No abstract

Hypoxic-ischemic and inflammatory (HII) induces the disruption of blood–brain barrier (BBB) which leads to inflammatory responses and neuronal cell death, resulting in brain secondary damage. Previous studies showed that melatonin produced potent neuroprotective effects in neonatal hypoxic-ischaemic models. However, the relationship between BBB disruption and melatonin in HII was still unclear. The present study therefore investigated the beneficial effects of melatonin on BBB after HII and the underlying mechanisms. HII animal model was conducted by receiving lipopolysaccharide followed by 90 min hypoxia-ischaemia in postnatal day 2 Sprague–Dawley rat pups. Melatonin was injected intraperitoneally 1 h before lipopolysaccharide injection and then once a day for 1 week to evaluate the long-term effects. In this study, we demonstrated that melatonin administration inhibited the disruption of BBB permeability and improved the white matter recovery in HII model rats. Melatonin significantly attenuated the degradation of junction proteins and the neuroprotective role was related to the inhibition of microglial toll-like receptor 4/ nuclear factor-kappa B signaling pathway both in vivo and in vitro. Taken together, our data demonstrated that therapeutic strategies targeting inflammation might be suitable for the therapy of preserving BBB integrity after HII.

Neonatal hypoxic-ischemic (HI) brain injury is a devastating disease that often leads to death and detrimental neurological deficits. The present study was designed to evaluate the ability of metformin to provide neuroprotection in a model of neonatal hypoxic-ischemic brain injury and to study the associated molecular mechanisms behind these protective effects. Here, we found that metformin treatment remarkably attenuated brain infarct volumes and brain edema at 24 h after HI injury, and the neuroprotection of metformin was associated with inhibition of neuronal apoptosis, suppression of the neuroinflammation and amelioration of the blood brain barrier breakdown. Additionally, metformin treatment conferred long-term protective against brain damage at 7 d after HI injury. Our study indicates that metformin treatment protects against neonatal hypoxic-ischemic brain injury and thus has potential as a therapy for this disease.

Neonatal hypoxic-ischemic brain injury is a devastating disease with limited treatment options. Preventive treatment with resveratrol has indicated to be well tolerated and has lower toxicity in both experimental models and human patients. However, whether resveratrol administration post-hypoxic-ischemic protects against neonatal hypoxic-ischemic injury is not known. Here we reported that post-treatment with resveratrol significantly reduced brain damage at 7-day after the injury. We found that resveratrol reduced the expression levels of key inflammatory factors at the mRNA and protein levels, and at least partially via inhibiting microglia activation. Moreover, resveratrol exerted an anti-apoptotic effect, as assessed by TUNEL staining, and altered the expression of the apoptosis-related genes Bax, Bcl-2 and caspase3. Our data indicate that post-treatment with resveratrol protects against neonatal hypoxic-ischemic brain injury and suggest a promising therapeutic strategy to this disease.

Hypoxic-ischemic encephalopathy (HIE) is detrimental to newborns and is associated with high mortality and poor prognosis. Thus, the primary aim of the present study was to determine whether glycine could (1) attenuate HIE injury in rats and hypoxic stress in PC12 cells and (2) downregulate mitochondria-mediated autophagy dependent on the adenosine monophosphate- (AMP-) activated protein kinase (AMPK) pathway. Experiments conducted using an in vivo HIE animal model and in vitro hypoxic stress to PC12 cells revealed that intense autophagy associated with mitochondrial function occurred during in vivo HIE injury and in vitro hypoxic stress. However, glycine treatment effectively attenuated mitochondria-mediated autophagy. Additionally, after identifying alterations in proteins within the AMPK pathway in rats and PC12 cells following glycine treatment, cyclosporin A (CsA) and 5-aminoimidazole-4-carboxamide-1-b-4-ribofuranoside (AICAR) were administered in these models and indicated that glycine protected against HIE and CoCl2 injury by downregulating mitochondria-mediated autophagy that was dependent on the AMPK pathway. Overall, glycine attenuated hypoxic-ischemic injury in neurons via reductions in mitochondria-mediated autophagy through the AMPK pathway both in vitro and in vivo.