Brain damage around birth may cause lifelong neurodevelopmental deficits. We examined the therapeutic potential of human umbilical cord blood-derived mononuclear cells containing multipotent stem cells to facilitate motor recovery after cerebral hypoxic-ischemic damage in neonatal rats. Left carotid artery ligation followed by 8% O 2 inhalation for 80 min was performed on postnatal d 7, succeeded by intraperitoneal transplantation of human umbilical cord blood-derived mononuclear cells on postnatal d 8 in a shamcontrolled design. Histologic and immunohistochemical analysis on postnatal d 21 revealed that neonates developed severe cerebral damage after the hypoxic-ischemic insult. These animals also suffered from contralateral spastic paresis, as evidenced by their locomotor behavior. After transplantation of human umbilical cord blood-derived mononuclear cells, spastic paresis was largely alleviated, resulting in a normal walking behavior. This "therapeutic" effect was accompanied by the fact that mononuclear cells had entered the brain and were incorporated around the lesion without obvious signs of transdifferentiation. This study demonstrates that intraperitoneal transplantation of human umbilical cord bloodderived mononuclear cells in a rat model of perinatal brain damage leads to both incorporation of these cells in the lesioned brain area and to an alleviation of the neurologic effects of cerebral palsy as assessed by footprint and walking pattern analysis. (Pediatr Res 59: [244][245][246][247][248][249] 2006)

Perinatal brain damage is associated not only with hypoxicischemic insults but also with intrauterine inflammation. A combination of antenatal inflammation and asphyxia increases the risk of cerebral palsy Ͼ70 times. The aim of the present study was to determine the effect of intracisternal (i.c.) administration of endotoxin [lipopolysaccharides (LPS)] on subsequent hypoxic-ischemic brain damage in neonatal rats. Seven-day-old Wistar rats were subjected to i.c. application of NaCl or LPS (5 g/pup). One hour later, the left common carotid artery was exposed through a midline neck incision and ligated with 6-0 surgical silk. After another hour of recovery, the pups were subjected to a hypoxic gas mixture (8% oxygen/92% nitrogen) for 60 min. The animals were randomized to four experimental groups: 1) sham control group, left common carotid artery exposed but not ligated (n ϭ 5); 2) LPS group, subjected to i.c. application of LPS (n ϭ 7); 3) hypoxic-ischemic study group, i.c. injection of NaCl and exposure to hypoxia after ligation of the left carotid artery (n ϭ 17); or 4) hypoxic-ischemic/LPS study group, i.c. injection of LPS and exposure to hypoxia after ligation of the left carotid artery (n ϭ 19). Seven days later, neonatal brains were assessed for neuronal cell damage. In a second set of experiments, rat pups received an i.c. injection of LPS (5 g/pup) and were evaluated for tumor necrosis factor-␣ expression by immunohistochemistry. Neuronal cell damage could not be observed in the sham control or in the LPS group. In the hypoxicischemic/LPS group, neuronal injury in the cerebral cortex was significantly higher than in animals that were subjected to hypoxia/ischemia after i.c. application of NaCl. Injecting LPS intracisternally caused a marked expression of tumor necrosis factor-␣ in the leptomeninges. Applying LPS intracisternally sensitizes the immature rat brain to a subsequent hypoxicischemic insult. Hypoxic-ischemic cerebral damage is an important contributor to perinatal mortality and morbidity, including long-term neurologic sequelae in term and preterm fetuses (1, 2). However, as shown in recent studies, perinatal brain injury may be associated not only with hypoxic-ischemic insults but also with an ascending intrauterine inflammation before or during birth (3). It is widely known that Gram-negative anaerobic bacteria are involved in colonization and infection of the genitourinary tract in pregnant women, which could affect labor and preterm birth. Because pregnant women with fever and bacteriuria give birth to infants with a higher incidence of neurologic defects at 1 y of age than do mothers who are free of urinary tract infection (4), it seems that human maternal endotoxemia is associated with fetal CNS damage. Furthermore, there is a growing body of evidence from epidemiologic studies that exposure to placental inflammation before or during birth is accompanied by cerebral white matter damage, especially in the very preterm fetuses, i.e. those born before 32 wk of gestation (3). In addition, the ...

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We conclude that creatine protects the immature brain from hypoxic-ischemic injury.