ABSTRACT
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.
Subject(s)
Alzheimer Disease/chemically induced , Alzheimer Disease/drug therapy , Cyclooxygenase 2 Inhibitors/pharmacology , Neuroprotective Agents/pharmacology , Pyridines/pharmacology , Salicylates/pharmacology , Sulfones/pharmacology , Alzheimer Disease/metabolism , Animals , Antibiotics, Antineoplastic/toxicity , Disease Models, Animal , Etoricoxib , Injections, Intraventricular , Lipid Peroxidation/drug effects , Male , Rats , Rats, Wistar , Streptozocin/toxicityABSTRACT
Intracerebroventricular (ICV) administration of streptozotocin (STZ) causes degeneration of hippocampal neurons through unknown mechanisms that further lead to dementia. On assumption that enzyme cyclooxygenase (COX), which catalyzes the production of pro-inflammatory prostaglandins, may be involved in ICV-STZ induced neurodegeneration, the present study was designed to investigate the effects of chronic treatment with selective inhibitor of COX-1, COX-2 or COX-3 on hippocampal neuronal density in ICV-STZ treated rats. Drugs were administered daily for 21 days, intraperitoneally, in sham control as well as ICV-STZ treated rats. After 21 days of treatment, rats were sacrificed and histological changes were observed in Cornus Ammonis (CA)-1 region of hippocampus at light microscopic level. Histopathological evaluation showed that valeryl salicylate (selective COX-1 inhibitor; 5 and 10 mg/kg; i.p.) and etoricoxib (selective COX-2 inhibitor; 5 and 10 mg/kg; i.p.) significantly increased the survival of hippocampus CA1 neurons in a dose dependent manner. On the contrary, phenacetin (selective COX-3 inhibitor; 20 and 40 mg/kg; i.p.) treatment had no effect on reduced neuronal density in ICV-STZ treated rats. In summary, these findings provide the first comprehensive description about the differential role of COX isozymes in ICV-STZ induced neuronal death in hippocampal CA1 regions of the rat brain.
