Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 1998 Sep 1;95(18):10954-9.
doi: 10.1073/pnas.95.18.10954.

Cyclooxygenase-2 inhibition prevents delayed death of CA1 hippocampal neurons following global ischemia

M Nakayama  1 , K Uchimura, R L Zhu, T Nagayama, M E Rose, R A Stetler, P C Isakson, J Chen, S H Graham
Affiliations

Cyclooxygenase-2 inhibition prevents delayed death of CA1 hippocampal neurons following global ischemia

M Nakayama et al. Proc Natl Acad Sci U S A. .

Abstract

The inducible isoform of the enzyme cyclooxygenase-2 (COX2) is an immediate early gene induced by synaptic activity in the brain. COX2 activity is an important mediator of inflammation, but it is not known whether COX2 activity is pathogenic in brain. To study the role of COX2 activity in ischemic injury in brain, expression of COX2 mRNA and protein and the effect of treatment with a COX2 inhibitor on neuronal survival in a rat model of global ischemia were determined. Expression of both COX2 mRNA and protein was increased after ischemia in CA1 hippocampal neurons before their death. There was increased survival of CA1 neurons in rats treated with the COX2-selective inhibitor SC58125 [1-[(4-methylsulfonyl) phenyl]-3-trifluoro-methyl-5-[(4-fluoro)phenyl] pyrazole] before or after global ischemia compared with vehicle controls. Furthermore, hippocampal prostaglandin E2 concentrations 24 h after global ischemia were decreased in drug-treated animals compared with vehicle-treated controls. These results suggest that COX2 activity contributes to CA1 neuronal death after global ischemia.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Dipped emulsion photomicrographs of COX2 in situ hybridization of coronal sections of the rat brain after global ischemia. Shown are nonischemic rat (A), and photos 2 h (B), 4 h (C), 8 h (D), 24 h (E), and 72 h (F) after 20 min of global ischemia.
Figure 2
Figure 2
Protein expression. (A) Western blot analysis of protein extracts obtained from rat hippocampi at 4 h, 8 h, 24 h, and 72 h after 15 min of global ischemia and nonischemic controls (C) and hippocampi 24 h after sham operation (S24). (B) Graph summarizing results of Western blots from four to six animals/group. Changes in COX2 expression are expressed as ratio to control lane optical density × area measurements (n = 4–6/group). ∗, P < 0.05 greater than control, Mann–Whitney U test; mean ± SE.
Figure 3
Figure 3
Photomicrographs of COX2 immunocytochemistry from coronal sections through anterior hippocampus: 24 h after 15 min of global ischemia (A); 24 h after global ischemia, antibody preabsorbed with recombinant murine COX2 protein (B); 24 h after sham operation (C); hylar region, 24 h after global ischemia (D); CA1 24 h after global ischemia (E); and hylar region, 24 h after sham operation (F). [Bars = 400 μm (A–C), 50 μm (D and F), and 25 μm (E).]
Figure 4
Figure 4
Effect of drug treatment upon hippocampal PGE2 concentrations. (A) Dose-response relationship of SC58125 and piroxicam upon PGE2 concentrations in nonischemic brain. Data shown as percent of maximal effect. (B) Effect of treatment with maximally effective doses of SC58125 (30 mg/kg) and piroxicam (30 mg/kg) upon PGE2 concentration in nonischemic hippocampus. (C) Effect of treatment with maximally effective doses of SC58125 (30 mg/kg) and piroxicam (30 mg/kg) upon PGE2 concentrations in hippocampus after global ischemia. ∗∗, P < 0.01 different than nonischemic controls; #, P < 0.05 different than piroxicam-treated group; ANOVA; mean ± SE.
Figure 5
Figure 5
Graph summarizing effect of SC58125 and piroxicam treatment upon CA1 neuronal counts in cresyl violet-stained sections. Brain temp. refers to minimum brain temperature during ischemia, if monitored. Treatment time refers to the first time that drugs were administered, either before (preischemia) or after global ischemia (postischemia). Sacrifice time refers to the time at which rats were euthanized for histology. (A) Animals were treated 15 min before and at 24 and 48 h after induction of 20 min of global ischemia. Rats were sacrificed 72 h after ischemia (n = 10/group). (B) Animals were treated 15 min before, and 24 and 48 h after, 15 min of global ischemia. Rats were sacrificed at 14 days (n = 10/group). (C) Animals were treated 1 h after 15 min of global ischemia. Rats were sacrificed at 14 days (n = 7–8/group). (D) Comparison of treatment with SC58125 30 mg/kg and piroxicam 30 mg/kg upon neuronal survival at 3 days (n = 8/group). (E) Naïve control rats (n = 5). ∗, P < 0.05 greater than vehicle-treated group; +, P < 0.05 different than SC58125-treated rats; ANOVA; mean ± SE.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. DeWitt D L, Smith W L. Proc Natl Acad Sci USA. 1988;85:1412–1416. - PMC - PubMed
    1. Reiger M K, DeWitt D L, Schindler M S, Smith W L. Arch Biochem Biophys. 1993;301:439–444. - PubMed
    1. Smith, W. L., DeWitt, D. L. & Shimokawa, T. (1991) Adv. Prostaglandin Thromboxane Leukotrine Res. 77–80. - PubMed
    1. Kujubu D A, Fletcher B S, Varnum B C, Lim R W, Herschman H R. J Biol Chem. 1991;266:12866–12872. - PubMed
    1. Kujubu D A, Herschman H R. J Biol Chem. 1992;267:7991–7994. - PubMed

Publication types

MeSH terms

Substances