Abstract
Aims Blood clots play the primary role in neurological deficits after germinal matrix hemorrhage (GMH). Previous studies have shown a beneficial effect in blood clot clearance after hemorrhagic stroke. The purpose of this study is to investigate interleukin-19's role in hematoma clearance after GMH and its underlying mechanism of IL-20R1/ERK/Nrf2 signaling pathway. Methods A total of 240 Sprague-Dawley P7 rat pups were used. GMH was induced by intraparenchymal injection of bacterial collagenase. rIL-19 was administered intranasally 1 hour post-GMH. IL-20R1 CRISPR was administered intracerebroventricularly, or Nrf2 antagonist ML385 was administered intraperitoneally 48 hours and 1 hour before GMH induction, respectively. Neurobehavior, Western blot, immunohistochemistry, histology, and hemoglobin assay were used to evaluate treatment regiments in the short- and long-term. Results Endogenous IL-19, IL-20R1, IL-20R2, and scavenger receptor CD163 were increased after GMH. rIL-19 treatment improved neurological deficits, reduced hematoma volume and hemoglobin content, reduced ventriculomegaly, and attenuated cortical thickness loss. Additionally, treatment increased ERK, Nrf2, and CD163 expression, whereas IL-20R1 CRISPR-knockdown plasmid and ML385 inhibited the effects of rIL-19 on CD163 expression. Conclusion rIL-19 treatment improved hematoma clearance and attenuated neurological deficits induced by GMH, which was mediated through the upregulation of the IL-20R1/ERK/Nrf2 pathways. rIL-19 treatment may provide a promising therapeutic strategy for the GMH patient population.
Highlights
Germinal matrix hemorrhage (GMH) is defined by the rupture of thin-walled blood vessels located in the germinal matrix of preterm/low-birthweight infants [1, 2]
Endogenous Expression of IL-19, IL-20R1, IL-20R2, and CD163 Increased after GMH
Endogenous IL-19 expression was significantly increased at 24 hours to 5 days, where peak expression was seen at 72 hours after GMH (Figures 2(a) and 2(b))
Summary
Germinal matrix hemorrhage (GMH) is defined by the rupture of thin-walled blood vessels located in the germinal matrix of preterm/low-birthweight infants [1, 2]. It is one of the leading causes of morbidity and mortality among preterm infants [3]. After the rupture of blood vessels, blood components permeate into the brain parenchyma [6, 7] Cytotoxins such as heme, peroxiredoxin 2 (PRX-2), and iron are released from metabolized blood cell (RBC) causing secondary brain injury through the increase in neuroinflammation, oxidative stress, neuronal death, and/or apoptosis [8, 9]. The intracerebroventricular blood clot directly impairs the Oxidative Medicine and Cellular Longevity circulation and absorption of the cerebrospinal fluid (CSF), leading to the development of PHH [10]
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