Broad-spectrum protein kinase inhibition by the staurosporine analog KT-5720 reverses ethanol withdrawal-associated loss of NeuN/Fox-3
Autor: | Anna R. Reynolds, Lynda J. Sharrett-Field, Jennifer N. Berry, Sydney R. Winchester, Mark A. Prendergast, Meredith A. Saunders |
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Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Health (social science) medicine.drug_class Carbazoles Nerve Tissue Proteins Neurotransmission Biology Toxicology Biochemistry Hippocampus Article Rats Sprague-Dawley 03 medical and health sciences Behavioral Neuroscience 0302 clinical medicine Organ Culture Techniques medicine Staurosporine Animals Pyrroles Nuclear protein Receptor Protein kinase A Protein Kinase Inhibitors Ethanol Kinase Nuclear Proteins Antigens Nuclear General Medicine Protein kinase inhibitor Molecular biology Cell biology Rats Substance Withdrawal Syndrome DNA-Binding Proteins 030104 developmental biology Neurology nervous system biology.protein NeuN 030217 neurology & neurosurgery medicine.drug |
Popis: | Chronic, intermittent ethanol (CIE) exposure is known to produce neuroadaptive alterations in excitatory neurotransmission that contribute to the development of dependence. Although activation of protein kinases (e.g., cyclic AMP [cAMP]-dependent protein kinase) is implicated in the synaptic trafficking of these receptors following CIE exposure, the functional consequences of these effects are yet to be fully understood. The present study sought to delineate the influence of protein kinase in regulating cytotoxicity following CIE exposure, as well as to examine the relative roles of ethanol exposure and ethanol withdrawal (EWD) in promoting these effects. Rat hippocampal explants were exposed to a developmental model of CIE with or without co-application of broad-spectrum protein kinase inhibitor KT-5720 (1 μM) either during ethanol exposure or EWD. Hippocampal cytotoxicity was assessed via immunofluorescence (IF) of neuron-specific nuclear protein (NeuN) with thionine staining of Nissl bodies to confirm IF findings. Concomitant application of ethanol and KT-5720 restored the loss of NeuN/Fox-3 IF in pyramidal CA1 and granule DG cell layers produced by CIE, but there was no restoration in CA3. Application of KT-5720 during EWD failed to significantly alter levels of NeuN IF, implying that ethanol exposure activates protein kinases that, in part, mediate the effects of EWD. KT-5720 application during EWD also restored thionine staining in CA1, suggesting kinase regulation of both neurons and non-neuronal cells. These data demonstrate that CIE exposure alters protein kinase activity to promote ethanol withdrawal-associated loss of NeuN/Fox-3 and highlight the influence of kinase signaling on distinct cell types in the developing hippocampus. |
Databáze: | OpenAIRE |
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