Abstract
Reversible blood-brain barrier (BBB) disruption has been uniformly reported in several animal models of postoperative cognitive dysfunction (POCD). Nevertheless, the precise mechanism underlying this occurrence remains unclear. Using an aged rat model of POCD, we investigated the dynamic changes in expression of molecules involved in BBB disintegration, matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9), as well as three of their endogenous tissue inhibitors of MMP (TIMP-1, -2, -3), and tried to establish the correlation between MMP/TIMP balance and surgery-induced hippocampal BBB disruption. We validated the increased hippocampal expression of angiotensin II (Ang II) and Ang II receptor type 1 (AT1) after surgery. We also found MMP/TIMP imbalance as early as 6 h after surgery, together with increased BBB permeability and decreased expression of Occludin and zonula occludens-1 (ZO-1), as well as increased basal lamina protein laminin at 24 h postsurgery. The AT1 antagonist candesartan restored MMP/TIMP equilibrium and modulated expression of Occludin and laminin, but not ZO-1, thereby improving BBB permeability. These events were accompanied by suppression of the surgery-induced canonical nuclear factor-κB (NF-κB) activation cascade. Nevertheless, AT1 antagonism did not affect nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) expression. Collectively, these findings suggest that surgery-induced Ang II release impairs BBB integrity by activating NF-κB signaling and disrupting downstream MMP/TIMP balance via AT1 receptor.
Highlights
An aging population and new medical developments make surgery increasingly frequent in elderly patients
We addressed whether disturbance of the well-balanced equilibrium of matrix metalloproteinase (MMP) and tissue inhibitors of matrix metalloproteinase (TIMP) could serve as a bridge mechanism between surgery-induced Ang angiotensin II (II) expression and postoperative blood-brain barrier (BBB) disruption
The major focus of the present study was to determine hippocampal expressions of MMPs and TIMPs after surgery, and to address whether a disturbed MMP/TIMP balance could serve as the underlying mechanism of surgery-induced BBB disruption
Summary
An aging population and new medical developments make surgery increasingly frequent in elderly patients. The development of POCD is considered a multifactorial process, with bloodbrain barrier (BBB) dysfunction and neuroinflammation cited as potential mechanisms (Terrando et al, 2011; He et al, 2012; Cao et al, 2015; Hu et al, 2014). Surgery/anesthesia disrupts BBB integrity, resulting in increased permeability, which facilitates migration of macrophages into the cerebral parenchyma and neuroinflammatory cascade in the hippocampus (Terrando et al, 2011; Cao et al, 2015), a structure critical for proper neurocognitive function. The exact mechanisms underlying surgery/anesthesia-induced reversible BBB disruption remain poorly understood
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