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Maier S.,Albert Ludwigs University of Freiburg | Szalkowski A.,Albert Ludwigs University of Freiburg | Kamphausen S.,Albert Ludwigs University of Freiburg | Kamphausen S.,University Medical Center Tuebingen | And 8 more authors.
PLoS ONE | Year: 2012

Recent studies have begun to carve out a specific role for the rostral part of the dorsal medial prefrontal cortex (dmPFC) and adjacent dorsal anterior cingulate cortex (dACC) in fear/anxiety. Within a novel general framework of dorsal mPFC/ACC areas subserving the appraisal of threat and concomitant expression of fear responses and ventral mPFC/ACC areas subserving fear regulation, the rostral dmPFC/dACC has been proposed to specifically mediate the conscious, negative appraisal of threat situations including, as an extreme variant, catastrophizing. An alternative explanation that has not been conclusively ruled out yet is that the area is involved in fear learning. We tested two different fear expression paradigms in separate fMRI studies (study 1: instructed fear, study 2: testing of Pavlovian conditioned fear) with independent groups of healthy adult subjects. In both paradigms the absence of reinforcement precluded conditioning. We demonstrate significant BOLD activation of an identical rostral dmPFC/dACC area. In the Pavlovian paradigm (study 2), the area only activated robustly once prior conditioning had finished. Thus, our data argue against a role of the area in fear learning. We further replicate a repeated observation of a dissociation between peripheral-physiological fear responding and rostral dmPFC/dACC activation, strongly suggesting the area does not directly generate fear responses but rather contributes to appraisal processes. Although we succeeded in preventing extinction of conditioned responding in either paradigm, the data do not allow us to definitively exclude an involvement of the area in fear extinction learning. We discuss the broader implications of this finding for our understanding of mPFC/ACC function in fear and in negative emotion more generally. © 2012 Maier et al.

Schaible A.M.,Friedrich - Schiller University of Jena | Koeberle A.,Friedrich - Schiller University of Jena | Northoff H.,University Medical Center Tuebingen | Lawrenz B.,University Hospital of Tuebingen | And 4 more authors.
Prostaglandins Leukotrienes and Essential Fatty Acids | Year: 2013

Pregnancy is accompanied by major immunological changes to maintain both tolerance for the fetus and immune competence. Leukotrienes are powerful 5-lipoxygenase-derived inflammatory mediators and the characteristics of leukotriene-related diseases (e.g., asthma, allergic rhinitis) change during pregnancy. Here, we show that pregnancy affects leukotriene synthesis in human blood and leukocytes. 5-Lipoxygenase product formation in stimulated blood of pregnant women was significantly higher than in non-pregnant females. Although a pregnancy-related increase in neutrophil and monocyte counts may explain these observations, granulocytes of pregnant donors have lower leukotriene-synthetic capacities. On the other hand, granulocytes from non-pregnant woman produced more leukotrienes when resuspended in plasma of pregnant women than of non-pregnant females. Together, we show that leukotriene biosynthesis in maternal blood is increased by the interrelations of higher leukocyte numbers, lower cellular capacity for leukotriene synthesis and stimulatory effects of plasma. This bias may affect leukotriene-related diseases during pregnancy and their pharmacological treatment. © 2013 Elsevier Ltd.

Pergola C.,Friedrich - Schiller University of Jena | Schaible A.M.,Friedrich - Schiller University of Jena | Nikels F.,Friedrich - Schiller University of Jena | Dodt G.,University of Tubingen | And 2 more authors.
Pharmacological Research | Year: 2015

5-Lipoxygenase (5-LO), the key enzyme in the biosynthesis of pro-inflammatory leukotrienes (LTs) from arachidonic acid, is regulated by androgens in human neutrophils and monocytes accounting for sex differences in LT formation. Here we show that progesterone suppresses the synthesis of 5-LO metabolites in human primary monocytes. 5-LO product formation in monocytes stimulated with Ca2+-ionophore A23187 or with lipopolysaccharide/formyl peptide was suppressed by progesterone at concentrations of 10-100 nM in cells from females and at 1 μM in cells from males. Progesterone down-regulated 5-LO product formation in a rapid and reversible manner, but did not significantly inhibit 5-LO activity in cell-free assays using monocyte homogenates. Also, arachidonic acid release and its metabolism to other eicosanoids in monocytes were not significantly reduced by progesterone. The inhibitory effect of progesterone on LTs was still observed when mitogen-activated protein kinases were pharmacologically blocked, stimulatory 1-oleoyl-2-acetyl-sn-glycerol was exogenously supplied, or extracellular Ca2+ was removed by chelation. Instead, suppression of PKA by means of two different pharmacological approaches (i.e. H89 and a cell-permeable PKA inhibitor peptide) prevented inhibition of 5-LO product generation by progesterone, to a similar extent as observed for the PKA activators prostaglandin E2 and 8-Br-cAMP, suggesting the involvement of PKA. In summary, progesterone affects the capacity of human primary monocytes to generate 5-LO products and, in addition to androgens, may account for sex-specific effects on pro-inflammatory LTs. © 2015 Elsevier Ltd. All rights reserved.

Maier S.J.,Albert Ludwigs University of Freiburg | Szalkowski A.,Albert Ludwigs University of Freiburg | Kamphausen S.,University Medical Center Tuebingen | Feige B.,Albert Ludwigs University of Freiburg | And 7 more authors.
Psychological Medicine | Year: 2014

Background Emotional dysregulation is becoming increasingly recognized as an important feature of attention deficit hyperactivity disorder (ADHD). In this study, two experiments were conducted investigating the neural response to either verbally instructed fear (IF) or uninstructed (classically conditioned) fear (UF) using the skin conductance response (SCR) and functional magnetic resonance imaging (fMRI). Method In the conditioning phase of the UF experiment (17 ADHD and 17 healthy controls), subjects experienced an unconditioned stimulus (UCS, unpleasant electrodermal stimulation) paired with a former neutral conditioned stimulus (CS+), whereas a control stimulus (CS-) was never paired with the UCS. In the subsequent test phase, only the CS+ and the CS-were presented. In the IF experiment (13 ADHD and 17 healthy controls), subjects were only told that an independently experienced UCS might occur together with the CS+ but not the CS-during testing. No UCS was presented. Results Groups did not detectably differ in SCR or neural responses to UF. In IF, ADHD patients showed a trend-line decreased SCR and significantly decreased activation of the dorsal anterior cingulate cortex (dACC), a region prominently involved in fear responding, to the CS+. This was accompanied by higher amygdala activation to the CS-. Conclusions During IF, ADHD patients showed deficits in regions centrally involved in fear learning and expression in terms of diminished CS+-related dACC and increased CS-related amygdala signals. This suggests an impaired processing of verbally transmitted aversive information, which is central for conveying fear information in social contexts. This result extends the growing literature on emotional alterations in ADHD. © 2013 Cambridge University Press.

Pergola C.,Friedrich - Schiller University of Jena | Jazzar B.,University of Tubingen | Rossi A.,University of Naples Federico II | Buehring U.,University of Tubingen | And 5 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2011

Lipoxygenases (LOs) are iron-containing enzymes that catalyze the conversion of arachidonic acid into hydroperoxyeicosatetraenoic acids (HPETEs) and other bioactive lipid mediators. In mammals, 5-LO, 15-LO, and 12-LO enzymes seem to have distinct roles in pathophysiological contexts, which have emphasized the need for selective inhibitors. Cinnamyl-3,4-dihydroxy-α- cyanocinnamate (CDC) has been proposed as potent and selective inhibitor of platelet-type 12-LO (p12-LO). Here, we re-evaluated the selectivity profile of CDC on LOs, and we show that CDC is a potent and direct inhibitor of 5-LO. CDC reduced 5-LO activity in cell-free assays (purified human recombinant enzyme or leukocyte homogenates), with IC50 values in the low nanomolar range (9-25 nM) and a selectivity index of approximately 35 and 15 over p12-LO and 15-LO1, respectively. Likewise, CDC inhibited 5-LO product formation in intact human polymorphonuclear leukocytes and monocytes (IC50 = 0.45-0.8 μM). A lower potency was observed for 15-LO1, whereas p12-LO activity in platelets was hardly affected. In human whole blood, CDC efficiently reduced the formation of 5-LO products, and similar effects were observed for 12(S)-H(P)ETE and 15(S)-H(P)ETE. Finally, CDC (3.5 and 7 mg/kg i.p.) was effective in vivo in the platelet-activating factor-induced shock in mice and reduced formation of the 5-LO product leukotriene B4 in the rat carrageenan-induced pleurisy after a single oral dose of 10 mg/kg. Together, our data demonstrate that CDC is a potent inhibitor of 5-LO with efficacy in vivo and encourage further development of CDC as the lead compound. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.

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