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Hypothermia (HT) by whole body (WBC) or selective head cooling (SHC) reduces hypoxic-ischemic (HI) brain injury; however, whether prolonged hypothermia and/or anesthesia disrupts immature brain development, eg, increases apoptosis, is unknown. Anesthesia increases apoptosis in immature animals. We investigated whether neuroprotective hypothermia and anesthesia disrupts normal brain development. Thirty-eight pigs <24 h old were randomized between five groups and were killed after 72 h: eighteen received a global hypoxic-ischemic insult under anesthesia, eight subsequently cooled by SHC with WBC to T(rectal) 34.5 degrees C for 24 h, followed by 48 h normothermia (NT) at T(rectal) 39.0 degrees C, while 10 remained normothermic. Sixteen underwent anesthetized sham hypoxic-ischemic, six then following normothermia and 10 following hypothermia protocols. There were four normothermic controls. The hypothermia groups demonstrated significant brain hypothermia. In the hypoxic-ischemic groups this conferred approximately 60% neuroprotection reducing histological injury scores in all brain areas. Immunohistochemical/histochemical analyses of neuronal, glial, endothelial, axonal, transcriptional apoptotic markers in areas devoid of histological lesions revealed no hypothermia/normothermia group and differences whether exposed to hypoxic-ischemic or not. Neither 36-h anesthesia nor 24-h hypothermia produced adverse effects at 4-day survival on a panel of brain maturation/neural death markers in newborn pigs. Longer survival studies are necessary to verify the safety of hypothermia in the developing brain.

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Objectives The concept of inflammation-induced sensitization is emerging in the field of perinatal brain injury, stroke, Alzheimer disease and multiple sclerosis. However, mechanisms underpinning this process remain unidentified. Methods We combined in vivo systemic lipopolysaccharide (LPS) or Interleukin-1β (IL-1β) induced sensitization of neonatal and adult rodent cortical neurons to excitotoxic neurodegeneration with in vitro IL-1β sensitization of human and rodent neurons to excitotoxic neurodegeneration. Within these inflammation-induced sensitization models we assessed metabotropic glutamatergic receptor (mGluR) signaling and regulation. Results We demonstrate for the first time that group I mGluRs mediate inflammation-induced sensitization to neuronal excitotoxicity in neonatal and adult neurons across species. Inflammation induced G protein–coupled receptor kinase 2 (GRK2) down-regulation and genetic deletion of GRK2 mimicked the sensitizing effect of inflammation on excitotoxic neurodegeneration. Thus, we identify GRK2 as a potential molecular link between inflammation and mGluR-mediated sensitization. Interpretation Collectively, our findings indicate that inflammation-induced sensitization is universal across species and ages and that group I mGluRs and GRK2 represent new avenues for neuroprotection in perinatal and adult neurological disorders.

Cerebral palsy remains a public health priority. Recognition of factors of susceptibility to perinatal brain lesions is key for the prevention of cerebral palsy. In most cases, the pathophysiology of these lesions is thought to involve prior exposure to predisposing factors that make the developing brain more vulnerable to perinatal events. The present study tested the hypothesis that exposure to chronic minimal stress throughout gestation would sensitize the offspring to neonatal excitotoxic brain lesions, which mimic lesions observed in cerebral palsy. Pregnant mice were exposed to chronic, ultramild stress, applied throughout gestation. Neonatal brain lesions were induced by intracerebral injection of glutamate analogs. Excitotoxic lesions were significantly worsened in pups exposed to gestational stress. Stress induced a significant rise of circulating corticosterone levels both in pregnant mothers and in newborn pups. The deleterious effects of stress on excitotoxicity were totally suppressed in mice with reduced levels of glucocorticoid receptors. Stress induced a significant increase of neopallial NMDA binding sites in the offspring. At adulthood, animals exposed to stress and neonatal excitotoxic challenge showed a significant impairment in the Morris water maze test when compared with animals exposed to the excitotoxic challenge but not the gestational stress. These findings suggest that stress during gestation, which may mimic low-level stress in human pregnancy, could be a novel risk factor for cerebral palsy.

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