Biochemical and Biophysical Research Communications
Blood–brain barrier dysfunction in mice induced by lipopolysaccharide is attenuated by dapsone
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).
References (40)
The blood–brain barrier in health and chronic neurodegenerative disorders
Neuron
(2008)- et al.
Structure and function of the blood–brain barrier
Neurobiol. Dis.
(2010) - et al.
The blood–brain barrier in brain homeostasis and neurological diseases
Biochim. Biophys. Acta
(2009) - et al.
The role of oxidative stress and NADPH oxidase in cerebrovascular disease
Trends Mol. Med.
(2008) - et al.
Phospholipid transfer protein (PLTP) deficiency impaired blood–brain barrier integrity by increasing cerebrovascular oxidative stress
Biochem. Biophys. Res. Commun.
(2014) - et al.
Pentosan polysulfate protects brain endothelial cells against bacterial lipopolysaccharide-induced damages
Neurochem. Int.
(2007) - et al.
Human serum amyloid P component attenuates the bacterial lipopolysaccharide-induced increase in blood–brain barrier permeability in mice
Neurosci. Lett.
(2003) - et al.
Dapsone inhibits IL-8 secretion from human bronchial epithelial cells stimulated with lipopolysaccharide and resolves airway inflammation in the ferret
Chest
(2011) - et al.
Apolipoprotein E controls cerebrovascular integrity via cyclophilin A
Nature
(2012) - et al.
Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease
J. Clin. Invest.
(2010)
Blood–brain barrier permeability precedes senile plaque formation in an Alzheimer disease model
Microcirculation
Blood–brain barrier dysfunction and recovery
J. Neural. Trans.
Fructose-1,6-bisphosphate ameliorates lipopolysaccharide-induced dysfunction of blood–brain barrier
Arch. Pharm. Res.
NADPH oxidase activity is higher in cerebral versus systemic arteries of four animal species: role of Nox2
Am. J. Physiol. Heart Circ. Physiol.
Normobaric hyperoxia protects the blood brain barrier through inhibiting Nox2 containing NADPH oxidase in ischemic stroke
Med. Gas Res.
Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain
J. Cereb. Blood Flow Metab.
Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein
Proc. Natl. Acad. Sci. U.S.A.
Dapsone
Dermatol. Online J.
Antioxidant, anticonvulsive and neuroprotective effects of dapsone and phenobarbital against kainic acid-induced damage in rats
Neurochem. Res.
Delayed administration of dapsone protects from tissue damage and improves recovery after spinal cord injury
J. Neurosci. Res.
Cited by (31)
Early-life stress affects peripheral, blood-brain barrier, and brain responses to immune challenge in juvenile and adult rats
2023, Brain, Behavior, and ImmunityGut microbiota and neurological effects of glyphosate
2019, NeuroToxicologyCitation Excerpt :It is well-established that LPS binds to LPS binding protein (LPB) or CD4 to activate TLR4, triggering an increase in NF-KB activity, which induces the transcription of inflammatory signalling and immune-related genes in different tissues. Besides the effect of cytokines, it has been suggested that LPS is also able to reach the brain minimally by crossing the blood-brain barrier (Banks and Robinson, 2010; Zhou et al., 2014) or by modulating afferent vagal fibres (Hansen et al., 2000). Concerning the present review, Clostridium is resistant to Gly, so it is not implicated in LPS-induced cerebral toxicity, because it belongs to the Gram-positive bacteria group.
Quantifying blood-brain-barrier leakage using a combination of evans blue and high molecular weight FITC-Dextran
2019, Journal of Neuroscience MethodsCitation Excerpt :Therefore, the method of air drying was adopted in following procedures. LPS is widely used to induce BBB dysfunction(Ivey et al., 2005; Jangula and Murphy, 2013; Zhou et al., 2014). To investigate whether the new method can be utilized to quantify BBB leakage, we tested it on the LPS-induced mice.
Acute lung injury leads to depression-like symptoms through upregulation of neutrophilic and neuronal NADPH oxidase signaling in a murine model
2017, International ImmunopharmacologyProtective effect of dapsone on cognitive impairment induced by propofol involves hippocampal autophagy
2017, Neuroscience LettersCitation Excerpt :Diaminodiphenyl sulfone (DDS, Dapsone), a traditionally used anti-leprosy agent [10], has recently been demonstrated to have neuroprotective effects [11–16]. We have also demonstrated that DDS can improve surgical stress induced depression-and anxiety-like behavior [17] and attenuate blood-brain barrier (BBB) dysfunction in mice induced by lipopolysaccharides [18]. However, whether DDS can mitigate propofol-induced cognitive alterations via the regulation of autophagy in aged rats has never been studied.
- 1
These authors contributed equally to this paper.