Astrocytic activation and delayed infarct expansion after permanent focal ischemia in rats. Part II: suppression of astrocytic activation by a novel agent (R)-(-)-2-propyloctanoic acid (ONO-2506) leads to mitigation of delayed infarct expansion and early improvement of neurologic deficits.
A novel agent, (R)-(-)-2-propyloctanoic acid (ONO-2506), has a unique property in that it modulates functions of activated cultured astrocytes, including pronounced inhibition of S-100beta synthesis. The present study examined whether administration of this agent would mitigate the delayed expansion of infarct volume and the neurologic deficits after permanent middle cerebral artery occlusion (pMCAO) in rats. Daily intravenous administration of ONO-2506 (10 mg/kg) abolished the delayed infarct expansion between 24 and 168 hours after pMCAO, whereas the acute infarct expansion until 24 hours was unaffected. The agent significantly reduced the expression of S-100beta and glial fibrillary acidic protein in the activated astrocytes and the number of terminal deoxynucleotidyl transferase-mediated 2;-deoxyuridine 5;-triphosphate-biotin nick end labeling-positive cells in the periinfarct area. The neurologic deficits were significantly improved, compared with the vehicle-treated groups, as early as 24 hours after the initial administration of ONO-2506. The agent had a wide therapeutic time window of 0 to 48 hours after pMCAO. These results indicate that because of the pharmacologic modulation of astrocytic activation induced by ONO-2506, symptoms can regress whereas delayed expansion of the lesion is arrested. Pharmacologic modulation of astrocytic activation may confer a novel therapeutic strategy against stroke.
Tateishi
Narito
N
Minase Research Institute, Ono Pharmaceutical Co. Ltd., Shimamoto, Mishima, Osaka, Japan.
Mori
Takashi
T
Kagamiishi
Yoshifumi
Y
Satoh
Souichi
S
Katsube
Nobuo
N
Morikawa
Eiharu
E
Morimoto
Tadashi
T
Matsui
Toru
T
Asano
Takao
T
D000818:Animals; D001253:Astrocytes / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002210:Caprylates / Q000494:pharmacology*; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009414:Nerve Growth Factors; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000097:blood / Q000134:cerebrospinal fluid; D013997:Time Factors
D002210:Caprylates; D005904:Glial Fibrillary Acidic Protein; D009414:Nerve Growth Factors; C459360:ONO2506; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins