The neurovascular unit and combination treatment strategies for stroke

Abstract

Tissue plasminogen activator (tPA) administered within 4.5h of symptom onset restores cerebral blood flow (CBF) and promotes neurological recovery of stroke patients. However, the narrow therapeutic time window and the risk of intracerebral hemorrhage after tPA treatment pose major hurdles to its clinical usage. In light of the failures of neuroprotective therapies in clinical trials, emerging concepts suggest that neuroprotection alone without restoration of tissue perfusion and vascular integrity may not be adequate for treatment of acute stroke. Here we review evidence of the use of adjuvant pharmacological agents to extend the therapeutic window for tPA via targeting the neurovascular unit and the underlying mechanisms of the combination therapy in experimental stroke.

Figure 1. Endothelial cell dysfunction and TLR signaling

In response to ischemic insult, endothelial cells express protease-activated receptor 1 (PAR-1), tissue factor (TF), and matrix metalloproteinases (MMPs). This process facilitates the accumulation of fibrin, platelet, and neutrophil, and results in microvascular obstruction. On the abluminal front, MMPs degrade neurovascular matrix, leading to acute BBB disruption. Release of endogenous ligands from damaged cells lead to the activation of TLRs, which signal through a number of adoptors and kinases, such as MyD88, IRAK, TRAF-6. These signaling cascades lead to the production of proinflammatory cytokines through the activation of transcription factors, such as NF-κB and AP-1, which contribute to neurovascular damage.

Figure 2. Effects of combination treatment with BORTEZOMIB and tPA on thrombolysis and vascular patency

Panel A shows a schematic representation of the ICA and the MCA. A large fragment of Evans blue labeled residual embolus (red) was detected within the origin of the MCA and intracranial segment of the ICA, which blocked plasma perfusion (green) from representative saline-treated rats (B). The combination treatment with bortezomib and tPA resulted in only a small fragment of residual embolus (C, red) at the origin of the MCA where was well perfused by FITC-dextran (C, green). Panels D and E are two-dimensional projections of fibrin/fibrinogen immunoreactivity (red) and vascular plasma perfusion (green) acquired from representative rats treated with saline (D), and combination of BORTEZOMIB and tPA (E). Intravascular fibrin/fibrinogen immunoreactivity was associated with the absence of plasma perfusion in saline treated rats (Arrows in D), suggesting intravascular fibrin deposition blocks plasma perfusion. The combination treatment with bortezomib and tPA reduced number of fibrin/fibrinogen immunoreactive vessels and preserved plasma perfusion compared with saline treated rats. Bars = 400μm for panels B and C, and 100μm for panels D and E.