Electroencephalogram analysis and neuroprotective profile of the N-acetylated-alpha-linked acidic dipeptidase inhibitor, GPI5232, in normal and brain-injured rats

We have evaluated the effects of the N-acetylated-alpha -linked acidic dipe ptidase (NAALADase) inhibitor, GPI5232 [2-[(pentafluorophenylmethyl)hydroxy phosphinyl]methyl)-pentanedioic acid], to not only decrease brain injury bu t also to alter the inherent electroencephalographic (EEG) changes observed in a rat model of transient middle cerebral artery occlusion (MCAo). Conti nuous i.v. infusion of GPI5232 starting 1 h after injury resulted in more t han a 50% reduction in brain infarct volume caused by 2 h of MCAo. This eff ect was dose-dependent and significant even when first treatment was delaye d for 2 h post-MCAo. At 24 h post-MCAo, EEG spectral analysis of the injure d hemisphere revealed functional improvement in GPI5232-treated rats. Signi ficant recovery in high-frequency EEG power (8-30 Hz) was measured in GPI52 32-treated animals in both parietal and temporal brain regions but not in v ehicle-treated animals. MCAo-injured rats were also predisposed to developi ng cortical brain seizures, and GPI5232-treated rats had significantly fewe r brain seizures than vehicle-treated animals. In separate experiments, acu te high doses of GPI5232 in normal rats did not significantly alter EEG bra in activity as evaluated by spectral analysis and did not produce any signs of seizure activity or behavioral abnormalities. These results show GPI523 2 to be an effective neuroprotective treatment when given postinjury by red ucing brain infarction and ameliorating the pathological EEG associated wit h focal brain ischemia.