Permeability of ergot alkaloids across the blood‐brain barrier in vitro and influence on the barrier integrity

Mulac, Dennis; Hüwel, Sabine; Galla, Hans‐Joachim; Humpf, Hans‐Ulrich

doi:10.1002/mnfr.201100431

Cited by 34 publications

(33 citation statements)

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“…These values are in a low range compared to the permeability of ergot alkaloid mycotoxins reported earlier using the same model system which showed higher permeation from the apical to the basolateral side [29]. For permeation from the basolateral to the apical side, the value for T-2 toxin was 1.94±0.16×10 −6 cm/s and for HT-2 toxin 2.31±0.36×10 −6 cm/s.…”

Section: Resultscontrasting

confidence: 53%

“…The assay was performed as described previously [29]. Briefly, cells were seeded on Collagen-G-coated 96-well plates (250,000 cells/cm 2 ) and cultured according to the treatment on Transwell® filter systems (DIV 2: plating medium replaced by serum-free medium on DIV 4 for 2 days).…”

Section: Methodsmentioning

confidence: 99%

“…Supplementation with physiological concentrations of hydrocortisone in the concurrent absence of serum is essential for the formation of barrier integrity in the used model where serum-free conditions allow improved reproducibility of experiments and permeability studies [28]. This model was already applied successfully in our group to study the effects of ergot alkaloid mycotoxins on the BBB [29]. In the present study, the general cytotoxicity of T-2 and HT-2 toxin on cells of the BBB (PBCEC) was evaluated by the CCK-8 assay which revealed strong cytotoxic effects of both toxins in low nanomolar ranges.…”

Section: Introductionmentioning

confidence: 99%

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Influence of T-2 and HT-2 Toxin on the Blood-Brain Barrier In Vitro: New Experimental Hints for Neurotoxic Effects

et al. 2013

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The trichothecene mycotoxin T-2 toxin is a common contaminant of food and feed and is also present in processed cereal derived products. Cytotoxic effects of T-2 toxin and its main metabolite HT-2 toxin are already well described with apoptosis being a major mechanism of action. However, effects on the central nervous system were until now only reported rarely. In this study we investigated the effects of T-2 and HT-2 toxin on the blood-brain barrier (BBB) in vitro. Besides strong cytotoxic effects on the BBB as determined by the CCK-8 assay, impairment of the barrier function starting at low nanomolar concentrations were observed for T-2 toxin. HT-2 toxin, however, caused barrier disruption at higher concentrations compared to T-2 toxin. Further, the influence on the tight junction protein occludin was studied and permeability of both toxins across the BBB was detected when applied from the apical (blood) or the basolateral (brain) side respectively. These results clearly indicate the ability of both toxins to enter the brain via the BBB.

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Section: Resultscontrasting

confidence: 53%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influence of T-2 and HT-2 Toxin on the Blood-Brain Barrier In Vitro: New Experimental Hints for Neurotoxic Effects

et al. 2013

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“…Ergocristine has been shown to reduce barrier function of an in vitro blood − brain barrier model with an apical concentration of at least 5 µM (compared with the 0.09 and 0.47 µM concentrations used in the current study), as measured by electrical resistance and sucrose permeability (Mulac et al, 2012). The structure of ergocristine is similar to ergovaline with the same basic tricyclic peptide group that only differs at two points (Klotz et al, 2010, Foote et al, 2011 and has similar inhibition constants for dopamine receptors (Larson et al, 1995).…”

mentioning

confidence: 77%

Acute exposure to ergot alkaloids from endophyte-infected tall fescue does not alter absorptive or barrier function of the isolated bovine ruminal epithelium

Foote

Penner

Walpole

et al. 2014

animal

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Ergot alkaloids in endophyte-infected (Neotyphodium coenophialum) tall fescue (Lolium arundinaceum) have been shown to cause a reduction in blood flow to the rumen epithelium as well as a decrease in volatile fatty acids (VFA) absorption from the washed rumen of steers. Previous data also indicates that incubating an extract of endophyte-infected tall fescue seed causes an increase in the amount of VFA absorbed per unit of blood flow, which could result from an alteration in the absorptive or barrier function of the rumen epithelium. An experiment was conducted to determine the acute effects of an endophyte-infected tall fescue seed extract (EXT) on total, passive or facilitated acetate and butyrate flux across the isolated bovine rumen as well as the barrier function measured by inulin flux and tissue conductance (G t ). Flux of ergovaline across the rumen epithelium was also evaluated. Rumen tissue from the caudal dorsal sac of Holstein steers ( n = 6), fed a common diet, was collected and isolated shortly after slaughter and mounted between two halves of Ussing chambers. In vitro treatments included vehicle control (80% methanol, 0.5% of total volume), Low EXT (50 ng ergovaline/ml) and High EXT (250 ng ergovaline/ml). Results indicate that there is no effect of acute exposure to ergot alkaloids on total, passive or facilitated flux of acetate or butyrate across the isolate bovine rumen epithelium ( P > 0.51). Inulin flux ( P = 0.16) and G t ( P > 0.17) were not affected by EXT treatment, indicating no alteration in barrier function due to acute ergot alkaloid exposure. Ergovaline was detected in the serosal buffer of the High EXT treatment indicating that the flux rate is~0.25 to 0.44 ng/cm 2 per hour. Data indicate that specific pathways for VFA absorption and barrier function of the rumen epithelium are not affected by acute exposure to ergot alkaloids from tall fescue at the concentrations tested. Ergovaline has the potential to be absorbed from the rumen of cattle that could contribute to reduced blood flow and motility and lead to reduced growth rates of cattle.Keywords: bovine, ergovaline absorption, fescue toxicosis, volatile fatty acid absorption ImplicationsResults from this experiment show that ergot alkaloids present in endophyte-infected tall fescue do not have an impact on nutrient absorption or barrier function of the isolated rumen epithelium of cattle following acute exposure. This indicates that previously observed reductions in nutrient absorption in live animals exposed to ergot alkaloids requires chronic exposure or is driven by the reduced blood flow. Results also show that ergovaline, one of the main causative agents of fescue toxicosis, is absorbed across the rumen epithelium, although it is at a fairly slow rate ∼1% of a daily dose.

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“…This formation of the -inine isomer is an equilibrium-driven process, but biological processes and compartments, such as crossing a cell barrier, can influence it. This was demonstrated by Mulac et al (2012) with a primary porcine brain endothelial-cell transport system and ergocristine and ergocristinine. Only ergocristine crossed the cell barrier, whereas biologically inactive ergocristinine accumulated within the cells.…”

Section: What Is Ergovaline?mentioning

confidence: 88%

Ergovaline, an endophytic alkaloid. 1. Animal physiology and metabolism

Klotz

Nicol

2016

Anim. Prod. Sci.

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Abstract. Ergovaline is an ergot alkaloid found in some endophyte-infected ryegrasses and it has been implicated in the expression of ergotism-like symptoms of grazing livestock, as well as in the protection of the plant against invertebrate predation and abiotic stresses. These selection pressures have resulted in a conflict between the needs of the pasture for persistence and the needs of the animal for production. Ergovaline has not been well studied in terms of animal physiology until recently. There are several putative mechanisms that limit the bioavailability of ergovaline, ranging from microbial biotransformation to post-absorptive hepatic detoxification. Although there are mechanisms that protect the animal from ergovaline exposure, tissues are very sensitive to ergovaline, indicating that ergovaline is very potent and that small quantities have the potential to cause noticeable physiological effects. The range of physiological effects, including decreased circulating prolactin, vasoconstriction and increased susceptibility to heat stress are all linked to the interaction of ergovaline with biogenic amine receptors found throughout the body. This review will focus on understanding the variation of ergovaline concentration in terms of bioavailability, the myriad of hurdles a molecule of ergovaline must overcome to cause an effect, what the ergovaline-induced effects are in New Zealand livestock and how this relates to the potency of ergovaline.

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Permeability of ergot alkaloids across the blood‐brain barrier in vitro and influence on the barrier integrity

Cited by 34 publications

References 38 publications

Influence of T-2 and HT-2 Toxin on the Blood-Brain Barrier In Vitro: New Experimental Hints for Neurotoxic Effects

Influence of T-2 and HT-2 Toxin on the Blood-Brain Barrier In Vitro: New Experimental Hints for Neurotoxic Effects

Acute exposure to ergot alkaloids from endophyte-infected tall fescue does not alter absorptive or barrier function of the isolated bovine ruminal epithelium

Ergovaline, an endophytic alkaloid. 1. Animal physiology and metabolism

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