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

Behav Brain Res. 2015 Oct 1;292:133-41. doi: 10.1016/j.bbr.2015.06.028. Epub 2015 Jun 19.


Chemotherapy is associated with long-term cognitive deficits in breast cancer survivors. Studies suggest that these impairments result in the loss of cognitive reserve and/or induce a premature aging of the brain. This study has been aimed to determine the potential underlying mechanisms that induce cognitive impairments by chemotherapeutic agents commonly used in breast cancer. Intact and ovariectomized (OVX) female rats were treated intravenously with either saline or a combination of cyclophosphamide (40 mg/kg) and doxorubicin (4 mg/kg). All subjects were tested for anxiety, locomotor activity, working, visual and spatial memory consecutively. Although anxiety and visual memory were not affected, chemotherapy significantly decreased locomotor activity and impaired working and spatial memory in female rats, independent of their hormonal status. The cognitive deficits observed are hippocampal dependent. Therefore, as a first step to identity the potential signaling pathways involved in this cognitive dysfunction, the protein levels of extracellular signal-regulated kinase 1/2 (Erk1/2), Akt (neuroprotectant) BDNF and (structural protein) PSD95 in hippocampal lysates were measured. Erk1/2 and Akt pathways are known to modulate synaptic plasticity, neuronal survival, aging and cancer. We found an increased activation of Erk1/2 and Akt as well as an increase in the protein levels of PSD95 in OVX female rodents. However, OVX females had a higher overall BDNF level, independent of chemotherapy. These studies provide additional evidence that commonly used chemotherapeutic agents affect cognitive function and impact synaptic plasticity/aging molecules which may be part of the underlying biology explaining cognitive change and can be potential therapeutic targets.

Keywords: AKT signaling; Aging; Behavior; Cognitive dysfunction; ERK signaling; Rat.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Behavior, Animal / drug effects
  • Brain-Derived Neurotrophic Factor / drug effects
  • Cognition / drug effects*
  • Cognition Disorders / chemically induced*
  • Cognition Disorders / enzymology
  • Cyclophosphamide / administration & dosage
  • Cyclophosphamide / adverse effects
  • Disks Large Homolog 4 Protein
  • Doxorubicin / administration & dosage
  • Doxorubicin / adverse effects
  • Female
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • MAP Kinase Signaling System / drug effects*
  • Membrane Proteins / metabolism
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Rats, Inbred SHR
  • Signal Transduction / drug effects
  • Spatial Memory / drug effects


  • Brain-Derived Neurotrophic Factor
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Doxorubicin
  • Cyclophosphamide
  • Proto-Oncogene Proteins c-akt