Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic

Abstract

Restorative cell-based and pharmacological therapies for experimental stroke substantially improve functional outcome. These therapies target several types of parenchymal cells (including neural stem cells, cerebral endothelial cells, astrocytes, oligodendrocytes, and neurons), leading to enhancement of endogenous neurogenesis, angiogenesis, axonal sprouting, and synaptogenesis in the ischaemic brain. Interaction between these restorative events probably underpins the improvement in functional outcome. This Review provides examples of cell-based and pharmacological restorative treatments for stroke that stimulate brain plasticity and functional recovery. The molecular pathways activated by these therapies, which induce remodelling of the injured brain via angiogenesis, neurogenesis, and axonal and dendritic plasticity, are discussed. The ease of treating intact brain tissue to stimulate functional benefit in restorative therapy compared with treating injured brain tissue in neuroprotective therapy might more readily help with translation of restorative therapy from the laboratory to the clinic.

Figure 1. Neurogenesis in the SVZ of the lateral ventricle of adult rodent non-ischaemic and ischaemic brain tissue

A and B show sagittal and coronal views, respectively, of rat brain tissue in the SVZ. SVZ cells in the non-ischaemic brain are proliferating, as shown by BrdU-positive cells (C, arrows, brown dots). After stroke, the number of these proliferating cells increased (D, brown). Confocal microscopic images (E and F) show that BrdU-positive cells (green) are positive for doublecortin (red), indicating that these are newly generated neuroblasts. G to I show doublecortin-positive cells (red) in the ischaemic (G and H) and non-ischaemic (I) hemispheres of rats treated with erythropoietin (G) and saline (H and I). Treatment of erythropoietin substantially increased doublecortin-positive cells in the SVZ and ischaemic striatum (G). Bars are 50 μm (D), 20 μm (E), and 10 μm (F). BrdU=5-bromo-2′-deoxyuridine. CC=corpus callosum. DG=dentate gyrus. EPO=erythropoietin. LV=lateral ventricle. OB=olfactory bulb. RMS=rostral migratory stream. Str=striatum. SVZ=subventricular zone.

Figure 2. Stroke induces angiogenesis within the ischaemic boundary

Immunostaining with antibodies against BrdU shows proliferative endothelial cells of cerebral blood vessels (A, arrowheads). Sprouting cerebral vessels are detected with immunoreactive von Willebrand factor (B, arrowhead) and shown on three-dimensional images obtained from confocal microscopy (C, arrowheads). Proliferating endothelial cells and sprouting vessels contribute to angiogenesis seen at the ischaemic boundary region (D). D is a three-dimensional image of angiogenesis at the cortical ischaemic boundary of a rat 14 days after stroke. Bars are 10 μm (A) and 50 μm (B). BrdU=5-bromo-2'-deoxyuridine.

Figure 3. Cerebral angiogenesis identified with MRI and confocal images

SWI of brain coronal sections shows dark areas at the ischaemic boundary (A and D, arrowheads), which match angiogenic areas detected with confocal microscopy (B and E, arrowheads). These areas show increased CBF measured with perfusion-weighted MRI (C and F, arrowheads). All images were acquired 6 weeks after stroke from rats treated with EPO (A to C) and saline (D to F). CBF=cerebral blood flow. EPO=erythropoietin. SWI=susceptibility-weighted imaging.

Figure 4. Diffusion tensor imaging measurements of FA and fibre tracking

(A) A three-dimensional DTT image shows tracking of axonal projections (red) in a selected area of the CC and cortex (green). (B) A confocal image shows similar patterns of axonal projections in the same area. Treatment of stroke with sildenafil increases axonal projections (C) and FA concentrations (E, arrow) at the ischaemic boundary compared with animals treated with saline (D and F, arrow). CC=corpus callosum. DTT=diffusion tensor tractography. FA=fractional anisotropy.