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Dual Effects of Aspirin on Spatial Learning and Memory of Male Rats Following Induction of Permanent Cerebral Ischemia

Document Type : Original Article

Authors

1 Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

2 Herbal and Traditional Medicines Research Center, Kerman University of Medical Sciences, Kerman, Iran

3 Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

4 Department of Anatomy, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran

5 Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

Abstract

Background: Ischemic stroke can lead to cognitive impairment, and nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to slow down the progression of Alzheimer›s disease (AD). This study focused on rodent models to investigate the impact of ischemic stroke and the potential benefits of aspirin in reducing cognitive impairment.
Methods: The Morris water maze (MWM) was used to evaluate memory and learning in seven groups (N=63) of Wistar rats. Brain ischemia was induced in rat models through temporary blocking of both common carotid arteries and permanent blocking of the middle cerebral artery (MCA). Aspirin 20, 40, and 80 mg/kg IP was administered 30 minutes and 2 hours after stroke induction in both ischemic and non-ischemic rats. Injections were continued for seven consecutive days in these groups, and learning and memory were evaluated after the last injection.
Results: Data analysis of the MWM test showed a significant increase in escape latency and swim path length to find the platform in the ischemic groups compared to control rats (P<0.005). Despite improvement in all experimental groups after intervention (P<0.001), the scores for spatial learning were significantly decreased by aspirin in no-ischemia+ASA groups compared to the control group (P<0.05). In the ischemia+ASA groups, aspirin at the dose of 20 mg/kg but not at the high dose (80 mg/kg) improved spatial learning compared to the control group.
Conclusion: Repeated treatments with aspirin may impair spatial learning and memory in normal rats, however, aspirin at a low dose of 20 mg/kg may improve learning impairment after ischemic stroke.

Keywords

Main Subjects

References
  1. Phipps MS, Cronin CA. Management of acute ischemic stroke. BMJ. 2020;368:l6983. doi: 10.1136/bmj.l6983.
  2. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al. Heart disease and stroke statistics-2020 update: a report from the American Heart Association. Circulation. 2020;141(9):e139-596. doi: 10.1161/ cir.0000000000000757.
  3. Katan M, Luft A. Global burden of stroke. Semin Neurol. 2018;38(2):208-11. doi: 10.1055/s-0038-1649503.
  4. Feigin VL, Norrving B, Mensah GA. Global burden of stroke. Circ Res. 2017;120(3):439-48. doi: 10.1161/ circresaha.116.308413.
  5. Gittins M, Lugo-Palacios D, Vail A, Bowen A, Paley L, Bray B, et al. Stroke impairment categories: a new way to classify the effects of stroke based on stroke-related impairments. Clin Rehabil. 2021;35(3):446-58. doi: 10.1177/0269215520966473.
  6. Weaver NA, Kancheva AK, Lim JS, Biesbroek JM, Wajer IM, Kang Y, et al. Post-stroke cognitive impairment on the MiniMental State Examination primarily relates to left middle cerebral artery infarcts. Int J Stroke. 2021;16(8):981-9. doi: 10.1177/1747493020984552.
  7. Nogles TE, Galuska MA. Middle cerebral artery stroke. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2025.
  8. Gao BY, Sun CC, Xia GH, Zhou ST, Zhang Y, Mao YR, et al. Paired associated magnetic stimulation promotes neural repair in the rat middle cerebral artery occlusion model of stroke. Neural Regen Res. 2020;15(11):2047-56. doi: 10.4103/1673- 5374.282266.
  9. Morris R, Armbruster K, Silva J, Widell DJ, Cheng F. The association between the usage of non-steroidal antiinflammatory drugs and cognitive status: analysis of longitudinal and cross-sectional studies from the Global Alzheimer’s Association Interactive Network and transcriptomic data. Brain Sci. 2020;10(12):961. doi: 10.3390/brainsci10120961.
  1. Smith JW, Al-Khamees O, Costall B, Naylor RJ, Smythe JW. Chronic aspirin ingestion improves spatial learning in adult and aged rats. Pharmacol Biochem Behav. 2002;71(1-2):233- 8. doi: 10.1016/s0091-3057(01)00675-x.
  2. Wong YS, Tsai CF, Hsu YH, Ong CT. Efficacy of aspirin, clopidogrel, and ticlopidine in stroke prevention: a population-based case-cohort study in Taiwan. PLoS One. 2020;15(12):e0242466. doi: 10.1371/journal.pone.0242466.
  3. Kim JT, Kim BJ, Park JM, Lee SJ, Cha JK, Park TH, et al. Risk of recurrent stroke and antiplatelet choice in breakthrough stroke while on aspirin. Sci Rep. 2020;10(1):16723. doi: 10.1038/ s41598-020-73836-0.
  4. Lau KE, Lui F. Physiology, prostaglandin I2. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2025.
  5. Morris RG, Garrud P, Rawlins JN, O’Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature. 1982;297(5868):681-3. doi: 10.1038/297681a0.
  6. Shamsara A, Sheibani V, Asadi-Shekaari M, NematollahiMahani SN. Neural like cells and acetyl-salicylic acid alter rat brain structure and function following transient middle cerebral artery occlusion. Biomol Concepts. 2018;9(1):155- 68. doi: 10.1515/bmc-2018-0014.
  7. Breitner JC. The role of anti-inflammatory drugs in the prevention and treatment of Alzheimer’s disease. Annu Rev Med. 1996;47:401-11. doi: 10.1146/annurev.med.47.1.401.
  8. Breitner JC, Gau BA, Welsh KA, Plassman BL, McDonald WM, Helms MJ, et al. Inverse association of anti-inflammatory treatments and Alzheimer’s disease: initial results of a co-twin control study. Neurology. 1994;44(2):227-32. doi: 10.1212/ wnl.44.2.227.
  9. Côté S, Carmichael PH, Verreault R, Lindsay J, Lefebvre J, Laurin D. Nonsteroidal anti-inflammatory drug use and the risk of cognitive impairment and Alzheimer’s disease. Alzheimers Dement. 2012;8(3):219-26. doi: 10.1016/j.jalz.2011.03.012.
  10. Khayyam N, Thavendiranathan P, Carmichael FJ, Kus B, Jay V, Burnham WM. Neuroprotective effects of acetylsalicylic acid in an animal model of focal brain ischemia. Neuroreport. 1999;10(2):371-4. doi: 10.1097/00001756-199902050- 00029.
  11. Shamsara A, Sheibani V, Esmaeilpour K, Eslaminejad T, Nematollahi-Mahani SN. Coadministration of the human umbilical cord matrix-derived mesenchymal cells and aspirin alters postischemic brain injury in rats. J Stroke Cerebrovasc Dis. 2015;24(9):2005-16. doi: 10.1016/j. jstrokecerebrovasdis.2015.04.049.
  12. Bazan NG, Eady TN, Khoutorova L, Atkins KD, Hong S, Lu Y, et al. Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke. Exp Neurol. 2012;236(1):122-30. doi: 10.1016/j.expneurol.2012.04.007.
  13. Pourmobini H, Afarinesh MR, Shamsara A, Eftekhar-Vaghefi SH, Asadi-Shekaari M. Chronically pre-treatment of pistachio alters the morphology of CA1 hippocampus neurons following transient focal cerebral ischemia in male Wistar rats. Acta Biomed. 2022;92(6):e2021394. doi: 10.23750/abm. v92i6.11622.
  14. Sepehri G, Parsania S, Hajzadeh MA, Haghpanah T, Sheibani V, Divsalar K, et al. The effects of co-administration of opium and morphine with nicotine during pregnancy on spatial learning and memory of adult male offspring rats. Iran J Basic Med Sci. 2014;17(9):694-701.
  15. Saberi Moghadam A, Sepehri G, Sheibani V, Haghpanah T, Divsalar K, Hajzadeh MA, et al. The effect of opium dependency of parent (s) on offspring’s spatial learning & memory in adult male rats. Iran J Basic Med Sci. 2013;16(5):694-9.
  16. Afarinesh MR, Shafiei F, Sabzalizadeh M, Haghpanah T, Taheri M, Parsania S, et al. Effect of mild and chronic neonatal hypothyroidism on sensory information processing in a rodent model: a behavioral and electrophysiological study. Brain Res Bull. 2020;155:29-36. doi: 10.1016/j. brainresbull.2019.11.015.
  17. Hunter AJ, Green AR, Cross AJ. Animal models of acute ischaemic stroke: can they predict clinically successful neuroprotective drugs? Trends Pharmacol Sci. 1995;16(4):123- 8. doi: 10.1016/s0165-6147(00)88999-3.
  18. Ma R, Xie Q, Li Y, Chen Z, Ren M, Chen H, et al. Animal models of cerebral ischemia: a review. Biomed Pharmacother. 2020;131:110686. doi: 10.1016/j.biopha.2020.110686.
  19. Dahlqvist P, Rönnbäck A, Bergström SA, Söderström I, Olsson T. Environmental enrichment reverses learning impairment in the Morris water maze after focal cerebral ischemia in rats. Eur J Neurosci. 2004;19(8):2288-98. doi: 10.1111/j.0953- 816X.2004.03248.x.
  20. Hedna VS, Bodhit AN, Ansari S, Falchook AD, Stead L, Heilman KM, et al. Hemispheric differences in ischemic stroke: is left-hemisphere stroke more common? J Clin Neurol. 2013;9(2):97-102. doi: 10.3988/jcn.2013.9.2.97.
  21. Abogessimengane BJ, Mishchenko TA, Novozhilova MO, Vedunova MV. Comparative analysis of the degree of ischemic brain damage in experimental right or left common carotid artery occlusion in vivo. Opera Med Physiol. 2020;7(2):12- 23. doi: 10.24411/2500-2295-2020-00002.
  22. Hirakawa M, Tamura A, Nagashima H, Nakayama H, Sano K. Disturbance of retention of memory after focal cerebral ischemia in rats. Stroke. 1994;25(12):2471-5. doi: 10.1161/01. str.25.12.2471.
  23. Kase CS, Wolf PA, Kelly-Hayes M, Kannel WB, Beiser A, D’Agostino RB. Intellectual decline after stroke: the Framingham Study. Stroke. 1998;29(4):805-12. doi: 10.1161/01.str.29.4.805.
  24. Fernandes MY, do Carmo MR, Fonteles AA, de Sousa Neves JC, da Silva AT, Pereira JF, et al. (-)-α-bisabolol prevents neuronal damage and memory deficits through reduction of proinflammatory markers induced by permanent focal cerebral ischemia in mice. Eur J Pharmacol. 2019;842:270- 80. doi: 10.1016/j.ejphar.2018.09.036.
  25. Jayaraj RL, Azimullah S, Beiram R, Jalal FY, Rosenberg GA. Neuroinflammation: friend and foe for ischemic stroke. J Neuroinflammation. 2019;16(1):142. doi: 10.1186/s12974- 019-1516-2.
  26. Lee W, Moon M, Kim HG, Lee TH, Oh MS. Heat stress-induced memory impairment is associated with neuroinflammation in mice. J Neuroinflammation. 2015;12:102. doi: 10.1186/ s12974-015-0324-6.
  27. Escobar I, Xu J, Jackson CW, Perez-Pinzon MA. Altered neural networks in the Papez circuit: implications for cognitive dysfunction after cerebral ischemia. J Alzheimers Dis. 2019;67(2):425-46. doi: 10.3233/jad-180875.
  28. Ermine CM, Somaa F, Wang TY, Kagan BJ, Parish CL, Thompson LH. Long-term motor deficit and diffuse cortical atrophy following focal cortical ischemia in athymic rats. Front Cell Neurosci. 2019;13:552. doi: 10.3389/fncel.2019.00552.
  29. Kawaguchi C, Takizawa S, Niwa K, Iwamoto T, Kuwahira I, Kato H, et al. Regional vulnerability to chronic hypoxia and chronic hypoperfusion in the rat brain. Pathophysiology. 2002;8(4):249-53. doi: 10.1016/s0928-4680(02)00014-7.
  30. De Cristóbal J, Cárdenas A, Lizasoain I, Leza JC, FernándezTomé 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 oxygenglucose deprivation. Stroke. 2002;33(1):261-7. doi: 10.1161/ hs0102.101299.
  31. De Cristóbal J, Moro MA, Dávalos A, Castillo J, Leza JC, Camarero J, et al. Neuroprotective effect of aspirin by inhibition of glutamate release after permanent focal cerebral ischaemia in rats. J Neurochem. 2001;79(2):456-9. doi: 10.1046/j.1471-4159.2001.00600.x.
  32. Fan H, Li X, Wang W, Lai Q, Tang X, Gao D, et al. Effects of NMDA-receptor antagonist on the expressions of Bcl- 2 and Bax in the subventricular zone of neonatal rats with hypoxia-ischemia brain damage. Cell Biochem Biophys. 2015;73(2):323-30. doi: 10.1007/s12013-015-0586-8.
  33. Choi DW, Hartley DM. Calcium and glutamate-induced cortical neuronal death. Res Publ Assoc Res Nerv Ment Dis. 1993;71:23-34.
  34. Belayev L, Busto R, Zhao W, Fernandez G, Ginsberg MD. Middle cerebral artery occlusion in the mouse by intraluminal suture coated with poly-L-lysine: neurological and histological validation. Brain Res. 1999;833(2):181-90. doi: 10.1016/ s0006-8993(99)01528-0.
  35. Bueters T, von Euler M, Bendel O, von Euler G. Degeneration of newly formed CA1 neurons following global ischemia in the rat. Exp Neurol. 2008;209(1):114-24. doi: 10.1016/j. expneurol.2007.09.005.
  36. Mirabito Colafella KM, Neuman RI, Visser W, Danser AHJ, Versmissen J. Aspirin for the prevention and treatment of preeclampsia: a matter of COX-1 and/or COX-2 inhibition? Basic Clin Pharmacol Toxicol. 2020;127(2):132-41. doi: 10.1111/ bcpt.13308.
  37. Mourikis P, Zako S, Dannenberg L, Helten C, Naguib D, Hohlfeld T, et al. Aspirin antiplatelet effects are associated with body weight. Vascul Pharmacol. 2020;125-126:106635. doi: 10.1016/j.vph.2019.106635.
  38. Gholami M, Sadegh M, Koroush-Arami M, Norouzi S, Jafari Arismani R, Asadi E, et al. Targeting memory loss with aspirin, a molecular mechanism perspective for future therapeutic approaches. Inflammopharmacology. 2023;31(6):2827-42. doi: 10.1007/s10787-023-01347-1.
  39. Wang T, Fu FH, Han B, Zhang LM, Zhang XM. Long-term but not short-term aspirin treatment attenuates diabetes-associated learning and memory decline in mice. Exp Clin Endocrinol Diabetes. 2011;119(1):36-40. doi: 10.1055/s-0030-1261933.
  40. Shahedi A, Eftekhar Vaghefi SH, Sheibani V, Malekpoor Afshar R. Effect of acetyl-salicylic acid on CA1 hippocampal neurons and spatial learning following transient middle cerebral artery occlusion in male rats. J Cell Tissue. 2014;5(2):139-47. doi: 10.52547/jct.5.2.139. [Persian].
  41. Kara Y, Doguc DK, Kulac E, Gultekin F. Acetylsalicylic acid and ascorbic acid combination improves cognition; via antioxidant effect or increased expression of NMDARs and nAChRs? Environ Toxicol Pharmacol. 2014;37(3):916-27. doi: 10.1016/j.etap.2014.02.019.
  42. Li H, Li W, Zhang X, Ma XC, Zhang RW. Aspirin use on incident dementia and mild cognitive decline: a systematic review and meta-analysis. Front Aging Neurosci. 2020;12:578071. doi: 10.3389/fnagi.2020.578071.
  43. Berger C, Xia F, Schabitz WR, Schwab S, Grau A. Highdose aspirin is neuroprotective in a rat focal ischemia model. Brain Res. 2004;998(2):237-42. doi: 10.1016/j. brainres.2003.11.049.
  44. Dodd WS, Laurent D, Dumont AS, Hasan DM, Jabbour PM, Starke RM, et al. Pathophysiology of delayed cerebral ischemia after subarachnoid hemorrhage: a review. J Am Heart Assoc. 2021;10(15):e021845. doi: 10.1161/jaha.121.021845.
  45. Patrono C. The multifaceted clinical readouts of platelet inhibition by low-dose aspirin. J Am Coll Cardiol. 2015;66(1):74-85. doi: 10.1016/j.jacc.2015.05.012.
  46. Kaiser D, Weise G, Möller K, Scheibe J, Pösel C, Baasch S, et al. Spontaneous white matter damage, cognitive decline and neuroinflammation in middle-aged hypertensive rats: an animal model of early-stage cerebral small vessel disease. Acta Neuropathol Commun. 2014;2:169. doi: 10.1186/ s40478-014-0169-8.
  47. Rawat C, Kukal S, Dahiya UR, Kukreti R. Cyclooxygenase-2 (COX-2) inhibitors: future therapeutic strategies for epilepsy management. J Neuroinflammation. 2019;16(1):197. doi: 10.1186/s12974-019-1592-3.
  48. Muller DN, Heissmeyer V, Dechend R, Hampich F, Park JK, Fiebeler A, et al. Aspirin inhibits NF-kappaB and protects from angiotensin II-induced organ damage. FASEB J. 2001;15(10):1822-4. doi: 10.1096/fj.00-0843fje.
  49. Jiang W, Yan Y, Chen M, Luo G, Hao J, Pan J, et al. Aspirin enhances the sensitivity of colon cancer cells to cisplatin by abrogating the binding of NF-κB to the COX-2 promoter. Aging (Albany NY). 2020;12(1):611-27. doi: 10.18632/ aging.102644.
  50. Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 2011;31(5):986-1000. doi: 10.1161/atvbaha.110.207449.
  51. Rapoport SI. Aspirin and celecoxib may help to rectify a neurotransmission imbalance in bipolar disorder. Med Hypotheses. 2021;149:110536. doi: 10.1016/j. mehy.2021.110536.
  52. Vane JR, Botting RM. Mechanism of action of antiinflammatory drugs. Scand J Rheumatol Suppl. 1996;102:9- 21. doi: 10.3109/03009749609097226.
  53. Wang Y, Chen X, Zhu W, Zhang H, Hu S, Cong X. Growth inhibition of mesenchymal stem cells by aspirin: involvement of the WNT/beta-catenin signal pathway. Clin Exp Pharmacol Physiol. 2006;33(8):696-701. doi: 10.1111/j.1440- 1681.2006.04432.x.
Journal of Kerman University of Medical Sciences
Volume 32
Pages 1-11
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