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The Effects of Chemotherapeutic Agents and a Mitochondrial Antioxidant on the Brain Transcriptome and Cognitive Function
Author(s) -
Cavalier Alyssa N.,
Clayton Zachary,
Wahl Devin,
Seals Douglas,
LaRocca Thomas
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.09524
Subject(s) - transcriptome , doxorubicin , downregulation and upregulation , pharmacology , oxidative stress , neurogenesis , biology , medicine , chemotherapy , gene expression , bioinformatics , gene , neuroscience , biochemistry
Cancer is the second leading cause of death in the United States, and over one‐third of patients will receive chemotherapy. One of most frequently reported side effects of chemotherapy is decreased cognitive function, commonly known as “chemobrain.” The underlying biological mechanisms of chemobrain are unclear, but could involve mitochondrial dysfunction and oxidative stress, which have been implicated in peripheral tissues, and could therefore be a therapeutic target. To investigate this possibility in the brain, we measured cognitive function and transcriptome changes by RNA‐seq in mice treated with doxorubicin, a common chemotherapy agent (single intraperitoneal injection, 10mg/kg, at 4 months old), or with doxorubicin plus the mitochondrial antioxidant, MitoQ (250 μM in drinking water for 4 weeks). We observed marked behavioral differences in doxorubicin‐treated mice, such as decreased overall exploration time in the novel object recognition test (NOR, an index of learning/memory). Despite these differences, we observed a trend towards reduced learning/memory (NOR) with doxorubicin treatment compared to sham. MitoQ did not prevent this; however, in RNA‐seq data, we found that doxorubicin increased expression of 127 genes and decreased expression of 154 genes (p < 0.01 vs. sham). These genes corresponded to ~80 transcriptional modules (FDR < 0.01), which were enriched for gene ontology terms related to synaptic transmission/plasticity, learning/memory, neurogenesis and neurotransmitter processing. MitoQ prevented most of these transcriptome changes (31 upregulated and 101 downregulated genes, p < 0.01 vs. sham) which corresponded to expression of only 16 transcriptional modules (none specifically related to brain function). Thus, our results suggest that MitoQ may have potential as a treatment for chemobrain at the biological level; however, its effects on brain/cognitive function require further investigation. Support or Funding Information AG060302