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Drug-induced decrease of protein kinase a activity reveals alteration in BDNF expression of bipolar affective disorder.

Félicien Karege·Michèle Schwald·Rachid El Kouaissi
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Abstract

Bipolar affective disorder (BAD) is a severe disease whose molecular and cellular bases are not well known. The aim of the present study was to probe the cAMP signaling downstream targets by pharmacologically manipulating the protein kinase A (PKA) enzyme, along with the assessment of brain-derived neurotrophic factor (BDNF) expression in lymphoblasts. The time course of lymphoblast PKA activity (up to 72 h) revealed optimal activity at 24 h. Then, the enzyme activity and protein levels of PKA Calpha subunit and phopsho-cAMP responsive element binding (CREB) were assayed in lymphoblasts derived from 12 BAD and 12 control (CT) subjects and cultured for 24 h in the presence of cAMP analog drugs. The results indicated that basal PKA activity and PKA Calpha subunit immunolabeling are increased in cells from BAD compared with controls. Enzyme activity was increased by Sp-isomer in BAD and in CT's cells, without change in protein levels. In contrast, the Rp-isomer decreased enzyme activity and protein levels. In drug-naive conditions, there was no change in BDNF expression of BAD cells compared with CT cells. Treatment with Sp-isomer induced increased BDNF in both groups, while treatment with Rp-isomer induced a significant decrease in BDNF expression of BAD compared with CT. The p-CREB changes followed changes in BDNF levels, with increased and decreased Sp-isomer and Rp-isomer treatment, respectively. Our results suggest that mood disorder is associated with PKA upregulation and this could mask alteration in BDNF expression, because slowing down of PKA signaling results in a decrease of BDNF expression. These findings, combined with previous reports, provide a new insight to explain pharmacological features in different diagnostic groups.

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8-Bromo Cyclic Adenosine MonophosphateActivating Transcription Factor 1AdultBipolar DisorderBlotting, WesternBrain-Derived Neurotrophic FactorCase-Control StudiesCells, CulturedCyclic AMP Response Element-Binding ProteinCyclic AMP-Dependent Protein KinasesDNA-Binding ProteinsFemaleGene Expression RegulationHumansLymphocyte ActivationLymphocytesMaleMiddle AgedProtein SubunitsRNA, MessengerReverse Transcriptase Polymerase Chain ReactionTime FactorsTranscription FactorsComparative StudyJournal Article

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Félicien Karege, Michèle Schwald, Rachid El Kouaissi. 2004. Drug-induced decrease of protein kinase a activity reveals alteration in BDNF expression of bipolar affective disorder.. https://doi.org/10.1038/sj.npp.1300384

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