, 36:9653 | Cite as

Age-related learning and memory deficits in rats: role of altered brain neurotransmitters, acetylcholinesterase activity and changes in antioxidant defense system

  • Saida Haider
  • Sadia Saleem
  • Tahira Perveen
  • Saiqa Tabassum
  • Zehra Batool
  • Sadia Sadir
  • Laraib Liaquat
  • Syeda Madiha


Oxidative stress from generation of increased reactive oxygen species or free radicals of oxygen has been reported to play an important role in the aging. To investigate the relationship between the oxidative stress and memory decline during aging, we have determined the level of lipid peroxidation, activities of antioxidant enzymes, and activity of acetylcholine esterase (AChE) in brain and plasma as well as biogenic amine levels in brain from Albino–Wistar rats at age of 4 and 24 months. The results showed that the level of lipid peroxidation in the brain and plasma was significantly higher in older than that in the young rats. The activities of antioxidant enzymes displayed an age-dependent decline in both brain and plasma. Glutathione peroxidase and catalase activities were found to be significantly decreased in brain and plasma of aged rats. Superoxide dismutase (SOD) was also significantly decreased in plasma of aged rats; however, a decreased tendency (non-significant) of SOD in brain was also observed. AChE activity in brain and plasma was significantly decreased in aged rats. Learning and memory of rats in the present study was assessed by Morris Water Maze (MWM) and Elevated plus Maze (EPM) test. Short-term memory and long-term memory was impaired significantly in older rats, which was evident by a significant increase in the latency time in MWM and increase in transfer latency in EPM. Moreover, a marked decrease in biogenic amines (NA, DA, and 5-HT) was also found in the brain of aged rats. In conclusion, our data suggest that increased oxidative stress, decline of antioxidant enzyme activities, altered AChE activity, and decreased biogenic amines level in the brain of aged rats may potentially be involved in diminished memory function.


Aging Memory AChE Antioxidant enzymes Biogenic amines 



Authors are grateful to Dr. Rafat Siddiqui for help in writing the manuscript. The study was financially supported from a grant from the University of Karachi, Karachi, Pakistan.

Conflict of interest

The authors declare no conflict of interest.


  1. Albert MS (1997) The ageing brain: normal and abnormal memory. Philos Trans R Soc Lond B Biol Sci 352:1703–1709PubMedCentralPubMedCrossRefGoogle Scholar
  2. Alper G, Girgin FK, Ozgonul M, Mentes G, Ersoz B (1999) MAO inhibitors and oxidant stress in aging brain tissue. Eur Neuropsychopharmacol 9:247–252PubMedCrossRefGoogle Scholar
  3. Bagheri M, Joghataei MT, Mohseni S, Roghani M (2011) Genistein ameliorates learning and memory deficits in amyloid beta((1-40)) rat model of Alzheimer’s disease. Neurobiol Learn Mem 3:270–276CrossRefGoogle Scholar
  4. Barnes CA, Meltzer J, Houston F, Orr G, Mcgann K, Wenk GL (2000) Chronic treatment of old rats with donepezil or galantamine: effects on memory, hippocampal plasticity and nicotinic receptors. Neuroscience 99:17–23PubMedCrossRefGoogle Scholar
  5. Beauchamp C, Fridovich I (1971) Superoxide dismutase: improved assays and an assay applicable to acrylamide gels. Anal Biochem 44:276–287PubMedCrossRefGoogle Scholar
  6. Bocarsly ME, Barson JR, Hauca JM, Hoebel BG, Leibowitz SF, Avena NM (2012) Effects of perinatal exposure to palatable diets on body weight and sensitivity to drugs of abuse in rats. Physiol Behav 107:568–575PubMedCentralPubMedCrossRefGoogle Scholar
  7. Butterfield DA, Abdul HM, Newman S, Reed T (2006) Redox proteomics in some age-related neurodegenerative disorders or models thereof. Neuro Rx 3:344–357CrossRefGoogle Scholar
  8. Cabalas-Picot I, Nicole A, Clement M, Bourke J, Signet P (1992) Age-related changes in antioxidant enzymes and lipid peroxidation in brains of control and transgenic mice overexpressing copper–zinc superoxide dismutase. Mutat Res 275:281–293CrossRefGoogle Scholar
  9. Cerejeira J, Batista P, Nogueira V, Firmino H, vaz-Serra A, Mukaetova-ladinska EB (2011) Low preoperative plasma cholinesterase activity as a risk marker of postoperative delirium in elderly patients. Age Ageing 40:621–626PubMedCrossRefGoogle Scholar
  10. Chidambara Murthy KN, Jayaprakasha GK, Singh RP (2002) Studies on antioxidant activity of pomegranate (Punicagranatum) peel extract using in vivo models. J Agric Food Chem 50:4791–4795PubMedCrossRefGoogle Scholar
  11. Chow CK, Tappel AL (1972) An enzymatic protective mechanism against lipid peroxidation damage to lungs of ozone-exposed rats. Lipids 7:518–524PubMedCrossRefGoogle Scholar
  12. Cohen BM, Renshaw PF, Stoll AL, Wurtman RJ, Yurgelun-Todd D, Babb SM (1995) Decreased choline uptake in older adults: and in vivo proton magnetic resonance spectroscopy study. JAMA 274:902–907PubMedCrossRefGoogle Scholar
  13. Das A, Dikshit M, Nath C (2001) Profile of acetylcholine esterase in brain areas of male and female rats of adult and old age. Life Sci 68:1545–1555PubMedCrossRefGoogle Scholar
  14. Dias CP, De Lima MN, Torres JP, Dormelles A, Garcia VA, Scalco F, Guimarães M, Constantino L, Budni P, Dal-Pizzol F, Schöder N (2007) Memantine reduces oxidative damage and enhances long-term recognition memory in aged rats. Neuroscience 146:1719–1725CrossRefGoogle Scholar
  15. Dringen R (2000) Metabolism and functions of glutathione in brain. Prog Neurobiol 62:649–671PubMedCrossRefGoogle Scholar
  16. Ellman GL, Courtney KD, Andres V, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholine esterase activity. Biochem Pharmacol 7:88–95PubMedCrossRefGoogle Scholar
  17. Enciu AM, Gherghiceanu M, Popescu BO (2013) Triggers and effectors of oxidative stress at blood–brain barrier level: relevance for brain ageing and neurodegeneration. Oxidative Med Cell Longev, 297512. doi: 10.1155/2013/297512.
  18. Fisher-Wellman K, Bell HK, Bloomer RJ (2009) Oxidative stress and antioxidant defense mechanisms linked to exercise during cardiopulmonary and metabolic disorders. Oxidative Med Cell Longev 2:43–51CrossRefGoogle Scholar
  19. Flohe L, Gunzler WA (1984) Assays of glutathione peroxidase. Methods Enzymol 105:114–121PubMedCrossRefGoogle Scholar
  20. Garcıa-Ayllon M-S, Riba-Llena I, Serra-Basante C, Alom J, Boopathy R, Saez-Valero J (2010) Altered levels of acetylcholinesterase in alzheimer plasma. PLoS ONE 14:e8701CrossRefGoogle Scholar
  21. Gorini A, Ghingini B, Villa RF (1996) Acetylcholinesterase activity of synaptic plasma membranes during aging: effect of l-acetylcarnitine. Dementia 7:147–154PubMedGoogle Scholar
  22. Haider S, Khaliq S, Ahmed SP, Haleem DJ (2006) Long-term tryptophan administration enhances cognitive performance and increases 5HT metabolism in the hippocampus of female rats. Amino Acids 31:421–425PubMedCrossRefGoogle Scholar
  23. Haider S, Khaliq S, Haleem DJ (2007) Enhanced serotonergic neurotransmission in the hippocampus following tryptophan administration improves learning acquisition and memory consolidation in rats. Pharmacol Rep 59:53–57PubMedGoogle Scholar
  24. Haider S, Tabassum S, Ali S, Saleem S, Khan AK, Haleem DJ (2011) Age-related decreases in striatal DA produces cognitive deficits in male rats. J Pharmacol Nutri Sci 1:20–27CrossRefGoogle Scholar
  25. Haider S, Khaliq S, Tabassum S, Haleem DJ (2012a) Role of Somatodendritic and postsynaptic 5-HT1A receptors on learning and memory functions in rats. Neurochem Res 37:2161–2166PubMedCrossRefGoogle Scholar
  26. Haider S, Naqvi F, Batool Z, Tabassum S, Perveen T, Saleem S, Haleem DJ (2012b) Decreased hippocampal 5-HT and DA levels following sub-chronic exposure to noise stress: impairment in both spatial and recognition memory in male rats. Sci Pharm 80:1001–1011PubMedCentralPubMedCrossRefGoogle Scholar
  27. Hald A, Lotharius J (2005) Oxidative stress and inflammation in Parkinson’s disease: is there a causal link? Exp Neurol 193:279–290PubMedCrossRefGoogle Scholar
  28. Hegazy HG, Ali EHA (2011) Modulation of monoamines and neurotransmitters in cerebral cortex and hippocampus of female senile rats by ginger and lipoic acid. Afr J Pharm Pharmacol 5:1080–1085Google Scholar
  29. Husain K, Somani SM (1998) Interaction of exercise training and chronic ethanol ingestion on testicular antioxidant system in rat. J Appl Toxicol 18:421–429PubMedCrossRefGoogle Scholar
  30. Hussain AM, Mitra AK (2000) Effect of aging on tryptophan hydroxylase in rat brain: implications on serotonin level. Drug Metab Dispos 28:1038–1042PubMedGoogle Scholar
  31. Jha R, Rizvi SI (2009) Age-dependent decline in erythrocyte acetylcholine esterase activity: correlation with oxidative stress. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 153:195–198PubMedCrossRefGoogle Scholar
  32. Kingsley M, Cunningham D, Mason L, Kilduff LP, McEneny J (2009) Role of creatine supplementation on exercise-induced cardiovascular function and oxidative stress. Oxidative Med Cell Longev 2:247–254CrossRefGoogle Scholar
  33. Koprowska M, Krotewicz M, Romaniuk A, Strzelczuk M (2004) Age-related changes in fear behavior and regional brain monoamines distribution in rats. Acta Neurobiol Exp (Wars) 64:131–142Google Scholar
  34. Lee CH, Hwang IK, Choi JH, Yoo K, Park OK, Huh S, Lee YL, Shin H, Won M (2010) Age-dependent changes in calretinini and its protein level in the gerbil hippocampus. Neurochem Res 35:122–129PubMedCrossRefGoogle Scholar
  35. Leutner S, Eckert A, Muller WE (2001) ROS generation, lipid peroxidation and antioxidant enzyme activities in the aging brain. J Neural Transm 108:955–967PubMedCrossRefGoogle Scholar
  36. Luine V, Bowling D, Hearns M (1990) Spatial memory deficits in aged rats: contributions of the cholinergic system assessed by ChAT. Brain Res 523:321–324PubMedCrossRefGoogle Scholar
  37. Mattson M, Maudsleey S, Martin B (2004) BDNF and 5-HT; a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci 27:589–594PubMedCrossRefGoogle Scholar
  38. Meneses A (1999) 5-HT system and cognition. Neurosci Biobehav Rev 23:1111–1125PubMedCrossRefGoogle Scholar
  39. Míguez JM, Aldegunde M, Paz-Valiñas L, Recio J, Sánchez-Barceló E (1999) Selective changes in the contents of noradrenaline, dopamine and serotonin in rat brain areas during aging. J Neural Transm 106:1089–1098Google Scholar
  40. Milic VD, Stankov K, Injac R, Djordjevic A, Srdjenovic B, Govedarica B (2009) Activity of antioxidative enzymes in erythrocytes after a single dose administration of doxorubicin in rats pretreated with fullerenol C(60)(OH)(24). Toxicol Mech Methods 19:24–28PubMedCrossRefGoogle Scholar
  41. Molochkina EM, Zorina OM, Fatkullina LD, Goloschapov AN, Burlakova EB (2005) H2O2 modifies membrane structure and activity of acetylcholine esterase. Chem Biol Interact 157:401–404PubMedCrossRefGoogle Scholar
  42. Montine TJ, Neely MD, Quinn JF, Beal MF, Markesbery WR, Roberts LJ (2002) Lipid peroxidation in aging brain and alzheimer's disease. Free Radic Biochem Med 33:620–626CrossRefGoogle Scholar
  43. Morgan DG, May PC (1990) Age-related changes in synaptic neurochemistry. In: Schneider EL, Rowe JW (eds) Handbook of the biology of aging. Academic Press, New York, pp 219–254Google Scholar
  44. Morris RG (1981) Spatial localization does not depend on the presence of local cues. Learn Motiv 12:239–260CrossRefGoogle Scholar
  45. Navarro A, Gomez C, Lopez-Cepero JM, Boveris A (2004) Beneficial effects of moderate exercise on mice aging: survival, behavior, oxidative stress, and mitochondrial electron transfer. Am J Physiol 286:505–511Google Scholar
  46. Nicolle MM, Gonzalez J, Sugaya K, Baskerville KA, Bryan D, Lund K (2001) Signatures of hippocampal oxidative stress in aged spatial learning-impaired rodents. Neuroscience 107:415–431PubMedCrossRefGoogle Scholar
  47. Ohashi S, Matsumoto M, Otani H, Mori K, Togashi H, Ueno KI, Kaku A, Yoshiokaa M (2002) Changes in synaptic plasticity in the rat hippocampo-medial prefrontal cortex pathway induced by repeated treatments with fluvoxamine. Brain Res 949:131–138PubMedCrossRefGoogle Scholar
  48. Okuda S, Roozendaal B, McGaugh LJ (2004) Glucocorticoid effects on object recognition memory requires training-associated emotional arousal. PNAS 101:853–858PubMedCentralPubMedCrossRefGoogle Scholar
  49. Pandey KB, Rizvi SI (2010) Markers of oxidative stress in erythrocytes and plasma during aging in humans. Oxidative Med Cell Longev 3:2–12CrossRefGoogle Scholar
  50. Papandreou MA, Dimakopoulou A, Linardaki ZI, Cordopatis P, Klimis-Zacas D, Margarity M (2009) Effect of a polyphenol-rich wild blueberry extract on cognitive performance of mice, brain antioxidant markers and acetylcholine esterase activity. Behav Brain Res 198:352–358PubMedCrossRefGoogle Scholar
  51. Papandreou MA, Tsachaki M, Efthimiopoulos S, Cordopatis P, Lamari FN, Margarity M (2011) Memory enhancing effects of saffron in aged mice are correlated with antioxidant protection. Behav Brain Res 219:197–204PubMedCrossRefGoogle Scholar
  52. Peters R (2006) Ageing and the brain. Postgrad Med J 82:84–88PubMedCentralPubMedCrossRefGoogle Scholar
  53. Reddy (2006) Amyloid precursor protein-mediated free radicals and oxidative damage: implications for the development and progression of alzheimer's disease. J Neurochem 96:1–13PubMedCrossRefGoogle Scholar
  54. Rizvi SI, Maurya PK (2007) Markers of oxidative stress in erythrocytes during aging in humans. Ann N Y Acad Sci 1100:373–382PubMedCrossRefGoogle Scholar
  55. Scandalios JG (2005) Oxidative stress: molecular perception and transduction of signals triggering antioxidant gene defenses. Br J Med Biol Res 38:995–1014CrossRefGoogle Scholar
  56. Schmitt JA, Wingen M, Ramaekers JG, Evers EA, Riedel WJ (2006) Serotonin and human cognitive performance. Curr Pharm Des 12:2473–2486PubMedCrossRefGoogle Scholar
  57. Shen ZX (1996) The significance of the activity of CSF cholinesterases in dementias. Med Hypotheses 47:363–376PubMedCrossRefGoogle Scholar
  58. Sigueira IR, Fochesatto C, Lucena da Silva Torres I, Dalmaz C, Netto CA (2005) Aging affects oxidative state in hippocampus, hypothalamus and adrenal glands of Wistar rats. Life Sci 78:271–278CrossRefGoogle Scholar
  59. Singh K, Kaur S, Kumari K, Singh G, Kaur A (2009) Alterations in lipid peroxidation and certain antioxidant enzymes in different age groups under physiological conditions. J Hum Ecol 27(2):143–147Google Scholar
  60. Sinha AK (1972) Colorimetric assay of catalase. Anal Biochem 47:389–394PubMedCrossRefGoogle Scholar
  61. Smith CD, Carnry JM, Starke-Reed PE, Oliver CN, Stadtman ER, Floyd RA, Markesbery WR (1991) Excess brain protein oxidation and enzyme dysfunction in normal aging and in alzheimer disease. Proc Natl Acad Sci U S A 88:10540–10543PubMedCentralPubMedCrossRefGoogle Scholar
  62. Starke-Reed PE, Oliver CN (1989) Protein oxidation and proteolysis during aging and oxidative stress. Arch Biochem Biophys 275:559–567PubMedCrossRefGoogle Scholar
  63. Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, Liu G, Tsien JZ (1999) Genetic enhancement of learning and memory in mice. Nature 401:63–69Google Scholar
  64. Tchantchou F, Chan A, Kifle L, Ortiz D, Shea TB (2005) Apple juice concentrate prevents oxidative damage and impaired maze performance in aged mice. J Alzheimers Dis 8:283–287PubMedGoogle Scholar
  65. Terry AV Jr, Buccafusco JJ (2003) The cholinergic hypothesis of age and alzheimer’s disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther 306:821–827PubMedCrossRefGoogle Scholar
  66. Tian L, Cai Q, Wei H (1998) Alterations of antioxidant enzymes and oxidative damage to macromolecules in different organs of rats during aging. Free Radic Biol Med 24:1477–1484PubMedCrossRefGoogle Scholar
  67. Tsunemi A, Utsuyama M, Seidler BK, Kobayashi S, Hirokawa K (2005) Age-related decline of brain monoamines in mice is reversed to young level by Japanese herbal medicine. Neurochem Res 30:75–81PubMedCrossRefGoogle Scholar
  68. Venero JL, Machado A, Cano J (1991) Turnover of dopamine and serotonin and their metabolites in the striatum of aged rats. J Neurochem 56:1940–1948PubMedCrossRefGoogle Scholar
  69. Volkow ND, Gur RC, Wang GJ, Fowler JS, Moberg PJ, Ding YS, Hitzemann R, Smith G, Logan J (1998) Association between decline in brain dopamine activity with age and cognitive and motor impairment in healthy individuals. Am J Psychiatry 155:344–349PubMedGoogle Scholar
  70. Zhang X (2004) Cholinergic activity and amyloid precursor protein processing in aging and Alzheimer's disease. Curr Drug Targets CNS Neurol Disord 3:137–152PubMedCrossRefGoogle Scholar

Copyright information

© American Aging Association 2014

Authors and Affiliations

  • Saida Haider
    • 1
  • Sadia Saleem
    • 1
  • Tahira Perveen
    • 1
  • Saiqa Tabassum
    • 1
  • Zehra Batool
    • 1
  • Sadia Sadir
    • 1
  • Laraib Liaquat
    • 1
  • Syeda Madiha
    • 1
  1. 1.Neurochemistry and Biochemical Neuropharmacology Research Unit, Department of BiochemistryUniversity of KarachiKarachiPakistan

Personalised recommendations