Partial Preventive Effect of Ibuprofen in a Mouse Model of Vascular Cognitive Impairment Induced by Unilateral Common Carotid Artery Occlusion

Abstract

Background: Vascular cognitive impairment (VCI) has been shown to be related to inflammation in previous clinical and animal studies. A recent study showed VCI and increase in inflammatory cytokines in a mouse model of right common carotid artery occlusion (rCCAO). We aimed to determine the preventive effect of an anti-inflammatory drug, ibuprofen, on VCI in an rCCAO mouse model.

Methods: C57BL/6 mice were rCCAO- or sham-operated. First, serial object recognition tests with respective vehicle and sham groups of mice were performed weekly to evaluate VCI until 4 weeks after surgery, and the discrimination index was compared. Histological observations were made 3 hours, 1 day, 1 week, and 4 weeks after surgery. Second, object recognition tests and histological studies with three groups of mice were performed 4 months after surgery to evaluate the preventive effect of ibuprofen on VCI. The experimental groups were sham (n = 15), vehicle (rCCAO-operated; n = 15), and ibuprofen (rCCAO-operated, ibuprofen-supplemented chow; n = 15).

Results: Until 4 weeks after rCCAO surgery, the discrimination index was lower in rCCAO-operated mice than in sham-operated mice, and the difference was marginally significant in week 1 (mean ± standard error: 0.35 ± 0.08 for rCCAO vs. 0.68 ± 0.12 for sham; t-test, p = 0.050). The index from week 2 to week 4 tended to be low in rCCAO-operated mice as compared to sham-operated mice, but the difference was not statistically significant. Eosin-positive neurons were not observed at all stages, but activated microglia, which was stained by using antibodies against Iba-1, was observed in some rCCAO-operated mice on day 1 and week 1. The preventive effect of ibuprofen was not sufficient on objective recognition tests (discrimination index, mean ± standard error: sham 0.36 ± 0.10, vehicle 0.01 ± 0.15 and ibuprofen 0.14 ± 0.13; analysis of variance, F = 1.987, p = 0.151), and no specific histological finding was observed 4 months after surgery.

Conslusion: The anti-inflammatory drug ibuprofen was not effective enough to prevent VCI induced by rCCAO. The effects of inflammation seemed to be evident only in the early phase in this model.