title: NMDA receptor antagonist felbamate reduces behavioral deficits and blood-brain barrier permeability changes after experimental subarachnoid hemorrhage in the rat.
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 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.
authors: Neurosurgical Clinic, Department of Neurosciences, Psychiatry and Anaesthesiology, University of Messina School of Medicine, Messina, Italy.
authors: Antonino
authors: A
authors: Germanò
authors: Mariella
authors: M
authors: Caffo
authors: Filippo Flavio
authors: FF
authors: Angileri
authors: Francesca
authors: F
authors: Arcadi
authors: Jennifer
authors: J
authors: Newcomb-Fernandez
authors: Gerardo
authors: G
authors: Caruso
authors: Francesco
authors: F
authors: Meli
authors: Jose A
authors: JA
authors: Pineda
authors: Stephen B
authors: SB
authors: Lewis
authors: Kevin K W
authors: KK
authors: Wang
authors: Placido
authors: P
authors: Bramanti
authors: Chiara
authors: C
authors: Costa
authors: Ronald L
authors: RL
authors: Hayes
mesh_terms: 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*
chemical_list: D018696:Neuroprotective Agents; D048448:Phenylcarbamates; D011409:Propylene Glycols; D016194:Receptors, N-Methyl-D-Aspartate; D005070:Evans Blue; D000078328:Felbamate