The majority of patients who report chemotherapy-related cognitive deficits are women. Many chemotherapeutic agents suppress ovarian function, decreasing circulating estrogen. Because estrogen regulates high affinity choline uptake (HACU) and HACU is the rate-limiting step for acetylcholine (ACh) synthesis, chemotherapeutic agents may indirectly impair cholinergic mediated cognitive processes. ACh suppresses cytokine synthesis, inhibits inflammation and prevents tissue damage and cell death by activating α7 nicotinic ACh receptors (nAChRs), thus impaired HACU and ACh synthesis following chemotherapy may exacerbate the adverse effects of neuroinflammation caused by tumors and chemotherapeutic agents. Since increasing available choline can maintain cholinergic function when demand for the precursor is high, and because choline is a full agonist at α7 nAChRs, increasing dietary choline may protect ACh systems from degeneration by attenuating pro-inflammatory processes.
We have demonstrated that one administration of cyclophosphamide (CYP) and doxorubicin (DOX) impairs HACU in the striatum (STR) and hippocampus (HCC) of non tumor-bearing (M-) and tumor-bearing MMTV-PyVT (M+) female mice. Further, we have shown that the effect of one administration of CYP+DOX on HACU is prevented by placing mice on a 2% choline diet, and a 2% choline diet slows tumor growth in female M+ mice.
The present study sought to determine whether a 2% choline diet could: 1) prevent the manifestation of spatial memory deficits resulting from repeated exposure to CYP (66.7mg/kg i.v.; ≈200mg/m2/wk) and DOX (6.7mg/kg i.v.; ≈20mg/m2/wk); 2) maintain HACU in the frontal cortex (CTX), STR and HCC of mice following 4 weekly administrations of CYP+DOX; 3) prevent reductions in circulating E2 consequent to repeated CYP+DOX exposure; 4) attenuate elevations of circulating cytokines induced by repeated CYP+DOX exposure and/or the presence of tumors; and 5) suppress tumor growth and enhance the antineoplastic effects of CYP+DOX treatment in female M+ mice.
Results indicate that M- and M+ mice exposed to CYP+DOX exhibit deficits in spatial memory 10-12 days following 4 weekly injections of CYP+DOX and 5 weeks following the final administration. HACU was reduced in the STR and HCC following a single exposure to CYP+DOX and this effect persisted in the STR. However, reduced HACU in the HCC was transient. Supplementation with a 2% choline diet prevented the manifestation of spatial memory deficits in M- and M+ mice and HACU in these mice did not differ from controls, suggesting that impaired HACU mediated the deficit in spatial memory. Although we did not observe an anticipated reduction in circulating estradiol due to CYP+DOX exposure, the regular appearance of proestrous was disrupted in groups exposed to either CYP+DOX or 2% choline diet, suggestive of amenorrhea. Circulating concentrations of cytokines, including G-CSF, IL6, IP10, MCP1 and RANTES, were altered by the presence of tumors as well as the administration of CYP+DOX. 2% choline significantly reduced circulating concentrations of IL-5, a cytokine associated with poor prognosis and metastasis, and total tumor volume was lower in mice placed on 2% choline diet when compared to tumor bearing mice on standard diet.
