Eltrombopag, a thrombopoietin mimetic, crosses the blood–brain barrier and impairs iron‐dependent hippocampal neuron dendrite development

Abstract

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 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 14DIV 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 was reduced in 6 μM ELT-treated neurons, resulting in blunted dendritic arbor complexity that was similar to DFO-treated neurons. Conclusions ELT treatment during development may impair neuronal structure due to neuronal ID. Pre-clinical in vivo studies are warranted to assess ELT safety during periods of rapid brain development.

Eltrombopag: a powerful chelator of cellular or extracellular iron(III) alone or combined with a second chelator

“…Although we have not measured ELT entry into cells directly, we believe, based on several independent lines of evidence, that rapid cellular uptake of ELT is likely. First, ELT is taken up rapidly into isolated hepatocytes37 and neuronal cells 38. Second, studies with other chelators have shown that chelator entry into cells is key to cellular iron mobilization.…”

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“…Dendrites were traced using the NeuronJ plugin (http://www.imagescience.org/meijering/ software/neuronj/) as previously described. 5 Sholl analysis was performed on the NeuronJ tracings using the Sholl Analysis plugin (http://fiji.sc/Sholl_Analysis). For the Sholl analysis, the single animals were selected as the unit of analysis (5 animals per group).…”

Eltrombopag for use in children with immune thrombocytopenia

“…37 It has also been shown to have a significant impact on neonatal iron levels. 38 In children with chronic ITP, there has been some suggestion that use of eltrombopag may increase the risk of iron deficiency. 21 If iron deficiency develops and no other cause is identified, it may be appropriate to continue eltrombopag therapy and give iron supplementation, ensuring that the doses of the 2 medications are spaced as far apart as possible.…”