Mouse model of focal cerebral ischemia using endothelin-1

Abstract

Intracerebral injection of the vasoconstrictor peptide, endothelin-1 (ET-1), has been used as a method to induce focal ischemia in rats. The relative technical simplicity of this model makes it attractive for use in mice. However, the effect of ET-1 on mouse brains has not been firmly established. In this study, we determined the ability of ET-1 to induce focal cerebral ischemia in four different mouse strains (CD1, C57/BL6, NOD/SCID, and FVB). In contrast to rats, intracerebral injection of ET-1 did not produce a lesion in any mouse strain tested. A combination of ET-1 injection with either CCA occlusion or N(G)-nitro-l-arginine methyl ester (l-NAME) injection produced only a small infarct and its size was strain-dependent. A triple combination of CCA occlusion with co-injection of ET-1 and l-NAME produced a lesion in all mouse strains tested, and this resulted in a significant motor deficit. However, lesion size was still relatively small and strain-dependent. This study shows that ET-1 has a much less potent effect for producing an infarct in mice than rats.

Models That Matter: White Matter Stroke Models

“…In contrast, a white matter stroke model generated by ET-1 injection into subcortical white matter in C57/BL6 mice [24] shows lesions that mimic small lacunar infarcts. Similar to Horie et al, [31] a dose-dependent mortality was seen, however, a significantly lower amount (360 ng) was sufficient to cause the white matter infarct. This additional discrepancy of tissue dependent ET-1 effects further complicates the modeling of white matter stroke in mice.…”

“…In the study carried out by Horie et al [31] intrastriatal microinjection of 1.0 μg ET-1 alone failed to cause a distinct lesion in multiple strains of mice. Furthermore, the injury is proven to be independent of ET-1 dose, because increasing the injection dose only contributed to postoperative mortality and not lesion formation.…”

“…For instance, Wiley et al [32] reported that the mouse brain expresses twice as many of ETB-R than ETA-R. As such, ET-1 administration could have a predominantly vasodilatory effect in mice. For that reason, Horie et al [31] combined injection of nitric oxide synthase (NOS) inhibitor L-N6-Nitroarginine methyl ester (L-NAME) (to counter ET-1-mediated vasodilation) and/or common carotid occlusion to produce striatal infarcts. Yet, the lesion size was still minimal and the effect was found to be mouse strain-dependent.…”

“…Compensation in behavior of the ipsilateral paw may be responsible for these results. Subcortical/striatal injury in the mouse also indicates decreased forelimb motor function after 2 days of ET-1 injection [31]. Further time point data is not available to assess long-term effects of these infarcts.…”

A Versatile Murine Model of Subcortical White Matter Stroke for the Study of Axonal Degeneration and White Matter Neurobiology

“…A number of prior models of subcortical stroke have been described including focal injections of endothelin-1 into the internal capsule, subcortical white matter and striatum in the rat [12][13][14] and mouse 6,15 . More recent models of small focal strokes have utilized cholesterol microemboli injection in the carotid artery 16 and photothrombotic occlusion of a single penetrating arteriole 17 .…”