We have evaluated the effects of the
N-acetylated-alpha-linked acidic dipeptidase (
NAALADase) inhibitor,
GPI5232 [2-[(pentafluorophenylmethyl)hydroxyphosphinyl]methyl)-pentanedioic
acid], to not only decrease
brain injury but also to alter the inherent electroencephalographic (EEG) changes observed in a rat model of transient
middle cerebral artery occlusion (MCAo). Continuous i.v. infusion of
GPI5232 starting 1 h after injury resulted in more than a 50% reduction in
brain infarct volume caused by 2 h of MCAo. This effect was dose-dependent and significant even when first treatment was delayed for 2 h post-MCAo. At 24 h post-MCAo, EEG spectral analysis of the injured hemisphere revealed functional improvement in
GPI5232-treated rats. Significant recovery in high-frequency EEG power (8-30 Hz) was measured in
GPI5232-treated animals in both parietal and temporal brain regions but not in vehicle-treated animals. MCAo-injured rats were also predisposed to developing cortical brain
seizures, and
GPI5232-treated rats had significantly fewer brain
seizures than vehicle-treated animals. In separate experiments, acute high doses of
GPI5232 in normal rats did not significantly alter EEG brain activity as evaluated by spectral analysis and did not produce any signs of seizure activity or behavioral abnormalities. These results show
GPI5232 to be an effective neuroprotective treatment when given postinjury by reducing
brain infarction and ameliorating the pathological EEG associated with focal
brain ischemia.