The science of stroke: mechanisms in search of treatments

Abstract

This review focuses on mechanisms and emerging concepts that drive the science of stroke in a therapeutic direction. Once considered exclusively a disorder of blood vessels, growing evidence has led to the realization that the biological processes underlying stroke are driven by the interaction of neurons, glia, vascular cells, and matrix components, which actively participate in mechanisms of tissue injury and repair. As new targets are identified, new opportunities emerge that build on an appreciation of acute cellular events acting in a broader context of ongoing destructive, protective, and reparative processes. The burden of disease is great, and its magnitude widens as a role for blood vessels and stroke in vascular and nonvascular dementias becomes more clearly established. This review then poses a number of fundamental questions, the answers to which may generate new directions for research and possibly new treatments that could reduce the impact of this enormous economic and societal burden.

Figures

Figure 1. Major sources of ROS in brain and blood vessels

Stroke risk factors and ischemia lead to the activation of several ROS-generating enzymatic systems. In ischemia, the increase in cytosolic Ca2+ activates the superoxide-producing enzyme NADPH oxidase (NOX), through PKC and NO derived from neuronal NOS (Brennan et al., 2009b; Girouard et al., 2009). Mitochondria become depolarized by the Ca2+ overload (Nicholls, 2008) and, possibly, by ROS derived from NADPH located near mitochondria (Girouard et al., 2009) producing large amounts of superoxide. The Ca2+-induced activation of proteases and/or the pro-oxidant environment convert xanthine dehydrogenase (XDH) to xanthine oxidase (XO) (Abramov et al., 2007), a superoxide-generating enzyme involved in purine degradation. Finally, the substrate deprivation induced by ischemia and the oxidative inactivation of essential co-factors like tetrahydrobiopterin (BH4) uncouple L-arginine oxidation from NO formation by NOS, resulting in superoxide production (NOS uncoupling) (Forstermann, 2010). Other potential sources of ROS include enzymes for arachidonic acid or catecholamine metabolism, but their participation in stroke-induced oxidative stress remains in question (Adibhatla and Hatcher, 2010; Kunz et al., 2007a).

Figure 2. The Ischemic Penumbra

The ischemic penumbra represents compromised but viable brain tissue lying distal to an occluded blood vessel. The top 3 MR images in this figure were taken in the same patient early after occlusion of the middle cerebral artery. The images are shown in the horizontal plane passing through the lateral ventricles. “Stunned but not dead tissue” is detected by magnetic resonance imaging (MRI) techniques that assess (i) the spatial extent of the perfusion or blood flow deficit that presents as red and yellow areas on perfusion weighted imaging (PWI, top left image), and (ii) severely damaged tissue in the ischemic core that presents as high-intensity areas on diffusion weighted imaging (DWI, top middle image) (Ebinger et al, 2009). In this patient, the perfusion deficit in this patient is larger than diffusion lesion. The top right image depicts the mismatch between core areas with a diffusion lesion (dark blue) and the larger areas with low perfusion (light blue). Over hours to days (see text), the core territory expands due to the complex cascades involving excitotoxicity, oxidative stress, programmed cell death mechanisms and inflammation, as the initial trigger of energy failure ultimately progresses to infarcted tissue The resulting infarct is shown in the image at the bottom of the figure and is about the size of the initial perfusion deficit in this untreated patient. In later stages, some patients may also partially recover in part, due to endogenous mechanisms of repair and remodeling (Chopp et al, 2007). MRI scans courtesy of G. Albers, Stanford.

Figure 3. The Neurovascular Unit

This schematic depicts a cerebral blood vessel and surrounding brain parenchyma that comprise the neurovascular unit. The neurovascular unit encompasses cell-cell and cell-matrix interactions between component vascular, glial and neuronal cells. Homeostatic signaling in the neurovascular unit sustains normal brain function. Dysfunctional neurovascular signaling mediates injury after stroke. During the recovery phase after stroke, neurovascular signaling may also be critically important with repair mechanisms that may involve angiogenesis, vasculogenesis and endothelial precursor mechanisms. As the blood-brain barrier heals, inflammation may convert from a deleterious to beneficial role. Reactive glia (astrocytes and pericytes) may secrete trophic factors. Synaptic and dendritic plasticity as well as axonal remyelination may provide parenchymal substrates for functional recovery. Emerging data now suggest that these phenomenon do not occur in isolation. All components of the NVU are likely to remodel in synchrony (Arai et al, 2009; Murphy and Corbett, 2009; Zhang and Chopp, 2009).