Cargando…

Intracellular Fe(2+) accumulation in endothelial cells and pericytes induces blood-brain barrier dysfunction in secondary brain injury after brain hemorrhage

After intracranial hemorrhage (ICH), iron is released from the hematoma and induces secondary brain injury. However, the detail effect of iron on blood-brain barrier (BBB) function is still unknown. We investigated whether hemoglobin (Hb), ferrous ammonium sulfate (FAS) or hemin which contains iron...

Descripción completa

Detalles Bibliográficos
Autores principales: Imai, Takahiko, Iwata, Sena, Hirayama, Tasuku, Nagasawa, Hideko, Nakamura, Shinsuke, Shimazawa, Masamitsu, Hara, Hideaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470176/
https://www.ncbi.nlm.nih.gov/pubmed/30996325
http://dx.doi.org/10.1038/s41598-019-42370-z
Descripción
Sumario:After intracranial hemorrhage (ICH), iron is released from the hematoma and induces secondary brain injury. However, the detail effect of iron on blood-brain barrier (BBB) function is still unknown. We investigated whether hemoglobin (Hb), ferrous ammonium sulfate (FAS) or hemin which contains iron have the detrimental effect on both human brain microvascular endothelial cells and pericytes by cellular function analysis in vitro. We developed an iron (Fe(2+))-detectable probe, Si-RhoNox-1, to investigate intracellular Fe(2+) accumulation (Fe(2+)(intra)). After FAS treatment, there was the correlation between Fe(2+)(intra) and cell death. Moreover, Hb or hemin treatment induced cell death, increased reactive oxygen species and promoted Fe(2+)(intra) in both cells. These changes were inhibited by the Fe(2+) chelator, 2,2′-bipyridil (BP). Furthermore, hemin induced endothelial barrier dysfunction via disruption of junction integrity. Based on in vitro studies, we used a hemin-injection ICH mice model in vivo. Hemin injection (10 mM/10 µL, i.c.) induced deleterious effects including BBB hyper-permeability, neuronal deficits, neuronal damage, altered proteins expression, and Fe(2+)(intra) in BBB composed cells. Lastly, BP (40 mg/kg, i.p.) administration attenuated neuronal deficits at 3 days after surgery. Collectively, Hb or hemin damaged BBB composed cells via Fe(2+)(intra). Therefore, the regulation of the Fe(2+) movement in BBB might be effective for treatment of ICH.