Experimental models, neurovascular mechanisms and translational issues in stroke research

Abstract

Numerous failures in clinical stroke trials have led to some pessimism in the field. This short review examines the following questions: Can experimental models of stroke be validated? How can combination stroke therapies be productively pursued? Can we achieve neuroprotection without reperfusion? And finally, can we move from a pure neurobiology view of stroke towards a more integrative approach targeting all cell types within the entire neurovascular unit? Emerging data from both experimental models and clinical findings suggest that neurovascular mechanisms may provide new opportunities for treating stroke. Ultimately, both bench-to-bedside and bedside-back-to-bench interactions may be required to overcome the translational hurdles for this challenging disease.

Figure 1

The original definition of the ischaemic penumbra as an electrophysiologic phenomenon. In areas of moderate blood flow loss, evoked potentials (upper panel) are affected whereas membrane potentials (lower panel) are maintained. With improved blood flow, partial recovery of evoked potentials is possible. Without reperfusion, the membrane potential ultimately collapses as anoxic depolarization occurs. Adapted from Astrup et al. (1977), with permission from Stroke and the American Heart Association.

Figure 2

(A) Spreading waves of cortical depression emanate from the ischaemic focus in mice subjected to focal occlusion of the middle cerebral artery. Each passage of these peri-ischaemic waves appears to expand areas of severely hypoperfused cortex, thus inducing a growth of the lesion over time. Upper panels show quantified data. Lower panels depict speckle contrast images of cerebral perfusion collected during representative experiment. Adapted from Shin et al. (2006), with permission from Annals of Neurology. (B) Normobaric hyperoxia suppresses spreading waves of cortical depression in mice subjected to focal occlusion of the middle cerebral artery (upper panel), prevents the collapse of penumbral tissue and ameliorates the expansion of critically ischaemic brain tissue (lower panel). Adapted from Shin et al. (2007), with permission from Brain.

Figure 3

(a) A search of the PubMed database reveals that the majority of basic cell death research in stroke is focused on neurons alone. The number of papers investigating mechanisms in glia and cerebral endothelium are relatively few. A change from a purely neurocentric focus to a more integrative approach is required to address the entire neurovascular unit in stroke. Adapted from Lo et al. (2005), with permission from Stroke. (b) A schematic of the neurovascular unit emphasizing the importance of cell–cell and cell–matrix signalling between neurons, astrocytes and endothelium. This simplified figure does not include many other cell types, including oligodendrocytes, pericytes and smooth muscle cells. Ultimately, all cell interactions must be considered in whole brain physiology and pathology. Adapted from Lo et al. (2004), with permission from Stroke.