Abstract
BackgroundThe dual inhibitors of receptor interacting protein kinase-1 and -3 (RIP1 and RIP3) play an important role in cell death processes and inflammatory responses. White matter injury (WMI), a leading cause of neurodevelopmental disabilities in preterm infants, which is characterized by extensive myelination disturbances and demyelination. Neuroinflammation, leads to the loss and differentiation-inhibition of oligodendrocyte precursor cells (OPCs), represents a major barrier to myelin repair. Whether the novel RIP1/RIP3 dual inhibitor ZJU-37 can promote transplanted OPCs derived from human neural stem cells (hOPCs) survival, differentiation and myelination remains unclear. In this study, we investigated the effect of ZJU-37 on myelination and neurobehavioral function in a neonatal rat WMI model induced by hypoxia and ischemia.MethodsIn vivo, P3 rat pups were subjected to right common carotid artery ligation and hypoxia, and then treated with ZJU-37 or/and hOPCs, then OPCs apoptosis, myelination, glial cell and NLRP3 inflammasome activation together with cognitive outcome were evaluated at 12 weeks after transplantation. In vitro, the effect of ZJU-37 on NLRP3 inflammasome activation in astrocytes induced by oxygen–glucose deprivation (OGD) were examined by western blot and immunofluorescence. The effect of ZJU-37 on OPCs apoptosis induced by the conditioned medium from OGD-injured astrocytes (OGD-astrocyte-CM) was analyzed by flow cytometry and immunofluorescence.ResultsZJU-37 combined with hOPCs more effectively decreased OPC apoptosis, promoted myelination in the corpus callosum and improved behavioral function compared to ZJU-37 or hOPCs treatment. In addition, the activation of glial cells and NLRP3 inflammasome was reduced by ZJU-37 or/and hOPCs treatment in the neonatal rat WMI model. In vitro, it was also confirmed that ZJU-37 can suppress NLRP3 inflammasome activation in astrocytes induced by OGD. Not only that, the OGD-astrocyte-CM treated with ZJU-37 obviously attenuated OPC apoptosis and dysdifferentiation caused by the OGD-astrocyte-CM.ConclusionsThe novel RIP1/RIP3 dual inhibitor ZJU-37 may promote OPC survival, differentiation and myelination by inhibiting NLRP3 inflammasome activation in a neonatal rat model of WMI with hOPC graft.
Highlights
Preterm birth is a global public health issue [1]
ZJU-37 combined with hOPCs more effectively decreased oligodendrocyte precursor cells (OPCs) apoptosis compared to ZJU-37 or hOPCs treatment alone, as confirmed by Platelet derived growth factor receptor alpha (PDGFRα) immunofluorescent and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining
The results suggested that ZJU-37 suppressed Nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation in oxygen–glucose deprivation (OGD)-induced astrocytes, and obviously attenuated OPC apoptosis and dysdifferentiation caused by the OGDastrocyte-Conditioned medium (CM)
Summary
Preterm birth is a global public health issue [1]. According to estimates by the World Health Organization, there are nearly 15 million preterm births annually worldwide, with an overall incidence of 11.1% [2]. Zhang et al Stem Cell Res Ther (2021) 12:462 as 25–50% of preterm birth survivors develop chronic neurodevelopmental disorders, which manifest as cognitive, motor, and sensory disorders [3, 4], among which the white matter injury (WMI) is the most common [5]. It characterized by extensive myelination disturbances, demyelination and inflammatory reaction which can damage axons [6]. White matter injury (WMI), a leading cause of neurodevelopmental disabilities in preterm infants, which is characterized by extensive myelination disturbances and demyelination. We investigated the effect of ZJU-37 on myelination and neurobehavioral function in a neonatal rat WMI model induced by hypoxia and ischemia
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
