Abstract TP429: The Protective and Withdrawal Effects of Atorvastatin on Endothelial Barrier in Cerebral Ischemia and Reperfusion Injury

Background and purpose— Statins can effectively attenuate focal cerebral ischemic injury. However, the role of statins in modulating permeability of endothelial barrier in ischemia-reperfusion (IR) and the impact of statins withdrawal on endothelial barrier during the acute phase of IR are unclear. Methods— Focal cerebral ischemia (2 hours) was created in adult male Sprague-Dawley rats (240 to 270 g) by middle cerebral artery occlusion (MCAO) using a suture. Rats were randomly treated with vehicle, atorvastatin daily for 7 days before MCAO (pretreatment), 3 days after MCAO (post operative treatment), or both 7 days before and 3 days after MCAO (continuous treatment). Brains were harvested at 24 and 72 hours after reperfusion for assays of brain edema (n=5), BBB leakage (n=5), calculations of occludin and claudin-5 positive vessels (n=5) and expression of occludin, claudin-5 and Phosphoinositide 3-kinase (PI3K)-γ (n=5), respectively. Results— 24 hours after reperfusion, pretreatment with atorvastatin significantly reduced BBB leakage (7.55±0.63ng/g versus 9.38±0.77ng/g; P<0.05) and brain edema (83.96%±1.11% versus 86.77%±1.26%; P<0.05), as evidenced by Evans blue extravasation and brain water content measurement. Immunofluorescence assay and western blot revealed atorvastatin significantly increased the expression of occludin and claudin-5 and attenuated IR-induced increased expression of PI3Kγ compared with vehicle treatment. 72 hours after reperfusion, post operative treatment with atorvastatin for 3 days and continuous treatment both attenuated the above IR injuries to endothelial barrier (P<0.05), particularly the latter. However, atorvastatin pretreatment no longer had protective effects on BBB leakage, brain edema and the expression of PI3Kγ (P<0.05), although pretreatment with atorvastain for 7 days increased the expression of occludin and claudin-5 up to 72 hours after reperfusion (P<0.05). Conclusions— These results demonstrate that protective effects of atorvastatin against endothelial barrier breakdown may be related to the up-regulation of occludin and claudin-5 and down-regulation of PI3Kγ. However, there are no withdrawal effects of atorvastain on endothelial barrier during the acute phase of IR (72 hours).