Mitochondrial ferritin upregulation reduced oxidative stress and blood-brain-barrier disruption by maintaining cellular iron homeostasis in a neonatal rat model of germinal matrix hemorrhage.

Germinal matrix hemorrhage (GMH) is a devasting neurological disease in premature newborns. After GMH, brain iron overload associated with hemoglobin degradation contributed to oxidative stress, causing disruption of the already vulnerable blood-brain barrier (BBB). Mitochondrial ferritin (FTMT), a novel mitochondrial outer membrane protein, is crucial in maintaining cellular iron homeostasis. We aimed to investigate the effect of FTMT upregulation on oxidative stress and BBB disruption associated with brain iron overload in rats. A total of 222 Sprague-Dawley neonatal rat pups (7 days old) were used to establish a collagenase-induced GMH model and an iron-overload model of intracerebral FeCl2 injection. Deferiprone was administered via gastric lavage 1 h after GMH and given daily until euthanasia. FTMT CRISPR Knockout and adenovirus (Ad)-FTMT were administered intracerebroventricularly 48 h before GMH and FeCl2 injection, respectively. Neurobehavioral tests, immunofluorescence, Western blot, Malondialdehyde measurement, and brain water content were performed to evaluate neurobehavior deficits, oxidative stress, and BBB disruption, respectively. The results demonstrated that brain expressions of iron exporter Ferroportin (FPN) and antioxidant glutathione peroxidase 4 (GPX4) as well as BBB tight junction proteins including Claudin-5 and Zona Occulta (ZO)-1 were found to be decreased at 72 h after GMH. FTMT agonist Deferiprone attenuated oxidative stress and preserved BBB tight junction proteins after GMH. These effects were partially reversed by FTMT CRISPR Knockout. Iron overload by FeCl2 injection resulted in oxidative stress and BBB disruption, which were improved by Ad-FTMT mediated FTMT overexpression. Collectively, FTMT upregulation is neuroprotective against brain injury associated with iron overload. Deferiprone reduced oxidative stress and BBB disruption by maintaining cellular iron homeostasis partially by the upregulating of FTMT after GMH. Deferiprone may be an effective treatment for patients with GMH.

Yuan Y ，He Q ，Yang X ，Flores JJ ，Huang L ，Luo X ，Zhang X ，Zhang Z ，Li R ，Gu L ，Dong S ，Zhu S ，Yi K ，Han M ，Wu L ，Zhou Y ，Zhang JH ，Xie Z ，Tang J ... -  《-》

Mitochondrial ferritin upregulation by deferiprone reduced neuronal ferroptosis and improved neurological deficits via NDRG1/Yap pathway in a neonatal rat model of germinal matrix hemorrhage.

Yuan Y ，Yang X ，Zhao Y ，Flores JJ ，Huang L ，Gu L ，Li R ，Zhang X ，Zhu S ，Dong S ，Kanamaru H ，He Q ，Tao Y ，Yi K ，Han M ，Chen X ，Wu L ，Zhang JH ，Xie Z ，Tang J ... -  《-》

Minocycline-induced attenuation of iron overload and brain injury after experimental germinal matrix hemorrhage.

Germinal matrix hemorrhage (GMH) is the most important adverse neurologic event during the newborn period. Evidence has shown that neonates with GMH and hydrocephalus have more severe damage compared to those with GMH alone. Our preliminary study demonstrated the role of iron in hydrocephalus and brain damage in adult rats following intraventricular hemorrhage. Therefore, the aim of the current study was to investigate iron accumulation and iron-handling proteins in a rat model of GMH and whether minocycline reduces iron overload after GMH and iron-induced brain injury in vivo. This study was divided into two parts. In the first part, rats received either a needle insertion or an intracerebral injection of 0.3 U of clostridial collagenase VII-S. Brain iron and brain iron handling proteins (heme oxygenase-1 and ferritin) were measured. In the second part, rats with a GMH were treated with minocycline or vehicle. Brain edema, brain cell death, hydrocephalus, iron-handling proteins and long-term motor function were examined. The result showed iron accumulation and upregulation of iron-handling proteins after GMH. Minocycline treatment significantly reduced GMH-induced brain edema, hydrocephalus and brain damage. Minocycline also suppressed upregulation of ferritin after GMH. In conclusion, the current study found that iron plays a role in brain injury following GMH and that minocycline reduces iron overload after GMH and iron-induced brain injury.

Guo J ，Chen Q ，Tang J ，Zhang J ，Tao Y ，Li L ，Zhu G ，Feng H ，Chen Z ... -  《-》

Function and Biomarkers of the Blood-Brain Barrier in a Neonatal Germinal Matrix Haemorrhage Model.

Andersson EA ，Rocha-Ferreira E ，Hagberg H ，Mallard C ，Ek CJ ... -  《Cells》

Overexpression of Mitochondrial Ferritin Enhances Blood-Brain Barrier Integrity Following Ischemic Stroke in Mice by Maintaining Iron Homeostasis in Endothelial Cells.

Wang P ，Ren Q ，Shi M ，Liu Y ，Bai H ，Chang YZ ... -  《Antioxidants》