Iranian Journal of Medical Sciences

Document Type : Original Article(s)


1 Physiology Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran

2 Department of Applied Cell Sciences, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran

3 Department of Physiology, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran


Background: Although a substantial body of research suggests curcumin (CUR) has the preventive potential in memory impairment, the mechanism by which CUR prevents memory loss is still being investigated. This study employs an inhibitory avoidance (IA) model to investigate whether CUR can prevent morphine (Mor)-induced memory impairment as well as the possible role of cAMP-response element binding (CREB) protein and nitric oxide (NO) signaling in this mechanism. 
Methods: This experimental study was conducted at the Animal Lab of the Physiology Research Center, Kashan University of Medical Sciences (Kashan, Iran) in 2018. Forty rats were randomly divided into four groups: control; CUR (pretreatment gavage of CUR [10 mg/Kg] for 35 days); Mor (7.5 mg/Kg/i.p.), and CUR+Mor (n=10 per group). Following the evaluation of the IA memory and locomotor activity of the animals, the CREB protein expression in the hippocampus and NO metabolites (NOx) level in the brain tissue were also investigated. The data were analyzed using Sigmaplot software (V.14.0) by using the ANOVA, Kruskal–Wallis, Holm-Sidak, and Dunn’s post hoc tests. P<0.05 was considered to be statistically significant. 
Results: In the Mor group, the IA memory of the rats was significantly impaired (P=0.001). CUR prevented the Mor-induced IA memory impairment (P=0.075). While the Mor treatment decreased the phosphorylated CREB (p-CREB) expression, the CUR+Mor cotreatment increased p-CREB expression (P=0.010). Nevertheless, the Mor treatment increased the total CREB expression (P=0.010). The NOx concentration in the brain tissue was decreased following the Mor treatment (P=0.500) but increased after the CUR+Mor cotreatment (P=0.001). 
Conclusion: The present findings suggest that CUR prevents the memory impairment of rats, possibly through NO and its downstream CREB signaling. 


  1. Yan D, Yao J, Liu Y, Zhang X, Wang Y, Chen X, et al. Tau hyperphosphorylation and P-CREB reduction are involved in acrylamide-induced spatial memory impairment: Suppression by curcumin. Brain Behav Immun. 2018;71:66-80. doi: 10.1016/j.bbi.2018.04.014. PubMed PMID: 29704550.
  2. Issuriya A, Kumarnsit E, Wattanapiromsakul C, Vongvatcharanon U. Histological studies of neuroprotective effects of Curcuma longa Linn. on neuronal loss induced by dexamethasone treatment in the rat hippocampus. Acta Histochem. 2014;116:1443-53. doi: 10.1016/j.acthis.2014.09.009. PubMed PMID: 25440530.
  3. Shabaninejad Z, Pourhanifeh MH, Movahedpour A, Mottaghi R, Nickdasti A, Mortezapour E, et al. Therapeutic potentials of curcumin in the treatment of glioblstoma. Eur J Med Chem. 2020;188:112040. doi: 10.1016/j.ejmech.2020.112040. PubMed PMID: 31927312.
  4. Lobos P, Cordova A, Vega-Vasquez I, Ramirez OA, Adasme T, Toledo J, et al. RyR-mediated Ca(2+) release elicited by neuronal activity induces nuclear Ca(2+) signals, CREB phosphorylation, and Npas4/RyR2 expression. Proc Natl Acad Sci U S A. 2021;118. doi: 10.1073/pnas.2102265118. PubMed PMID: 34389673; PubMed Central PMCID: PMCPMC8379958.
  5. Motaghinejad M, Motevalian M, Fatima S, Faraji F, Mozaffari S. The Neuroprotective Effect of Curcumin Against Nicotine-Induced Neurotoxicity is Mediated by CREB-BDNF Signaling Pathway. Neurochem Res. 2017;42:2921-32. doi: 10.1007/s11064-017-2323-8. PubMed PMID: 28608236.
  6. Eun CS, Lim JS, Lee J, Lee SP, Yang SA. The protective effect of fermented Curcuma longa L. on memory dysfunction in oxidative stress-induced C6 gliomal cells, proinflammatory-activated BV2 microglial cells, and scopolamine-induced amnesia model in mice. BMC Complement Altern Med. 2017;17:367. doi: 10.1186/s12906-017-1880-3. PubMed PMID: 28716085; PubMed Central PMCID: PMCPMC5514491.
  7. Malboosi N, Nasehi M, Hashemi M, Vaseghi S, Zarrindast MR. The neuroprotective effect of NeuroAid on morphine-induced amnesia with respect to the expression of TFAM, PGC-1alpha, DeltafosB and CART genes in the hippocampus of male Wistar rats. Gene. 2020;742:144601. doi: 10.1016/j.gene.2020.144601. PubMed PMID: 32198124.
  8. Zarrindast MR, Ardjmand A, Rezayof A, Ahmadi S. The time profile of morphine effect on different phases of inhibitory avoidance memory in rat. Arch Iran Med. 2013;16:34-7. doi: 013161/AIM.0011. PubMed PMID: 23273234.
  9. Baudonnat M, Guillou JL, Husson M, Bohbot VD, Schwabe L, David V. Morphine Reward Promotes Cue-Sensitive Learning: Implication of Dorsal Striatal CREB Activity. Front Psychiatry. 2017;8:87. doi: 10.3389/fpsyt.2017.00087. PubMed PMID: 28611691; PubMed Central PMCID: PMCPMC5447690.
  10. Mohamed RMP, Kumar J, Yap E, Mohamed IN, Sidi H, Adam RL, et al. Try to Remember: Interplay between Memory and Substance Use Disorder. Curr Drug Targets. 2019;20:158-65. doi: 10.2174/1389450118666170622092824. PubMed PMID: 28641520.
  11. Mumtaz F, Rashki A, Imran Khan M, Shadboorestan A, Abdollahi A, Ghazi-Khansari M, et al. Neuroprotective effect of sumatriptan in pentylenetetrazole-induced seizure is mediated through N-methyl-D-aspartate/nitric oxide and cAMP response element-binding protein signaling pathway. Fundam Clin Pharmacol. 2022;36:250-61. doi: 10.1111/fcp.12728. PubMed PMID: 34545607.
  12. Longobardi C, Damiano S, Andretta E, Prisco F, Russo V, Pagnini F, et al. Curcumin Modulates Nitrosative Stress, Inflammation, and DNA Damage and Protects against Ochratoxin A-Induced Hepatotoxicity and Nephrotoxicity in Rats. Antioxidants (Basel). 2021;10. doi: 10.3390/antiox10081239. PubMed PMID: 34439487; PubMed Central PMCID: PMCPMC8389288.
  13. Banafshe HR, Mohsenpour M, Ardjmand A. Effects Following Intracerebroventricular Injection of Immunosuppressant Cyclosporine A On Inhibitory Avoidance Learning and Memory in Mice. Galen Med J. 2018;7:e1044. doi: 10.22086/gmj.v0i0.1044. PubMed PMID: 34466427; PubMed Central PMCID: PMCPMC8343945.
  14. Someya E, Mori A, Sakamoto K, Ishii K, Nakahara T. Stimulation of mu-opioid receptors dilates retinal arterioles by neuronal nitric oxide synthase-derived nitric oxide in rats. Eur J Pharmacol. 2017;803:124-9. doi: 10.1016/j.ejphar.2017.03.043. PubMed PMID: 28341346.
  15. Guide for the Care and Use of Laboratory Animals. 8th ed. Washington: National Academies Press; 2011.
  16. Liu D, Wang Z, Gao Z, Xie K, Zhang Q, Jiang H, et al. Effects of curcumin on learning and memory deficits, BDNF, and ERK protein expression in rats exposed to chronic unpredictable stress. Behav Brain Res. 2014;271:116-21. doi: 10.1016/j.bbr.2014.05.068. PubMed PMID: 24914461.
  17. Hadjiasgary A, Banafshe HR, Ardjmand A. Intra-CA1 administration of FK-506 (tacrolimus) in rat impairs learning and memory in an inhibitory avoidance paradigm. Iran J Basic Med Sci. 2015;18:130-7. PubMed PMID: 25810886; PubMed Central PMCID: PMCPMC4366723.
  18. Schrader M, Jarrett BJM, Kilner RM. Larval environmental conditions influence plasticity in resource use by adults in the burying beetle, Nicrophorus vespilloides. Evolution. 2022;76:667-74. doi: 10.1111/evo.14339. PubMed PMID: 34463348; PubMed Central PMCID: PMCPMC9293066.
  19. Alinaghipour A, Mazoochi T, Ardjmand A. Low-dose ethanol ameliorates amnesia induced by a brief seizure model: the role of NMDA signaling. Neurol Res. 2019;41:624-32. doi: 10.1080/01616412.2019.1602322. PubMed PMID: 30967097.
  20. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248-54. doi: 10.1006/abio.1976.9999. PubMed PMID: 942051.
  21. Esmaili Z, Heydari A. Effect of acute caffeine administration on PTZ-induced seizure threshold in mice: Involvement of adenosine receptors and NO-cGMP signaling pathway. Epilepsy Res. 2019;149:1-8. doi: 10.1016/j.eplepsyres.2018.10.013. PubMed PMID: 30391360.
  22. Tavassoli M, Ardjmand A. Pentylenetetrazol and Morphine Interaction in a State-dependent Memory Model: Role of CREB Signaling. Basic Clin Neurosci. 2020;11:557-72. doi: 10.32598/bcn.11.4.1482.1. PubMed PMID: 33613894; PubMed Central PMCID: PMCPMC7878041.
  23. Gupta SC, Patchva S, Aggarwal BB. Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J. 2013;15:195-218. doi: 10.1208/s12248-012-9432-8. PubMed PMID: 23143785; PubMed Central PMCID: PMCPMC3535097.
  24. Moore TL, Bowley B, Shultz P, Calderazzo S, Shobin E, Killiany RJ, et al. Chronic curcumin treatment improves spatial working memory but not recognition memory in middle-aged rhesus monkeys. Geroscience. 2017;39:571-84. doi: 10.1007/s11357-017-9998-2. PubMed PMID: 29047012; PubMed Central PMCID: PMCPMC5745216.
  25. Sarlak Z, Oryan S, Moghaddasi M. Interaction between the antioxidant activity of curcumin and cholinergic system on memory retention in adult male Wistar rats. Iran J Basic Med Sci. 2015;18:398-403. PubMed PMID: 26019804; PubMed Central PMCID: PMCPMC4439456.
  26. Venkatesan UM, Rabinowitz AR, Riccitello RM. Breaking the Percent Memory Retention Ceiling using Bayesian Statistics. J Int Neuropsychol Soc. 2021;27:396-400. doi: 10.1017/S1355617720000892. PubMed PMID: 33012298.
  27. Akinyemi AJ, Oboh G, Oyeleye SI, Ogunsuyi O. Anti-amnestic Effect of Curcumin in Combination with Donepezil, an Anticholinesterase Drug: Involvement of Cholinergic System. Neurotox Res. 2017;31:560-9. doi: 10.1007/s12640-017-9701-5. PubMed PMID: 28102474.
  28. Sevastre-Berghian AC, Fagarasan V, Toma VA, Baldea I, Olteanu D, Moldovan R, et al. Curcumin Reverses the Diazepam-Induced Cognitive Impairment by Modulation of Oxidative Stress and ERK 1/2/NF-kappaB Pathway in Brain. Oxid Med Cell Longev. 2017;2017:3037876. doi: 10.1155/2017/3037876. PubMed PMID: 29098059; PubMed Central PMCID: PMCPMC5643119.
  29. Srivastava P, Dhuriya YK, Kumar V, Srivastava A, Gupta R, Shukla RK, et al. PI3K/Akt/GSK3beta induced CREB activation ameliorates arsenic mediated alterations in NMDA receptors and associated signaling in rat hippocampus: Neuroprotective role of curcumin. Neurotoxicology. 2018;67:190-205. doi: 10.1016/j.neuro.2018.04.018. PubMed PMID: 29723552.
  30. Guitart X, Thompson MA, Mirante CK, Greenberg ME, Nestler EJ. Regulation of cyclic AMP response element-binding protein (CREB) phosphorylation by acute and chronic morphine in the rat locus coeruleus. J Neurochem. 1992;58:1168-71. doi: 10.1111/j.1471-4159.1992.tb09377.x. PubMed PMID: 1531356.
  31. Akbarabadi A, Sadat-Shirazi MS, Kabbaj M, Nouri Zadeh-Tehrani S, Khalifeh S, Pirri F, et al. Effects of Morphine and Maternal Care on Behaviors and Protein Expression of Male Offspring. Neuroscience. 2021;466:58-76. doi: 10.1016/j.neuroscience.2021.04.011. PubMed PMID: 33915201.
  32. Gago B, Suarez-Boomgaard D, Fuxe K, Brene S, Reina-Sanchez MD, Rodriguez-Perez LM, et al. Effect of acute and continuous morphine treatment on transcription factor expression in subregions of the rat caudate putamen. Marked modulation by D4 receptor activation. Brain Res. 2011;1407:47-61. doi: 10.1016/j.brainres.2011.06.046. PubMed PMID: 21782156.
  33. Wang DM, Yang YJ, Zhang L, Zhang X, Guan FF, Zhang LF. Naringin Enhances CaMKII Activity and Improves Long-Term Memory in a Mouse Model of Alzheimer’s Disease. Int J Mol Sci. 2013;14:5576-86. doi: 10.3390/ijms14035576. PubMed PMID: 23478434; PubMed Central PMCID: PMCPMC3634479.
  34. Alghamdi BS, Alshehri FS. Melatonin Blocks Morphine-Induced Place Preference: Involvement of GLT-1, NF-kappaB, BDNF, and CREB in the Nucleus Accumbens. Front Behav Neurosci. 2021;15:762297. doi: 10.3389/fnbeh.2021.762297. PubMed PMID: 34720901; PubMed Central PMCID: PMCPMC8551802.
  35. Nam SM, Choi JH, Yoo DY, Kim W, Jung HY, Kim JW, et al. Effects of curcumin (Curcuma longa) on learning and spatial memory as well as cell proliferation and neuroblast differentiation in adult and aged mice by upregulating brain-derived neurotrophic factor and CREB signaling. J Med Food. 2014;17:641-9. doi: 10.1089/jmf.2013.2965. PubMed PMID: 24712702; PubMed Central PMCID: PMCPMC4060834.
  36. Farahmandfar M, Kadivar M, Naghdi N. Possible interaction of hippocampal nitric oxide and calcium/calmodulin-dependent protein kinase II on reversal of spatial memory impairment induced by morphine. Eur J Pharmacol. 2015;751:99-111. doi: 10.1016/j.ejphar.2015.01.042. PubMed PMID: 25661847.
  37. Al-Hasani R, Bruchas MR. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology. 2011;115:1363-81. doi: 10.1097/ALN.0b013e318238bba6. PubMed PMID: 22020140; PubMed Central PMCID: PMCPMC3698859.
  38. Pigott BM, Garthwaite J. Nitric Oxide Is Required for L-Type Ca(2+) Channel-Dependent Long-Term Potentiation in the Hippocampus. Front Synaptic Neurosci. 2016;8:17. doi: 10.3389/fnsyn.2016.00017. PubMed PMID: 27445786; PubMed Central PMCID: PMCPMC4925670.
  39. Yu SY, Gao R, Zhang L, Luo J, Jiang H, Wang S. Curcumin ameliorates ethanol-induced memory deficits and enhanced brain nitric oxide synthase activity in mice. Prog Neuropsychopharmacol Biol Psychiatry. 2013;44:210-6. doi: 10.1016/j.pnpbp.2013.03.001. PubMed PMID: 23500667.
  40. Zhu W, Su J, Liu J, Jiang C. The involvement of neuronal nitric oxide synthase in the anti-epileptic action of curcumin on pentylenetetrazol-kindled rats. Biomed Mater Eng. 2015;26:S841-50. doi: 10.3233/BME-151376. PubMed PMID: 26406082.