, Chattopadhyay S, Mukherjee T (2001) Free radical scavenging behavior of folic acid. Free Radic Biol Med 12:1390–1399CrossRefGoogle Scholar
  26. Kono Y (1978) Generation of superoxide radical during autoxidation of hydroxylamine and an assay for superoxide dismutase. Arch Biochem Biophys 186:189–195CrossRefPubMedGoogle Scholar
  27. Kruman II, Carsten Culmsee, Chan SL, Kruman Y, Guo Z, Penix LR, Mattson MP (2000) Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci 20:6920–6926PubMedGoogle Scholar
  28. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin-Phenol reagents. J Biol Chem 193:265–275PubMedGoogle Scholar
  29. Luck H (1971) Catalase. In: Bergmeyer HU (ed) Methods of enzymatic analysis. Academic Press, New York, pp 885–893Google Scholar
  30. Mark RE, Griffin ST, Graham DI (1997) Aging associated changes in human brain. J Neuropathol Exp Neurol 56:1269–1275CrossRefGoogle Scholar
  31. Markesbery WR (1997) Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med 23:134–147CrossRefPubMedGoogle Scholar
  32. Mattson MP (2003) Gene diet interactions in brain aging and neurodegenerative disorders. Ann Int Med 139:5Google Scholar
  33. Mattson MP, Kruman II, Duan W (2002) Folic acid and homocysteine in age-related disease. Ageing Res Rev 1:95–111CrossRefPubMedGoogle Scholar
  34. Miller AL, Kelley GS (1997) Homocysteine metabolism: nutritional modulation and impact on health & disease. Altern Med Rev 2:234–254Google Scholar
  35. Morrison JH, Hof PR (1997) Life and death of neurons in the aging brain. Science 278:412–419CrossRefPubMedGoogle Scholar
  36. Navarro A, Boveris A (2004) Rat brain and liver mitochondria develop oxidative stress and lose enzymatic activities on aging. Am J Physiol Regul Integr Comp Physiol 287:R1244–R1249PubMedGoogle Scholar
  37. Plaa GL, Witschi H (1976) Chemical, drugs and lipid peroxidation. Ann Rev Pharmacol Toxicol 15:125–141CrossRefGoogle Scholar
  38. Racek J, Rusnakova H, Trefil L, Siala KK (2005) The influence of folate and antioxidants on homocysteine levels and oxidative stress in patients with hyperlipidemia and hyperhomocysteinemia. Physiol Res 54:87–95PubMedGoogle Scholar
  39. Reynolds EH (1968) Mental effects of anticonvulsants and folic acid metabolism. Brain 91:197–214CrossRefPubMedGoogle Scholar
  40. Selhub J, Jacques PF, Wilson PWF, Rush D, Rosenberg IH (1993) Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 270:2693–2698CrossRefPubMedGoogle Scholar
  41. Semsci I, Rao G, Ricahrdson A (1991) Expression of superoxide dismutase and catalase in rat brain as a function of age. Mech Ageing Dev 58:13–19CrossRefGoogle Scholar
  42. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Angostino RB, Wilson PWF, Wolf PF (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 346:476–483CrossRefPubMedGoogle Scholar
  43. Starkebaum G, Harlan JM (1986) Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest 77:1370–1376CrossRefPubMedGoogle Scholar
  44. Stocker R, Frie B (1991) Endogenous antioxidant defense in human blood plasma. In: Sies H (ed) Oxidative stress: oxidants and antioxidants. Academic Press, London, pp 213–243Google Scholar
  45. Uysal M, Sekin S, Kocak-Toker N, Oz M (1989) Increased hepatic lipid peroxidation in aged mice. Mech Ageing Dev 48:85–89CrossRefPubMedGoogle Scholar
  46. West R (2004) The neural basis of age related declines in prospective memory. In: Cabeza R, Nyberg L, Park D (eds) Cognitive neuroscience of aging: linking cognitive and cerebral aging. Oxford University Press, New York, pp 246–264Google Scholar
  47. Wills ED (1966) Mechanisms of lipid peroxide formation in animal tissues. Biochem J 99:667–676PubMedGoogle Scholar
  48. Zhu Y, Carvey PM, Ling Z (2006) Age-related change in glutathione and glutathione related enzymes in rat brain. Brain Res 1090:35–44CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Rashmi Singh
    • 1
  • Shalinder S. Kanwar
    • 1
  • Pooja K. Sood
    • 1
  • Bimla Nehru
    • 1
  1. 1.Department of BiophysicsPanjab UniversityChandigarhIndia

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