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) ofAplysiato examine the effects of DOX on levels of phosphorylated ERK (pERK) and phosphorylated p38 (p-p38) MAPK. In addition,Aplysianeurons 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.

Prophylactic effects of ellagic acid and rosmarinic acid on doxorubicin‐induced neurotoxicity in rats

“…DOX induced reduction in brain 5‐HT, DA, and NE accompanied with significant elevation of CHE activity. The observed results confirmed by Liu et al . showed that treatment by DOX blocked 5‐HT activity.…”

Doxorubicin and cyclophosphamide induce cognitive dysfunction and activate the ERK and AKT signaling pathways

“…However, hyperactivation of ERK signaling may lead to detrimental effects on cognition consistent with our results that ERK 1/2 is activated in OVX rats treated with chemotherapeutic agents. A recent study found that doxorubicin exposure in both rat cortical neurons and Aplysia sensory neurons induced the activation of ERK and p38 MAPK [44]. It is also possible that the differential activation of these MAPK isoforms may ultimately influence synaptic plasticity through the regulation of the transcriptional repressor CREB2 [44].…”

“…A recent study found that doxorubicin exposure in both rat cortical neurons and Aplysia sensory neurons induced the activation of ERK and p38 MAPK [44]. It is also possible that the differential activation of these MAPK isoforms may ultimately influence synaptic plasticity through the regulation of the transcriptional repressor CREB2 [44]. Both pathways have sites where they can intersect.…”

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

“…DOX concentrations used in vitro vary widely (0.5 to 20 μM) 12, 45, 46, 59, 60 . However, in vivo measurement of the amount of DOX in rodent brain after intraperitoneal injection is approximately 0.25 μM 11 .…”