Chlorogenic acid alleviates hypoxic-ischemic brain injury in neonatal mice

Recent studies have shown that chlorogenic acid(CGA),which is present in coffee,has protective effects on the nervous system.However,its role in neonatal hypoxic-ischemic brain injury remains unclear.In this study,we established a newborn mouse model of hypoxic-ischemic brain injury using a modified Rice-Vannucci method and performed intraperitoneal injection of CGA.We found that CGA intervention effectively reduced the volume of cerebral infarct,alleviated cerebral edema,restored brain tissue structure after injury,and promoted axon growth in injured brain tissue.Moreover,CGA pretreatment alleviated oxygen-glucose deprivation damage of primary neurons and promoted neuron survival.In addition,changes in ferroptosis-related proteins caused by hypoxic-ischemic brain injury were partially reversed by CGA.Furthermore,CGA intervention upregulated the expression of the key ferroptosis factor glutathione peroxidase 4 and its upstream glutamate/cystine antiporter related factors SLC7A11 and SLC3A2.In summary,our findings reveal that CGA alleviates hypoxic-ischemic brain injury in neonatal mice by reducing ferroptosis,providing new ideas for the treatment of neonatal hypoxic-ischemic brain injury.

Iron metabolism, oxidative stress, and neonatal brain injury

The brain injury associated with neonatal hypoxia ischemia（HI）is a major contributor to neonatal mortality and neurodevelopment retardation.Approximately 30-40%of infants with brain injury will die and 20-40%of survivors will develop significant neurological disorders and lifelong disability.

Human umbilical cord-derived mesenchymal stem cells promote repair of neonatal brain injury caused by hypoxia/ischemia in rats

Administration of human umbilical cord-derived mesenchymal stem cells(hUC-MSCs)is believed to be an effective method for treating neurodevelopmental disorde rs.In this study,we investigated the possibility of hUC-MSCs treatment of neonatal hypoxic/ischemic brain injury associated with maternal immune activation and the underlying mechanism.We established neonatal rat models of hypoxic/ischemic brain injury by exposing pregnant rats to lipopolysaccharide on day 16 or 17 of pregnancy.Rat offspring were intranasally administe red hUC-MSCs on postnatal day 14.We found that polypyrimidine tract-binding protein-1(PTBP-1)participated in the regulation of lipopolysaccharide-induced maternal immune activation,which led to neonatal hypoxic/ischemic brain injury.Intranasal delive ry of hUC-MSCs inhibited PTBP-1 expression,alleviated neonatal brain injury-related inflammation,and regulated the number and function of glial fibrillary acidic protein-positive astrocytes,there by promoting plastic regeneration of neurons and im p roving brain function.These findings suggest that hUC-MSCs can effectively promote the repair of neonatal hypoxic/ischemic brain injury related to maternal immune activation through inhibition of PTBP-1 expression and astrocyte activation.

Vulnerability of premyelinating oligodendrocytes to white-matter damage in neonatal brain injury

Premature birth is a significant economic and public health burden, and its incidence is rising. Periventricular leukomalacia （PVL） is the predominant form of brain injury in premature infants and the leading cause of cerebral palsy. PVL is characterized by selective white-matter damage with prominent oligodendroglial injury. The maturation-dependent vulnerability of developing and premyelinating oligodendrocytes to excitotoxic, oxidative, and inflammatory forms of injury is a major factor in the pathogenesis of PVL. Recent studies using mouse models of PVL reveal that synapses between axons and developing oligodendrocytes are quickly and profoundly damaged in immature white matter. Axon-glia synapses are highly vulnerable to white-matter injury in the developing brain, and the loss of synapses between axons and premyelinating oligodendrocytes occurs before any cellular loss in the immature white matter. Microglial activation and astrogliosis play important roles in triggering white-matter injury. Impairment of white-matter development and function in the neonatal period contributes critically to functional and behavioral deficits. Preservation of the integrity of the white matter is likely key in the treatment of PVL and subsequent neurological consequences and disabilities.

Monocytes in neonatal stroke and hypoxic-ischemic encephalopathy:Pathophysiological mechanisms and therapeutic possibilities

Neonatal arterial ischemic stroke(NAIS)and neonatal hypoxic-ischemic encephalopathy(HIE)are common causes of neurological impairments in infants,for which treatment options are very limited.NAIS and HIE induce an innate immune response that involves the recruitment of peripheral immune cells,including monocytes,into the brain.Monocytes and monocyte-derived cells have the potential to contribute to both harmful and beneficial pathophysiological processes,such as neuroinflammation and brain repair,but their roles in NAIS and HIE remain poorly understood.Furthermore,recent evidence indicates that monocyte-derived macrophages can persist in the brain for several months following NAIS and HIE in mice,with possible long-lasting consequences that are still unknown.This review provides a comprehensive overview of the mechanisms of monocyte infiltration and their potential functions in the ischemic brain,focusing on HIE and NAIS.Therapeutic strategies targeting monocytes and the possibility of using monocytes for cell-based therapies are also discussed.

AD-16 Protects Against Hypoxic-Ischemic Brain Injury by Inhibiting Neuroinflammation

Neuroinflammation is a key contributor to the pathogenic cascades induced by hypoxic-ischemic(HI)insult in the neonatal brain.AD-16 is a novel anti-inflammatory compound,recently found to exert potent inhibition of the lipopolysaccharide-induced production of pro-inflammatory and neurotoxic mediators.In this study,we evaluated the effect of AD-16 on primary astrocytes and neurons under oxygen-glucose deprivation(OGD)in vitro and in mice with neonatal HI brain injury in vivo.We demonstrated that AD-16 protected against OGD-induced astrocytic and neuronal cell injury.Single dose post-treatment with AD-16(1 mg/kg)improved the neurobehavioral outcome and reduced the infarct volume with a therapeutic window of up to 6 h.Chronic administration reduced the mortality rate and preserved whole-brain morphology following neonatal HI.The in vitro and in vivo effects suggest that AD-16 offers promising therapeutic efficacy in attenuating the progression of HI brain injury and protecting against the associated mortality and morbidity.

Biomarkers of hypoxic-ischemic encephalopathy:a systematic review

Background Current diagnostic criteria for hypoxic–ischemic encephalopathy in the early hours lack objective measurement tools.Therefore,this systematic review aims to identify putative molecules that can be used in diagnosis in daily clinical practice(PROSPERO ID:CRD42021272610).Data sources Searches were performed in PubMed,Web of Science,and Science Direct databases until November 2020.English original papers analyzing samples from newborns>36 weeks that met at least two American College of Obstetricians and Gynecologists diagnostic criteria and/or imaging evidence of cerebral damage were included.Bias was assessed by the Newcastle–Ottawa Scale.The search and data extraction were verified by two authors separately.Results From 373 papers,30 met the inclusion criteria.Data from samples collected in the first 72 hours were extracted,and increased serum levels of neuron-specific enolase and S100-calcium-binding protein-B were associated with a worse prognosis in newborns that suffered an episode of perinatal asphyxia.In addition,the levels of glial fibrillary acidic protein,ubiquitin carboxyl terminal hydrolase isozyme-L1,glutamic pyruvic transaminase-2,lactate,and glucose were elevated in newborns diagnosed with hypoxic–ischemic encephalopathy.Moreover,pathway analysis revealed insulin-like growth factor signaling and alanine,aspartate and glutamate metabolism to be involved in the early molecular response to insult.Conclusions Neuron-specific enolase and S100-calcium-binding protein-B are potential biomarkers,since they are correlated with an unfavorable outcome of hypoxic-ischemic encephalopathy newborns.However,more studies are required to determine the sensitivity and specificity of this approach to be validated for clinical practice.