title: Eltrombopag, a thrombopoietin mimetic, crosses the blood-brain barrier and impairs iron-dependent hippocampal neuron dendrite development.
abstract: Essentials Potential neurodevelopmental side effects of thrombopoietin mimetics need to be considered. The effects of eltrombopag (ELT) on neuronal iron status and dendrite development were assessed. ELT crosses the blood-brain barrier and causes iron deficiency in developing neurons. ELT blunts dendrite maturation, indicating a need for more safety studies before neonatal use.
  
  
  
  Background Thrombocytopenia is common in sick neonates. Thrombopoietin mimetics (e.g. eltrombopag [ELT]) might provide an alternative therapy for selected neonates with severe and prolonged thrombocytopenia, and for infants and young children with different varieties of thrombocytopenia. However, ELT chelates intracellular iron, which may adversely affect developing organs with high metabolic requirements. Iron deficiency (ID) is particularly deleterious during brain development, impairing neuronal myelination, dopamine signaling and dendritic maturation and ultimately impairing long-term neurological function (e.g. hippocampal-dependent learning and memory). Objective To determine whether ELT crosses the blood-brain barrier (BBB), causes neuronal ID and impairs hippocampal neuron dendrite maturation. Methods ELT transport across the BBB was assessed using primary bovine brain microvascular endothelial cells. Embryonic mouse primary hippocampal neuron cultures were treated with ELT or deferoxamine (DFO, an iron chelator) from 7 days in vitro (DIV) through 14 DIV and assessed for gene expression and neuronal dendrite complexity. Results ELT crossed the BBB in a time-dependent manner. 2 and 6 μm ELT increased Tfr1 and Slc11a2 (iron-responsive genes involved in neuronal iron uptake) mRNA levels, indicating neuronal ID. 6 μm ELT, but not 2 μm ELT, decreased BdnfVI, Camk2a and Vamp1 mRNA levels, suggesting impaired neuronal development and synaptic function. Dendrite branch number and length were reduced in 6 μm ELT-treated neurons, resulting in blunted dendritic arbor complexity that was similar to DFO-treated neurons. Conclusions Eltrombopag treatment during development may impair neuronal structure as a result of neuronal ID. Preclinical in vivo studies are warranted to assess ELT safety during periods of rapid brain development.
authors.affiliation: Department of Pediatrics, School of Medicine, University of Minnesota, Minneapolis, MN, USA.|Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA.|Center for Neurobehavioral Development, School of Medicine, University of Minnesota, Minneapolis, MN, USA.
authors.forename: T W
authors.identifier: 0000-0001-5486-9471
authors.initials: TW
authors.lastname: Bastian
authors.affiliation: Department of Neurosurgery, The Pennsylvania State University, Hershey, PA, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Duck
authors.affiliation: Department of Pediatrics, School of Medicine, University of Minnesota, Minneapolis, MN, USA.
authors.forename: G C
authors.initials: GC
authors.lastname: Michalopoulos
authors.affiliation: Department of Neurosurgery, The Pennsylvania State University, Hershey, PA, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Chen
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Z-J
authors.initials: ZJ
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, The Pennsylvania State University, Hershey, PA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Connor
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA.|Center for Neurobehavioral Development, School of Medicine, University of Minnesota, Minneapolis, MN, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Lanier
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Sola-Visner
authors.affiliation: Department of Pediatrics, School of Medicine, University of Minnesota, Minneapolis, MN, USA.|Center for Neurobehavioral Development, School of Medicine, University of Minnesota, Minneapolis, MN, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Georgieff
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000503:physiopathology; D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000493:pharmacokinetics*; D001692:Biological Transport; D032701:Biomimetics; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002417:Cattle; D002614:Chelating Agents / Q000737:chemistry / Q000493:pharmacokinetics; D003676:Deferoxamine / Q000494:pharmacology; D003712:Dendrites / Q000187:drug effects* / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006834:Hydrazines / Q000737:chemistry / Q000493:pharmacokinetics*; D007501:Iron / Q000737:chemistry*; D051379:Mice; D008833:Microcirculation; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D013921:Thrombocytopenia / Q000503:physiopathology; D013926:Thrombopoietin
chemical_list: D001565:Benzoates; D002614:Chelating Agents; D006834:Hydrazines; D011720:Pyrazoles; D049452:Green Fluorescent Proteins; D013926:Thrombopoietin; D007501:Iron; D003676:Deferoxamine; C520809:eltrombopag
keywords: dendrites; gene expression; growth; iron; thrombocytopenia