Skip to main content
PMC home page
Neuroscience Bulletin logoLink to Neuroscience Bulletin
. 2010 Feb 3;26(1):17–27. doi: 10.1007/s12264-010-0713-x

Protective effects of selective and non-selective cyclooxygenase inhibitors in an animal model of chronic stress

选择性和非选择性环氧合酶抑制剂对慢性压力小鼠模型具有保护作用

Anil Kumar 1, Beenta Kumari 1, Puneet Kumar 1,✉
PMCID: PMC5560377  PMID: 20101269

Abstract

Objective

Cyclooxygenase isoenzyme is known to be expressed in different regions of brain, and is mainly used for the treatment of pain and inflammation. Recently, it is proposed that cyclooxygenase isoenzyme may also play a key role in the pathophysiology of various brain-related disorders. The present study was aimed to explore the protective effect of cyclooxygenase inhibitors on stress by using an animal model of chronic stress.

Methods

The animals were forced to swim individually for a period of 6 min every day for 15 d. Then, the behavior (locomotor activity, anxiety and memory) and biochemical (lipid peroxidation, nitrite level, reduced glutathione, and catalase) alterations were assessed.

Results

Forced swimming for 15 d caused impaired locomotor activity, anxiety-like behavior and decreased percentage of memory retention, as compared to naïve mice (without chronic fatigue treatment). Biochemical analysis revealed significant increases in lipid peroxidation and nitrite level, while levels of reduced glutathione and catalase activity were both decreased. Chronic treatment with naproxen (14 mg/kg, i.p.), rofecoxib (5 mg/kg, i.p.), meloxicam (5 mg/kg, i.p.), nimesulide (5 mg/kg, i.p.) and valdecoxib (10 mg/kg, i.p.) significantly attenuated these behavioral and biochemical (oxidative damage) alterations in chronic-stressed mice.

Conclusion

The cyclooxygenase inhibitors could be used in the management of chronic fatigue-like conditions.

Keywords: chronic fatigue syndrome, naproxen, valdecoxib, rofecoxib, nimesulide, meloxicam

References

  • [1].Munhoz C.D., Garcia-Buenoz B., Madrigal J.L.M., Lepsch L.B., Scavone C., Leza J.C. Stress-induced neuroinflammation: mechanisms and new pharmacological targets. Braz J Med Biol Res. 2008;41:1037–1046. doi: 10.1590/S0100-879X2008001200001. [DOI] [PubMed] [Google Scholar]
  • [2].Chambers D., Bagnall A.M., Hempel S., Forbes C. Interventions for the treatment, management and rehabilitation of patients with chronic fatigue syndrome/myalgic encephalomyelitis: an updated systematic review. J R Soc Med. 2006;99:506–520. doi: 10.1258/jrsm.99.10.506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [3].Jason L.A., Corradi K., Gress S., Williams S., Torres-Harding S. Causes of death among patients with chronic fatigue syndrome. Health Care Women Int. 2006;27:615–626. doi: 10.1080/07399330600803766. [DOI] [PubMed] [Google Scholar]
  • [4].Sanders P., Korf J. Neuroaetiology of chronic fatigue syndrome: an overview. World J Biol Psychiatry. 2007;8:1–7. doi: 10.1080/15622970701310971. [DOI] [PubMed] [Google Scholar]
  • [5].McEven B.S., Sapolsky R.M. Stress and cognitive function. Curr Opin Neurobiol. 1995;5:205–216. doi: 10.1016/0959-4388(95)80028-X. [DOI] [PubMed] [Google Scholar]
  • [7].Porsolt R.D., Bertin A., Jafre M. Behavioral despair in rats and mice: Reversal by antidepressants. Psychopharmacology. 1977;51:291–298. [Google Scholar]
  • [8].Thomas M.A., Smith A.P. An investigation of the longterm benefits of antidepressant medication in the recovery of patients with chronic fatigue syndrome. Hum Psychopharmacol. 2006;21:503–509. doi: 10.1002/hup.805. [DOI] [PubMed] [Google Scholar]
  • [9].Fulle S., Mecocci P., Fano G. Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome. Free Radic Biol Med. 2000;29:1252–1259. doi: 10.1016/S0891-5849(00)00419-6. [DOI] [PubMed] [Google Scholar]
  • [10].Fontella F.U., Siqueira I.R., Vasconcellos A.P., Tabajara A.S., Netto C.A., Dalmaz C. Repeated restraint stress induces oxidative damage in rat hippocampus. Neurochem Res. 2005;30:105–111. doi: 10.1007/s11064-004-9691-6. [DOI] [PubMed] [Google Scholar]
  • [11].Silakova J.M., Hewett J.A., Hewett S.J. Naproxen reduces excitotoxic neurodegeneration in vivo with an extended therapeutic window. J Pharmacol Exp Ther. 2004;309:1060–1066. doi: 10.1124/jpet.103.063867. [DOI] [PubMed] [Google Scholar]
  • [12].Dhir A., Padi S.S.V., Naidu P.S., Kulkarni S.K. Protective effect of naproxen (nonselective COX-inhibitors) or rofecoxib (selective COX-2 inhibitor) in immobilization stress-induced behavioural and biochemical alterations in mice. Eur J Pharmacol. 2006;535:192–198. doi: 10.1016/j.ejphar.2006.01.064. [DOI] [PubMed] [Google Scholar]
  • [13].Minghetti L. Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases. J Neuropathol Exp Neurol. 2004;63:901–910. doi: 10.1093/jnen/63.9.901. [DOI] [PubMed] [Google Scholar]
  • [14].Asanuma M., Miyazaki I., Ogawa N. Neuroprotective effects of nonsteroidal anti-inflammatory drugs on neurodegenerative diseases. Curr Pharm Des. 2004;10:695–700. doi: 10.2174/1381612043453072. [DOI] [PubMed] [Google Scholar]
  • [15].Galvao R.I., Diogenes J.P., Maia G.C., Filho E.A., Vasconcelos S.M., de Menezes D.B., et al. Tenoxicam exerts a neuroprotective action after cerebral ischemia in rats. Neurochem Res. 2005;30:39–46. doi: 10.1007/s11064-004-9684-5. [DOI] [PubMed] [Google Scholar]
  • [16].Klivenyi P., Kiaei M., Gardian G., Calingasan N.Y., Beal M.F. Additive neuroprotective effects of creatine and cyclooxygenase 2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurochem. 2004;88:576–582. doi: 10.1046/j.1471-4159.2003.02160.x. [DOI] [PubMed] [Google Scholar]
  • [17].Katori M., Majima M. Cyclooxygenase-2: its rich diversity of roles and possible application of its selective inhibitors. Inflamm Res. 2000;49:367–392. doi: 10.1007/s000110050605. [DOI] [PubMed] [Google Scholar]
  • [18].Reddy D.S., Kulkarni S.K. Possible role of nitric oxide in the nootropic and antiamnesic effects of neurosteroids on aging and dizocilpine-induced learning impairment. Brain Res. 1998;799:215–229. doi: 10.1016/S0006-8993(98)00419-3. [DOI] [PubMed] [Google Scholar]
  • [19].Kulkarni S.K., Reddy D.S. Animal behavioral models for testing antianxiety agents. Method Find Exp Clin Pharmacol. 1996;18:219–230. [PubMed] [Google Scholar]
  • [20].Ioth J., Nabeshima T., Kameyania T. Utility of an elevated plusmaze for dissociation of amnesic and behavioral effects of drugs in mice. Eur J Pharmacol. 1999;194:71–74. doi: 10.1016/0014-2999(91)90125-A. [DOI] [PubMed] [Google Scholar]
  • [21].Wills E.D. Mechanism of lipid peroxide formation in animal tissues. Biochem J. 1966;99:667–676. doi: 10.1042/bj0990667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Ellman G.L. Tissue sulfhydryl groups. Arch Biochem Biophys. 1959;82:70–77. doi: 10.1016/0003-9861(59)90090-6. [DOI] [PubMed] [Google Scholar]
  • [23].Luck H. Catalase. Methods of Enzymatic Analysis. New York: Bergmeyer HU (eds) Academic Press; 1971. pp. 885–893. [Google Scholar]
  • [24].Green L.C., Wagner D.A., Glagowski J. Analysis of nitrate, nitrite and [15N] nitrate in biological fluids. Anal Biochem. 1982;126:131–138. doi: 10.1016/0003-2697(82)90118-X. [DOI] [PubMed] [Google Scholar]
  • [25].Lowry O.H., Rosenberg N.J., Farr A.L., Randall R.J. Protein measurement with the Folin-phenol reagent. J Biol Chem. 1951;193:265–275. [PubMed] [Google Scholar]
  • [26].Kaur G., Kulkarni S.K. Reversal of forced swimming-induced chronic fatigue in mice by antidepressant and herbal psychotropic drugs. Indian Drugs. 1998;35:771–777. [Google Scholar]
  • [27].Devanur L.D., Kerr J.R. Chronic fatigue syndrome. J Clin Virol. 2006;37:139–150. doi: 10.1016/j.jcv.2006.08.013. [DOI] [PubMed] [Google Scholar]
  • [28].Cleare A.J. The HPA axis and the genesis of chronic fatigue syndrome. Trends Endocrinol Metab. 2004;15:55–59. doi: 10.1016/j.tem.2003.12.002. [DOI] [PubMed] [Google Scholar]
  • [29].Kaur G., Kulkarni S.K. Comparative study of antidepressants and herbal psychotropic drugs in a mouse model chronic fatigue. J Chronic Fatigue Syndr. 2000;6:23–35. doi: 10.1300/J092v06n02_04. [DOI] [Google Scholar]
  • [30].Singh A., Naidu P.S., Gupta S., Kulkarni S.K. Effect of natural and synthetic antioxidants in a mouse model of chronic fatigue syndrome. J Med Food. 2002;5:211–220. doi: 10.1089/109662002763003366. [DOI] [PubMed] [Google Scholar]
  • [31].Kumar A., Garg R., Kumar P. Nitric oxide modulation mediates the protective effect of trazodone in a mouse model of chronic fatigue syndrome. Pharmacol Rep. 2008;60:664–672. [PubMed] [Google Scholar]
  • [32].Schonfeldt-Locuona C., Connemann B.J., Wolf R.C., Braun M., Freudenmann R.W. Bupropion augmentation in the treatment of chronic fatigue syndrome with coexistent major depression. Episode Pharmacopsych. 2006;39:152–154. doi: 10.1055/s-2006-946706. [DOI] [PubMed] [Google Scholar]
  • [33].Greenberg S., Frid M. Chronic fatigue syndrome-exercise and physical activity. Harefuah. 2006;145:276–280. [PubMed] [Google Scholar]
  • [34].Metz G.A., Jadavji N.M., Smith L.K. Modulation of motor function by stress: a novel concept of the effects of stress and corticosterone on behavior. Eur J Neurosci. 2005;22:1190–1200. doi: 10.1111/j.1460-9568.2005.04285.x. [DOI] [PubMed] [Google Scholar]
  • [35].Domanski E., Przekop F., Wolinska-Witort E., Mateusiak K., Chomicka L., Garwacki S. Differential behavioral and hormonal responses to two different stressors (foot shocking and immobilization) in sheep. Exp Clin Pharmacol. 1986;88:165–172. doi: 10.1055/s-0029-1210592. [DOI] [PubMed] [Google Scholar]
  • [36].Bristow D.J., Holmes D.S. Cortisol levels and anxiety related behaviors in cattle. Physiol Behav. 2007;90:626–628. doi: 10.1016/j.physbeh.2006.11.015. [DOI] [PubMed] [Google Scholar]
  • [37].Dhir A., Padi S.S.V., Naidu P.S., Kulkarni S.K. Protective effect of naproxen (nonselective COX-2-inhibitors) or rofecoxib (selective COX-2 inhibitor) in immobilization stress-induced behavioral and biochemical alterations in mice. Eur J Pharmacol. 2006;535:192–198. doi: 10.1016/j.ejphar.2006.01.064. [DOI] [PubMed] [Google Scholar]
  • [38].Goyal R., Kumar A. Protective effects of alprazolam in acute immobilization stress-induced certain behavioral and biochemical alterations in mice. Pharmacol Rep. 2007;59:284–290. [PubMed] [Google Scholar]
  • [39].Jain N.K., Kulkarni S.K., Singh A. Lipopolysaccharidemediated immobility in mice: reversal by cyclooxygenase enzyme inhibitor. Methods Find Exp Clin Pharmacol. 2001;23:441–444. doi: 10.1358/mf.2001.23.8.662131. [DOI] [PubMed] [Google Scholar]
  • [40].Mattamml M.B., Strong R., Lakshmi V.M., Chung H.D., Stephenson A.H. Prostaglandin H synthetase-mediated metabolism of dopamine: implication for Parkinson’s disease. J Neurochem. 1995;64:1645–1650. doi: 10.1046/j.1471-4159.1995.64041645.x. [DOI] [PubMed] [Google Scholar]
  • [41].Cook D.B., Nagelkirk P.R., Peckerman A., Poluri A., Mores J., Natelson B.H. Exercise and cognitive performance in chronic fatigue syndrome. Med Sci Sports Exerc. 2005;37:1460–1467. doi: 10.1249/01.mss.0000179921.48404.ef. [DOI] [PubMed] [Google Scholar]
  • [42].Roozendaal B. Glucocorticoids and the regulation of memory consolidation. Psychoneuroendocrinol. 2000;25:213–238. doi: 10.1016/S0306-4530(99)00058-X. [DOI] [PubMed] [Google Scholar]
  • [43].Garcia R. Stress hippocampal plasticity and spatial learning. Synapse. 2001;40:180–183. doi: 10.1002/syn.1040. [DOI] [PubMed] [Google Scholar]
  • [44].McEwen B.S., Albeck D., Cameron H. Stress and the brain: a paradoxical role for adrenal steroids. Vitam Horm. 1995;51:371–402. doi: 10.1016/S0083-6729(08)61045-6. [DOI] [PubMed] [Google Scholar]
  • [45].Kaufmann W.E., Worley P.F., Pegg J., Bremer M., Isakson P. Cyclooxygenase 2 expression during rat neocortical development and in Rett syndrome. Brain Dev. 1997;19:25–34. doi: 10.1016/S0387-7604(96)00047-2. [DOI] [PubMed] [Google Scholar]
  • [46].Cakala M., Malik A.R., Storsznajder J.B. Inhibitor of cyclooxygenase-2 protects against amyloid beta peptide-evoked memory impairment in mice. Pharmacol Rep. 2007;59:164–172. [PubMed] [Google Scholar]
  • [47].Luine V., Villegas M., Martinez C., McEwen B.S. Repeated stress causes reversible impairments of spatial memory performance. Brain Res. 1994;639:167–170. doi: 10.1016/0006-8993(94)91778-7. [DOI] [PubMed] [Google Scholar]
  • [48].Madrigal J.L., Olivenza R., Moro M.A., Lizasoain I., Lorenzo P., Rodrigo J., et al. Glutathione depletion, lipid peroxidation and mitochondrial dysfunction are induced by chronic stress in rat brain. Neuropsychopharmacology. 2001;24:420–429. doi: 10.1016/S0893-133X(00)00208-6. [DOI] [PubMed] [Google Scholar]
  • [49].McEwen B.S. The neurobiology of stress: From serendipity to clinical relevance. Brain Res. 2000;886:172–189. doi: 10.1016/S0006-8993(00)02950-4. [DOI] [PubMed] [Google Scholar]
  • [50].Reagan L.P., McEwen B.S. Controversies surrounding glucocorticoids-mediated cell death in the hippocampus. J Chem Neuroanat. 1997;13:149–167. doi: 10.1016/S0891-0618(97)00031-8. [DOI] [PubMed] [Google Scholar]
  • [51].McIntosh L.J., Hong K.E., Sapolsky R.M. Glucocorticoids may alter antioxidant enzyme capacity in the brain: baseline studies. Brain Res. 1998;791:209–214. doi: 10.1016/S0006-8993(98)00115-2. [DOI] [PubMed] [Google Scholar]
  • [52].Maes M. Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms. Curr Opin Psychiatry. 2009;22(1):75–83. doi: 10.1097/YCO.0b013e32831a4728. [DOI] [PubMed] [Google Scholar]
  • [53].Tomoda A., Joudoi T., Rabab el M., Matsumoto T., Park T.H., Miike T. Cytokine production and modulation: comparison of patients with chronic fatigue syndrome and normal controls. Psychiatry Res. 2005;134:101–104. doi: 10.1016/j.psychres.2005.01.002. [DOI] [PubMed] [Google Scholar]
  • [54].Lorusso L., Mikhaylova S.V., Capelli E., Ferrari D., Ngonga G.K., Ricevuti G. Immunological aspects of chronic fatigue syndrome. Autoimmun Rev. 2009;8:287–291. doi: 10.1016/j.autrev.2008.08.003. [DOI] [PubMed] [Google Scholar]
  • [55].Richard R.S., Wang L., Jelinek H. Erythrocyte oxidative damage in chronic fatigue syndrome. Arch Med Res. 2007;38:94–98. doi: 10.1016/j.arcmed.2006.06.008. [DOI] [PubMed] [Google Scholar]
  • [56].Ozcan M.E., Gulec M., Ozerol E., Polat R., Akyol O. Antioxidant enzyme activities and oxidative stress in affective disorders. Int Clin Psychopharmacol. 2004;19:89–95. doi: 10.1097/00004850-200403000-00006. [DOI] [PubMed] [Google Scholar]
  • [57].Amoroso S., D’Alessio A., Sirabella R., Di Renzo G., Annunziato L. Ca2+-independent caspase-3 but not Ca2+-dependent caspase-2 activation induced by oxidative stress leads to SH-SY5Y human neuroblastoma cell apoptosis. J Neurosci Res. 2002;68:454–462. doi: 10.1002/jnr.10199. [DOI] [PubMed] [Google Scholar]
  • [58].Braughler J.M., Hall E.D. Central nervous system trauma and stroke. Biochemical considerations for free radical dormation and lipid peroxidation. Free Rad Biol Med. 1989;6:289–301. doi: 10.1016/0891-5849(89)90056-7. [DOI] [PubMed] [Google Scholar]
  • [59].Hu Y., Cardounel A., Gursoy E., Anderson P., Kalimi M. Anti-stress effects of dehydroepiandrosterone. Protection of rats against repeated immobilization stressinduced weight loss, glucocorticoid receptor production, and lipid peroxidation. Biochem Pharmacol. 2000;59:753–762. doi: 10.1016/S0006-2952(99)00385-8. [DOI] [PubMed] [Google Scholar]
  • [60].Olivenza R., Moro M.A., Lizasoain I., Lorenzo P., Fernández A.P., Rodrigo J., et al. Chronic stress induces the expression of inducible nitric oxide synthase in rat brain cortex. J Neurochem. 2000;74:785–791. doi: 10.1046/j.1471-4159.2000.740785.x. [DOI] [PubMed] [Google Scholar]
  • [61].Matsumoto K., Yobimoto K., Huong N.T.T., Abdel-Fattah M., Hein T.V., Watanable H. Psychological stress-induced enhancement of brain lipid peroxidation via nitric oxide systems and its modulation by anxiolytic and anxiogenic drugs in mice. Brain Res. 1999;839:74–84. doi: 10.1016/S0006-8993(99)01715-1. [DOI] [PubMed] [Google Scholar]
  • [62].Maes M., Mihylova I., Kubera M., Bosmans E. Not in the mind but in the cell: increased production of cyclooxygenase-2 and inducible NO synthase in chronic fatigue syndrome. Neuro Endocrinol Lett. 2007;28:463–469. [PubMed] [Google Scholar]
  • [63].Torres R.L., Torresi L.S., Gamaro G.D., Fontella F.U., Silveira P.P., Moreira J.S.R., et al. Lipid peroxidation and total radical-trapping potential of the lungs of rats submitted to chronic and subchronic stress. Braz J Med Biol Res. 2004;37:185–192. doi: 10.1590/S0100-879X2004000200004. [DOI] [PubMed] [Google Scholar]
  • [64].Bilici M., Efe H., Koroglu M.A., Uydu H.A., Bekaroglu M., Deger O. Antioxidative enzyme activities and lipid peroxidation in major depression: alterations by antidepressant treatments. J Affect Disord. 2001;64:43–51. doi: 10.1016/S0165-0327(00)00199-3. [DOI] [PubMed] [Google Scholar]
  • [65].Sapolsky R.M. The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death. Biol Psychiatry. 2000;48:755–765. doi: 10.1016/S0006-3223(00)00971-9. [DOI] [PubMed] [Google Scholar]

Articles from Neuroscience Bulletin are provided here courtesy of Springer

RESOURCES