Brain Remodelling following Endothelin-1 Induced Stroke in Conscious Rats

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.

A pilot study on transient ischemic stroke induced with endothelin-1 in the rhesus monkeys

“…This suggested there were no side-effects from the surgery influencing the behavioral deficits on D8 and D15. These findings were consistent with previous findings in rodents7891011 and marmosets1213. In these researches, executive function, motor function and sensorimotor behavior was impaired after intracranial ET-1 injection.…”

“…ET-1 has recently been used to induce focal ischemia leading to impaired executive memory function and to impaired pure-motor and sensorimotor behaviors that are dependent on the specific area of ischemic insult in rodents7891011. There have been a few non-human primate studies utilizing ET-1 induced cerebral ischemia models developed in marmoset monkeys1213.…”

A NeuroD1 AAV-Based Gene Therapy for Functional Brain Repair after Ischemic Injury through In Vivo Astrocyte-to-Neuron Conversion

“…ET-1 has been previously used to induce ischemic lesions in rat models of stroke. 37,47 Accordingly, we found that intra-BLA infusion of ET-1 (1-21) (3 mL/side, 400 pmol) induced a robust lesion in BLA ( Figure S5). Behaviorally, rats infused with ET-1 showed a significant reduction in the acquisition of a conditioned freezing response to the tone, in comparison to a saline-infused control group ( Figure 8B, day 21).…”

Functional repair after ischemic injury through high efficiency in situ astrocyte-to-neuron conversion

“…This interval was based on pilot studies showing a significant impairment in fear acquisition combined with significant 385 neuronal injury approximately 21 days after the ET-1 stroke. The 21-day time point also 386 helped to maximize glial scar formation following ET-1 lesion (Abeysinghe et al, 2014), 387 an important factor to consider when using cell conversion strategies. ET-1 has been 388 previously used to induce ischemic lesions in rat models of stroke 23, 33 .…”