Glial cell line-derived neurotrophic factor protects against ischemia/hypoxia-induced brain injury in neonatal rat. Ikeda T,Xia X Y,Xia Y X,Ikenoue T,Han B,Choi B H Acta neuropathologica Ischemic/hypoxic brain damage induced in 7-day-old rats was significantly attenuated in a dose-dependent manner by intracerebral injection of glial cell line-derived neurotrophic factor (GDNF; 2 or 4 microg) within 30 min after the insult. Whereas the great majority of the vehicle-treated animals showed massive infarction involving more than 75% of the affected cerebral hemisphere, GDNF injection resulted in a remarkable reduction in both the incidence and severity of the brain damage (incidence ranging from 76% to 93% in controls to 34% to 64% in the 2.0-microg group and 7% to 29% in 4.0-microg group). The induction of immunoreactive 70-kDa heat shock protein (HSP70) in cerebral cortical neurons was also significantly reduced in GDNF-treated animals as compared to controls. The mechanisms responsible for the neuroprotective effects of GDNF remain unknown, although it has been speculated that these may be endogeneous. The higher expression of GDNF and its mRNA in developing brains may be one of the factors responsible for the relative resistance to ischemia of fetal and neonatal as opposed to adult brains. GDNF may possibly act by protecting against oxidative stress or by scavenging free radicals generated during ischemia. The results of our study strongly suggest that GDNF may prove to be an effective and potent protective agent against perinatal ischemic/hypoxic encephalopathy.

Lactate receptor HCAR1 regulates neurogenesis and microglia activation after neonatal hypoxia-ischemia. eLife Neonatal cerebral hypoxia-ischemia (HI) is the leading cause of death and disability in newborns with the only current treatment being hypothermia. An increased understanding of the pathways that facilitate tissue repair after HI may aid the development of better treatments. Here, we study the role of lactate receptor HCAR1 in tissue repair after neonatal HI in mice. We show that HCAR1 knockout mice have reduced tissue regeneration compared with wildtype mice. Furthermore, proliferation of neural progenitor cells and glial cells, as well as microglial activation was impaired. Transcriptome analysis showed a strong transcriptional response to HI in the subventricular zone of wildtype mice involving about 7300 genes. In contrast, the HCAR1 knockout mice showed a modest response, involving about 750 genes. Notably, fundamental processes in tissue repair such as cell cycle and innate immunity were dysregulated in HCAR1 knockout. Our data suggest that HCAR1 is a key transcriptional regulator of pathways that promote tissue regeneration after HI. 10.7554/eLife.76451

Measurement of the urinary lactate:creatinine ratio for the early identification of newborn infants at risk for hypoxic-ischemic encephalopathy. Huang C C,Wang S T,Chang Y C,Lin K P,Wu P L The New England journal of medicine BACKGROUND:Newborn infants with perinatal asphyxia are prone to the development of hypoxic-ischemic encephalopathy. There are no reliable methods for identifying infants at risk for this disorder. METHODS:We measured the ratio of lactate to creatinine in urine by proton nuclear magnetic resonance spectroscopy within 6 hours and again 48 to 72 hours after birth in 58 normal infants and 40 infants with asphyxia. The results were correlated with the subsequent presence or absence of hypoxic-ischemic encephalopathy. RESULTS:Hypoxic-ischemic encephalopathy did not develop in any of the normal newborns but did develop in 16 of the 40 newborns with asphyxia. Within six hours after birth, the mean (+/-SD) ratio of urinary lactate to creatinine was 16.75+/-27.38 in the infants who subsequently had hypoxic-ischemic encephalopathy, as compared with 0.09+/-0.02 in the normal infants (P<0.001) and 0.19+/-0.12 in the infants with asphyxia in whom hypoxic-ischemic encephalopathy did not develop (P<0.001). A ratio of 0.64 or higher within six hours after birth had a sensitivity of 94 percent and a specificity of 100 percent for predicting the development of hypoxic-ischemic encephalopathy. The sensitivity and specificity of measurements obtained 48 to 72 hours after birth were much lower. The mean ratio of urinary lactate to creatinine was significantly higher in the infants who had adverse outcomes at one year (25.36+/-32.02) than in the infants with favorable outcomes (0.63+/-1.50) (P<0.001). CONCLUSIONS:Measurement of the urinary lactate: creatinine ratio soon after birth may help identify infants at high risk for hypoxic-ischemic encephalopathy. 10.1056/NEJM199907293410504

Treatment advances in neonatal neuroprotection and neurointensive care. Johnston Michael V,Fatemi Ali,Wilson Mary Ann,Northington Frances The Lancet. Neurology Knowledge of the nature, prognosis, and ways to treat brain lesions in neonatal infants has increased remarkably. Neonatal hypoxic-ischaemic encephalopathy (HIE) in term infants, mirrors a progressive cascade of excito-oxidative events that unfold in the brain after an asphyxial insult. In the laboratory, this cascade can be blocked to protect brain tissue through the process of neuroprotection. However, proof of a clinical effect was lacking until the publication of three positive randomised controlled trials of moderate hypothermia for term infants with HIE. These results have greatly improved treatment prospects for babies with asphyxia and altered understanding of the theory of neuroprotection. The studies show that moderate hypothermia within 6 h of asphyxia improves survival without cerebral palsy or other disability by about 40% and reduces death or neurological disability by nearly 30%. The search is on to discover adjuvant treatments that can further enhance the effects of hypothermia. 10.1016/S1474-4422(11)70016-3