NMDA receptor antagonist felbamate reduces behavioral deficits and blood-brain barrier permeability changes after experimental subarachnoid hemorrhage in the rat

Antonino Germanò, Mariella Caffo, Filippo Flavio Angileri, Francesca Arcadi, Jennifer Newcomb-Fernandez, Gerardo Caruso, Francesco Meli, Jose A. Pineda, Stephen B. Lewis, Kevin K W Wang, Placido Bramanti, Chiara Costa, Ronald L. Hayes

Research output: Contribution to journalArticle

Abstract

Increased levels of glutamate and aspartate have been detected after subarachnoid hemorrhage (SAH) that correlate with neurological status. The NMDA receptor antagonist felbamate (FBM; 2-phenyl-1,3-propanediol dicarbamate) is an anti-epileptic drug that elicits neuroprotective effects in different experimental models of hypoxia-ischemia. The aim of this dose-response study was to evaluate the effect of FBM after experimental SAH in rats on (1) behavioral deficits (employing a battery of assessment tasks days 1-5 post-injury) and (2) blood-brain barrier (BBB) permeability changes (quantifying microvascular alterations according to the extravasation of protein-bound Evans Blue by a spectrophotofluorimetric technique 2 days post-injury). Animals were injected with 400 μL of autologous blood into the cisterna magna. Within 5 min, rats received daily oral administration of FBM (15, 30, or 45 mg/kg) for 2 or 5 days. Results were compared with sham-injured controls treated with oral saline or FBM (15, 30, or 45 mg/kg). FBM administration significantly ameliorated SAH-related changes in Beam Balance scores on days 1 and 2 and Beam Balance time on days 1-3, Beam Walking performance on days 1 and 2, and Body Weight on days 3-5. FBM also decreased BBB permeability changes in frontal, temporal, parietal, occipital, and cerebellar cortices; subcortical and cerebellar gray matter; and brainstem. This study demonstrates that, in terms of behavioral and microvascular effects, FBM is beneficial in a dose-dependent manner after experimental SAH in rats. These results reinforce the concept that NMDA excitotoxicity is involved in the cerebral dysfunction that follows SAH.

Original languageEnglish
Pages (from-to)732-744
Number of pages13
JournalJournal of Neurotrauma
Volume24
Issue number4
DOIs
Publication statusPublished - Apr 2007

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Keywords

  • Behavioral deficits
  • Blood-brain barrier
  • Cognitive deficits
  • Felbamate
  • NMdA receptor
  • Subarachnoid hemorrhage

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Germanò, A., Caffo, M., Angileri, F. F., Arcadi, F., Newcomb-Fernandez, J., Caruso, G., Meli, F., Pineda, J. A., Lewis, S. B., Wang, K. K. W., Bramanti, P., Costa, C., & Hayes, R. L. (2007). NMDA receptor antagonist felbamate reduces behavioral deficits and blood-brain barrier permeability changes after experimental subarachnoid hemorrhage in the rat. Journal of Neurotrauma, 24(4), 732-744. https://doi.org/10.1089/neu.2006.0181