Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory

Abstract

Rationale-The concern that adjuvant cancer chemotherapy agents cause cognitive impairment in a significant number of patients has been expressed by patients and healthcare providers, but clinical studies have yielded conflicting results to date.Objective-We directly tested two commonly used chemotherapeutic agents in a mouse model of learning and memory.Materials and methods-In the present study, mice were conditioned to respond for a liquid reinforcer (Ensure solution) in the presence of an audible tone on day 1 as a measure of acquisition and were then required to perform the same response on day 2 as a measure of retrieval and retention. Methotrexate and 5-fluorouracil were administered prior to the day 1 session.Results-Methotrexate (1.0-32 mg/kg) alone failed to alter mean latency acquisition, retrieval, or reinforced response rates. Similar to scopolamine, a known amnesic in this assay, 5-fluorouracil (3-75 mg/kg) failed to alter response rates or acquisition latency on day 1 but significantly altered latency to retrieve a previously learned response on day 2. In combination, 3.2 mg/kg methotrexate plus 75 mg/kg 5-fluorouracil significantly increased day 1 and day 2 acquisition and retrieval latencies without altering responserates or motivation to respond as measured by progressive ratio responding. Conclusion-Takentogether, these data demonstrate that 5-fluorouracil causes increased latencies for retrieval of previously learned behavioral responses and that combination of chemotherapeutic agents may produce greater delays than either agent alone, including when neither agent alone does so.

The Effects of Chemotherapy on Cognitive Function in a Mouse Model: A Prospective Study

“…5-8; but see ref. 9). Typically, a single hippocampus-sensitive test of learning and memory is conducted and the consistent finding is druginduced impairment.…”

“…Deficits can be wide ranging but typically include loss of memory and working memory, impaired attentional processes, and poor problem solving-a pattern that suggests dysfunction in hippocampal and frontal lobe brain areas. The adverse effects of anticancer drugs on cognition have been confirmed in animals and the deficits are often similar to those observed in patients (4)(5)(6)(7)(8)(9). The congruence of data from animal models points to the biologic basis of the problem and argues against the notion that such effects are psychosocial in nature, resulting from the challenges of coping with a serious disease and difficult treatment.…”

Methotrexate reduces hippocampal blood vessel density and activates microglia in rats but does not elevate central cytokine release

“…A number of cytostatics are associated with cognitive impairment, but methotrexate (MTX), a cytostatic drug that frequently has been used in regimens of adjuvant chemotherapy for breast cancer, appears to be potentially more harmful then others. This has been shown in a number of clinical [30][31][32] and animal studies [12,35,41]. Therefore, in this paper, we study the effect of MTX on a number of neurobiological processes which may be involved in the cognitive impairment seen after treatment with chemotherapy.…”

Chemobrain: revisión de estudios que evalúan el deterioro cognitivo de supervivientes de cáncer tratados con quimioterapia

“…Los datos electrofisiológicos sugieren deterioro en la percepción de imputs auditivos como posible factor etiológico del daño cognitivo (39) . La combinación de agentes quimioterapéuti-cos (como 5-FU+metotrexato) produce mayor dificultad de recuperar comportamientos ya aprendidos que cuando se emplean en monoterapia (40) . Además, el empleo de animales permite analizar la efectividad de algunos fármacos, como el antioxidante Nacetilcisteina, en la prevención de dichas alteraciones comprobando si restan o no eficacia al tratamiento antineoplásico.…”