Transient improvement in cognitive function and synaptic plasticity in rats following cancer chemotherapy.
BACKGROUND
Cancer chemotherapy has been associated with cognitive impairment. Several issues complicate such findings including the patients' health, use of multiple chemotherapeutic agents, and proper assessment of cognition. To control these factors, we conducted cognitive studies in female rats receiving cyclophosphamide or 5-fluorouracil (5FU).


METHODS
Young (7 months) female Fischer-344 rats received five injections of cyclophosphamide (100 mg/kg), 5FU (150 mg/kg), or saline i.p. every 4 weeks for a total of 18 weeks. Aged (18 months) female Fischer-344 rats were treated with cyclophosphamide (80 mg/kg i.p.) for 16 weeks. After 8 to 10 weeks of recovery, rats were tested in two maze learning tasks, the Morris water maze and the Stone 14-unit T-maze. Neuronal synaptic function was assessed by examining long-term potentiation (LTP) in hippocampal slices obtained from young cyclophosphamide-treated rats.


RESULTS
Despite the toxic effects induced by chemotherapy, cyclophosphamide- and 5FU-treated rats showed significantly better maze performance compared with controls. Following 29 to 42 weeks of recovery from chemotherapy, no significant effects were observed on maze performance. In aged rats, cyclophosphamide treatment for 14 weeks also produced toxicity, but no impairment in Stone maze learning after 16 weeks of recovery. When assessed during cyclophosphamide treatment, evidence of impaired LTP emerged; however, with 8 weeks of recovery following five cyclophosphamide treatments, we observed enhanced LTP.


CONCLUSIONS
Despite toxicity accompanying chemotherapy, no evidence of impaired cognitive performance emerged after recovery. Indeed, following 7 to 9 weeks of recovery, we noted evidence of improved learning and LTP.
Lee
Garrick D
GD
Laboratory of Experimental Gerontology, Intramural Research Program, National Institute on Aging, Baltimore, Maryland 21224, USA.
Longo
Dan L
DL
Wang
Yue
Y
Rifkind
Joseph M
JM
Abdul-Raman
Lilanie
L
Mamczarz
Jacek A
JA
Duffy
Kara B
KB
Spangler
Edward L
EL
Taub
Dennis D
DD
Mattson
Mark P
MP
Ingram
Donald K
DK
D000367:Age Factors; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D003071:Cognition / Q000187:drug effects*; D003520:Cyclophosphamide / Q000009:adverse effects*; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects*; D006624:Hippocampus / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects*; D018782:Maze Learning / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy*; D009924:Organ Culture Techniques; D051381:Rats; D011916:Rats, Inbred F344
D000970:Antineoplastic Agents; D003520:Cyclophosphamide; D005472:Fluorouracil