Effects of Peripheral and Intra-hippocampal Administration of Sodium Salicylate on Spatial Learning and Memory of Rats

Document Type: Original Article


1 Department of Physiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran

2 Department of Neuroscience, School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran, Iran

3 Student of Information Technology, Kermanshah University of Technology, Kermanshah, Iran


Cyclooxygenases  (COXs) are known to play some roles in physiological mechanisms related to learning and memory. Since sodium salicylate is an inhibitor of COX, we have evaluated the effect of peripheral and intra-hippocampal administration of sodium salicylate on spatial learning and memory in male rats.
Materials and Methods
Male rats were studied in two groups; the first group received different intraperitoneal (i.p.) sodium salicylate doses (0, 200, 300, and 400 mg/kg) and the second group received intra-hippocampal doses of the drug (0, 30, 50, and 100 μg/0.5 μl/side). The spatial performance of rats was tested using Morris water maze (MWM) task. The spatial learning and memory parameters were analyzed using ANOVA.
Peripheral and intra-hippocampal administration of sodium salicylate did not lead to a statistically significant change in the mean time (escape latency), and also the distance traveled for finding the hidden platform during the training days, compared with the control group. But at the probe trial, the percentage of time spent in the target quadrant by rats which received the highest doses of drug significantly increased.
We found that both peripheral and intra-hippocampal administration of sodium salicylate facilitates the process of spatial memory consolidation in the MWM.


1. Turini ME, DuBois RN. Cyclooxygenase-2: a therapeutic target. Annu Rev Med  2002; 53: 35-57.

2. Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 1998; 38:97-120.

3. DeWitt DL, Smith WL. Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence. Proc Natl Acad Sci USA 1988; 85: 1412-1416.

4. Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem 1991; 266:12866-12872.

5. Herschman HR. Prostaglandin synthase 2. Biochim Biophys Acta 1996; 1299:125-140.

6. Smith WL, Marnett LJ, DeWitt DL. Prostaglandin and thromboxane biosynthesis. Pharmacol Ther 1991; 49:153-179.

7. Murray HJ, O'Connor JJ. A role for COX-2 and p38 mitogen activated protein kinase in long-term depression in the rat dentate gyrus in vitro. Neuropharmacology 2003; 44:374-380.

8. Yamagata K, Andreasson KI, Kaufmann WE, Barnes CA, Worley PF. Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 1993; 11:371-386.

9. Rall JM, Mach SA, Dash PK. Intrahippocampal infusion of a cyclooxygenase-2 inhibitor attenuates memory acquisition in rats. Brain Res 2003; 968:273-276.

10. Katzung BG. Basic and clinical pharmacology. 8th ed. McGraw – Hill: Appleton & Lang; 2000.

11. Leroux P, Hennebert C, Catteau J, Legros H, Hennebert O, Laudenbach V, et al. Neuroprotective effects vary across nonsteroidal antiinflammatory drugs in a mouse model of developing excitotoxic brain injury. Neuroscience 2010; 167:716-723.

12. Amann R, Peskar BA. Anti-inflammatory effects of aspirin and sodium salicylate. Eur J Pharmacol 2002; 447:1-9.

13. De Cristóbal J, Cárdenas A, Lizasoain I, Leza JC, Fernández-Tomé P, Lorenzo P, et al. Inhibition of glutamate release via recovery of ATP levels accounts for a neuroprotective effect of aspirin in rat cortical neurons exposed to oxygen-glucose deprivation. Stroke 2002; 33:261-267.

14. Castillo J, Leira R, Moro MA, Lizasoain I, Serena J, Dávalos A. Neuroprotective effects of aspirin in patients with acute cerebral infarction. Neurosci Lett  2003; 339:248-250.

15. Guitton MJ, Caston J, Ruel J, Johnson RM, Pujol R, Puel JL. Salicylate induces tinnitus through activation of cochlear NMDA receptors. J Neurosci 2003; 23: 3944-3952.

16. Liu Y, Li X, Ma C, Liu J, Lu H. Salicylate blocks L-type calcium channels in rat inferior colliculus neurons. Hear Res 2005; 205: 271-276.

17. Liu Y, Li X. Effects of salicylate on voltage-gated sodium channels in rat inferior colliculus neurons. Hear Res 2004; 193: 68-74.

18. Kaufmann WE, Worley PF, Pegg J, Bremer M, Isakson P. COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci USA 1996; 93: 2317-2321.

19. Hölscher C. Inhibitors of cyclooxygenases produce amnesia for a passive avoidance task in the chick. Eur J Neurosci 1995; 7: 1360-1365.

20. Kunz T, Oliw EH. The selective cyclooxygenase-2 inhibitor rofecoxib reduces kainate-induced cell death in the rat hippocampus. Eur J Neurosci 2001; 13: 569-575.

21. Mesches MH, Gemma C, Veng LM, Allgeier C, Young DA, Browning MD, et al. Sulindac improves memory and increases NMDA receptor subunits in aged Fischer 344 rats. Neurobiol Aging  2004; 25:315-324.

22. Yermakova AV, O'Banion MK. Down regulation of neuronal cyclooxygenase-2 expression in end stage Alzheimer's disease. Neurobiol Aging  2001; 22:823-836.

23. Jonker C, Comijs HC, Smit JH. Does aspirin or other NSAIDs reduce the risk of cognitive decline in elderly persons? Results from a population-based study. Neurobiol Aging  2003; 24: 583-588.

24. Jain NK, Patil CS, Kulkarni SK, Singh A. Modulatory role of cyclooxygenase inhibitors in aging- and scopolamine or lipopolysaccharide-induced cognitive dysfunction in mice. Behav Brain Res  2002; 133:369-376.

25. Rao SK, Andrade C, Reddy K, Madappa KN, Thyagarajan S, Chandra S. Memory protective effect of indomethacin against electroconvulsive shock-induced retrograde amnesia in rats. Biol Psychiatry 2002; 51:770-773.

26. Bruce-Jones PN, Crome P, Kalra L. Indomethacin and cognitive function in healthy elderly volunteers. Br J Clin Pharmacol 1994; 38:45-51.

27. Baker KB, Kim JJ. Effects of stress and hippocampal NMDA receptor antagonism on recognition memory in rats. Learn Mem 2002; 9:58-65.

28. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. New York: Academic press; 1986.

29. Pourmotabbed A, Nedaei SE, Cheraghi M, Moradian S, Touhidi A, Aeinfar M, et al. Effect of prenatal pentylenetetrazol-induced kindling on learning and memory of male offspring. Neuroscience 2011; 172:205-211.

 30. Li RC, Row BW, Gozal E, Kheirandish L, Fan Q, Brittian KR, et al. Cyclooxygenase 2 and intermittent hypoxia-induced spatial deficits in the rat. Am J Respir Crit Care Med 2003; 168:469-475.

31. Teather LA, Packard MG, Bazan NG. Post-training cyclooxygenase-2 (COX-2) inhibition impairs memory consolidation. Learn Mem 2002; 9: 41-47.

32. Kimura H, Okamoto K, Sakai Y. Modulatory effects of prostaglandin D2, E2 and F2 alpha on the postsynaptic actions of inhibitory and excitatory amino acids in cerebellar Purkinje cell dendrites in vitro. Brain Res 1985; 33:235-244.

33. Partington CR, Edwards MW, Daly JW. Regulation of cyclic AMP formation in brain tissue by alpha-adrenergic receptors: requisite intermediacy of prostaglandins of the E series. Proc Natl Acad Sci USA  1980; 77:3024-3028.

34. Dumuis A, Sebben M, Haynes L, Pin JP, Bockaert J. NMDA receptors activate the arachidonic acid cascade system in striatal neurons. Nature 1988; 336:68-70.

35. Coleman RA, Smith WL, Narumiya S. International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol Rev 1994; 46:205-229.

36. McGaugh JL. Dissociating learning and performance: drug and hormone enhancement of memory storage. Brain Res Bull 1989; 23:339-345.

37. Breder CD, Dewitt D, Kraig RP. Characterization of inducible cyclooxygenase in rat brain. J Comp Neurol 1995; 355: 296-315.

38. Ishida T, Sato T, Irifune M, Tanaka K, Nakamura N, Nishikawa T. Effect of acetaminophen, a cyclooxygenase inhibitor, on Morris water maze task performance in mice. J Psychopharmacol 2007; 21:757-767.

39. Sharifzadeh M, Naghdi N, Khosrovani S, Ostad SN, Sharifzadeh K, Roghani A. Post-training intrahippocampal infusion of the COX-2 inhibitor celecoxib impaired spatial memory retention in rats. Eur J Pharmacol 2005; 511:159-166.

40. Ghahremani MH, Eghtesad E, Tahsili-Fahadan P, Sharifzadeh M, Amini M, Tootian Z. Inhibition of the cyclooxygenase pathway attenuates morphine-induced conditioned place preference in mice. Pharmacol Biochem Behav 2006; 85:356-361.

41. Bauer CA, Brozoski TJ, Holder TM, Caspary DM. Effects of chronic salicylate on GABAergic activity in rat inferior colliculus. Hear Res 2000; 147:175-182.

42. Gong N, Zhang M, Zhang XB, Chen L, Sun GC, Xu TL .The aspirin metabolite salicylate enhances neuronal excitation in rat hippocampal CA1 area through reducing GABAergic inhibition. Neuropharmacology 2008; 54:454-463.

43. Pernia-Andrade AJ, Tortorici V, Vanegas H. Induction of opioid tolerance by lysine-acetylsalicylate in rats. Pain  2004; 111:191-200.

44. Wang HT, Luo B, Huang YN, Zhou KQ, Chen L. Sodium salicylate suppresses serotonin-induced enhancement of GABAergic spontaneous inhibitory postsynaptic currents in rat inferior colliculus in vitro. Hear Res 2008; 236:42-51.

45. Yoshihara T, Ichitani Y. Hippocampal N-methyl-D-aspartate receptor-mediated encoding and retrieval processes in spatial working memory: delay-interposed radial maze performance in rats. Neuroscience  2004; 129:1-10.

46. Xu XM, Sansores-Garcia L, Chen XM, Matijevic-Aleksic N, Du M, Wu KK. Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate. Proc Natl Acad Sci USA  1999; 96:5292-5297.

47. Chen C, Magee JC, Bazan NG. Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic plasticity. J Neurophysiol  2002; 87:2851-2857.

48. Andreasson KI, Savonenko A, Vidensky S, Goellner JJ, Zhang Y, Shaffer A, et al. Age-dependent cognitive deficits and neuronal apoptosis in cyclooxygenase-2 transgenic mice. J Neurosci  2001; 21:8198-8209.