Effects of immunomodulatory and organism-associated molecules on the permeability of an In Vitro blood-brain barrier model to amphotericin B and fluconazole

Vasilios Pyrgos, Diane Mickiene, Tin Sein, Margaret Cotton, Andrea Fransesconi, Isaac Mizrahi, Martha Donoghue, Nikkida Bundrant, Su Young Kim, Matthew Hardwick, Shmuel Shoham, Thomas J. Walsh

Research output: Contribution to journalArticle

Abstract

Amphotericin B (AMB) is used to treat fungal infections of the central nervous system (CNS). However, AMB shows poor penetration into the CNS and little is known about the factors affecting its permeation through the blood-brain barrier (BBB). Therefore, we studied immunomodulatory and organism-associated molecules affecting the permeability of an in vitro BBB model to AMB. We examined the effects of interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), lipopolysaccharide (LPS), lipoteichoic acid (LTA), zymosan (ZYM), dexamethasone (DEX), cyclosporine, and tacrolimus on transendothelial electrical resistance (TEER); endothelial tight junctions; filamentous actin; and permeability to deoxycholate AMB (DAMB), liposomal AMB (LAMB), and fluconazole. Proinflammatory cytokines and organism-associated molecules significantly decreased the mean TEER by 40.7 to 100% (P ≤ 0.004). DEX increased the mean TEER by 18.2 to 26.4% (P ≤ 0.04). TNF-α and LPS increased the permeability to AMB by 8.2 to 14.5% compared to that for the controls (1.1 to 2.4%) (P ≤ 0.04). None of the other molecules affected the model's permeability to AMB. By comparison, the BBB model's permeability to fluconazole was >78% under all conditions studied, without significant differences between the controls and the experimental groups. LPS and TNF-α decreased tightjunction protein zona occludens 1 (ZO-1) between endothelial cells. In conclusion, IL-1β, ZYM, and LTA increased the permeability of the BBB to small ions but not to AMB, whereas TNF-α and LPS, which disrupted the endothelial layer integrity, increased the permeability to AMB.

Original languageEnglish (US)
Pages (from-to)1305-1310
Number of pages6
JournalAntimicrobial Agents and Chemotherapy
Volume54
Issue number3
DOIs
StatePublished - Mar 2010
Externally publishedYes

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Fluconazole
Amphotericin B
Blood-Brain Barrier
Permeability
Lipopolysaccharides
Electric Impedance
Zymosan
Interleukin-1beta
Dexamethasone
Central Nervous System Fungal Infections
Zonula Occludens-1 Protein
Tight Junctions
Tacrolimus
In Vitro Techniques
Cyclosporine
Actins
Central Nervous System
Endothelial Cells
Tumor Necrosis Factor-alpha
Ions

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Effects of immunomodulatory and organism-associated molecules on the permeability of an In Vitro blood-brain barrier model to amphotericin B and fluconazole. / Pyrgos, Vasilios; Mickiene, Diane; Sein, Tin; Cotton, Margaret; Fransesconi, Andrea; Mizrahi, Isaac; Donoghue, Martha; Bundrant, Nikkida; Kim, Su Young; Hardwick, Matthew; Shoham, Shmuel; Walsh, Thomas J.

In: Antimicrobial Agents and Chemotherapy, Vol. 54, No. 3, 03.2010, p. 1305-1310.

Research output: Contribution to journalArticle

Pyrgos, V, Mickiene, D, Sein, T, Cotton, M, Fransesconi, A, Mizrahi, I, Donoghue, M, Bundrant, N, Kim, SY, Hardwick, M, Shoham, S & Walsh, TJ 2010, 'Effects of immunomodulatory and organism-associated molecules on the permeability of an In Vitro blood-brain barrier model to amphotericin B and fluconazole', Antimicrobial Agents and Chemotherapy, vol. 54, no. 3, pp. 1305-1310. https://doi.org/10.1128/AAC.01263-09
Pyrgos, Vasilios ; Mickiene, Diane ; Sein, Tin ; Cotton, Margaret ; Fransesconi, Andrea ; Mizrahi, Isaac ; Donoghue, Martha ; Bundrant, Nikkida ; Kim, Su Young ; Hardwick, Matthew ; Shoham, Shmuel ; Walsh, Thomas J. / Effects of immunomodulatory and organism-associated molecules on the permeability of an In Vitro blood-brain barrier model to amphotericin B and fluconazole. In: Antimicrobial Agents and Chemotherapy. 2010 ; Vol. 54, No. 3. pp. 1305-1310.
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abstract = "Amphotericin B (AMB) is used to treat fungal infections of the central nervous system (CNS). However, AMB shows poor penetration into the CNS and little is known about the factors affecting its permeation through the blood-brain barrier (BBB). Therefore, we studied immunomodulatory and organism-associated molecules affecting the permeability of an in vitro BBB model to AMB. We examined the effects of interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), lipopolysaccharide (LPS), lipoteichoic acid (LTA), zymosan (ZYM), dexamethasone (DEX), cyclosporine, and tacrolimus on transendothelial electrical resistance (TEER); endothelial tight junctions; filamentous actin; and permeability to deoxycholate AMB (DAMB), liposomal AMB (LAMB), and fluconazole. Proinflammatory cytokines and organism-associated molecules significantly decreased the mean TEER by 40.7 to 100{\%} (P ≤ 0.004). DEX increased the mean TEER by 18.2 to 26.4{\%} (P ≤ 0.04). TNF-α and LPS increased the permeability to AMB by 8.2 to 14.5{\%} compared to that for the controls (1.1 to 2.4{\%}) (P ≤ 0.04). None of the other molecules affected the model's permeability to AMB. By comparison, the BBB model's permeability to fluconazole was >78{\%} under all conditions studied, without significant differences between the controls and the experimental groups. LPS and TNF-α decreased tightjunction protein zona occludens 1 (ZO-1) between endothelial cells. In conclusion, IL-1β, ZYM, and LTA increased the permeability of the BBB to small ions but not to AMB, whereas TNF-α and LPS, which disrupted the endothelial layer integrity, increased the permeability to AMB.",
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AU - Pyrgos, Vasilios

AU - Mickiene, Diane

AU - Sein, Tin

AU - Cotton, Margaret

AU - Fransesconi, Andrea

AU - Mizrahi, Isaac

AU - Donoghue, Martha

AU - Bundrant, Nikkida

AU - Kim, Su Young

AU - Hardwick, Matthew

AU - Shoham, Shmuel

AU - Walsh, Thomas J.

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N2 - Amphotericin B (AMB) is used to treat fungal infections of the central nervous system (CNS). However, AMB shows poor penetration into the CNS and little is known about the factors affecting its permeation through the blood-brain barrier (BBB). Therefore, we studied immunomodulatory and organism-associated molecules affecting the permeability of an in vitro BBB model to AMB. We examined the effects of interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), lipopolysaccharide (LPS), lipoteichoic acid (LTA), zymosan (ZYM), dexamethasone (DEX), cyclosporine, and tacrolimus on transendothelial electrical resistance (TEER); endothelial tight junctions; filamentous actin; and permeability to deoxycholate AMB (DAMB), liposomal AMB (LAMB), and fluconazole. Proinflammatory cytokines and organism-associated molecules significantly decreased the mean TEER by 40.7 to 100% (P ≤ 0.004). DEX increased the mean TEER by 18.2 to 26.4% (P ≤ 0.04). TNF-α and LPS increased the permeability to AMB by 8.2 to 14.5% compared to that for the controls (1.1 to 2.4%) (P ≤ 0.04). None of the other molecules affected the model's permeability to AMB. By comparison, the BBB model's permeability to fluconazole was >78% under all conditions studied, without significant differences between the controls and the experimental groups. LPS and TNF-α decreased tightjunction protein zona occludens 1 (ZO-1) between endothelial cells. In conclusion, IL-1β, ZYM, and LTA increased the permeability of the BBB to small ions but not to AMB, whereas TNF-α and LPS, which disrupted the endothelial layer integrity, increased the permeability to AMB.

AB - Amphotericin B (AMB) is used to treat fungal infections of the central nervous system (CNS). However, AMB shows poor penetration into the CNS and little is known about the factors affecting its permeation through the blood-brain barrier (BBB). Therefore, we studied immunomodulatory and organism-associated molecules affecting the permeability of an in vitro BBB model to AMB. We examined the effects of interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), lipopolysaccharide (LPS), lipoteichoic acid (LTA), zymosan (ZYM), dexamethasone (DEX), cyclosporine, and tacrolimus on transendothelial electrical resistance (TEER); endothelial tight junctions; filamentous actin; and permeability to deoxycholate AMB (DAMB), liposomal AMB (LAMB), and fluconazole. Proinflammatory cytokines and organism-associated molecules significantly decreased the mean TEER by 40.7 to 100% (P ≤ 0.004). DEX increased the mean TEER by 18.2 to 26.4% (P ≤ 0.04). TNF-α and LPS increased the permeability to AMB by 8.2 to 14.5% compared to that for the controls (1.1 to 2.4%) (P ≤ 0.04). None of the other molecules affected the model's permeability to AMB. By comparison, the BBB model's permeability to fluconazole was >78% under all conditions studied, without significant differences between the controls and the experimental groups. LPS and TNF-α decreased tightjunction protein zona occludens 1 (ZO-1) between endothelial cells. In conclusion, IL-1β, ZYM, and LTA increased the permeability of the BBB to small ions but not to AMB, whereas TNF-α and LPS, which disrupted the endothelial layer integrity, increased the permeability to AMB.

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