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.