NMDA receptor antagonist felbamate reduces behavioral deficits and blood-brain barrier permeability changes after experimental subarachnoid hemorrhage in the rat.
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 muL 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.
Germanò
Antonino
A
Neurosurgical Clinic, Department of Neurosciences, Psychiatry and Anaesthesiology, University of Messina School of Medicine, Messina, Italy.
Caffo
Mariella
M
Angileri
Filippo Flavio
FF
Arcadi
Francesca
F
Newcomb-Fernandez
Jennifer
J
Caruso
Gerardo
G
Meli
Francesco
F
Pineda
Jose A
JA
Lewis
Stephen B
SB
Wang
Kevin K W
KK
Bramanti
Placido
P
Costa
Chiara
C
Hayes
Ronald L
RL
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001835:Body Weight / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005070:Evans Blue; D000078328:Felbamate; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D048448:Phenylcarbamates / Q000627:therapeutic use*; D004856:Postural Balance / Q000187:drug effects; D011409:Propylene Glycols / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013050:Spectrometry, Fluorescence; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology*
D018696:Neuroprotective Agents; D048448:Phenylcarbamates; D011409:Propylene Glycols; D016194:Receptors, N-Methyl-D-Aspartate; D005070:Evans Blue; D000078328:Felbamate