Using homozygous human
apolipoprotein E2 (
apoE2) (2/2)-,
apoE3 (3/3)-, or
apoE4 (4/4)-knock-in (KI) mice, we have shown that delayed
infarct expansion and reactive
astrocytosis after permanent
middle cerebral artery occlusion (pMCAO) were markedly exacerbated in 4/4-KI mice as compared with 2/2- or 3/3-KI mice. Here, we probed the putative causal relationship between enhanced astrocytic activation and exacerbation of brain damage in 4/4-KI mice using
arundic acid (ONO-2506, Ono
Pharmaceutical Co. Ltd), which is known to oppose astrocytic activation through its inhibitory action on S100B synthesis. In all of the KI mice, administration of
arundic acid (10 mg/kg day, intraperitoneal, started immediately after pMCAO) induced significant amelioration of brain damage at 5 days after pMCAO in terms of
infarct volumes (results expressed as the mean
infarct volume (mm(3)) +/-1s.d. in 2/2-, 3/3-, or 4/4-KI mice in the vehicle groups: 16 +/- 2, 15 +/- 2, or 22 +/- 2; in the
arundic acid groups: 11 +/- 2 (P < 0.001), 11 +/- 2 (P < 0.001), or 12 +/- 2 (P < 0.001), as compared with the vehicle groups),
neurologic deficits, and S100/
glial fibrillary acidic protein burden in the peri-
infarct area. The beneficial effects of
arundic acid were most pronounced in 4/4-KI mice, wherein delayed
infarct expansion together with deterioration of
neurologic deficits was almost completely mitigated. The above results support the notion that the
apoE4 isoform exacerbates brain damage during the subacute phase of pMCAO through augmentation of astrocytic activation. Thus, pharmacological modulation of astrocytic activation may confer a novel therapeutic strategy for ischemic brain damage, particularly in
APOE epsilon4 carriers.