A novel apoE-derived therapeutic reduces vasospasm and improves outcome in a murine model of subarachnoid hemorrhage.
BACKGROUND
Recent clinical observations demonstrate that the APOE4 genotype increases the development of delayed ischemic deficit and worsens prognosis following aneurysmal subarachnoid hemorrhage (SAH). In the current study, we use targeted replacement mice expressing only human apoE3 or apoE4 to model the isoform-specific effects of apoE following SAH. We then test the hypothesis that an apoE-derived therapeutic peptide reduces vasospasm and improves functional recovery after SAH.


METHODS
Experimental SAH was induced in APOE3- and APOE4-targeted replacement mice. For 3 days following injury, daily functional assessments were made. Mice were then sacrificed and the cerebral vasculature visualized to quantify vasospasm. In a separate experiment, C57Bl/6 mice were treated with intravenous injection of vehicle, low-dose, or high-dose apoE-mimetic peptide every 12 hours for 3 days post-SAH. Functional endpoints were assessed on a daily basis, followed by measurement of middle cerebral artery diameter.


RESULTS
Mice expressing the apoE4 isoform had greater functional deficit, mortality, cerebral edema, and vasospasm as compared with their apoE3 counterparts. Mice treated with the apoE-mimetic peptide had decreased mortality, functional deficits, and histological evidence of vasospasm as compared with vehicle-treated animals.


CONCLUSIONS
Consistent with the clinical literature, the apoE4 isoform is associated with an increased incidence of vasospasm and poor functional recovery after experimental SAH. An apoE-derived peptide represents a novel therapeutic approach for the treatment of SAH.
Gao
Junling
J
Multidisciplinary Neuroprotection Laboratories, Durham, NC, USA.
Wang
Haichen
H
Sheng
Huaxin
H
Lynch
John R
JR
Warner
David S
DS
Durham
Lori
L
Vitek
Michael P
MP
Laskowitz
Daniel T
DT
D000818:Animals; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000502:physiology*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000627:therapeutic use; D020127:Recovery of Function; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D020301:Vasospasm, Intracranial / Q000209:etiology* / Q000517:prevention & control*
D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D011994:Recombinant Proteins