A novel RIP1/RIP3 dual inhibitor promoted OPC survival and myelination in a rat neonatal white matter injury model with hOPC graft

Abstract

Background The 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. Methods In 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. Results ZJU-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. Conclusions The 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.

Pleiotrophin ameliorates white matter injury of neonatal rats by activating the mTOR/YY1/Id4 signaling pathway

“…The development of the brain white matter in P2‐5 neonatal rats is similar to that in human preterm infants with a gestational age of 23–32 weeks. Several studies have used a P3 neonatal rat WMI model, so we chose P3 rats 28,29,40,41 . Furthermore, in our study, we only selected male rats because other studies indicated that male neonatal rats had more severe brain damage than female rats under the same conditions 42 .…”

“…Several studies have used a P3 neonatal rat WMI model, so we chose P3 rats. 28,29,40,41 Furthermore, in our study, we only selected male rats because other studies indicated that male neonatal rats had more severe brain damage than female rats under the same conditions. 42 Moreover, clinical studies have shown that the severity of brain injuries in male newborns is higher than that in female newborns, and the recovery ability of males is lower than that of females.…”

Small-Molecule Receptor-Interacting Protein 1 (RIP1) Inhibitors as Therapeutic Agents for Multifaceted Diseases: Current Medicinal Chemistry Insights and Emerging Opportunities

“…In addition to the aforementioned RIP1 type I, II, and III kinase inhibitors (Figure ), ,,, many compounds with new scaffolds or ones originating from natural products have also been reported in recent years. For example, a new class of dual-targeting inhibitors of RIP1 and RIP3 was designed and synthesized in Xia’s laboratory, among which compound ZJU-37 ( 67 ) (Figure A) showed the highest potency. A national invention patent (ZL201810826696.1, China), has been issued for the use of this compound to prevent and treat RIP1- and RIP3-related diseases.…”

Alteration of the Oligodendrocyte Lineage Varies According to the Systemic Inflammatory Stimulus in Animal Models That Mimic the Encephalopathy of Prematurity

“…Through its receptor 1 (TNFR1), TNF-α initiates three cell death pathways, i.e., 1) necroptosis, 2) RIP-1-dependent apoptosis and 3) RIP-1-independent apoptosis linked to the TNFR-associated death domain (TRADD) ( Cao and Mu, 2021 ). Interestingly, an inhibitor of RIP-1/RIP-3 prevents OPC apoptosis following a hypoxic stimulus in the neonatal rat brain ( Zhang et al, 2021 ). The neutralisation of TNF-α in the culture medium of LPS-activated microglia partially prevents OPC/Pre-OL death ( Pang et al, 2010 ; Taylor et al, 2010 ).…”