Increasing dietary choline to prevent chemotherapy related cognitive deficits and attenuate tumor growth in MMTV‐PyVT mice.

Abstract

Women constitute the majority of patients who report deficits of learning, memory, attention and processing speed during and following chemotherapy. These chemotherapy‐related cognitive deficits (CRCDs) are persistent and can impair day‐to‐day functioning for decades, adversely impacting quality of life. Many chemotherapeutic agents suppress ovarian function, decreasing circulating estrogen levels, a fact that may underlie the manifestation and/or persistence of CRCDs in females. Because estrogen regulates high affinity choline uptake (HACU) and HACU is the rate‐limiting step for acetylcholine synthesis, chemotherapeutic agents may indirectly impair processes mediated by cholinergic systems. Both tumors and chemotherapeutic agents can elevate pro‐inflammatory cytokines/chemokines, a consequence that may mediate the manifestation of CRCDs. Because acetylcholine (ACh) suppresses cytokine synthesis, inhibits inflammation and prevents tissue damage and cell death by activating α7 nicotinic acetylcholine receptors (nAChRs) located on cytokine producing cells, 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 maintain cholinergic function and protect cholinergic systems from degeneration by attenuating pro‐inflammatory processes.We have previously demonstrated that a single administration of the chemotherapeutic agents cyclophosphamide (CYP) and doxorubicin (DOX) resulted in a small, non‐significant, reduction in circulating estradiol (E2), and impaired HACU in the striatum (STR) and hippocampus (HCC) of nontumor‐bearing (C57Bl/6J) and tumor‐bearing (MMTV‐PyVT) female mice. We further demonstrated that the effect of a single administration of CYP+DOX on HACU could be prevented by placing mice on a 2% choline diet 2 weeks prior to exposure to CYP+DOX, and that a 2% choline diet could slow the growth of tumors in female tumor‐bearing MMTV‐PyVT mice. The present study sought to determine whether a 2% choline diet could: 1) maintain HACU in the frontal cortex, STR and HCC of nontumor‐bearing and tumor‐bearing mice following 4 weekly administrations of CYP+DOX, a regimen similar to that used for the treatment of some breast cancer patients; 2) prevent reductions in circulating E2 consequent to repeated CYP+DOX exposure; 3) attenuate elevations of central and circulating cytokines induced by repeated CYP+DOX exposure and/or the presence of tumors; 4) prevent spatial memory deficits in the Morris water maze following repeated exposure to CYP+DOX; and 5) suppress tumor growth and enhance the antineoplastic effects of CYP+DOX treatment in female tumor‐bearing MMTV‐PyVT mice. The results of these studies are discussed.Support or Funding InformationSupported by: NCCIH 1R21AT009734