Abstract
The extent of stroke damage in patients affects the range of subsequent pathophysiological responses that influence recovery. Here we investigate the effect of lesion size on development of new blood vessels as well as inflammation and scar formation and cellular responses within the subventricular zone (SVZ) following transient focal ischemia in rats (n = 34). Endothelin-1-induced stroke resulted in neurological deficits detected between 1 and 7 days (P<0.001), but significant recovery was observed beyond this time. MCID image analysis revealed varying degrees of damage in the ipsilateral cortex and striatum with infarct volumes ranging from 0.76–77 mm3 after 14 days, where larger infarct volumes correlated with greater functional deficits up to 7 days (r = 0.53, P<0.05). Point counting of blood vessels within consistent sample regions revealed that increased vessel numbers correlated significantly with larger infarct volumes 14 days post-stroke in the core cortical infarct (r = 0.81, P<0.0001), core striatal infarct (r = 0.91, P<0.005) and surrounding border zones (r = 0.66, P<0.005; and r = 0.73, P<0.05). Cell proliferation within the SVZ also increased with infarct size (P<0.01) with a greater number of Nestin/GFAP positive cells observed extending towards the border zone in rats with larger infarcts. Lesion size correlated with both increased microglia and astrocyte activation, with severely diffuse astrocyte transition, the formation of the glial scar being more pronounced in rats with larger infarcts. Thus stroke severity affects cell proliferation within the SVZ in response to injury, which may ultimately make a further contribution to glial scar formation, an important factor to consider when developing treatment strategies that promote neurogenesis.
Highlights
The degree of brain injury varies between each stroke victim and infarct volume has been shown to directly correlate with functional improvements 90 days post-stroke [1]
We have previously reported the benefits of predicting stroke outcome using the ET-1 model of stroke in conscious rats, where variability in stroke severity reliably correlates with infarct volumes up to 3 day post-stroke [14]
By 14 days Nestin expressing reactive astrocytes are detected within the glial scar and possibly indicate a new cell population of reactive astrocytes that have migrated from the subventricular zone (SVZ) to the site of injury in response to stroke. These results indicate that without intervention, newly generated stem cells extend towards the damaged brain but have a greater propensity to become astrocytes that in turn contribute to glial scar formation that poses a major obstacle to brain repair
Summary
The degree of brain injury varies between each stroke victim and infarct volume has been shown to directly correlate with functional improvements 90 days post-stroke [1]. With the development of treatment strategies that promote brain repair, a similar comprehensive evaluation of patients following stroke will be required to assist in defining patients more likely to respond to brain restoration treatments and rule out those that lack the biological factors required to achieve improved functional outcomes [14,15]. This highlights the need to further understand endogenous repair mechanisms and their response to different grades of stroke severity and subsequent damage
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