Ischemic tolerance induced by chronic cerebral hypoperfusion and its relationship with changes in cerebral blood flow

Abstract

[한글]

[영문]Cerebral infarction often develops in the vicinity where has been chronically hypoperfused by severe atherosclerotic stenosis. Stroke is less severe when the chronically hypoperfused area induced by bilateral carotid artery occlusion (BCAL) is subjected to severe ischemia in rats. It has been suggested that both cellular and vascular responses are induced by chronic cerebral hypoperfusion, and play roles in this protective mechanisms. However, temporal courses of cellular and vascular responses induced by the BCAL and molecular mechanisms that mediate cellular responses are not well known. This study was aimed at investigating temporal courses of cellular and vascular responses following induction of sublethal cerebral hypoperfusion. We also investigated expression of hypoxia inducible factor (HIF)-1α, heat shock protein (HSP)70 and toll-like receptor (TLR)4, which are known to be involved in ischemic tolerance.Chronic cerebral hypoperfusion was induced in Wistar rats with the BCAL. Rats were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) at 1, 4, 7, 14, 21 and 28 days after the BCAL (BCAL-MCAO group) and in rats with sham operation for the BCAL (control-MCAO group). MCAO/R was induced by a nylon suture model. Regional cerebral perfusion (rCP) was determined in the territory of the MCA by laser Doppler flowmetry (LDF). Infarct volumes were assessed based on 2,3,5-triphenyltetrazolium chloride staining. mRNA and protein expression were examined by reverse transcriptase polymerase chain reaction and western blot. Cellular localization was determined using double label staining by immunofluorescence. rCP was decreased by 63.5% immediately after BCAL, when compared with baseline. rCP, which was initially decreased by the BCAL, recovered to the baseline level 14 days later. When compared with the control-MCAO group, infarct volumes were significantly reduced from 7 days after BCAL (P<0.05). HIF-1α and HSP70 proteins increased at 1 day after BCAL. TLR4 expression increased from 1 day to 28 days after BCAL. These proteins were co-localized in neurons and endothelial cells. In this study, decrease in stroke severity induced by MCAO/R was significant before the rCP recovered after the BCAL. These findings suggest that protective cellular responses occur earlier than adaptive mechanisms by vascular remodeling. After chronic cerebral hypoperfusion, HIF-1α, HSP70 and TLR4 appeared to be involved in this endogeneous neuroprotective mechanism by neurons and endothelial cells.