Temporal brain transcriptome analysis reveals key pathological events after germinal matrix hemorrhage in neonatal rats

Abstract

Germinal matrix hemorrhage (GMH) is a common complication in preterm infants and is associated with high risk of adverse neurodevelopmental outcomes. We used a rat GMH model and performed RNA sequencing to investigate the signaling pathways and biological processes following hemorrhage. GMH induced brain injury characterized by early hematoma and subsequent tissue loss. At 6 hours after GMH, gene expression indicated an increase in mitochondrial activity such as ATP metabolism and oxidative phosphorylation along with upregulation of cytoprotective pathways and heme metabolism. At 24 hours after GMH, the expression pattern suggested an increase in cell cycle progression and downregulation of neurodevelopmental-related pathways. At 72 hours after GMH, there was an increase in genes related to inflammation and an upregulation of ferroptosis. Hemoglobin components and genes related to heme metabolism and ferroptosis such as Hmox1, Alox15, and Alas2 were among the most upregulated genes. We observed dysregulation of processes involved in development, mitochondrial function, cholesterol biosynthesis, and inflammation, all of which contribute to neurodevelopmental deterioration following GMH. This study is the first temporal transcriptome profile providing a comprehensive overview of the molecular mechanisms underlying brain injury following GMH, and it provides useful guidance in the search for therapeutic interventions.

ALAS2 overexpression alleviates oxidative stress-induced ferroptosis in aortic aneurysms via GATA1 activation

“…Further, another study reported a link between ALAS2 and ferroptosis. Specifically, Song et al found that ALAS2 expression was regulated by the ferroptosis response in a rat germinal matrix hemorrhage model, which may affect the molecular mechanisms of brain injury ( 36 ). These studies highlight the potential of ALAS2 to serve as an interventional target for a range of iron-related diseases.…”

The mechanism of Zhenzhu Pills treating intracerebral hemorrhage secondary injury based on network pharmacology and molecular docking

“…[ 50 ] HMOX1 is also a key target in the process of ferroptosis. [ 51 ] In the acute stage of ICH, HMOX1 catalyzes excessive heme decomposition, resulting in iron overload, which may directly lead to ferroptosis. This similar mechanism has been confirmed in acute myocardial injury caused by hemolysis.…”

Germinal matrix hemorrhage induces immune responses, brain injury, and motor impairment in neonatal rats

“…25 In addition, ferroptosis and mitochondrial dysfunction were found at early time points after GMH in the PND5 GMH rat model. 27 Brain injury after GMH includes the acute physical effects of bleeding 14 and the secondary injury arising from heme and free iron-induced cytotoxicity and regulated neural cell death, which can persist for a long time and are associated with long-term neurological disabilities and thus have attracted much attention in the study of post-hemorrhagic brain injury mechanisms. It has been shown that even low-grade GMH may impair normal oligodendrogenesis thus leading to white matter injury, 41 and immune cell infiltration and inflammation have been shown to play important roles in GMH-induced secondary brain injury.…”

“…Following anesthesia with isoflurane (5% for induction and 3.5% for maintenance) in a mixture of oxygen and nitrogen, 0.3 U collagenase VII (Sigma) in 2 µl saline or saline alone was injected into the right middle medial striatum for induction of GMH as previously described. 27 Briefly, injections were administered at 1 μL/min for 2 min in the right hemisphere 1 mm rostral of the bregma and 4 mm lateral of the midline, and 3.5 mm in depth using a 28G needle and a 25 μL Hamilton syringe connected to an infusion pump (CMA/100 microinjection pump). The animals were allowed to recover on a heating pad set to 35°C before being returned to their dams.…”

“…Our previous GMH datasets (BioProject ID: PRJNA756842) were collected from the BioSample database and the timepoint was 24 h after GMH induction, 27 and the differentially expressed genes (DEGs) were identified using the limma, deseq2, and edegR packages in R (4.1.0). The resulting p -values were adjusted using the Benjamini and Hochberg approach for controlling the false discovery rate.…”