Blood–brain barrier dysfunction in mice induced by lipopolysaccharide is attenuated by dapsone

https://doi.org/10.1016/j.bbrc.2014.09.093Get rights and content

Highlights

  • LPS-induced BBB leakage in mice was suppressed by dapsone.

  • Expression of tight junction proteins was restored by dapsone.

  • ROS level in brain vessels was decreased by dapsone.

  • NOX2 expression and NADPH oxidase activity were reduced by dapsone.

Abstract

Blood–brain barrier (BBB) dysfunction is a key event in the development of many central nervous system (CNS) diseases, such as septic encephalopathy and stroke. 4,4′-Diaminodiphenylsulfone (DDS, Dapsone) has displayed neuroprotective effect, but whether DDS has protective role on BBB integrity is not clear. This study was designed to examine the effect of DDS on lipopolysaccharide (LPS)-induced BBB disruption and oxidative stress in brain vessels. Using in vivo multiphoton imaging, we found that DDS administration significantly restored BBB integrity compromised by LPS. DDS also increased the expression of tight junction proteins occludin, zona occludens-1 (ZO-1) and claudin-5 in brain vessels. Level of reactive oxygen species (ROS) was reduced by DDS treatment, which may due to decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and NOX2 expression. Our results showed that LPS-induced BBB dysfunction could be attenuated by DDS, indicated that DDS has a therapeutic potential for treating CNS infection and other BBB related diseases.

Introduction

The blood–brain barrier (BBB) is comprised of brain microvascular endothelial cells and regulates the permeation of molecules between the peripheral circulation and the central nervous system (CNS) [1]. The main structures responsible for the maintenance of the integrity and function of BBB are the intercellular tight junction proteins [2]. BBB dysfunction is considered to be an early and significant event in the pathogenesis of a variety of CNS diseases [3], [4], [5], so the protection of BBB integrity is regarded as one of the important issues for the treatment of many cerebral diseases [6].

Dysfunction of BBB can be induced by various extrinsic or intrinsic stimuli [7]. Such as sepsis, during which lipopolysaccharide (LPS) is released into circulation, promoting the generation of reactive oxygen species (ROS) in BBB [8]. A major sources of ROS during BBB dysfunction are nicotinamide adenine dinucleotide phosphate (NADPH) oxidases [9]. There are several members in the NADPH oxidase family, among which NOX2 containing NADPH oxidase is highly expressed in cerebral endothelium [10]. Reducing expression of NOX2 can protect mice from a variety of stimuli that produce cerebrovascular dysfunction [11], [12], [13].

4,4′-Diaminodiphenylsulfone (DDS, Dapsone) is currently used to treat leprosy [14] and is known to possess neuroprotective effect against ischemia, spinal cord injury and other brain damage [15], [16], [17], [18], [19]. One of its modes of action is anti-oxidant [17], [20]. DDS reduces ROS generation in Caenorhabditis elegans thus extends its lifespan [20]. In non-phagocytic human diploid fibroblasts and a mouse lung injury model, DDS also suppresses ROS production by inhibiting the NOX system [21], [22]. As BBB integrity is disrupted during the pathological process of many CNS disease, especially stroke, and DDS treatment reduces the infarction volume in rat ischemia model [18], so we hypothesize that DDS may have a protective role on BBB integrity, and may be via reducing oxidative stress status.

The present study focus on effect of DDS on LPS-induced BBB disruption in mice. Our data showed that DDS inhibited LPS-induced BBB dysfunction, restored expression of tight junction, as well as decreased ROS level, NOX2 expression and NADPH oxidase activity in brain vessels, indicated that DDS can protect the integrity of BBB during septic encephalopathy.

Section snippets

Animals and drug administration

Female C57BL/6J mice (20–25 g body weight, 3 month-old) were housed under standard conditions in conventional cages and kept on standard chow diet and water ad libitum with 12-h light and dark cycles. The experiments were designed as follows: LPS (Sigma, St. Louis, MO) was dissolved in saline solution, and DDS (Sigma, St. Louis, MO) was dissolved in 4.5% polyethylene glycol in saline solution (PEG) [16]. Mice in control group were intraperitoneal (i.p.) injected with 100 μl saline solution,

BBB dysfunction induced by LPS was attenuated by DDS

To determine whether DDS has protective effect on BBB integrity, we examined the in vivo BBB permeability for TMR-dextran with multiphoton microscopy. We found that mice in control group displayed intact BBB, while LPS treatment increased BBB permeability significantly (Fig. 1A), the relative fluorescence intensity across a cross-section of vessels increased to 6.4 ± 0.7-fold in LPS group compared with control (p < 0.01) (Fig. 1B). Administration of 5 mg/kg DDS significantly inhibited LPS-induced

Discussion

Increased oxidative stress is very common during inflammatory response induced by systematic infection, and would lead to BBB leakage [24], [27], [28]. We have previously reported that in a chronic oxidative stress model, dietary supplementation of vitamin E significantly restored BBB integrity via reducing cerebrovascular oxidative stress level [23]. As dapsone is also an antioxidant and has displayed neuroprotective effects against ischemia, spinal cord injury and other brain damage [15], [16]

Acknowledgments

This work was supported by the National High Technology Research and Development Program of China (Nos. 2012CB911000, 2012CB911004) and the National Natural Science Foundation of China (NSFC; Grants No. 81171015).

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    These authors contributed equally to this paper.

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