Acetylcholine and necroptosis are players in follicular development in primates

Acetylcholine (ACh) in the ovary and its actions were linked to survival of human granulosa cells in vitro and improved fertility of rats in vivo. These effects were observed upon experimental blockage of the ACh-degrading enzyme (ACH esterase; ACHE), by Huperzine A. We now studied actions of Huperzine A in a three-dimensional culture of macaque follicles. Because a form of programmed necrotic cell death, necroptosis, was previously identified in human granulosa cells in vitro, we also studied actions of necrostatin-1 (necroptosis inhibitor). Blocking the breakdown of ACh by inhibiting ACHE, or interfering with necroptosis, did not improve the overall follicle survival, but promoted the growth of macaque follicles from the secondary to the small antral stage in vitro, which was correlated with oocyte development. The results from this translational model imply that ovarian function and fertility in primates may be improved by pharmacological interference with ACHE actions and necroptosis.