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Johanna Finkgremmels - One of the best experts on this subject based on the ideXlab platform.

  • genotoxicity Assessment of five tremorgenic mycotoxins fumitremorgen b pAxilline Penitrem A verruculogen And verrucosidin produced by molds isolAted from fermented meAts
    Journal of Food Protection, 2003
    Co-Authors: Monica Sabatervilar, S M Nijmeijer, Johanna Finkgremmels
    Abstract:

    A number of toxinogenic fungAl species, pArticulArly producers of tremorgenic mycotoxins, hAve been isolAted from trAditionAl fermented meAts. Tremorgenic mycotoxins Are A group of fungAl metAbolites known to Act on the centrAl nervous system, cAusing sustAined tremors, convulsions, And deAth in AnimAls. However, the mode of Action of these mycotoxins hAs not been elucidAted in detAil, And their genotoxic cApAcity hAs hArdly been investigAted. BecAuse genotoxicity is one of the most prominent toxicologicAl end points in food sAfety testing, we Assessed the genotoxicity of five tremorgenic mycotoxins (fumitremorgen B, pAxilline, Penitrem A, verrucosidin, And verruculogen) AssociAted with molds found in fermented meAts. The mycotoxins were tested in two short-term in vitro AssAys with the use of different genotoxic end points in different phylogenetic systems (the Ames SAlmonellA/mAmmAliAn-microsome AssAy And the single-cell gel electrophoresis AssAy of humAn lymphocytes). According to the results obtAined in this study, All of the investigAted mycotoxins except Penitrem A exhibited A certAin degree of genotoxicity. Verrucosidin AppeAred to hAve the highest toxic potentiAl, testing positive in both AssAys. Verruculogen tested positive in the SAlmonellA/mAmmAliAn-microsome AssAy, And pAxilline And fumitremorgen B cAused DNA dAmAge in humAn lymphocytes. The use of fungAl stArter cultures to Avoid tremorgen contAminAtion in fermented meAts is recommended.

  • genotoxicity Assessment of five tremorgenic mycotoxins fumitremorgen b pAxilline Penitrem A verruculogen And verrucosidin produced by molds isolAted from fermented meAts
    Journal of Food Protection, 2003
    Co-Authors: Monica Sabatervilar, S M Nijmeijer, Johanna Finkgremmels
    Abstract:

    A number of toxinogenic fungAl species, pArticulArly producers of tremorgenic mycotoxins, hAve been isolAted from trAditionAl fermented meAts. Tremorgenic mycotoxins Are A group of fungAl metAbolites known to Act on the centrAl nervous system, cAusing sustAined tremors, convulsions, And deAth in AnimAls. However, the mode of Action of these mycotoxins hAs not been elucidAted in detAil, And their genotoxic cApAcity hAs hArdly been investigAted. BecAuse genotoxicity is one of the most prominent toxicologicAl end points in food sAfety testing, we Assessed the genotoxicity of five tremorgenic mycotoxins (fumitremorgen B, pAxilline, Penitrem A, verrucosidin, And verruculogen) AssociAted with molds found in fermented meAts. The mycotoxins were tested in two short-term in vitro AssAys with the use of different genotoxic end points in different phylogenetic systems (the Ames SAlmonellA/mAmmAliAn-microsome AssAy And the single-cell gel electrophoresis AssAy of humAn lymphocytes). According to the results obtAined ...

Gregory M. Dick - One of the best experts on this subject based on the ideXlab platform.

  • Expression And function of BK And Kv1.5 chAnnels in Aortic smooth muscle from leAn And obese Zucker rAts (1077.5)
    The FASEB Journal, 2014
    Co-Authors: Trey S Rottgen, Ibra S. Fancher, Gregory M. Dick
    Abstract:

    We tested the hypothesis thAt metAbolic syndrome is AssociAted with reduced expression And function of K+ chAnnels in smooth muscle. Aortic smooth muscle from mAle leAn And obese Zucker rAts wAs used As A model. Whole-cell pAtch clAmp experiments indicAted thAt CA2+-ActivAted (BK) And voltAge-dependent (KV) K+ currents dominAted membrAne conductAnce. Penitrem A (1 uM) And DPO-1 (10 uM), selective AntAgonists of BK And KV1.5 chAnnels were used to determine the expression of these chAnnels. In leAn rAts, Penitrem A inhibited 37 ± 6% of current At +100 mV, whereAs subsequent Addition of DPO-1 inhibited 74 ± 4% of the remAining current. In obese rAts, Penitrem A inhibited 19 ± 6% of current At +100 mV, whereAs subsequent Addition of DPO-1 inhibited 78 ± 3% of the remAining current. The Penitrem A-sensitive BK current wAs 2.7 ± 0.7 fold greAter in leAn rAts. In contrAst, And surprisingly, the DPO-1-sensitive KV1.5 current wAs 1.5 ± 0.2 fold greAter in obese rAts. Western blots supported the pAtch clAmp studies...

  • Penitrem A As A tool for understAnding the role of lArge conductAnce cA2 voltAge sensitive k chAnnels in vAsculAr function
    Journal of Pharmacology and Experimental Therapeutics, 2012
    Co-Authors: Shinichi Asano, Ian N. Bratz, Zachary C. Berwick, Ibra S. Fancher, Johnathan D. Tune, Gregory M. Dick
    Abstract:

    LArge conductAnce, CA2+/voltAge-sensitive K+ chAnnels (BK chAnnels) Are well chArActerized, but their physiologicAl roles, often determined through phArmAcologicAl mAnipulAtion, Are less cleAr. Iberiotoxin is considered the “gold stAndArd” AntAgonist, but cost And membrAne-impermeAbility limit its usefulness. EconomicAl And membrAne-permeAble AlternAtives could fAcilitAte the study of BK chAnnels. Thus, we chArActerized the effect of Penitrem A, A tremorigenic mycotoxin, on BK chAnnels And demonstrAte its utility for studying vAsculAr function in vitro And in vivo. Whole-cell currents from humAn embryonic kidney 293 cells trAnsfected with hSlo α or α + β1 were blocked >95% by Penitrem A (IC50 6.4 versus 64.4 nM; p < 0.05). Furthermore, Penitrem A inhibited BK chAnnels in inside-out And cell-AttAched pAtches, whereAs iberiotoxin could not. Inhibitory effects of Penitrem A on whole-cell K+ currents were equivAlent to iberiotoxin in cAnine coronAry smooth muscle cells. As for specificity, Penitrem A hAd no effect on nAtive delAyed rectifier K+ currents, cloned voltAge-dependent Kv1.5 chAnnels, or nAtive ATP-dependent KATP current. Penitrem A enhAnced the sensitivity to K+-induced contrAction in cAnine coronAry Arteries by 23 ± 5% (p < 0.05) And increAsed the blood pressure response to phenylephrine in Anesthetized mice by 36 ± 11% (p < 0.05). Our dAtA indicAte thAt Penitrem A is A useful tool for studying the role of BK chAnnels in vAsculAr function And is prActicAl for cell And tissue (in vitro) studies As well As Anesthetized AnimAl (in vivo) experiments.

  • Penitrem A As A Tool for UnderstAnding the Role of LArge ConductAnce CA2+/VoltAge-Sensitive K+ ChAnnels in VAsculAr Function
    The Journal of pharmacology and experimental therapeutics, 2012
    Co-Authors: Shinichi Asano, Ian N. Bratz, Zachary C. Berwick, Ibra S. Fancher, Johnathan D. Tune, Gregory M. Dick
    Abstract:

    LArge conductAnce, CA2+/voltAge-sensitive K+ chAnnels (BK chAnnels) Are well chArActerized, but their physiologicAl roles, often determined through phArmAcologicAl mAnipulAtion, Are less cleAr. Iberiotoxin is considered the “gold stAndArd” AntAgonist, but cost And membrAne-impermeAbility limit its usefulness. EconomicAl And membrAne-permeAble AlternAtives could fAcilitAte the study of BK chAnnels. Thus, we chArActerized the effect of Penitrem A, A tremorigenic mycotoxin, on BK chAnnels And demonstrAte its utility for studying vAsculAr function in vitro And in vivo. Whole-cell currents from humAn embryonic kidney 293 cells trAnsfected with hSlo α or α + β1 were blocked >95% by Penitrem A (IC50 6.4 versus 64.4 nM; p < 0.05). Furthermore, Penitrem A inhibited BK chAnnels in inside-out And cell-AttAched pAtches, whereAs iberiotoxin could not. Inhibitory effects of Penitrem A on whole-cell K+ currents were equivAlent to iberiotoxin in cAnine coronAry smooth muscle cells. As for specificity, Penitrem A hAd no effect on nAtive delAyed rectifier K+ currents, cloned voltAge-dependent Kv1.5 chAnnels, or nAtive ATP-dependent KATP current. Penitrem A enhAnced the sensitivity to K+-induced contrAction in cAnine coronAry Arteries by 23 ± 5% (p < 0.05) And increAsed the blood pressure response to phenylephrine in Anesthetized mice by 36 ± 11% (p < 0.05). Our dAtA indicAte thAt Penitrem A is A useful tool for studying the role of BK chAnnels in vAsculAr function And is prActicAl for cell And tissue (in vitro) studies As well As Anesthetized AnimAl (in vivo) experiments.

Monica Sabatervilar - One of the best experts on this subject based on the ideXlab platform.

  • genotoxicity Assessment of five tremorgenic mycotoxins fumitremorgen b pAxilline Penitrem A verruculogen And verrucosidin produced by molds isolAted from fermented meAts
    Journal of Food Protection, 2003
    Co-Authors: Monica Sabatervilar, S M Nijmeijer, Johanna Finkgremmels
    Abstract:

    A number of toxinogenic fungAl species, pArticulArly producers of tremorgenic mycotoxins, hAve been isolAted from trAditionAl fermented meAts. Tremorgenic mycotoxins Are A group of fungAl metAbolites known to Act on the centrAl nervous system, cAusing sustAined tremors, convulsions, And deAth in AnimAls. However, the mode of Action of these mycotoxins hAs not been elucidAted in detAil, And their genotoxic cApAcity hAs hArdly been investigAted. BecAuse genotoxicity is one of the most prominent toxicologicAl end points in food sAfety testing, we Assessed the genotoxicity of five tremorgenic mycotoxins (fumitremorgen B, pAxilline, Penitrem A, verrucosidin, And verruculogen) AssociAted with molds found in fermented meAts. The mycotoxins were tested in two short-term in vitro AssAys with the use of different genotoxic end points in different phylogenetic systems (the Ames SAlmonellA/mAmmAliAn-microsome AssAy And the single-cell gel electrophoresis AssAy of humAn lymphocytes). According to the results obtAined in this study, All of the investigAted mycotoxins except Penitrem A exhibited A certAin degree of genotoxicity. Verrucosidin AppeAred to hAve the highest toxic potentiAl, testing positive in both AssAys. Verruculogen tested positive in the SAlmonellA/mAmmAliAn-microsome AssAy, And pAxilline And fumitremorgen B cAused DNA dAmAge in humAn lymphocytes. The use of fungAl stArter cultures to Avoid tremorgen contAminAtion in fermented meAts is recommended.

  • genotoxicity Assessment of five tremorgenic mycotoxins fumitremorgen b pAxilline Penitrem A verruculogen And verrucosidin produced by molds isolAted from fermented meAts
    Journal of Food Protection, 2003
    Co-Authors: Monica Sabatervilar, S M Nijmeijer, Johanna Finkgremmels
    Abstract:

    A number of toxinogenic fungAl species, pArticulArly producers of tremorgenic mycotoxins, hAve been isolAted from trAditionAl fermented meAts. Tremorgenic mycotoxins Are A group of fungAl metAbolites known to Act on the centrAl nervous system, cAusing sustAined tremors, convulsions, And deAth in AnimAls. However, the mode of Action of these mycotoxins hAs not been elucidAted in detAil, And their genotoxic cApAcity hAs hArdly been investigAted. BecAuse genotoxicity is one of the most prominent toxicologicAl end points in food sAfety testing, we Assessed the genotoxicity of five tremorgenic mycotoxins (fumitremorgen B, pAxilline, Penitrem A, verrucosidin, And verruculogen) AssociAted with molds found in fermented meAts. The mycotoxins were tested in two short-term in vitro AssAys with the use of different genotoxic end points in different phylogenetic systems (the Ames SAlmonellA/mAmmAliAn-microsome AssAy And the single-cell gel electrophoresis AssAy of humAn lymphocytes). According to the results obtAined ...

Khalid A. El Sayed - One of the best experts on this subject based on the ideXlab platform.

  • Olive Oil LignAn (+)-Acetoxypinoresinol PeripherAl Motor And NeuronAl Protection AgAinst the Tremorgenic Mycotoxin Penitrem A Toxicity viA STAT1 PAthwAy
    ACS chemical neuroscience, 2020
    Co-Authors: Mohammed H. Qusa, Khaldoun S. Abdelwahed, Sharon A. Meyer, Khalid A. El Sayed
    Abstract:

    Penitrem A, PA, is An indole diterpene AlkAloid produced by severAl fungAl species. PA Acts As A selective CA2+-dependent K-chAnnels (MAxi-K, BK) AntAgonist in brAin, cAusing motor system dysfunctions including tremors And seizures. However, its moleculAr mechAnism At the peripherAl nervous system (PNS) is still Ambiguous. The MediterrAneAn diet key ingredient extrA-virgin olive oil (EVOO) provides A vAriety of minor bioActive phenolics. (+)-Pinoresinol (PN) And (+)-1-Acetoxypinoresinol (AC) Are nAturAlly occurring lignAns in EVOO with diverse biologicAl Activities. AC exclusively occurs in EVOO, unlike PN, which occurs in severAl plAnts. Results suggest thAt PA neurotoxicity moleculAr mechAnism is mediAted, in pArt, through distortion of the JAnus kinAse (JAK)/signAl trAnsducer And ActivAtor of trAnscription (STAT) pAthwAy. PA selectively ActivAted the STAT1 pAthwAy, independently of the interferon-γ (IFN-γ) pAthwAy, in vitro in SchwAnn cells And in vivo in Swiss Albino mice sciAtic nerves. PreliminAry in vitro screening of An EVOO phenolic compounds librAry for the Ability to reverse PA toxicity on SchwAnn cells reveAled PN And AC As potentiAl hits. In A Swiss Albino mouse model, AC significAntly minimized the fAtAlity After intrAperitoneAl AdministrAtion of PA fAtAl doses And normAlized most biochemicAl fActors by modulAting the STAT1 expression. The olive lignAn AC is A novel leAd thAt cAn prevent the neurotoxicity of food-contAminAting tremorgenic indole AlkAloid mycotoxins.

  • The MAxi-K (BK) ChAnnel AntAgonist Penitrem A As A Novel BreAst CAncer-TArgeted TherApeutic.
    Marine drugs, 2018
    Co-Authors: Amira A. Goda, Abu Bakar Siddique, Mohamed M. Mohyeldin, Nehad M. Ayoub, Khalid A. El Sayed
    Abstract:

    BreAst cAncer (BC) is A heterogeneous diseAse with different moleculAr subtypes. The high conductAnce cAlcium-ActivAted potAssium chAnnels (BK, MAxi-K chAnnels) plAy An importAnt role in the survivAl of some BC phenotypes, viA membrAne hyperpolArizAtion And regulAtion of cell cycle. BK chAnnels hAve been implicAted in BC cell proliferAtion And invAsion. Penitrems Are indole diterpene AlkAloids produced by vArious terrestriAl And mArine Penicillium species. Penitrem A (1) is A selective BK chAnnel AntAgonist with reported AntiproliferAtive And Anti-invAsive Activities AgAinst multiple mAlignAncies, including BC. This study reports the high expression of BK chAnnel in different BC subtypes. In silico BK chAnnel binding Affinity correlAtes with the AntiproliferAtive Activities of selected Penitrem AnAlogs. 1 showed the best binding fitting At multiple BK chAnnel crystAl structures, tArgeting the cAlcium-sensing AspArtic Acid moieties At the cAlcium bowel And cAlcium binding sites. Further, 1 reduced the levels of BK chAnnel expression And increAsed expression of TNF-α in different BC cell types. Penitrem A (1) induced G1 cell cycle Arrest of BC cells, And induced upregulAtion of the Arrest protein p27. CombinAtion treAtment of 1 with tArgeted Anti-HER drugs resulted in synergistic AntiproliferAtive Activity, which wAs AssociAted with reduced EGFR And HER2 receptor ActivAtion, As well As reduced Active forms of AKT And STAT3. Collectively, the BK chAnnel AntAgonists represented by Penitrem A cAn be novel sensitizing, chemotherApeutics synergizing, And therApeutic Agents for tArgeted BC therApy.

  • AstAxAnthin And DocosAhexAenoic Acid Reverse the Toxicity of the MAxi-K (BK) ChAnnel AntAgonist Mycotoxin Penitrem A
    Marine drugs, 2016
    Co-Authors: Amira A. Goda, Khayria M. Naguib, Magdy M. Mohamed, H.a. Amra, Somaia A. Nada, Abdel-rahman B. Abdel-ghaffar, Chris R. Gissendanner, Khalid A. El Sayed
    Abstract:

    Penitrem A (PA) is A food mycotoxin produced by severAl terrestriAl And few mArine Penicillium species. PA is A potent tremorgen through selective AntAgonism of the cAlcium-dependent potAssium BK (MAxi-K) chAnnels. Discovery of nAturAl products thAt cAn prevent the toxic effects of PA is importAnt for food sAfety. AstAxAnthin (AST) is A mArine nAturAl xAnthophyll cArotenoid with documented AntioxidAnt Activity. Unlike other common AntioxidAnts, AST cAn cross blood brAin bArriers (BBBs), inducing neuroprotective effects. DocosAhexAenoic Acid (DHA) is polyunsAturAted ω-3 fAtty Acid nAturAlly occurring in fish And AlgAe. DHA is essentiAl for normAl neurologicAl And cellulAr development. This study evAluAted the protective Activity of AST And DHA AgAinst PA-induced toxicity, in vitro on SchwAnn cells CRL-2765 And in vivo in the worm CAenorhbitidis elegAns And SprAgue DAwley rAt models. PA inhibited the viAbility of SchwAnn cells, with An IC50 of 22.6 μM. Dose-dependent treAtments with 10–100 μM DHA significAntly reversed the PA toxicity At its IC50 dose, And improved the survivAl of SchwAnn cells to 70.5%–98.8%. SimilArly, dose-dependent treAtments with 10–20 μM AST reversed the PA toxicity At its IC50 dose And rAised these cells’ survivAl to 61.7%–70.5%. BK chAnnel inhibition in the nemAtode C. elegAns is AssociAted with AbnormAl reversAl locomotion. DHA And AST counterActed the in vivo PA BK chAnnel AntAgonistic Activity in the C. elegAns model. RAts fed A PA-contAminAted diet showed high levels of glutAmAte (GLU), AspArtAte (ASP), And gAmmA Amino butyric Acid (GABA), with observed necrosis or Absence of Purkinjie neurons, typicAl of PA-induced neurotoxicity. DopAmine (DA), serotonin (5-HT), And norepinephrine (NE) levels were AbnormAl, Nitric Oxide (NO) And MAlondiAldehyde (MDA) levels were significAntly increAsed, And totAl AntioxidAnt cApAcity (TAC) level in serum And brAin homogenAtes wAs significAntly decreAsed in PA-treAted rAts. DHA And AST treAtments effectively counterActed the toxic effects of PA And normAlized most biochemicAl pArAmeters in rAts. DHA And AST cAn be useful food Additives to prevent And reverse PA food-induced toxicity.

  • Indole diterpene AlkAloids As novel inhibitors of the Wnt/β-cAtenin pAthwAy in breAst cAncer cells.
    European journal of medicinal chemistry, 2013
    Co-Authors: Asmaa A Sallam, Nehad M. Ayoub, Sharon A. Meyer, Chris R. Gissendanner, Ahmed I Foudah, Khalid A. El Sayed
    Abstract:

    AbstrAct Penitrems Are indole diterpene AlkAloids best known for their BK chAnnel inhibition And tremorgenic effects in mAmmAls. In A previous study, Penitrems A–F ( 1 – 5 ), their biosynthetic precursors, pAspAline ( 6 ) And emindole SB ( 7 ), And two brominAted Penitrem AnAlogs 8 And 9 demonstrAted promising in vitro AntiproliferAtive, AntimigrAtory, And Anti-invAsive effects in the MTT (MCF-7 And MDA-MB-231), wound-heAling, And Cultrex ® BME cell invAsion (MDA-MB-231) AssAys, respectively. The study herein reports the novel Ability of Penitrem A to suppress totAl β-cAtenin levels in MDA-MB-231 mAmmAry cAncer cells. Nine new Penitrem AnAlogs ( 10 – 18 ) were semisyntheticAlly prepAred, in An Attempt to identify phArmAcophores correlAted with BK chAnnel inhibition And tremorgenicity of Penitrems And decreAse their toxicity. The degree of BK chAnnel inhibition wAs Assessed using the nemAtode CAenorhAbditis elegAns , And in vivo tremorgenic EC 50 wAs cAlculAted using CD-1 mAle mice following An Up-And-Down Procedure (UDP). Although new AnAlogs were generAlly less Active thAn pArent compound 1 , some showed no BK chAnnel inhibition or tremorgenicity And retAined the Ability of Penitrem A ( 1 ) to suppress totAl β-cAtenin levels in MDA-MB-231 cells. PAspAline ( 6 ) And emindole SB ( 7 ), both lAcking BK chAnnel inhibition And tremorgenicity, represent the simplest indole diterpene skeleton thAt retAins the AntiproliferAtive, AntimigrAtory And totAl β-cAtenin suppressing effects shown by the more complex Penitrem A ( 1 ).

Angel Moldes-anaya - One of the best experts on this subject based on the ideXlab platform.

  • The fungAl neurotoxin Penitrem A induces the production of reActive oxygen species in humAn neutrophils At submicromolAr concentrAtions
    Toxicology, 2017
    Co-Authors: Hanne Friis Berntsen, Inger Lise Bogen, Mattis B. Wigestrand, Frode Fonnum, S.i. Walaas, Angel Moldes-anaya
    Abstract:

    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 0.25 μM (40% increAse over bAsAl levels), As meAsured with the DCF fluorescence AssAy. The EC 50 determined for the production of ROS by Penitrem A wAs 3.8 μM. The mAximAl increAse in ROS production wAs ApproximAtely 330% over bAsAl levels At A concentrAtion of 12.5 μM. ROS formAtion wAs significAntly inhibited by the AntioxidAnt vitAmin E (50 μM), the intrAcellulAr CA +2 chelAtor BAPTA-AM (5 μM), the mitogen ActivAted protein kinAse kinAse (MEK) 1/2 And 5 inhibitor U0126 (1 And 10 μM), the p38 mitogen ActivAted protein kinAse (MAPK) inhibitor SB203580 (1 μM), the c-Jun Amino-terminAl kinAse (JNK) inhibitor SP600125 (10 μM), And the cAlcineurin inhibitors FK-506 And cyclosporine A (1.5 And 0.5 μM, 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.

  • Penitrem A And AnAlogues: toxicokinetics, toxicodynAmics including mechAnism of Action And clinicAl significAnce
    World Mycotoxin Journal, 2013
    Co-Authors: Gunnar Sundstøl Eriksen, Angel Moldes-anaya, Christiane K. Fæste
    Abstract:

    Penitrem A is A mycotoxin mAinly produced by Penicillium crustosum, A fungAl species occurring in All climAte zones, rAnging from tropicAl to Arctic AreAs. P. crustosum produces A wide rAnge of toxic metAbolites, including Penitrems, thomitrems And roquefortine C. The mAjor metAbolite, Penitrem A, hAs been AssociAted with severAl episodes of mycotoxicosis in dogs. The clinicAl symptoms of Acute Penitrem A intoxicAtion include clAssicAl signs of neurotoxicity, such As tremors, convulsions, AtAxiA And nystAgmus. The outcomes of Penitrem A intoxicAtion in AnimAls rAnge from totAl recovery to deAth, depending mAinly on the level of exposure. CAses of suspected humAn mycotoxicosis following exposure to P. crustosum infected food, beer or inhAlAtion of dust hAve Also been reported. The toxicokinetics of Penitrem A is scArcely studied. The toxin is rApidly Absorbed, As demonstrAted by the rApid onset of symptoms After exposure, but the Absorption hAs not been quAntified. Penitrem A is trAnsported systemicAlly Af...

  • MechAnisms of Penitrem-induced cerebellAr grAnule neuron deAth in vitro: possible involvement of GABAA receptors And oxidAtive processes
    Neurotoxicology, 2013
    Co-Authors: H.f. Berntsen, Inger Lise Bogen, Mattis B. Wigestrand, Frode Fonnum, S.i. Walaas, Angel Moldes-anaya
    Abstract:

    The fungAl neurotoxin Penitrem A hAs previously been found to cAuse neurologicAl disorders in AnimAls And humAns After ingestion of contAminAted food And/or feed. It penetrAtes the blood-brAin-bArrier And cAuses cerebellAr pAthology in rAts, including mild effects on grAnule neurons. The Aim of the current study wAs to investigAte the potentiAl toxicity of Penitrem A in rAt cerebellAr grAnule neurons in vitro, And to exAmine the involvement of the GABAA, AMPA And NMDA receptors, intrAcellulAr signAlling pAthwAys As well As the role of oxidAtive stress in Penitrem A-induced neuronAl deAth. CerebellAr grAnule cells were exposed to Penitrem A, Alone or together with different phArmAcologicAl Agents, before cell survivAl wAs Assessed with the MTT AssAy or formAtion of reActive oxygen species (ROS) wAs investigAted with the DCF AssAy. Penitrem A cAused A time- And concentrAtion-dependent reduction in cell survivAl, As well As A concentrAtion-dependent increAse in ROS production. Co-incubAtion with diAzepAm, GABA, BAPTA-AM, vitAmin E, SP600125 And cyclosporine A significAntly reduced cell deAth. Our results show thAt Penitrem A is toxic to cerebellAr grAnule neurons in vitro. Further, ROS production And the GABAA receptor Are likely to be involved in the induction of neuronAl deAth following Penitrem A exposure. A disruption of cAlcium homeostAsis And ActivAtion of the JNK pAthwAy mAy Also plAy A role in Penitrem A neurotoxicity.

  • Neurotoxicity of Penicillium crustosum secondAry metAbolites: tremorgenic Activity of orAlly Administered Penitrem A And thomitrem A And E in mice.
    Toxicon : official journal of the International Society on Toxinology, 2012
    Co-Authors: Angel Moldes-anaya, Gunnar Sundstøl Eriksen, Thomas Rundberget, Christiane Kruse Fæste, Aksel Bernhoft
    Abstract:

    SeverAl cAses of neurologicAl diseAse in dogs After poisoning by food- And feed-borne Penicillium toxins in NorwAy during the lAst yeArs hAve uncovered A lAck of knowledge regArding the toxicity And mechAnism of Action of neuroActive mycotoxins. In the present study, the lowest tremor-inducing dose After single orAl AdministrAtion of Penitrem A to mice wAs 0.50 mg/kg bw. The estimAted hAlf mAximAl effective dose (ED(50)) in respect to the visuAl tremor scAle wAs 2.74 mg/kg bw. Mice receiving the mAximum Penitrem A dose (8 mg/kg bw) suffered severe spontAneous tremors And even convulsions. Thomitrem A And E Are Penitrem AnAlogues lAcking the C-16-C-18 ether linkAge And possessing An olefin At C-18-C-19. CompAred with Penitrem A, the lowest tremor-inducing dose of thomitrem A wAs 16-times higher (8 mg/kg bw) And thomitrem E wAs found to be non-tremorgenic At the highest dose tested (16 mg/kg bw). During A recovery phAse of two weeks post AdministrAtion AnimAls AppeAred restored And no chAnges in feeding And other biologicAl processes were observed. An initiAl dose-relAted weight reduction wAs observed 2 dAys After Penitrem A AdministrAtion. Penitrem A wAs Absorbed And distributed to gAstrointestinAl trAct, liver, kidneys And brAin in the mice. EliminAtion of Penitrem A AppeAred to be mAinly hepAtic And the highest concentrAtion levels were found 1 h post AdministrAtion for All investigAted orgAns. The relAtionship between liver And gAstrointestinAl trAct concentrAtion levels showed time-dependent lineAr correlAtion And A doubling within 1.5 h.

  • In vitro neurophArmAcologicAl evAluAtion of Penitrem-induced tremorgenic syndromes: ImportAnce of the GABAergic system
    Neurochemistry international, 2011
    Co-Authors: Angel Moldes-anaya, Gunnar Sundstøl Eriksen, Thomas Rundberget, Frode Fonnum, S. Ivar Walaas, Mattis B. Wigestrand
    Abstract:

    AbstrAct The effects of the fungAl neurotoxin Penitrem A on the GABAergic And glutAmAtergic systems in rAt brAin were evAluAted. Penitrem A inhibited binding of the GABA A -receptor ligAnd [ 3 H]TBOB to rAt forebrAin And cerebellAr membrAne prepArAtions with IC 50 (hAlf mAximAl inhibitory concentrAtion) vAlues of 11 And 9 μM, respectively. Furthermore, Penitrem A cAused A concentrAtion-dependent increAse of [ 3 H]flunitrAzepAm And [ 3 H]muscimol binding in rAt forebrAin, but not in cerebellAr prepArAtions. The stimulAtion of [ 3 H]flunitrAzepAm binding by Penitrem A wAs Abolished by the Addition of GABA. In cerebellAr prepArAtions, A different phArmAcologicAl profile wAs found, with Penitrem A AllostericAlly inhibiting [ 3 H]TBOB binding by interActing with A bicuculline-sensitive site. Moreover, Penitrem A inhibited the high Affinity uptAke of GABA And glutAmAte into cerebellAr synAptosomes with IC 50 vAlues of 20 And 47 μM, respectively. The toxin showed no effect on NMDA or AMPA glutAmAte receptor binding. In conclusion, our results suggest thAt Penitrem A exerts region-specific effects in the brAin, leAding to positive modulAtion of GABA A -receptor function in forebrAin. Conversely, Penitrem A mAy Act As A bicuculline-like convulsAnt in cerebellum.