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

Ludmila Belayev, Raul Busto, Masuhiro Ikeda, Lee L. Rubin, Akiharu Kajiwara, Louise Morgan, Myron D. Ginsberg

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42 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)277-285
Number of pages9
JournalBrain research
Volume787
Issue number2
DOIs
StatePublished - Mar 23 1998

Keywords

  • BBB
  • BBB022
  • Evans blue
  • Middle cerebral artery occlusion
  • Rat

ASJC Scopus subject areas

  • Neuroscience(all)

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