Increasing dietary choline attenuates spatial memory deficits resulting from exposure to the chemotherapeutic agents cyclophosphamide and doxorubicin.

BACKGROUND: Choline supplementation (+Ch) improves cognitive function in impaired animals and humans. Chemotherapy-related cognitive deficits (CRCDs) occur in cancer patients, and these deficits persist following treatment, adversely impacting quality of life. To date, there are no approved treatments for this condition. AIM: Because +Ch improves impaired memory, it was of interest to determine whether +Ch can attenuate spatial memory deficits induced by the chemotherapeutic agents doxorubicin (DOX) and cyclophosphamide (CYP). METHODS: Female BALB/C mice, 64 days of age, were trained in the Morris water maze and baseline performance determined on day 15. Following baseline assessment, mice were placed on +Ch diet (2.0% Ch) or remained on standard diet (0.12% Ch). Mice received intravenous injections of DOX (2.5 mg/kg) and CYP (25 mg/kg), or equivalent volumes of saline (0.9% NaCl), on days 16, 23, 30, and 37, and spatial memory was assessed weekly from day 22 to 71. RESULTS: DOX and CYP produced a prolonged impairment in spatial memory as indicated by an increased latency to the correct zone (p < 0.05), and a decrease in time in the correct zone (p < 0.05), % of total swim distance in the correct zone (p < 0.05) and % entries to the correct zone (p < 0.05). These effects were attenuated by +Ch. CONCLUSION: Although it remains to be determined whether this effect extends to other cognitive domains and whether +Ch is prophylactic or therapeutic, these findings suggest that +Ch may be an effective intervention for CRCDs.

Doxorubicin and cyclophosphamide lead to long-lasting impairment of spatial memory in female, but not male mice.

Self-reports of chemotherapy-related cognitive deficits (CRCDs) are more prevalent among women than men, suggesting that women may be more vulnerable to the cognitive-impairing effects of chemotherapy. However, there have been no direct comparisons of females and males using objective measures of cognitive function either during or following exposure to the same chemotherapeutic regimen. The present study used an animal model, and a prospective longitudinal design, to assess sex differences in the manifestation and persistence of spatial memory deficits resulting from exposure to doxorubicin (DOX) and cyclophosphamide (CYP), commonly used anticancer drugs. The spatial memory of female and male BALB/C mice was assessed using the Morris water maze prior to, during and following 4 weekly intravenous injections of DOX (2.5mg/kg) and CYP (25mg/kg) or vehicle. Females receiving DOX+CYP experienced significant deficits in spatial memory during and following injections when compared to baseline or females receiving vehicle. These deficits persisted for at least 34 days following the final injection. In contrast, males receiving DOX+CYP injections did not exhibit alterations in spatial memory relative to baseline or males receiving vehicle. These findings indicate that females may be more vulnerable than males to the cognitive-impairing effects of DOX+CYP and demonstrate that deficits in females persist for at least several weeks following drug exposure. Preclinical studies of CRCDs should parallel clinical work by including females and examine sex specific factors as potential mechanisms.