Effect of aromatase inhibitors on learning and memory and modulation of hippocampal dickkopf-1 and sclerostin in female mice.

Abstract

There has been conflicting reports on the effect of third generation aromatase inhibitors on cognition in estrogen-deficient states. Since aromatase inhibitors themselves cause estrogen deprivation, the present work was designed to evaluate the comparative effect of three aromatase inhibitors on behavioral measures of learning and memory in female mice. Further, in view of the reports of estrogen and Wnt signaling pathway in cognition, the role of two Wnt signaling antagonists (dickkopf-1 and sclerostin) in mediation of cognitive effects of aromatase inhibitors was evaluated. Three behavioral paradigms were used for evaluating cognitive functions viz. Morris water maze, active avoidance learning and spontaneous alternation behavior following 10-15days of administration with aromatase inhibitors and the levels of dickkopf-1 and sclerostin were evaluated in hippocampus of female mice. Anastrozole and letrozole (but not exemestane) impaired learning and memory as indicated by increase in escape latency and path length during spatial acquisition, reduction of % quadrant dwell time in Morris water maze, reduction of % avoidance and increase in escape responses in active avoidance learning and decrease in % alternation in a cross maze. The behavioral effects correlated well with the levels of dickkopf-1 and sclerostin in the mouse hippocampus. The highest impairment in learning and memory occurred with letrozole followed by anastrozole while exemestane was without such effects. The present study demonstrates that aromatase inhibitors have adverse impact on cognition. Furthermore, modulation of Wnt signaling following estrogen depletion possibly contributed to observed effects in case of anastrozole and letrozole.