The role of cyclooxygenase 2 in the cognitive impairment induced by alcohol or stress in rats

Document Type : Original Article


1 Department of Pharmacology and Toxicology, School of Pharmacy and Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

2 Department of Toxicology and Pharmacology, Faculty of Pharmacy; Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran


Background: Cognitive impairment is an unpleasant and progressive mental disorder characterized by learning and memory disabilities. Stress and alcohol are two known environmental factors that increase cognitive impairment. This study was designed to evaluate the relative role of cyclooxygenase 2 in alcohol or stress-induced cognitive impairment. Materials and Methods: Male Wistar rats were randomly divided into groups with six rats in each. The groups included sham, control, alcohol (15% ethanol in drinking water), and restraint stress (restraint 6 h per day). Three separated groups received celecoxib at a dose of 20 mg/kg in addition to those listed above. The treatments continued daily for 28 days. The object recognition task (ORT) and Morris water maze (MWM) are used to evaluate the learning and memory. Results: Alcohol or restrain stress significantly increased the time and distance needed to find the hidden platform in MWM. Furthermore, they decreased the recognition index in ORT compared to the control group. Administration of celecoxib significantly decreased the required time and traveled distance to reach the platform in alcohol-treated animals but not in the stress-exposed rats. Celecoxib also significantly increased the recognition index both in alcohol- or restraint stress-exposed animals. Conclusion: We found that either alcohol or restraint stress impairs memory in rats. In MWM, celecoxib improved the alcohol-induced memory impairment but could not show a reduction in memory deterioration due to restraint stress. In ORT, celecoxib reversed memory impairment due to both alcohol and restraint stress.


Boison D, Aronica E. Comorbidities in neurology: Is adenosine the common link? Neuropharmacology 2015;97:18-34.  Back to cited text no. 1
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:280-92.  Back to cited text no. 2
Andersen SL, Sweigart B, Sebastiani P, Drury J, Sidlowski S, Perls TT. Reduced prevalence and incidence of cognitive impairment among centenarian offspring. J Gerontol A Biol Sci Med Sci 2019;74:108-13.  Back to cited text no. 3
Laksmidewi AA, Suputra G, Widyadharma IP. High serum lead levels increase the incidence of cognitive impairment of public fueling station operators. Open Access Maced J Med Sci 2019;7:599-602.  Back to cited text no. 4
Scarmeas N, Anastasiou CA, Yannakoulia M. Nutrition and prevention of cognitive impairment. Lancet Neurol 2018;17:1006-15.  Back to cited text no. 5
Rodberg EM, den Hartog CR, Anderson RI, Becker HC, Moorman DE, Vazey EM. Stress facilitates the development of cognitive dysfunction after chronic ethanol exposure. Alcohol Clin Exp Res 2017;41:1574-83.  Back to cited text no. 6
Duric V, Clayton S, Leong ML, Yuan LL. Comorbidity factors and brain mechanisms linking chronic stress and systemic illness. Neural Plast 2016;2016:5460732.  Back to cited text no. 7
Zhao X, Li Y, Peng T, Seese RR, Wang Z. Stress impairs consolidation of recognition memory after blocking drug memory reconsolidation. Neurosci Lett 2011;501:50-4.  Back to cited text no. 8
Kim JJ, Yoon KS. Stress: Metaplastic effects in the hippocampus. Trends Neurosci 1998;21:505-9.  Back to cited text no. 9
Piirainen S, Youssef A, Song C, Kalueff AV, Landreth GE, Malm T, et al. Psychosocial stress on neuroinflammation and cognitive dysfunctions in Alzheimer's disease: The emerging role for microglia? Neurosci Biobehav Rev 2017;77:148-64.  Back to cited text no. 10
Squeglia LM, Jacobus J, Tapert SF. The effect of alcohol use on human adolescent brain structures and systems. Handb Clin Neurol 2014;125:501-10.  Back to cited text no. 11
Stragier E, Martin V, Davenas E, Poilbout C, Mongeau R, Corradetti R, et al. Brain plasticity and cognitive functions after ethanol consumption in C57BL/6J mice. Transl Psychiatry 2015;5:e696.  Back to cited text no. 12
Hendriks H, van de Rest O, Snippe A, Kieboom J, Hogenelst K. Alcohol consumption, drinking patterns, and cognitive performance in young adults: A cross-sectional and longitudinal analysis. Nutrients 2020;12:200.  Back to cited text no. 13
Huang WJ, Zhang X, Chen WW. Association between alcohol and Alzheimer's disease. Exp Ther Med 2016;12:1247-50.  Back to cited text no. 14
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;21:8198-209.  Back to cited text no. 15
Kumar A, Rani A, Scheinert RB, Ormerod BK, Foster TC. Nonsteroidal anti-inflammatory drug, indomethacin improves spatial memory and NMDA receptor function in aged animals. Neurobiol Aging 2018;70:184-93.  Back to cited text no. 16
Kumar P, Padi SS, Naidu PS, Kumar A. Cyclooxygenase inhibition attenuates 3-nitropropionic acid-induced neurotoxicity in rats: Possible antioxidant mechanisms. Fundam Clin Pharmacol 2007;21:297-306.  Back to cited text no. 17
Mhillaj E, Morgese MG, Tucci P, Furiano A, Luongo L, Bove M, et al. Celecoxib prevents cognitive impairment and neuroinflammation in soluble amyloid β-treated rats. Neuroscience 2018;372:58-73.  Back to cited text no. 18
Hosseini-Sharifabad A, Naghibzadeh S, Hajhashemi V. The effect of lead, restraint stress or their co-exposure on the movement disorders incidence in male mice. Res Pharm Sci 2019;14:343-50.  Back to cited text no. 19
Lueptow LM. Novel object recognition test for the investigation of learning and memory in mice. J Vis Exp 2017;(126):55718.  Back to cited text no. 20
Rajput P, Jangra A, Kwatra M, Mishra A, Lahkar M. Alcohol aggravates stress-induced cognitive deficits and hippocampal neurotoxicity: Protective effect of melatonin. Biomed Pharmacother 2017;91:457-66.  Back to cited text no. 21
Campos AC, Fogaça MV, Aguiar DC, Guimarães FS. Animal models of anxiety disorders and stress. Braz J Psychiatry 2013;35 Suppl 2:S101-11.  Back to cited text no. 22
Barnhart CD, Yang D, Lein PJ. Using the Morris water maze to assess spatial learning and memory in weanling mice. PLoS One 2015;10:e0124521.  Back to cited text no. 23
Kumar A, Garg R, Prakash AK. Effect of St. John's Wort (Hypericum perforatum) treatment on restraint stress-induced behavioral and biochemical alteration in mice. BMC Complement Altern Med 2010;10:18.  Back to cited text no. 24
Luine V, Gomez J, Beck K, Bowman R. Sex differences in chronic stress effects on cognition in rodents. Pharmacol Biochem Behav 2017;152:13-9.  Back to cited text no. 25
Islam BU, Zaidi SK, Kamal MA, Tabrez S. Exploration of various proteins for the treatment of Alzheimer's disease. Curr Drug Metab 2017;18:808-13.  Back to cited text no. 26
Hasanein P, Seifi R, Hajinezhad MR, Emamjomeh A. Rosmarinic acid protects against chronic ethanol-induced learning and memory deficits in rats. Nutr Neurosci 2017;20:547-54.  Back to cited text no. 27
Shimizu K, Matsubara K, Uezono T, Kimura K, Shiono H. Reduced dorsal hippocampal glutamate release significantly correlates with the spatial memory deficits produced by benzodiazepines and ethanol. Neuroscience 1998;83:701-6.  Back to cited text no. 28
Tiwari V, Chopra K. Resveratrol prevents alcohol-induced cognitive deficits and brain damage by blocking inflammatory signaling and cell death cascade in neonatal rat brain. J Neurochem 2011;117:678-90.  Back to cited text no. 29
Hoozemans JJ, O'Banion MK. The role of COX-1 and COX-2 in Alzheimer's disease pathology and the therapeutic potentials of non-steroidal anti-inflammatory drugs. Curr Drug Targets CNS Neurol Disord 2005;4:307-15.  Back to cited text no. 30
Seyedabadi M, Gharghabi M, Gurevich EV, Gurevich VV. Receptor-Arrestin Interactions: The GPCR Perspective. Biomolecules 2021:11:218.  Back to cited text no. 31
Mandegary A, Torshabi M, Seyedabadi M, Amirheidari B, Sharif E, Ghahremani MH. Indomethacin-enhanced anticancer effect of arsenic trioxide in A549 cell line: involvement of apoptosis and phospho-ERK and p38 MAPK pathways. Biomed Res Int 2013:2013:237543.  Back to cited text no. 32
Khedmat S, Seyedabadi M, Ghahremani MH, Ostad SN. Cyclooxygenase 2 plays a role in Emdogain-induced proliferation. J Periodontal Res 2011:46:67-73.  Back to cited text no. 33
Esmaeeli A, Ebrahimi F, Tanha K, Assadi M, Seyedabadi M. Low-dose angiotensin AT1 receptor β-arrestin-biased ligand, TRV027, protects against cisplatin-induced nephrotoxicity. Pharmacol Rep 2020:72:1676-84.  Back to cited text no. 34
Seyedabadi M, Rahimian R, Ghia JE. The role of alpha7 nicotinic acetylcholine receptors in inflammatory bowel disease: involvement of different cellular pathways. Expert Opin Ther Targets 2018:22:161-76.  Back to cited text no. 35
Seyedabadi M, Fakhfouri G, Ramezani V, Mehr SE, Rahimian R. The role of serotonin in memory: interactions with neurotransmitters and downstream signaling. Exp Brain Res 2014:232:723-38.  Back to cited text no. 36