Mixed lineage kinase domain-like protein (MLKL) is a critical molecule mediating cell necroptosis. However, its role in brain injury remains obscure. We first investigated the functions and mechanisms of MLKL in mediating neuronal damage in developing brain after hypoxia-ischemia. Neuronal necroptosis was induced by oxygen-glucose deprivation (OGD) plus caspase inhibitor zVAD treatment (OGD/zVAD). We found that two important necroptosis related proteins, receptor-interacting protein 1 and 3 (RIP1, RIP3) were upregulated. Furthermore, the interaction of RIP1-RIP3 with MLKL increased. Inhibition of MLKL through siRNA diminished RIP1-RIP3-MLKL interaction and attenuated neuronal death induced by OGD/zVAD. The translocation of oligomerized MLKL to the neuronal membrane leading to the injury of cellular membrane is the possible new mechanism of neuronal necroptosis. Animal experiment with neonatal rats further proved that MLKL inhibition attenuated brain damage induced by hypoxia-ischemia. These findings suggest that MLKL is a target to attenuate brain damage in developing brain.

Background: The aim of this study was to summarize current evidence evaluating the association between antenatal infection and intraventricular hemorrhage (IVH) in preterm infants. Materials and methods: We searched for published articles on antenatal infection and IVH in 3 English (PubMed, the Cochrane Library, and EBSCO) and 3 Chinese (VEIPU, CNKI, and WANFANG) databases on May 19, 2019. In addition, the references of these articles were screened. The included studies had to meet all of the following criteria: preterm infants (<37 weeks); comparing antenatal infection with no infection; the outcomes included IVH (all grades), mild IVH, or sereve IVH; the type of study was randomized controlled trial or cohort study. Results: A total of 23 cohort studies involving 13,605 preterm infants met our inclusion criteria. Antenatal infection increased the risk of IVH (odds ratios ([OR] 2.18, 95% confidence intervals [CI] 1.58–2.99), mild IVH (OR 1.95, 95% CI 1.09–3.49) and severe IVH (OR 2.65, 95% CI 1.52–4.61). For type of antenatal infection, the ORs and 95% CI were as follows: 2.21 (1.60–3.05) for chorioamnionitis, 2.26 (1.55–3.28) for histologic chorioamnionitis, 1.88 (1.22–2.92) for clinical chorioamnionitis, and 1.88 (1.14–3.10) for ureaplasma. Conclusions: Antenatal infection may increase the risk of developing IVH in the preterm infant. The evidence base is however of low quality and well-designed studies are needed.