Abstract
We have evaluated the effects of theN-acetylated-α-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.
Footnotes
-
↵1 The facilities in which the animals were maintained were fully accredited by the American Association for the Accreditation of Laboratory Animal Care (AALAC). In conducting the research described in this report, the investigators adhered to the Guide for the Care and Use of Laboratory Animals, as promulgated by the Committee on the Care and Use of Laboratory Animals of the Institute of Laboratory Resources, National Research Council.
-
↵2 Preliminary versions of these data were published in abstract form [Neurosci Abstr (2000)43:100].
-
The views of the authors do not purport or reflect the position of the Department of the Army or the Department of Defense (para 4-3, AR 360-5).
- Abbreviations:
- GPI5232
- 2-[(pentafluorophenylmethyl)hydroxyphosphinyl]methyl)-pentanedioic acid
- NAALADase
- N-acetylated-α-linked acidic dipeptidase
- 2-PMPA
- 2-(phosphonomethyl)pentanedioic acid
- EEG
- electroencephalogram
- MCA
- middle cerebral artery
- MCAo
- MCA occlusion
- NAAG
- N-acetyl-aspartylglutamate
- PI
- protective index
- SWS
- slow-wave sleep
- TTC
- 2,3,5-triphenyltetrazolium chloride
- PDA
- polymorphic delta activity
- Received April 6, 2001.
- Accepted June 16, 2001.
- U.S. Government
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
