Elsevier

Neuroscience

Volume 156, Issue 4, 28 October 2008, Pages 1111-1117
Neuroscience

Systems neuroscience
Prostacyclin receptor deletion aggravates hippocampal neuronal loss after bilateral common carotid artery occlusion in mouse

https://doi.org/10.1016/j.neuroscience.2008.07.073Get rights and content

Abstract

Transient global cerebral ischemia causes delayed neuronal death in the hippocampal CA1 region. It also induces an increase in cyclooxygenase 2 (COX-2), which generates several metabolites of arachidonic acid, known as prostanoids, including prostacyclin (PGI2). To determine the role of the PGI2 receptor (IP) in post-ischemic delayed cell death, wild-type and IP knockout (IP−/−) C57Bl/6 mice were subjected to 12-min bilateral common carotid artery occlusion or sham surgery, followed by 7 days of reperfusion. In the sham-operated mice, no statistical difference in CA1 hippocampal neuronal density was observed between the wild-type (2836±18/mm2) and IP−/− (2793±43/mm2) mice. Interestingly, in animals subjected to ischemia, surviving neuronal density in wild-type mice decreased to 50.5±7.9% and that of IP−/− mice decreased to 23.0±4.5% of their respective sham-operated controls (P<0.05). The results establish a role for the IP receptor in protecting pyramidal hippocampal neurons after this global ischemic model and suggest that IP receptor agonists could be developed to prevent delayed pyramidal neuronal cell death.

Section snippets

Animals

Experiments and procedures were conducted in accordance with the National Institutes of Health guidelines for the use of experimental animals. Protocols were approved by the Johns Hopkins Animal Care and Use Committee and were designed to minimize distress and number of animals. WT and IP−/− C57Bl/6 male mice (22–29 g) were obtained from our breeding colony, which was originated by Dr. Shuh Narumiya (Kyoto University, Kyoto, Japan) (Murata et al., 1997), and genotyped as described previously (

Mouse genotype and cerebral vessel anatomy

Polymerase chain reaction confirmed the IP−/− genotype of the mice (Fig. 1A). Because vessel anatomy/plasticity of the PcomA can affect outcome in the global ischemia model, we compared the major features of vessel anatomy of the mice. We found that the vessel anatomy of the PcomA of the IP−/− and WT mice was not remarkably different. Following the scale system of Murakami et al. (1997), the mean score values of PcomA plasticity were 1.5±0.2 in IP−/− (n=12) and 1.3±0.2 in WT (n=10) mice. The

Discussion

In this study, we showed that in mice subjected to 12 min of forebrain global cerebral ischemia followed by 7 days of reperfusion, genetic deletion of the PGI2 IP receptor results in greater delayed neuronal loss in the CA1 region of the hippocampus than that seen in WT mice. The data imply a protective role for the IP receptor in delayed pyramidal neuron cell death. Our findings in C57Bl/6 male mice are also consistent with those of other studies showing that relatively selective IP receptor

Acknowledgments

The authors would like to thank Claire Levine for her assistance in preparing this manuscript and Adam Sapirstein, Zengjing Yang, Ité Alonzo, Ellen Gordes, and every member of the Doré laboratory team for their helpful contributions. Part of this work was presented at the 2006 annual meeting of the Society for Neuroscience, Atlanta, GA. Grant support: This work was supported in part by the National Institutes of Heath: NINDS (NS046400) and the NIA (AG022971) (S.D.).

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