title: Attenuation of a delayed increase in the extracellular glutamate level in the peri-infarct area following focal cerebral ischemia by a novel agent ONO-2506.
abstract: A novel agent, ONO-2506 [(R)-(-)-2-propyloctanoic acid, ONO Pharmaceutical Co. Ltd.] was previously shown to mitigate delayed infarct expansion through inhibition of the enhanced production of S-100beta, while inducing a prompt symptomatic improvement that attained a significant level as early as 24h after drug administration. To elucidate the mechanism underlying the prompt symptomatic improvement, the present study aimed to examine whether ONO-2506 modulates the level of extracellular glutamate ([Glu]e) in the rat subjected to transient middle cerebral artery occlusion (tMCAO). In this model, it had been shown that ONO-2506 reduces the infarct volume, improves the neurological deficits, and enhances the mRNA expression of glial glutamate transporters (GLT-1 and GLAST). The [Glu]e levels in the ischemic cortices were continuously measured using intracerebral microdialysis. The alterations in the [Glu]e levels in the sham-operated and tMCAO-operated groups with or without drug administration were compared. In the tMCAO groups, the [Glu]e level increased during tMCAO to a similar extent, returned to normal on reperfusion, and increased again around 5h. In the saline-treated group, however, the [Glu]e level further increased from 15 h on to reach about 280% of the normal level at 24h. This secondary increase in the [Glu]e level in the late phase of reperfusion was prevented by ONO-2506. The intracerebral infusion of glutamate transporter inhibitor, l-trans-pyrrolidine-2,4-dicarboxylic acid, at 24h after tMCAO induced an increase in the [Glu]e level, which was marked in both the sham-operated and ONO-2506-treated groups, but much less pronounced in the saline-treated group. The above results suggest that functional modulation of activated astrocytes by pharmacological agents like ONO-2506 may inhibit the secondary rise of [Glu]e level in the late phase of reperfusion, leading to amelioration of delayed infarct expansion and neurological deficits.
authors.affiliation: Institute of Laboratory Animal Science, Saitama Medical Center/School, 1981 Kamoda, Kawagoe, Saitama 350-8550, Japan. t.mori@saitama-med.ac.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Mori
authors.forename: Narito
authors.initials: N
authors.lastname: Tateishi
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Kagamiishi
authors.forename: Taiji
authors.initials: T
authors.lastname: Shimoda
authors.forename: Souichi
authors.initials: S
authors.lastname: Satoh
authors.forename: Sakiko
authors.initials: S
authors.lastname: Ono
authors.forename: Nobuo
authors.initials: N
authors.lastname: Katsube
authors.forename: Takao
authors.initials: T
authors.lastname: Asano
mesh_terms: D000818:Animals; D002210:Caprylates / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D007700:Kinetics; D017551:Microdialysis; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values
chemical_list: D002210:Caprylates; C459360:ONO2506; D018698:Glutamic Acid