Doxorubicin Induces Dysregulation of AMPA Receptor and Impairs Hippocampal Synaptic Plasticity Leading to Learning and Memory Deficits

Doxorubicin (Dox) is a chemotherapeutic agent used widely to treat a variety of malignant cancers. However, Dox chemotherapy is associated with several adverse effects, including “chemobrain,” the observation that cancer patients exhibit through learning and memory difficulties extending even beyond treatment. This study investigated the effect of Dox treatment on learning and memory as well as hippocampal synaptic plasticity. Dox-treated mice (5 mg/kg weekly x 5) demonstrated impaired performance in the Y-maze spatial memory task and a significant reduction in hippocampal long-term potentiation. The deficit in synaptic plasticity was mirrored by deficits in the functionality of synaptic `α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) channels, including reduced probability of opening, decreased dwell open time, and increased closed times. Furthermore, a reduction in the AMPAR subunit GluA1 level, its downstream signaling molecule Ca(2)+/calmodulin-dependent protein kinase (CaMKII), and brain-derived neurotrophic factor (BDNF) were observed. This was also accompanied by an increase in extracellular signal regulated kinase (ERK) and protein kinase B (AKT) activation. Together these data suggest that Dox-induced cognitive impairments are at least partially due to alterations in the expression and functionality of the glutamatergic AMPAR system

Phenyl-2-aminoethyl selenide ameliorates hippocampal long-term potentiation and cognitive deficits following doxorubicin treatment.

Chemotherapy-induced memory loss ("chemobrain") can occur following treatment with the widely used chemotherapeutic agent doxorubicin (DOX). However, the mechanisms through which DOX induces cognitive dysfunction are not clear, and there are no commercially available therapies for its treatment or prevention. Therefore, the aim of this study was to determine the therapeutic potential of phenyl-2-aminoethyl selenide (PAESe), an antioxidant drug previously demonstrated to reduce cardiotoxicity associated with DOX treatment, against DOX-induced chemobrain. Four groups of male athymic NCr nude (nu/nu) mice received five weekly tail-vein injections of saline (Control group), 5 mg/kg of DOX (DOX group), 10 mg/kg PAESe (PAESe group), or 5 mg/kg DOX and 10 mg/kg PAESe (DOX+PAESe group). Spatial memory was evaluated using Y-maze and novel object location tasks, while synaptic plasticity was assessed through the measurement of field excitatory postsynaptic potentials from the Schaffer collateral circuit. Western blot analyses were performed to assess hippocampal protein and phosphorylation levels. In this model, DOX impaired synaptic plasticity and memory, and increased phosphorylation of protein kinase B (Akt) and extracellular-regulated kinase (ERK). Co-administration of PAESe reduced Akt and ERK phosphorylation and ameliorated the synaptic and memory deficits associated with DOX treatment