Although medical treatment of unruptured
ectopic pregnancy using
methotrexate has been established, development of more potent and safer medical treatment is needed due to limited indications and side effects of
methotrexate.
Brain-derived neurotrophic factor (
BDNF) signals through its
receptor tyrosine kinase B (TrkB) to regulate the growth of malignant trophoblastic,
choriocarcinoma cell. We investigated possible involvement of this signaling system in nonmalignant human trophoblast growth in both ectopic and intrauterine pregnancy. Here, we demonstrated the expression of
BDNF in syncytiotrophoblasts and extravillous trophoblasts (EVTs) together with TrkB in cytotrophoblasts and EVTs in human placental villi during both normal and
ectopic pregnancies. Treatment of cultured villous explants with soluble TrkB ectodomain or a Trk receptor inhibitor
K252a suppressed cytotrophoblast differentiation by inhibiting EVT outgrowth reflected by decreased levels of an EVT marker,
human leukocyte antigen-G. These inhibitors also decreased cytotrophoblast proliferation and cellular viability based on histopathological analyses and monitoring
glucose metabolism, together with increased apoptosis in cytotrophoblasts based on in situ
terminal deoxynucleotidyl transferase-mediated
2'-deoxyuridine 5'-triphosphate nick end-labeling and
caspase-3/7 assays. After
xenotransplantation of human placental villi into SCID mice as an in vivo model of
ectopic pregnancy, treatment with
K252a suppressed transplanted villi growth as reflected by decreased cytotrophoblast differentiation and proliferation, reduced tissue levels of
chorionic gonadotropin-β, and increased apoptosis and
caspase-3/7 activities. Thus, paracrine signaling by the
BDNF/TrkB system is important for human cytotrophoblast differentiation, proliferation, and survival, and inhibition of
BDNF/TrkB signaling in cytotrophoblasts could provide a novel medical treatment for
ectopic pregnancy.