The chemotherapy agent, thioTEPA, yields long-term impairment of hippocampal cell proliferation and memory deficits but not depression-related behaviors in mice.
ThioTEPA is a chemotherapeutic agent used in the treatment of cancers, and more recently has been proposed as a component of high-dose therapy for young patients with recurrent malignant brain tumors. We previously demonstrated a significant dose-dependent reduction of cell proliferation in the dentate gyrus of the hippocampus in mice immediately following a 3-day regiment of thioTEPA. The aim of this study was to evaluate the long-term effects of thioTEPA treatment on hippocampal cell proliferation and potential effects on memory deficit or depression-related behavior in C57BL/6J mice. A 3-day regimen of thioTEPA (10mg/kg/d, i.p.) yielded a significant reduction in cell proliferation immediately after treatment as assessed by BrdU incorporation, and none of the labeled progeny that initially survived the treatment were detectable one week later. Following a 3-week rebound in proliferation following treatment, a significant deficit in proliferation reappeared and persisted for at least 21 weeks following treatment. ThioTEPA-treated mice subjected to an object recognition test 1, 2, 3, 4, 8, 12, 20 or 30 weeks following treatment demonstrated significant memory deficits at 12 and 20 weeks. Mice demonstrated a similar deficit in an object placement test when tested 20 weeks following thioTEPA treatment. However, no observable effects on performance in the Porsolt forced swim test or the tail suspension test were observed in thioTEPA-treated mice. Together, these studies suggest that cumulative long-term negative effects of thioTEPA treatment on proliferation of new cells in the dentate gyrus may contribute to cognitive impairments associated with its use in the treatment of cancer.
Mondie
Christopher M
CM
Department of Biology, Rider University, Lawrenceville, NJ 08648, USA.
Vandergrift
Kelley A
KA
Wilson
Courtney L
CL
Gulinello
Maria E
ME
Weber
E Todd
ET
D000704:Analysis of Variance; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D003863:Depression / Q000139:chemically induced / Q000473:pathology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects*; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D021641:Recognition, Psychology / Q000187:drug effects; D013852:Thiotepa / Q000009:adverse effects / Q000494:pharmacology*; D013997:Time Factors
D018906:Antineoplastic Agents, Alkylating; D013852:Thiotepa; D001973:Bromodeoxyuridine