1. ¹Institute of Medical Science, Saitama Medical Center/School, Kawagoe, Saitama, Japan
2. ²Section of Immunobiology, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, Connecticut, USA
3. ³Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, Florida, USA
4. ⁴Minase Research Institute, Ono Pharmaceutical Co. Ltd, Mishima, Osaka, Japan
5. ⁵Department of Neurosurgery, Saitama Medical Center/School, Kawagoe, Saitama, Japan

Correspondence: Dr T Asano or Dr T Mori, Department of Neurosurgery, Saitama Medical Center/School, 1981 Kamoda, Kawagoe, Saitama 350-8550, Japan. E-mails: asano@saitama-med.ac.jp, t_mori@saitama-med.ac.jp

Received 12 August 2004; Revised 13 October 2004; Accepted 25 October 2004; Published online 2 February 2005.

Abstract

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 (mm³) 1s.d. in 2/2-, 3/3-, or 4/4-KI mice in the vehicle groups: 162, 152, or 222; in the arundic acid groups: 112 (P<0.001), 112 (P<0.001), or 122 (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 4 carriers.