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The Fungal Neurotoxin Penitrem A Induces the Production of Reactive Oxygen Species in Human Neutrophils at Submicromolar Concentrations

The Fungal Neurotoxin Penitrem A Induces the Production of Reactive Oxygen Species in Human Neutrophils at Submicromolar Concentrations

H F Berntsen, I L Bogen, M B Wigestrand, F Fonnum, S I Walaas, A Moldes-Anaya

Toxicology. 2017 Dec 1;392:64-70.

PMID: 29037868

Abstract:

Penitrem A is a fungal neurotoxin that recurrently causes intoxication in animals, and occasionally also in humans. We have previously reported that penitrem A induced the production of reactive oxygen species (ROS) in rat cerebellar granule cells, opening for a new mechanism of action for the neurotoxin. The aim of this study was to examine the potential of penitrem A to induce ROS production in isolated human neutrophil granulocytes, and to study possible mechanisms involved. Penitrem A significantly increased the production of ROS in human neutrophils at concentrations as low as 0.25μM (40% increase over basal levels), as measured with the DCF fluorescence assay. The EC50 determined for the production of ROS by penitrem A was 3.8μM. The maximal increase in ROS production was approximately 330% over basal levels at a concentration of 12.5μM. ROS formation was significantly inhibited by the antioxidant vitamin E (50μM), the intracellular Ca+2 chelator BAPTA-AM (5μM), the mitogen activated protein kinase kinase (MEK) 1/2 and 5 inhibitor U0126 (1 and 10μM), the p38 mitogen activated protein kinase (MAPK) inhibitor SB203580 (1μM), the c-Jun amino-terminal kinase (JNK) inhibitor SP600125 (10μM), and the calcineurin inhibitors FK-506 and cyclosporine A (1.5 and 0.5μM, respectively). These finding suggest that penitrem A is able to induce an increase in ROS production in neutrophils via the activation of several MAPK-signalling pathways. We suggest that this increase may partly explain the pathophysiology generated by penitrem A neuromycotoxicosis in both humans and animals.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP12627359	Penitrem A		12627-35-9	Price

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