Doxorubicin attenuates serotonin-induced long-term synaptic facilitation by phosphorylation of p38 mitogen-activated protein kinase.

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.

Characterization and reversal of Doxorubicin-mediated biphasic activation of ERK and persistent excitability in sensory neurons of Aplysia californica.

Doxorubicin (DOX), a common chemotherapeutic agent, impairs synaptic plasticity. DOX also causes a persistent increase in basal neuronal excitability, which occludes serotonin-induced enhanced excitability. Therefore, we sought to characterize and reverse DOX-induced physiological changes and modulation of molecules implicated in memory induction using sensory neurons from the marine mollusk Aplysia californica. DOX produced two mechanistically distinct phases of extracellular signal-regulated kinase (ERK) activation, an early and a late phase. Inhibition of MEK (mitogen-activated protein kinase (MAPK)/ERK kinase) after DOX treatment reversed the late ERK activation. MEK inhibition during treatment enhanced the late ERK activation possibly through prolonged downregulation of MAPK phosphatase-1 (MKP-1). Unexpectedly, the late ERK activation negatively correlated with excitability. MEK inhibition during DOX treatment simultaneously enhanced the late activation of ERK and blocked the increase in basal excitability. In summary, we report DOX-mediated biphasic activation of ERK and the reversal of the associated changes in neurons, a potential strategy for reversing the deleterious effects of DOX treatment.