|A growing body of evidence suggests that acute and chronic cognitive impairments are a common side-effect of chemotherapy. In fact, chemotherapy induced cognitive deficits or “chemobrain” are known to occur in up to 75% of cancer survivors, but the mechanisms of these impairments are not fully understood. Elucidating the mechanisms of memory deficits due to chemobrain is crucial for developmental specific therapies. In the present study, we investigated the effects of a chemotherapeutic agent, doxorubicin (DOX), on memory using a rodent model of chemobrain. Additionally, we explored the therapeutic potential of Phenyl-2-Amino-Ethyl Selenide (PAESe) on altered synaptic plasticity and memory due to chemobrain. In addition, we investigated the direct effect of different concentrations DOX in in vitro and ex vivo models of chemobrain. Hippocampal neurons were exposed to three different concentrations of DOX (250nM, 500nM, and 1000nM) for 6 hours while acute brain slices were incubated with two concentrations of DOX (250nM and 1000nM) for the same time. Our results indicated that DOX exposure increased Akt, ERK1/2, and p38 phosphorylation, but it did not affect GSK3β phosphorylation. This result suggests that the possible effects of chemobrain are due to p38 dysregulation. Indeed, several studies illustrate the correlation between increased p38 phosphorylation and cognitive decline. We also explored the effects of intravenously injection of DOX (cumulative dose 25 mg/kg), DOX+PAESe (cumulative dose 25 mg/kg and 50 mg/kg), and PAESe (cumulative dose 50 mg/kg) on spatial memory. Nude mice received five doses of assigned drugs for four weeks. The results revealed that DOX treated animals had impaired memory, reduced LTP, and reduced CREB-1 phosphorylation. These deficits were rescued by PAESe treatment. The principal goal of our research is to develop a new novel therapeutic strategy for the treatment of chemobrain.