Protection against blood–brain barrier disruption in focal cerebral ischemia by the type IV phosphodiesterase inhibitor BBB022: a quantitative study

• Published in: Brain research 1998-03, Vol.787 (2), p.277-285
• Main Authors: Belayev, Ludmila, Busto, Raul, Ikeda, Masuhiro, Rubin, Lee L, Kajiwara, Akiharu, Morgan, Louise, Ginsberg, Myron D
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; 3',5'-Cyclic-AMP Phosphodiesterases - metabolism; Animals; BBB; BBB022; Biological and medical sciences; Blood-Brain Barrier - drug effects; Brain - pathology; Brain Ischemia - drug therapy; Brain Ischemia - pathology; Coloring Agents; Cyclic AMP - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 4; Evans Blue; Male; Medical sciences; Middle cerebral artery occlusion; Neostriatum - metabolism; Neostriatum - pathology; Neurology; Organic Chemicals; Phosphodiesterase Inhibitors - therapeutic use; Pyrrolidinones - therapeutic use; Rat; Rats; Rats, Sprague-Dawley; Rolipram; Tight Junctions - drug effects; Tight Junctions - physiology; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(97)01499-6

We examined the effect of BBB022, a type IV phosphodiesterase inhibitor, on blood–brain barrier (BBB) integrity after transient middle cerebral artery occlusion (MCAo) in rats. Male Sprague–Dawley rats were anesthetized with halothane and subjected to 120 min of temporary MCAo by retrograde intraluminal insertion of a nylon suture coated with poly- l-lysine. The drug (BBB022 in saline, 1 mg kg −1 h −1, i.v.) or vehicle (0.9% saline, 1–2 ml kg −1 h −1) was administered by infusion after the onset of MCAo. Four animal groups were studied: Groups A and B were treated by infusion of vehicle or drug over 5 h, and groups C and D over 48 h. Damage to the BBB was judged by extravasation of Evans blue (EB) dye, which was administered i.v. at 3 h after the onset of MCAo in groups A and B; and at 46 h in groups C and D. Fluorometric quantitation of EB was performed 1 or 2 h later in six brain regions. In the 5-h infusion series (group B), BBB022 decreased dye extravasation in the ipsilateral cortex, striatum and hemisphere (hemisphere mean±S.E.M.: 41.2±5.4 vs. 82.4±9.2 μg/g, p=0.005) compared to the vehicle-treated group (A). The 48-h infusion of BBB022 (group D) also decreased dye extravasation in the ipsilateral cortex (7.4±2.5 vs. 29.0±8.3 μg/g, p=0.05), striatum (17.2±2.2 vs. 50.8±12.1 μg/g, p=0.03) and hemisphere (30.7±4.0 vs. 93.2±18 μg/g, p=0.01) compared to the vehicle-treated group (C). BBB022 also significantly improved the neurological score at 3 and 5 h after MCAo (in the 5-h infusion group) and at 60 min, 24 h and 48 h (in the 48-h infusion group) compared to the vehicle groups. These data indicate that BBB022 prevents ischemic damage to the BBB after focal cerebral ischemia in rats.