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. 2003 Aug;86(3):545-55.
doi: 10.1046/j.1471-4159.2003.01812.x.

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

Eduardo Candelario-Jalil  1 , Armando González-Falcón, Michel García-Cabrera, Dalia Alvarez, Said Al-Dalain, Gregorio Martínez, Olga Sonia León, Joe E Springer
Affiliations

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

Eduardo Candelario-Jalil et al. J Neurochem. 2003 Aug.

Abstract

We investigated the relative contribution of COX-1 and/or COX-2 to oxidative damage, prostaglandin E2 (PGE2) 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 PGE2 levels after 2 and 24-48 h of reperfusion. The late increase in PGE2 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.

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Figures

Figure 1
Figure 1
Hippocampal CA1 neuronal counts as a function of reperfusion time following 5 min transient global cerebral ischemia in the gerbil. Values are mean counts of normal-appearing CA1 neurons per mm linear length ± S.D. *p<0.05 and **p<0.01 compared with the sham-operated control group.
Figure 2
Figure 2
Effect of selective inhibition of COX-2 with Rofecoxib (A) and COX-1 with Valeryl Salicylate (B) on the number of surviving neurons in the CA1 hippocampal subfield 7 days after 5 min transient global cerebral ischemia in Mongolian gerbils. Values are mean counts of normal-appearing CA1 neurons per mm linear length ± S.D. (*p<0.05 between ischemia+vehicle and ischemia+drug treatments, **p<0.01 between sham and ischemia).
Figure 3
Figure 3
Representative photomicrographs depicting neuronal cell loss in the hippocampal CA1 region at 7 days following (A) sham surgery, (B) ischemia + vehicle, (C) ischemia + Valeryl Salicylate (20 mg/kg, starting 6 h after ischemia), and (D) ischemia + Rofecoxib (20 mg/kg, starting 6 h after ischemia). Magnification bar equals 100 microns.
Figure 4
Figure 4
Time course of hippocampal PGE2 production following 5 min of transient global cerebral ischemia in the gerbil. *p<0.05 with respect to sham-operated animals.
Figure 5
Figure 5
Effect of Rofecoxib (COX-2 inhibitor) and Valeryl Salicylate (COX-1 inhibitor) on the increase in hippocampal PGE2 seen at 2 h (A) and 24 h (B) after transient global cerebral ischemia in gerbils. In panel (C) is shown the effect of selective inhibition of COX-1 and COX-2 on the basal concentrations of PGE2 in the normal gerbil hippocampus. *p<0.05 and **p<0.01 with respect to vehicle-treated animals. In panel (C), *p<0.05 and **p<0.01 with respect to sham-vehicle group.
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