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 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.
Williams
A J
AJ
Department of Neuropharmacology and Molecular Biology, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
Lu
X M
XM
Slusher
B
B
Tortella
F C
FC
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D002544:Cerebral Infarction / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects*; D043425:Glutamate Carboxypeptidase II; D005977:Glutarates / Q000494:pharmacology; D008297:Male; D020768:Middle Cerebral Artery / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000517:prevention & control; D013997:Time Factors; D005464:Fluorobenzenes; D005466:Fluorocarbons
D002268:Carboxypeptidases; D043425:Glutamate Carboxypeptidase II; D005977:Glutarates; D018696:Neuroprotective Agents; D011480:Protease Inhibitors; C436737:(2-((pentafluorophenylmethyl)hydroxyphosphinyl) methyl)pentanedioic acid; D005464:Fluorobenzenes; D005466:Fluorocarbons