Arundic acid (ONO-2506) ameliorates delayed ischemic brain damage by preventing astrocytic overproduction of S100B.
After focal cerebral ischemia, the infarct volume increases rapidly within acute infarct expansion (initial 12 to 24 h) and continues slowly during delayed infarct expansion (25 to 168 h). While acute infarct expansion represents progressive necrosis within the ischemic core, delayed infarct expansion starts as disseminated apoptotic cell death in a narrow rim surrounding the infarct border, which gradually coalesces to form a larger infarct. Discovery of a distinct correlation between reactive astrogliosis along the infarct border and delayed infarct expansion in the rodent ischemia model led us to investigate the possible causal relationship between the two events. Specifically, the calcium binding protein S100B exerts detrimental effects on cell survival through activation of various intracellular signaling pathways, resulting in altered protein expression. Arundic acid [(R)-(-)-2-propyloctanoic acid, ONO-2506] is a novel agent that inhibits S100B synthesis in cultured astrocytes. In the rodent ischemia model, this agent was shown to inhibit both the astrocytic overexpression of S100B and the subsequent activation of signaling pathways in the peri-infarct area. Concurrently, delayed infarct expansion was prevented, and neurologic deficits were promptly ameliorated. The results of subsequent studies suggest that the efficacy of arundic acid is mediated by restoring the activity of astroglial glutamate transporters via enhanced genetic expression.
Asano
T
T
Department of Neurosurgery, Saitama Medical Center/ School, Kawagoe, Saitama 350-8550, Japan. asano@ns2.saitama-med.ac.jp
Mori
T
T
Shimoda
T
T
Shinagawa
R
R
Satoh
S
S
Yada
N
N
Katsumata
S
S
Matsuda
S
S
Kagamiishi
Y
Y
Tateishi
N
N
D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001925:Brain Damage, Chronic / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002210:Caprylates / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D000882:Haplorhini; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000096:biosynthesis* / Q000378:metabolism*
D001057:Apolipoproteins E; D002210:Caprylates; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; C459360:ONO2506; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human; C579159:S100b protein, mouse; C579158:S100b protein, rat