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

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. SUMMARY: 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.

Thyroid hormone-dependent formation of a subcortical band heterotopia (SBH) in the neonatal brain is not exacerbated under conditions of low dietary iron (FeD).

Thyroid hormones (TH) are critical for brain development and insufficiencies can lead to structural abnormalities in specific brain regions. Administration of the goitrogen propylthiouracil (PTU) reduces TH production by inhibiting thyroperoxidase (TPO), an enzyme that oxidizes iodide for the synthesis of TH. TPO activity is iron (Fe)-dependent and dietary iron deficiency (FeD) also reduces circulating levels of TH. We have previously shown that modest degrees of TH insufficiency induced in pregnant rat dams alters the expression of TH-responsive genes in the cortex and hippocampus of the neonate, and results in the formation of a subcortical band heterotopia (SBH) in the corpus callosum (Royland et al., 2008, Bastian et al., 2014, Gilbert et al., 2014). The present experiment investigated if FeD alone was sufficient to induce a SBH or if FeD would augment SBH formation at lower doses of PTU. One set of pregnant rats was administered 0, 1, 3, or 10ppm of PTU via drinking water starting on gestational day (GD) 6. FeD was induced in a 2nd set of dams beginning on GD2. A third set of dams received the FeD diet from GD2 paired with either 1ppm or 3ppm PTU beginning on GD6. All treatments continued until the time of sacrifice. On PN18, one female pup from each litter was sacrificed and the brain examined for SBH. We observed lower maternal, PN2 and PN18 pup serum T4 in response to PTU. FeD reduced serum T4 in pups on PN16, but did not affect serum T4 in dams or PN2 pups. Neither did FeD in combination with PTU alter T4 levels in dams on PN18 or pups on PN2 compared to PTU treatment alone. By PN16, however more severe T4 reductions were observed in pups when FeD was combined with PTU. SBH increased with increasing dosage of PTU, but counter to our hypothesis, no SBH was detected in the offspring of FeD dams. As such, T4 levels in dams and newborn pups rather than older neonates appear to be a better predictor SBH associated with TH insufficiency. These data indirectly support previous work indicating prenatal TH insufficiency but not postnatal TH insufficiency in offspring is required for SBH formation.