Brain-Derived Neurotrophic Factor/Tyrosine Kinase B Signaling Regulates Human Trophoblast Growth in an in Vivo Animal Model of Ectopic Pregnancy

Abstract

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.

BNDF methylation in mothers and newborns is associated with maternal exposure to war trauma

“…BDNF crosses the blood-brain barrier and is present in the bloodstream and peripheral tissues as well, exerting neuro-protective effects throughout the body [4–6]. During the prenatal period, BDNF potentiates placental development and facilitates cytotrophoblast differentiation, proliferation, migration, and survival necessary for fetal growth [7, 8]. …”

“…Moreover, despite knowledge that BDNF plays a key role in regulating placental and fetal development [7, 52], there are no reports, either human or animal, testing prenatal stress exposures and BDNF methylation in placenta. The present study addresses these gaps by examining prenatal exposure to maternal psychosocial stress among mothers and newborns in a war-torn region of the eastern Democratic Republic of Congo.…”

Depressive Temperament in Relatives of Patients with Schizophrenia Is Associated with Suicidality in Patients with Schizophrenia

“…The affective temperament of an individual is one of the structural, biological, and genetic factors determining the risk of depression and mania15) and clinical characteristics proposed to be associated with suicidal risk include affective temperaments types. Several studies have shown that affective temperaments which are accepted as precursors of mood disorders may be an important factor in predicting suicidality 6).…”

Maternal obesity alters brain derived neurotrophic factor (BDNF) signaling in the placenta in a sexually dimorphic manner

“…Surprisingly, maternal obesity is associated with decreased placental apoptosis [20], suggesting contextually restrictive proBDNF/p75NTR signaling. However, BDNF and TRKB are expressed in the placenta [21], reported to play critical roles in implantation [22], placental development [22, 23], and fetal growth [24]. In addition to its involvement in placental development, BDNF/TRKB signaling regulates energy homeostasis and mediates mitochondrial function [25].…”