Comparison of apolipoprotein E isoform-specific effects after experimental cerebral ischemia.

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Using homozygous human apolipoprotein E2 (apoE2) (2/2)-, apoE3 (3/3)-, or apoE4 (4/4)-knock-in (KI) mice, the present study was undertaken to examine the following four aspects : (i)comparison of the apoE isoform specificity on the occurrence of early infarct expansion after focal cerebral ischemia ; (ii)comparison of the apoE isoform specificity on the occurrence of delayed infarct expansion after focal cerebral ischemia ; (iii)the analysis on the possible mechanisms underlying the apoE4 isoform-specific exacerbation of brain damage ; and (iv)the possible therapeutic intervention for this pathology.In 2002, infarct volume and neurologic deficits were found to be significantly worse in 4/4-KI mice than in 2/2- and 3/3-KI mice at 24 hours after focal cerebral ischemia, indicating that the apoE4 isoform exacerbates acute infarct expansion.In 2003, the results demonstrated that delayed infarct expansion and astrocytic activation during the subacute phase (1 to 7 days) of focal cerebral is … More chemia were markedly exacerbated in 4/4-KI mice in an isoform-specific fashion (apoE4>apoE3=apoE2). The above data indicated that the apoE4 isoform acts to augment reactive astrocytosis and the associated inflammatory responses, leading to exacerbation of delayed infarct expansion.In 2004 and 2005, the present study was performed to probe the putative causal relationship between enhanced astrocytic activation and exacerbation of brain damage in 4/4-KI mice using a modulating agent of reactive astrocytes, (R)-(-)-2-propyloctanoic acid (suppression of astrocytic activation through the negative regulation of S-100 protein synthesis). In addition, the present study was aimed to extend the possible clinical application of the agent against apoE4 isoform-specific exacerbation of brain damage. The results clearly showed that 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 significantly mitigated. The attenuation of the S100/GFAP immunoreactive burden in the peri-infarct area induced by arundic acid in 4/4-KI mice was much greater than that in 2/2- or 3/3-KI mice. The aggravation of delayed infarct expansion in 4/4-KI mice was accompanied by pronounced astrocytic activation in the peri-infarct area (as evidenced by an increase in the S100B/GFAP immunoreactive burden) as compared with the other two genetic lines of KI mice. The above results indicate that the apoE4 isoform exacerbates brain injury during the subacute phase of focal cerebral ischemia through augmentation of astrocytic activation.Based on the above data obtained from the consecutive studies during the past four years (2002 to 2005), the present study demonstrated (i)experimental evidence of the apoE4 isoform-specific exacerbation of brain damage ; (ii)causal relationship between enhanced astrocytic activation and exacerbation of brain damage in the pathogenesis of this phenomenon ; (iii)a novel therapeutic strategy by pharmacological modulation of astrocytic activation against apoE4 isoform-specific neuronal vulnerability after stroke. Less