Modulation of astrocytic activation by arundic acid (ONO-2506) mitigates detrimental effects of the apolipoprotein E4 isoform after permanent focal ischemia in apolipoprotein E knock-in mice.
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.
Mori
Takashi
T
Institute of Medical Science, Saitama Medical Center/School, Kawagoe, Japan. t_mori@saitama-med.ac.jp
Town
Terrence
T
Tan
Jun
J
Tateishi
Narito
N
Asano
Takao
T
D000818:Animals; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001786:Blood Glucose; D001794:Blood Pressure; D001831:Body Temperature; D002545:Brain Ischemia / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002210:Caprylates / Q000494:pharmacology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009418:S100 Proteins / Q000378:metabolism
D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D001786:Blood Glucose; D002210:Caprylates; D005904:Glial Fibrillary Acidic Protein; C459360:ONO2506; D009418:S100 Proteins