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• NBP treatment reduces the brain infarct volume and brain tissue loss. • NBP treatment enhances neuronal rehabilitation, promotes neurite growth and remyelination. • NBP treatment improves long-term neurobehavioral development and prognosis after hypoxia-ischemia. • NBP treatment inhibits endoplasmic reticulum stress-induced cell apoptosis. • NBP treatment alleviates blood-brain barrier disruption. Dl-3-n-butylphthalide (NBP) has been demonstrated to exert neuroprotective effects in experimental models and human patients. This study was performed to assess the therapeutic effects and the underlying molecular mechanisms of NBP in a neonatal hypoxic-ischemic rat model. The results showed that NBP treatment significantly reduced the infarct volume, improved histological recovery, decreased neuronal cell loss, enhanced neuronal cell rehabilitation, promoted neurite growth and decreased white matter injury. In addition, NBP treatment effectively improved long-term neurobehavioral development and prognosis after HI injury. We further demonstrated an inhibitory effect of NBP on endoplasmic reticulum (ER) stress-induced apoptosis, evidenced by reduction in ER stress-related protein expressions (GRP78, XBP-1, PDI and CHOP), decrease in TUNEL-positive cells, down-regulation in pro-apoptosis protein (Bax and cleaved caspase-3), up-regulation in anti-apoptosis protein (Bcl-2). Moreover, NBP exerted a protective effect in blood-brain barrier disruption, which ameliorated brain edema and reduced the degeneration of the tight junction proteins (Occludin and Claudin-5) and adherens junction proteins (P120-Catenin, VE-Cadherin and β-Catenin). Overall, our findings demonstrated that NBP treatment attenuated HI brain injury through inhibiting ER stress-induced apoptosis and alleviating blood-brain barrier disruption in newborn rats. This work provides an effective therapeutic strategy to reduce brain damage and enhance recovery after neonatal HI brain injury. [ABSTRACT FROM AUTHOR]

Neonatal hypoxic-ischemic (HI) brain injury remains a devastating clinical disease associated with high mortality and lifetime disability. Neonatal HI injury damages the architecture of neurovascular unit (NVU), thus, therapy targeting the NVU may provide effective neuroprotection against HI. This study was designed to investigate whether fibroblast growth factor 10 (FGF10) protected the NVU against HI and afforded observable neuroprotection in a rat model of neonatal HI brain injury. The results showed that FGF10 treatment significantly reduced brain damage post HI, characterized by reduction in brain infarct volume and tissue loss. Further interesting findings showed that FGF10 treatment exerted neuroprotective effects on HI brain injury in neonate rats through protecting the NVU against HI, evidenced by inhibition of neuronal cell apoptosis, suppression of gliosis, and amelioration of blood-brain barrier disruption. Collectively, our study indicates that FGF10 treatment exhibits great potential for protecting NVU against HI and attenuates neonatal brain injury, suggesting a potential novel therapeutic agent to this disease. • FGF10 decreases neuronal death via inhibiting neuronal apoptosis • FGF10 attenuates the activation of microglia and astrocytes through modulating TLR4/NF-κB signaling pathway • FGF10 ameliorates blood-brain barrier disruption via reducing tight junction and adherens junction proteins degradation and pericytes loss • FGF10 exerts protective effects on the neurovascular unit in a rat model of neonatal HI brain injury. [ABSTRACT FROM AUTHOR]

• Echinatin attenuates brain injury and improves behavioral functions of neonatal rats after hypoxic-ischemic brain damage. • RNA-Sequencing reveals upregulation of TLR4 pathway in neonatal rats after hypoxic-ischemic brain damage. • Echinatin alleviates neuroinflammation and pyroptosis through inhibiting TLR4/NF-kB pathway in hypoxic-ischemic brain damage. Hypoxic ischemic encephalopathy (HIE) is a primary cause of neonatal death and disabilities. The pathogenetic process of HIE is closely associated with neuroinflammation. Therefore, targeting and suppressing inflammatory pathways presents a promising therapeutic strategy for the treatment of HIE. Echinatin is an active component of glycyrrhiza, with anti-inflammatory and anti-oxidative properties. It is commonly combined with other traditional Chinese herbs to exert heat-clearing and detoxifying effects. This study aimed to investigate the anti-inflammatory and neuroprotective effects of Echinatin in neonatal rats with hypoxic-ischemic brain damage, as well as in PC12 cells exposed to oxygen-glucose deprivation (OGD). In vivo , Echinatin effectively reduced cerebral edema and infarct volume, protected brain tissue morphology, improved long-term behavioral functions, and inhibited microglia activation. These effects were accompanied by the downregulation of inflammatory factors and pyroptosis markers. The RNA sequencing analysis revealed an enrichment of inflammatory genes in rats with hypoxic-ischemic brain damage, and Protein-protein interaction (PPI) network analysis identified TLR4, MyD88, and NF-κB as the key regulators. In vitro , Echinatin reduced the levels of TLR4 relevant proteins, inhibited nuclear translocation of NF-κB, reduced the expression of downstreams inflammatory cytokines and pyroptosis proteins, and prevented cell membrane destructions. These findings demonstrated that Echinatin could inhibit the TLR4/NF-κB pathway, thereby alleviating neuroinflammation and pyroptosis. This suggests that Echinatin could be a potential candidate for the treatment of HIE. [ABSTRACT FROM AUTHOR]

Perinatal asphyxia often results in neonatal cerebral hypoxia-ischemia (HI), which is associated with high mortality and severe long-term neurological deficits in newborns. Currently, there are no effective drugs to mitigate the functional impairments post-HI. Previous studies have shown that fibroblast growth factor 21 (FGF21) has a potential neuroprotective effect against brain injury. However, the effect of FGF21 on neonatal HI brain injury is unclear. In the present study, both in vivo and in vitro models were used to assess whether recombinant human FGF21 (rhFGF21) could exert a neuroprotective effect after HI and explore the associated mechanism. The results showed that the rhFGF21 treatment remarkably reduced the infarct volume, ameliorated the body weight and improved the tissue structure after HI in neonatal rats. In addition, the rhFGF21 treatment lengthened the running endurance times in the rotarod test and decreased the mean escape latencies and increased the number of platform crossings in the Morris water maze test at 21 d post-HI insult. In contrast, the FGFR1 inhibitor PD173074 and PI3K inhibitor LY294002 partially reversed these therapeutic effects. In isolated primary cortical neurons, the rhFGF21 treatment protected primary neurons from oxygen-glucose deprivation (OGD) insult by inhibiting neuronal apoptosis and promoting neuronal survival. Both our in vivo and in vitro results reveal that rhFGF21 could inhibit neuronal apoptosis by activating the PI3K/Akt signaling pathway via FGF21/FGFR1/β-klotho complex formation. Therefore, rhFGF21 may be a promising therapeutic agent for promoting functional recovery after HI-induced neonatal brain injury. • rhFGF21 reduces the brain infarct volume and ameliorates the histological structure. • rhFGF21 improves motor and learning disabilities in rats after hypoxia-ischemia. • rhFGF21 activates the PI3K/Akt pathway via FGFR1/β-klotho post hypoxia-ischemia. • rhFGF21 attenuates OGD-induced primary cortical neuronal death. • rhFGF21 protects neurons against OGD injury by inhibiting neuronal apoptosis. [ABSTRACT FROM AUTHOR]

Melatonin has neuroprotective effects in many diseases, including neonatal hypoxic-ischaemic (HI) brain injury. The purpose of this study was to evaluate the neuroprotective effects of melatonin both in vivo and in vitro and associated molecular mechanisms behind these effects. Postnatal day 7 male and female rat pups were subjected to unilateral HI, melatonin was injected intraperitoneally 1 h before HI and an additional six doses were administered at 24 h intervals. The pups were sacrificed at 24 h and 7 d after HI. Pre-treatment with melatonin significantly reduced brain damage at 7 d after HI, with 15 mg/kg melatonin achieving over 30% recovery in tissue loss compared to vehicle-treated animals. Autophagy and apoptotic cell death as indicated by autophagy associated proteins, cleaved caspase 3 and Tunel staining, was significantly inhibited after melatonin treatment in vivo as well as in PC12 cells. Melatonin treatment also significantly increased the GAP43 in the cortex. In conclusion, melatonin treatment reduced neonatal rat brain injury after HI, and this appeared to be related to inhibiting autophagy as well as reducing apoptotic cell death. [ABSTRACT FROM AUTHOR]