Acute treatment with methotrexate induces hippocampal dysfunction in a mouse model of breast cancer

Methotrexate (MTX) is a well-known cytostatic agent used in adjuvant chemotherapy for breast cancer, that has neurological side effects, including depression and cognitive impairment. We investigated the neurotoxic effects of MTX on the hippocampus and hippocampus-dependent behaviors in breast cancer cell line (FM3A)-inoculated tumor-bearing mice. In addition, we evaluated the changes in inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in the hippocampus of tumor-bearing mice after treatment with MTX. Depressive-like behavior test (tail-suspension test, TST) and learning and memory tasks (passive avoidance) were administered 24h after MTX (40 mg/kg, i.p.) injection. MTX-treated tumor-bearing mice showed significant depressive-like behaviors and cognitive impairment. Treatment with MTX significantly decreased the number of doublecortin (a marker for immature progenitor neurons)-positive cells in the hippocampal dentate gyrus of tumor-free and tumor-bearing mice. Moreover, treatment with MTX significantly upregulated proinflammatory enzymes, including iNOS and COX-2, in tumor-bearing mice. These findings indicate that the acute neurotoxic effect of MTX leads to hippocampal dysfunction including depressive-like behaviors and memory deficits, which may be related to an inhibition of neurogenesis and an increase of the inflammatory response in the hippocampus of a mouse model of breast cancer.