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Attenuation of prostaglandin E2 elimination across the mouse blood-brain barrier in lipopolysaccharide-induced inflammation and additive inhibitory effect of cefmetazole.

ABSTRACT: BACKGROUND: Peripheral administration of lipopolysaccharide (LPS) induces inflammation and increases cerebral prostaglandin E2 (PGE2) concentration. PGE2 is eliminated from brain across the blood-brain barrier (BBB) in mice, and this process is inhibited by intracerebral or intravenous pre-administration of anti-inflammatory drugs and antibiotics such as cefmetazole and cefazolin that inhibit multidrug resistance-associated protein 4 (Mrp4/Abcc4)-mediated PGE2 transport. The purpose of this study was to examine the effect of LPS-induced inflammation on PGE2 elimination from brain, and whether antibiotics further inhibit PGE2 elimination in LPS-treated mice. METHODS: [3H]PGE2 elimination across the BBB of intraperitoneally LPS-treated mice was assessed by the brain efflux index (BEI) method. Transporter protein amounts in brain capillaries were quantified by liquid chromatography-tandem mass spectrometry. RESULTS: The apparent elimination rate of [3H]PGE2 from brain was lower by 87%, in LPS-treated mice compared with saline-treated mice. The Mrp4 protein amount was unchanged in brain capillaries of LPS-treated mice compared with saline-treated mice, while the protein amounts of organic anion transporter 3 (Oat3/Slc22a8) and organic anion transporting polypeptide 1a4 (Oatp1a4/Slco1a4) were decreased by 26% and 39%, respectively. Either intracerebral or intravenous pre-administration of cefmetazole further inhibited PGE2 elimination in LPS-treated mice. However, intracerebral or intravenous pre-administration of cefazolin had little effect on PGE2 elimination in LPS-treated mice, or in LPS-untreated mice given Oat3 and Oatp1a4 inhibitors. These results indicate that peripheral administration of cefmetazole inhibits PGE2 elimination across the BBB in LPS-treated mice. CONCLUSION: PGE2 elimination across the BBB is attenuated in an LPS-induced mouse model of inflammation. Peripheral administration of cefmetazole further inhibits PGE2 elimination in LPS-treated mice.

SUBMITTER: Akanuma S

PROVIDER: S-EPMC3224590 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Attenuation of prostaglandin E2 elimination across the mouse blood-brain barrier in lipopolysaccharide-induced inflammation and additive inhibitory effect of cefmetazole.

Akanuma Shin-Ichi S Uchida Yasuo Y Ohtsuki Sumio S Tachikawa Masanori M Terasaki Tetsuya T Hosoya Ken-Ichi K

Fluids and barriers of the CNS 20111021

<h4>Background</h4>Peripheral administration of lipopolysaccharide (LPS) induces inflammation and increases cerebral prostaglandin E2 (PGE2) concentration. PGE2 is eliminated from brain across the blood-brain barrier (BBB) in mice, and this process is inhibited by intracerebral or intravenous pre-administration of anti-inflammatory drugs and antibiotics such as cefmetazole and cefazolin that inhibit multidrug resistance-associated protein 4 (Mrp4/Abcc4)-mediated PGE2 transport. The purpose of th ...[more]

PMID: 22014165

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Project description:BackgroundCachexia-anorexia syndrome is a complex metabolic condition characterized by skeletal muscle wasting, reduced food intake and prominent involvement of systemic and central inflammation. Here, the gut barrier function was investigated in pancreatic cancer-induced cachexia mouse models by relating intestinal permeability to the degree of cachexia. We further investigated the involvement of the gut-brain axis and the crosstalk between tumour, gut and hypothalamus in vitro.MethodsTwo distinct mouse models of pancreatic cancer cachexia (KPC and 4662) were used. Intestinal inflammation and permeability were assessed through fluorescein isothiocyanate dextran (FITC-dextran) and lipopolysaccharide (LPS), and hypothalamic and systemic inflammation through mRNA expression and plasma cytokines, respectively. To simulate the tumour-gut-brain crosstalk, hypothalamic (HypoE-N46) cells were incubated with cachexia-inducing tumour secretomes and LPS. A synthetic mimic of C26 secretome was produced based on its secreted inflammatory mediators. Each component of the mimic was systematically omitted to narrow down the key mediator(s) with an amplifying inflammation. To substantiate its contribution, cyclooxygenase-2 (COX-2) inhibitor was used.ResultsIn vivo experiments showed FITC-dextran was enhanced in the KPC group (362.3 vs. sham 111.4 ng/mL, P < 0.001). LPS was increased to 140.9 ng/mL in the KPC group, compared with sham and 4662 groups (115.8 and 115.8 ng/mL, P < 0.05). Hypothalamic inflammatory gene expression of Ccl2 was up-regulated in the KPC group (6.3 vs. sham 1, P < 0.0001, 4662 1.3, P < 0.001), which significantly correlated with LPS concentration (r = 0.4948, P = 0.0226). These data suggest that intestinal permeability is positively related to the cachexic degree. Prostaglandin E2 (PGE2) was confirmed to be present in the plasma and PGE2 concentration (log10) in the KPC group was much higher than in 4662 group (1.85 and 0.56 ng/mL, P < 0.001), indicating a role for PGE2 in pancreatic cancer-induced cachexia. Parallel to in vivo findings, in vitro experiments revealed that the cachexia-inducing tumour secretomes (C26, LLC, KPC and 4662) amplified LPS-induced hypothalamic IL-6 secretion (419%, 321%, 294%, 160%). COX-2 inhibitor to the tumour cells reduced PGE2 content (from 105 to 102 pg/mL) in the secretomes and eliminated the amplified hypothalamic IL-6 production. Moreover, results could be reproduced by addition of PGE2 alone, indicating that the increased hypothalamic inflammation is directly related to the PGE2 from tumour.ConclusionsPGE2 secreted by the tumour may play a role in amplifying the effects of bacteria-derived LPS on the inflammatory hypothalamic response. The cachexia-inducing potential of tumour mice models parallels the loss of intestinal barrier function. Tumour-derived PGE2 might play a key role in cancer-related cachexia-anorexia syndrome via tumour-gut-brain crosstalk.

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Dataset Information

Attenuation of prostaglandin E2 elimination across the mouse blood-brain barrier in lipopolysaccharide-induced inflammation and additive inhibitory effect of cefmetazole.

Publications

Attenuation of prostaglandin E2 elimination across the mouse blood-brain barrier in lipopolysaccharide-induced inflammation and additive inhibitory effect of cefmetazole.

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