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

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 (PGI(2)). To determine the role of the PGI(2) 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/mm(2)) and IP(-/-) (2793+/-43/mm(2)) 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.

Fig. 1

Genotype and vascular features of IP^−/− and WT mice. (A) IP^−/− genotype was determined by PCR. (B) Mice of each genotype were injected with black latex to assess the major features of vessel anatomy of the PcomA. (C) Status of the PcomA in WT and IP^−/− mice was evaluated qualitatively by a 0–3 scoring system as described in Experimental Procedures. No significant anatomical differences in the PcomA were observed in IP^−/− and WT mice. arb, Arbitrary.

Fig. 2

MABP and relative CBF of sham-operated mice and mice subjected to 12 min of forebrain global ischemia followed by 7 days of reperfusion. The changes in MABP (A) and CBF (B) that occurred during and immediately after ischemia were not significantly different in WT and IP^−/− mice.

Fig. 3

Neuronal viability in the hippocampal CA1 region of sham-operated mice and mice subjected to 12 min of global ischemia followed by 7 days of reperfusion. (A) Typical histological features of the neurons in the CA1 region (arrows point to surviving neurons). (B) Statistical results show significantly greater neuronal loss in the CA1 region of IP^−/− mice than of WT mice. * P<0.05; IS: ischemia.