TY - JOUR
T1 - NMDA receptor antagonist felbamate reduces behavioral deficits and blood-brain barrier permeability changes after experimental subarachnoid hemorrhage in the rat
AU - Germanò, Antonino
AU - Caffo, Mariella
AU - Angileri, Filippo Flavio
AU - Arcadi, Francesca
AU - Newcomb-Fernandez, Jennifer
AU - Caruso, Gerardo
AU - Meli, Francesco
AU - Pineda, Jose A.
AU - Lewis, Stephen B.
AU - Wang, Kevin K.W.
AU - Bramanti, Placido
AU - Costa, Chiara
AU - Hayes, Ronald L.
PY - 2007/4
Y1 - 2007/4
N2 - 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.
AB - 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.
KW - Behavioral deficits
KW - Blood-brain barrier
KW - Cognitive deficits
KW - Felbamate
KW - NMdA receptor
KW - Subarachnoid hemorrhage
UR - http://www.scopus.com/inward/record.url?scp=34249849556&partnerID=8YFLogxK
U2 - 10.1089/neu.2006.0181
DO - 10.1089/neu.2006.0181
M3 - Article
C2 - 17439355
AN - SCOPUS:34249849556
SN - 0897-7151
VL - 24
SP - 732
EP - 744
JO - Journal of neurotrauma
JF - Journal of neurotrauma
IS - 4
ER -