title: Doxorubicin attenuates serotonin-induced long-term synaptic facilitation by phosphorylation of p38 mitogen-activated protein kinase.
abstract: Doxorubicin (DOX) is an anthracycline used widely for cancer chemotherapy. Its primary mode of action appears to be topoisomerase II inhibition, DNA cleavage, and free radical generation. However, in non-neuronal cells, DOX also inhibits the expression of dual-specificity phosphatases (also referred to as MAPK phosphatases) and thereby inhibits the dephosphorylation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK), two MAPK isoforms important for long-term memory (LTM) formation. Activation of these kinases by DOX in neurons, if present, could have secondary effects on cognitive functions, such as learning and memory. The present study used cultures of rat cortical neurons and sensory neurons (SNs) of Aplysia to examine the effects of DOX on levels of phosphorylated ERK (pERK) and phosphorylated p38 (p-p38) MAPK. In addition, Aplysia neurons were used to examine the effects of DOX on long-term enhanced excitability, long-term synaptic facilitation (LTF), and long-term synaptic depression (LTD). DOX treatment led to elevated levels of pERK and p-p38 MAPK in SNs and cortical neurons. In addition, it increased phosphorylation of the downstream transcriptional repressor cAMP response element-binding protein 2 in SNs. DOX treatment blocked serotonin-induced LTF and enhanced LTD induced by the neuropeptide Phe-Met-Arg-Phe-NH2. The block of LTF appeared to be attributable to overriding inhibitory effects of p-p38 MAPK, because LTF was rescued in the presence of an inhibitor (SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole]) of p38 MAPK. These results suggest that acute application of DOX might impair the formation of LTM via the p38 MAPK pathway.
authors.affiliation: Department of Neurobiology and Anatomy, W. M. Keck Center for the Neurobiology of Learning and Memory, University of Texas Medical School at Houston, Houston, Texas 77030.
authors.forename: Rong-Yu
authors.initials: RY
authors.lastname: Liu
authors.affiliation: Department of Neurobiology and Anatomy, W. M. Keck Center for the Neurobiology of Learning and Memory, University of Texas Medical School at Houston, Houston, Texas 77030.
authors.forename: Yili
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurobiology and Anatomy, W. M. Keck Center for the Neurobiology of Learning and Memory, University of Texas Medical School at Houston, Houston, Texas 77030.
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Coughlin
authors.affiliation: Department of Neurobiology and Anatomy, W. M. Keck Center for the Neurobiology of Learning and Memory, University of Texas Medical School at Houston, Houston, Texas 77030.
authors.forename: Leonard J
authors.initials: LJ
authors.lastname: Cleary
authors.affiliation: Department of Neurobiology and Anatomy, W. M. Keck Center for the Neurobiology of Learning and Memory, University of Texas Medical School at Houston, Houston, Texas 77030 John.H.Byrne@uth.tmc.edu.
authors.forename: John H
authors.initials: JH
authors.lastname: Byrne
mesh_terms: D000818:Animals; D001048:Aplysia; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018920:Coculture Techniques; D004317:Doxorubicin / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects*; D036881:Long-Term Synaptic Depression; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D059005:Topoisomerase II Inhibitors; D012701:Serotonin; D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Aplysia; ERK; chemotherapy; p38 MAPK; serotonin; synaptic plasticity