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Sporadic Alzheimer's disease is an age-related neurological and psychiatric disorder characterized by impaired energy metabolism. Oxidative stress and neuroinflammation have been implicated in pathophysiology of sporadic type of dementia. The central streptozotocin administration induces behavioral and biochemical alterations resembling those in sporadic type of Alzheimer's patients. The present study was designed to investigate the effects of chronic pretreatment with cyclooxygenase-1 or cyclooxygenase-2 or cyclooxygenase-3 selective inhibitors on cognitive dysfunction and oxidative stress markers in intracerebroventricular streptozotocin-treated rats. Chronic treatment with valeryl salicylate (5 and 10 mg/kg, i.p.) and etoricoxib (5 and 10 mg/kg, i.p.) on a daily basis for a period of 21 days, beginning 1 h prior to first intracerebroventricular streptozotocin injection, significantly improved streptozotocin-induced cognitive impairment. However, phenacetin (20 and 40 mg/kg, i.p.) failed to restore the cognitive performances of streptozotocin-treated rats. Besides, improving cognitive dysfunction, chronic administration of highly selective cyclooxygenase-1 and/or cyclooxygenase-2 inhibitors (valeryl salicylate and etoricoxib, respectively), but not cyclooxygenase-3 inhibitor (phenacetin), significantly reduced elevated malondialdehyde, nitrite levels, and restored reduced glutathione and superoxide dismutase levels. Furthermore, cyclooxygenase-1 and/or cyclooxygenase-2 inhibitors significantly increased the survival of pyramidal neurons. In summary, we demonstrate for the first time that both cyclooxygenase-1 and cyclooxygenase-2 isoforms, but not cyclooxygenase-3, are involved in the progression of neuronal damage in intracerebroventricular streptozotocin-treated rats.