Effect of chronic administration of arachidonic acid on the performance of learning and memory in aged rats

  • Takayuki Inoue
  • Michio Hashimoto
  • Masanori Katakura
  • Shahdat Hossain
  • Kentaro Matsuzaki
  • Osamu Shido
Keywords: arachidonic acid; spatial learning, senescent, reference and working memory, radial maze.


Background: Arachidonic acid (AA, C20:4, ω-6) is a ω-6 polyunsaturated fatty acid (PUFA) and plays diverse roles in cell signaling. Numerous reports on the effects of ω-3 PUFAs, such as docosahexaenoic acid (DHA, C22:6, ω-3) and eicosapentaenoic acid (EPA, C20:5, ω-3) on learning and memory impairments of rats are available, however, the role of AA on brain cognition is largely unknown.

Objective: In this study, our aim was to investigate the effect of oral administration of AA on spatial memory- related learning ability in aged (100 weeks) male rats.

Design: One group was per orally administered 240 mg/kg per day AA oil and the other group was administered the similar volume of control oil. Five weeks after the start of the administration, rats were tested with the partially baited eight-arm radial maze to evaluate two types of spatial memory-related learning ability displayed by reference memory errors (RMEs) and working memory errors (WMEs). Also, the time required to complete the task was recorded. The levels of lipid peroxide (LPO) and reactive oxygen species (ROS) were measured, as an indicator oxidative stress in the plasma and brain corticohippocampal brain tissues.

Results: The scores of RMEs and WMEs, which are analogous to long-term and short-term memory, respectively, were not affected, however, the trial time was shorter in the AA-administered rats than that of the controls. AA also significantly increased the degree of oxidative stress both in the plasma and corticohippocampal brain tissues.

Conclusions: Our results suggest that though AA deposition in the corticohippocampal tissues of senescent rats caused a faster performance activity, which is reminiscent to hyperactive behavior of animals, the spatial learning ability-related memory of the rats, however, was not improved.


Download data is not yet available.


  1. Li D, Ng A, Mann NJ, Sinclair AJ. Contribution of meat fat to dietary arachidonic acid. Lipids 1998; 33: 437–40. doi: 10.1007/s11745-998-0225-7

  2. Hashimoto M, Hossain S, Shimada T, Sugioka K, Yamasaki H, Fujii Y, et al. Docosahexaenoic acid provides protection from impairment of learning ability in Alzheimer's disease model rats. J Neurochem 2002; 81: 1084–91. doi: 10.1046/j.1471-4159.2002.00905.x

  3. Smith GI, Atherton P, Reeds DN, Mohammed BS, Rankin D, Rennie MJ, et al. Omega-3 polyunsaturated fatty acids augment the muscle protein anabolic response to hyperinsulinaemia-hyperaminoacidaemia in healthy young and middle-aged men and women. Clin Sci (Lond) 2011; 121: 267–78. doi: 10.1042/CS20100597

  4. Le HD, Meisel JA, de Meijer VE, Gura KM, Puder M. The essentiality of arachidonic acid and docosahexaenoic acid. Prostaglandins Leukot Essent Fatty Acids 2009; 81: 165–70. doi: 10.1016/j.plefa.2009.05.020

  5. Hadley KB, Ryan AS, Forsyth S, Gautier S, Salem N. The essentiality of arachidonic acid in infant development. Nutrients 2016; 8: 216. doi: 10.3390/nu8040216

  6. Burke PA, Ling PR, Forse RA, Bistrian BR. Conditionally essential fatty acid deficiencies in end-stage liver disease. Nutrition 1999; 15: 302–4. doi: 10.1016/S0899-9007(99)00002-7

  7. Harrison JL, Rowe RK, Lifshitz J. Lipid mediators of inflammation in neurological injury: shifting the balance toward resolution. Neural Regen Res 2016; 11: 77–8. doi: 10.4103/1673-5374.175046

  8. Samuelsson B, Dahlén SE, Lindgren JA, Rouzer CA, Serhan CN. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science 1987; 237: 1171–6. doi: 10.1126/science.2820055

  9. Kam PC, See AU. Cyclo-oxygenase isoenzymes: physiological and pharmacological role. Anaesthesia 2000; 55: 442–9. doi: 10.1046/j.1365-2044.2000.01271.x

  10. Katori M, Majima M. Cyclooxygenase-2: its rich diversity of roles and possible application of its selective inhibitors. Inflamm Res 2000; 49: 367–92. doi: 10.1007/s000110050605

  11. Kinsella JE, Broughton KS, Whelan JW. Dietary unsaturated fatty acids: interactions and possible needs in relation to eicosanoid synthesis. J Nutr Biochem 1990; 1: 123–41. doi: 10.1016/0955-2863(90)90011-9

  12. Calder PC. Polyunsaturated fatty acids and inflammatory processes: new twists in an old tale. Biochimie 2009; 91: 791–5. doi: 10.1016/j.biochi.2009.01.008

  13. Cheng Y, Austin SC, Rocca B, Koller BH, Coffman TM, Grosser T, et al. Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 2002; 296: 539–41. doi: 10.1126/science.1068711

  14. Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest 2006; 116: 4–15. doi: 10.1172/JCI27291

  15. Arehart E, Gleim S, Kasza Z, Fetalvero KM, Martin KA, Hwa J. Prostacyclin, atherothrombosis, and cardiovascular disease. Curr Med Chem 2007; 14: 2161–9. doi: 10.2174/092986707781389637

  16. Roberts MD, Iosia M, Kerksick CM, Taylor LW, Campbell B, Wilborn CD, et al. Effects of arachidonic acid supplementation on training adaptations in resistance-trained males. J Int Soc Sports Nutr 2007; 4: 21. doi: 10.1186/1550-2783-4-21

  17. Borkman M, Storlien LH, Pan DA, Jenkins AB, Chisholm DJ, Campbell LV. The relation between insulin sensitivity and the fatty-acid composition of skeletal-muscle phospholipids. N Engl J Med 1993; 328: 238–44. doi: 10.1056/NEJM199301283280404

  18. Matsumoto Y, Yamaguchi T, Watanabe S, Yamamoto T. Involvement of arachidonic acid cascade in working memory impairment induced by interleukin-1 beta. Neuropharmacology 2004; 46: 1195–200. doi: 10.1016/j.neuropharm.2004.02.012

  19. Kotani S, Nakazawa H, Tokimasa T, Akimoto K, Kawashima H, Toyoda-Ono Y, et al. Synaptic plasticity preserved with arachidonic acid diet in aged rats. Neurosci Res 2003; 46: 453–61. doi: 10.1016/S0168-0102(03)00123-8

  20. Li C, Wang Q, Li L, Liu Y, Diao H. Arachidonic acid attenuates learning and memory dysfunction induced by repeated isoflurane anesthesia in rats. Int J Clin Exp Med 2015; 8: 12365–73. www.ijcem.com/ISSN:1940-5901/IJCEM0010535

  21. Barnes JN. Exercise, cognitive function, and aging. Adv Physiol Educ 2015; 39: 55–62. doi: 10.1152/advan.00101.2014

  22. McGahon B, Clements MP, Lynch MA. The ability of aged rats to sustain long-term potentiation is restored when the age-related decrease in membrane arachidonic acid concentration is reversed. Neuroscience 1997; 81: 9–16. doi: 10.1016/S0306-4522(97)00116-4

  23. Murray CA, Lynch MA. Evidence that increased hippocampal expression of the cytokine interleukin-1 beta is a common trigger for age- and stress-induced impairments in long-term potentiation. J Neurosci 1998; 18: 2974–81. doi: 10.1523/JNEUROSCI.18-08-02974.1998

  24. Gamoh S, Hashimoto M, Sugioka K, Shahdat Hossain M, Hata N, Misawa Y, et al. Chronic administration of docosahexaenoic acid improves reference memory-related learning ability in young rats. Neuroscience 1999; 93: 237–41. 24. doi: 10.1016/S0306-4522(99)00107-4

  25. Gamoh S, Hashimoto M, Hossain S, Masumura S. Chronic administration of docosahexaenoic acid improves the performance of radial arm maze task in aged rats. Clin Exp Pharmacol Physiol 2001; 28: 266–70. doi: 10.1046/j.1440-1681.2001.03437.x

  26. Hashimoto M, Tanabe Y, Fujii Y, Kikuta T, Shibata H, Shido O. Chronic administration of docosahexaenoic acid ameliorates the impairment of spatial cognition learning ability in amyloid beta-infused rats. J Nutr 2005; 135: 549–55. doi: 10.1093/jn/135.3.549

  27. Hashimoto M, Tozawa R, Katakura M, Shahdat H, Haque AM, Tanabe Y, et al. Protective effects of prescription n-3 fatty acids against impairment of spatial cognitive learning ability in amyloid β-infused rats. Food Funct 2011; 2: 386–94. doi: 10.1039/c1fo00002k

  28. Katakura M, Hashimoto M, Inoue T, Mamun AA, Tanabe Y, Arita M, et al. Chronic arachidonic acid administration decreases docosahexaenoic acid- and eicosapentaenoic acid-derived metabolites in kidneys of aged Rats. PLoS One 2015; 10: e0140884. doi: 10.1371/journal.pone.0140884

  29. Hashimoto M, Inoue T, Katakura M, Hossain S, Mamun AA, Matsuzaki K, et al. Differential effects of docoosahexaenoic and arachidonic acid on fatty acid composition and myosin heavy chain-related genes of slow- and fast-twitch skeletal muscle tissues. Mol Cell Biochem 2016; 415: 169–81. doi: 10.1007/s11010-016-2689-y

  30. Lowry OH, Rosenberg NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193: 265–75. PMID: 14907713

  31. Lepage G, Roy CC. Direct transesterification of all classes of lipids in a one-step reaction. J Lipid Res 1986; 27: 114–20. PMID: 3958609

  32. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95: 351–8. doi: 10.1016/0003-2697(79)90738-3

  33. Okaichi Y, Ishikura Y, Akimoto K, Kawashima H, Toyoda-Ono Y, Kiso Y, et al. Arachidonic acid improves aged rats' spatial cognition. Physiol Behav 2005; 84: 617–23. doi: 10.1016/0003-2697(79)90738-3

  34. Coffey ET, Herrero I, Sihra TS, Sánchez-Prieto J, Nicholls DG. Glutamate exocytosis and MARCKS phosphorylation are enhanced by a metabotropic glutamate receptor coupled to a protein kinase C synergistically activated by diacylglycerol and arachidonic acid. J Neurochem 1994; 63: 1303–10. doi: 10.1046/j.1471-4159.1994.63041303.x

  35. Thomas MH, Pelleieux S, Vitale N, Olivier JL. Dietary arachidonic acid as a risk factor for age-associated neurodegenerative diseases: potential mechanisms. Biochimie 2016; 130: 168–77. doi: 10.1016/j.biochi.2016.07.013

  36. Dickson DW. The pathogenesis of senile plaques. J Neuropathol Exp Neurol 1997; 56(4): 321–39. PMID:9100663

  37. Cheng X, Yang L, He P, Li R, Shen Y. Differential activation of tumor necrosis factor receptors distinguishes between brains from Alzheimer's disease and non-demented patients. J Alzheimers Dis 2010; 19(2): 621–30. doi: 10.3233/JAD-2010-1253

  38. Janelsins MC, Mastrangelo MA, Park KM, Sudol KL, Narrow WC, Oddo S, et al. Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice. Am J Pathol 2008; 173(6): 1768–82. doi: 10.2353/ajpath.2008.080528

  39. Pyo H, Jou I, Jung S, Hong S, Joe EH. Mitogen-activated protein kinases activated by lipopolysaccharide and beta-amyloid in cultured rat microglia. Neuroreport 1998; 9(5): 871–4. PMID: 9579682

  40. Lue LF, Walker DG, Rogers J. Modeling microglial activation in Alzheimer’s disease with human postmortem microglial cultures. Neurobiol Aging 2001; 22(6): 945–56. doi: 10.1016/S0197-4580(01)00311-6

  41. Rao JS, Rapoport S, Kim HW. Altered neuroinflammatory, arachidonic acid cascade and synaptic markers in postmortem Alzheimer's disease brain. Transl Psychiatry 2017; 7(5): e1127. doi: 10.1038/tp.2017.97.

  42. Chang R, Yee K-L, Sumbria RK. Tumor necrosis factor α Inhibition for Alzheimer’s Disease. J Cent Nerv Syst Dis 2017; 9: 1179573517709278. doi: 10.1177/1179573517709278

  43. Tokuda H, Kontani M, Kawashima H, Akimoto K, Kusumoto A, Kiso Y, et al. Arachidonic acid-enriched triacylglycerol improves cognitive function in elderly with low serum levels of arachidonic acid. J Oleo Sci 2014; 63: 219–27. doi: 10.5650/jos.ess13195

  44. Lynch MA, Errington ML, Bliss TV. Nordihydroguaiaretic acid blocks the synaptic component of long-term potentiation and the associated increases in release of glutamate and arachidonate: an in vivo study in the dentate gyrus of the rat. Neuroscience 1989; 30: 693–701. doi: 10.1016/0306-4522(89)90162-0

  45. Amamoto T, Okada M, Kawachi A, Nakanishi H, Yazawa K, Fujiwara M, et al. [Relationship between hippocampal arachidonic acid content and induction of LTP in aged rats]. Nihon Shinkei Seishin Yakurigaku Zasshi 1999; 19: 273–7. PMID:10803212

  46. Murray CA, Lynch MA. Dietary supplementation with vitamin E reverses the age-related deficit in long term potentiation in dentate gyrus. J Biol Chem 1998; 273: 12161–8. doi: 10.1074/jbc.273.20.12161

How to Cite
Inoue T, Hashimoto M, Katakura M, Hossain S, Matsuzaki K, Shido O. Effect of chronic administration of arachidonic acid on the performance of learning and memory in aged rats. fnr [Internet]. 2019Mar.25 [cited 2019Apr.23];630. Available from: https://foodandnutritionresearch.net/index.php/fnr/article/view/1441
Original Articles