Abstract
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.
Highlights
Chemotherapy is associated with cognitive deficits including memory impairments in a subset of cancer survivors[1, 2]
DOX-mediated impairment of long-term synaptic facilitation (LTF) is rescued by inhibition of p38 MAPK12, suggesting that the DOX-mediated activation of p38 mitogen-activated protein kinases (MAPK) may dominate over extracellular signal-regulated kinase (ERK) and contribute to the deficits in synaptic facilitation and enhancement of synaptic depression
The temporal profiles of pERK and p-p38 MAPK resulting from varying durations of DOX treatment (2.5 μM for 30, 60, 90, and 120 min; Fig. 1a) were examined to determine whether the dynamics of activation of these kinases differ
Summary
Chemotherapy is associated with cognitive deficits including memory impairments in a subset of cancer survivors[1, 2]. To examine the effects of DOX on neurons, the invertebrate model system Aplysia was chosen for its utility in studying long-term cellular and synaptic deficits caused by DOX treatment[12]. DOX-mediated impairment of LTF is rescued by inhibition of p38 MAPK12, suggesting that the DOX-mediated activation of p38 MAPK may dominate over ERK and contribute to the deficits in synaptic facilitation and enhancement of synaptic depression. Activation of ERK is sufficient to induce long-lasting changes in excitability of Aplysia SNs34 and is required for enhanced long-term excitability by transforming growth factor β-1 (TGFβ-1)[31]. Enhancement of basal excitability of the presynaptic cell by DOX accompanied by deficits in synaptic facilitation suggest divergent roles of kinase activation in mediating neuronal excitability and synaptic plasticity. It is of particular interest to determine if the DOX-induced increase in basal neuronal excitability depends upon either or both ERK and p38 MAPK activation
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