Assessment of the relative contribution of COX‐1 and COX‐2 isoforms to ischemia‐induced oxidative damage and neurodegeneration following transient global cerebral ischemia

Abstract

We investigated the relative contribution of COX-1 and/or COX-2 to oxidative damage, prostaglandin E 2 (PGE 2 ) production and hippocampal CA1 neuronal loss in a model of 5 min transient global cerebral ischemia in gerbils. Our results revealed a biphasic and significant increase in PGE 2 levels after 2 and 24-48 h of reperfusion. The late increase in PGE 2 levels (24 h) was more potently reduced by the highly selective COX-2 inhibitor rofecoxib (20 mg/kg) relative to the COX-1 inhibitor valeryl salicylate (20 mg/kg). The delayed rise in COX catalytic activity preceded the onset of histopathological changes in the CA1 subfield of the hippocampus. Post-ischemia treatment with rofecoxib (starting 6 h after restoration of blood flow) significantly reduced measures of oxidative damage (glutathione depletion and lipid peroxidation) seen at 48 h after the initial ischemic episode, indicating that the late increase in COX-2 activity is involved in the delayed occurrence of oxidative damage in the hippocampus after global ischemia. Interestingly, either selective inhibition of COX-2 with rofecoxib or inhibition of COX-1 with valeryl salicylate significantly increased the number of healthy neurons in the hippocampal CA1 sector even when the treatment began 6 h after ischemia. These results provide the first evidence that both COX isoforms are involved in the progression of neuronal damage following global cerebral ischemia, and have important implications for the potential therapeutic use of COX inhibitors in cerebral ischemia.

Wide therapeutic time window for nimesulide neuroprotection in a model of transient focal cerebral ischemia in the rat

“…Present results that nimesulide protects neurons when administered several hours after stroke is consistent with our previous studies which have found that COX-2 selective inhibitors have a wide therapeutic window for protection in global cerebral ischemia [9][10][11][12], thus extending our observations to a model of transient focal ischemic stroke.…”

“…Moreover, administration of highly selective COX-2 inhibitors has been proven to reduce brain damage and prostaglandin accumulation following cerebral ischemia [9][10][11][12]50,51]. The observations that enhanced COX-2 activity contributes to amplify cerebral injury after stroke offer an interesting prospect for targeting the late phase of the damage with COX-2 inhibitors.…”

Thrombin-Induced Oxidative Stress Contributes to the Death of Hippocampal NeuronsIn Vivo: Role of Microglial NADPH Oxidase

“…Specifically, alternate sections were obtained at 3.3, 3.6, 4.16, and 4.3 mm posterior to the bregma, and two regions from each level (n ϭ 8 regions for each animal) were used to count cells in the CA1 region. The number of neurons within the CA1 layer was counted using a light microscope (Olympus Optical) at a magnification of 400ϫ and expressed as the number of CA1 neurons per millimeter of linear length as described previously with some modifications (Candelario-Jalil et al, 2003). To maintain consistency across animals, a rectangular box (0.5 ϫ 0.05 mm) was centered over the CA1 cell layer beginning 1.5 mm lateral to the midline.…”

Alzheimer's Disease: Characterization, Evolution and Implications of the Neuroinflammatory Process

“…79 E o aàoàβáàdese pe heàu àpapelàfu da e talà na fisiopatologia da DA, ainda não está suficientemente comprovado que os depósitos de pla asàdeàβáàeàdeàe a a hadosà eu ofi ila esàseja à os causadores da doença. 80,81 A formação de neurofibrilas parece estar mais diretamente relacionada ao declínio da habilidade cognitiva, mas sua ocorrência aparentemente se dá muito ta dia e teà à a u ulaçãoà deà βá.à Po à out oà lado,à evidências experimentais apontam que protofibrilas e olig e osà βá 1-40 eà βá 1-42 contribuiriam mais do que asà pla asà deà βáà pa aà aà i jú iaà te idualà e,à consequentemente, da disfunção neuronal. 82 Além destesà efeitosà t xi os,à oà βáà podeà p o ove à aà neurodegeneração por mecanismos paralelos, incluindo a ativação de células microgliais e de astrócitos.…”

“…88 Apesar da contribuição desta isoforma à inflamação na DA não estar comprovada, há vários relatos na literatura de sua relação com a produção de PGE 2 em vários modelos experimentais de injúria aguda cerebral. 73,81 As células microgliais, macrófagos e astrócitos expressam rapidamente a iNOS quando submetidos à estimulação por LPS ou citocinas, levando à produção de NO em altas concentrações durante longos períodos, por via independente de Ca 2+ . O papel da iNOS nos mecanismos inflamatórios associados à DA foi evidenciado pelo aumento da presença de nitrotirosina em cérebros com DA, indicando exposição e dano oxidativo por peroxinitrito, um produto intermediário da síntese de NO, podendo explicar outra via de dano neuronal e tecidual.…”