Minocycline Pretreatment Prevents Blood-Brain Barrier Disruption in Septic Rats

Abstract

Introduction: The aim of the study was to explore the mechanism by which minocycline protects the blood-brain barrier (BBB) in septic rats.

Methods: A sepsis rat model was generated in healthy, male Sprague-Dawley rats by cecal ligation and puncture (CLP). The rats were randomly divided into four groups and treated as follows: sham-operated plus normal saline (Sham + S group), CLP plus normal saline (CLP + S group), CLP plus minocycline pretreatment (CLP + M1 group), and CLP plus minocycline treatment (CLP + M2 group). Rats in the CLP + M1 group received 45 mg/kg minocycline by intraperitoneal injection every 12 h for 72 h. Rats in the Sham + S and CLP + S groups were injected with the same volume of normal saline every 12 h for 72 h. Rats in the CLP + M2 group were intraperitoneally injected with 45 mg/kg minocycline immediately after CLP and once every 12 h for 72 h. All rats were sacrificed at 72 h after operation. Tumor necrosis factor α and interleukin 6 levels, the expression of ionized calcium-binding adaptor molecule-1 (Iba-1), and the permeability of the BBB were measured. The expression of matrix metalloproteinases-9 (MMP-9) and the tight junction proteins zonula occludens-1 (ZO-1) and occludin was detected by Western blot. In addition, Evans blue (EB) staining, immunohistochemistry, and ELISA analysis were carried out.

Results: Minocycline pretreatment significantly inhibited microglial activation, decreased the sepsis-induced expression of MMP-9, increased the expression of ZO-1 and occludin, and improved the permeability of the BBB. Minocycline treatment failed to inhibit microglial activation, decrease the sepsis-induced expression of MMP-9, increase the expression of ZO-1 or occluding, or improve the permeability of the BBB.

Conclusions: Minocycline pretreatment can effectively improve the altered permeability of the BBB caused by sepsis. The mechanism may be related to the inhibition of microglial activation and MMP-9 expression and increased expression of ZO-1 and occludin.

Keywords: Blood–brain barrier; Matrix metalloproteinases; Microglia; Minocycline; Sepsis.