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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sensory deficits are frequently observed in cerebral palsy patients. The motor response to smell was found to be abnormal in an animal model of cerebral palsy following fetal hypoxia-ischemia. We hypothesized that fetal hypoxia-ischemia causes long-lasting and selective olfactory tract injury. A population of newborn rabbits with motor deficits was selected after spontaneous delivery following uterine ischemia at 22 days gestation (E22, 70% term). MnCl(2), 20 mg/kg, was administered in both nostrils at postnatal day 1 (E32). One nostril was occluded to control for smell augmentation through the other open nostril by intermittent amyl acetate stimulation for 6 h. T1-weighted MRI images were obtained on newborn rabbits. Amyl acetate exposure increased augmentation of Mn(2+) uptake in olfactory epithelium on the open side in control group but the augmentation was decreased after hypoxia. The proportion of animals with a greater enhancement in the open side increased in controls after amyl acetate, but not in hypoxia. Mn(2+) took longer to arrive at the olfactory bulbs and the rate of subsequent increase was slower in hypoxia. Concomitantly, the thickness of olfactory epithelium and the number of mature olfactory neurons, detected on olfactory marker protein immunostaining, were significantly less in the hypoxic group. Functional MRI studies are superior to neurobehavioral smell testing in the rabbit kits as they are more sensitive and quantifiable measures and do not depend upon the motor response. Antenatal hypoxia-ischemia causes long-lasting injury to neuronal tracts of the olfactory system including olfactory epithelium.
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PMID:Sensory deficits and olfactory system injury detected by novel application of MEMRI in newborn rabbit after antenatal hypoxia-ischemia. 1686 Oct 7

Periventricular white-matter injury is the major form of brain injury associated with prematurity and the leading cause of cerebral palsy in survivors of premature birth. Progress in understanding the pathogenesis of periventricular white-matter injury requires the development of animal models that are relevant to the unique physiology of the preterm human brain and that replicate the major neuropathologic features of human injury. The sheep is the most extensively studied true fetal preparation. The neurodevelopment of the preterm sheep fetus (0.65 gestation) is comparable to that of the preterm human between approximately 24 and 28 weeks. The size of the fetal sheep permits chronic instrumentation so that well-defined insults can be studied with reliable measurements of blood flow and metabolism in cerebral white-matter. We review here recent developments in the understanding of the role of cerebral hypoxia-ischemia and vulnerable oligodendrocyte progenitors in the pathogenesis of periventricular white-matter injury in the immature sheep fetus. We focus on recent developments in high-resolution spatially defined cerebral blood flow measurements in utero. We determined ovine white-matter maturation between 90 and 120 days' gestation, as defined by immunohistochemical localization of oligodendrocyte lineage-specific antibodies. There was considerable spatial and temporal heterogeneity in oligodendrocyte maturation in the immature periventricular white-matter. Oligodendrocyte maturation in the 90- to 105-day fetal sheep closely coincided with that of the preterm human during the high-risk period for white-matter injury. Hence, the immature state of the 90- to 105-day fetal periventricular white-matter is an optimal and dynamic developmental window to study the role of cellular-maturational factors in the pathogenesis of white-matter injury. We conclude with a review of the significant advantages of the instrumented fetal sheep to accelerate progress in the translation of preventive therapies for periventricular white-matter injury and cerebral palsy.
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PMID:Role of instrumented fetal sheep preparations in defining the pathogenesis of human periventricular white-matter injury. 1697 Aug 47

Cerebral palsy (CP) and related developmental disorders are more common in males than in females, but the reasons for this disparity are uncertain. Males born very preterm also appear to be more vulnerable to white matter injury and intraventricular hemorrhage than females. Experimental studies in adult animals and data from adult patients with stroke indicate that sex hormones such as estrogens provide protection against hypoxic-ischemic injury, and the neonatal brain is also influenced by these hormones. However, hormonal influences on the fetus and neonates are substantially different from those on adults. Recent data from neonatal rodents subjected to hypoxia-ischemia also demonstrate differences between males and females. Knockout of the gene for poly (ADP-ribose) polymerase (PARP-1), a major step in the cascade of injury, protected male but not female mouse pups from hypoxic-ischemic injury. Other reports demonstrated major differences between male and female neurons grown separately in cell culture, suggesting that sex differences in the fetal or neonatal period result from intrinsic differences in cell death pathways. This new information indicates that there are important neurobiological differences between males and females with respect to their response to brain injuries. This information is relevant to understanding the pathogenesis of CP as well as to the design of future clinical trials of potential neuroprotective strategies.
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PMID:Sex and the pathogenesis of cerebral palsy. 1751 38

Disorders of the maternal-placental-fetal unit often results in fetal brain injury, which in turn results in one of the highest burdens of disease, because of the lifelong consequences and cost to society. Investigating hypoxia-ischemia in the perinatal period requires the factoring of timing of the insult, determination of end-points, taking into account the innate development, plasticity, and enhanced recovery. Prenatal hypoxia-ischemia is believed to account for a majority of cerebral palsy cases. We have modeled sustained and repetitive hypoxia-ischemia in the pregnant rabbit in utero to mimic the insults of abruptio placenta and labor, respectively. Rabbits have many advantages over other animal species; principally, their motor development is in the perinatal period, akin to humans. Sustained hypoxia-ischemia at 70% (E22) and 79% (E25) caused stillbirths and multiple deficits in the postnatal survivors. The deficits included impairment in multiple tests of spontaneous locomotion, reflex motor activity, motor responses to olfactory stimuli, and the coordination of suck and swallow. Hypertonia was observed in the E22 and E25 survivors and persisted for at least 11 days. Noninvasive imaging using MRI suggests that white matter injury in the internal capsule could explain some of the hypertonia. Further investigation is underway in other vulnerable regions such as the basal ganglia, thalamus and brain stem, and development of other noninvasive determinants of motor deficits. For the first time critical mechanistic pathways can be tested in a clinically relevant animal model of cerebral palsy.
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PMID:A model of cerebral palsy from fetal hypoxia-ischemia. 1726 27

Periventricular leukomalacia (PVL), a common neonatal brain white matter (WM) lesion, is frequently associated with cerebral palsy. Growing evidence has indicated that in addition to ischemia/reperfusion injury, cytokine-induced brain injury associated with maternal or fetal infection may also play an important role in the pathogenesis of PVL. Recent studies have shown that administration of lipopolysaccharide (LPS) to pregnant rats causes enhanced expression of the cytokines, i.e., IL-1 beta, TNF-alpha, and IL-6, in fetal brains. In recent years, it has been shown that erythropoietin (EPO) has a critical role in the development, maintenance, protection and repair of the nervous system. In the present study we investigated the effect of EPO on LPS-induced WM injury in Sprague-Dawley rats. LPS (500 microg/kg) suspension in pyrogen-free saline was administered intraperitoneally to pregnant rats at 18 and 19 days of gestation. The control group was treated with pyrogen-free saline. They were given 5,000 U/kg recombinant human EPO. Seven-day-old Sprague-Dawley rat pups were divided into four groups: control group, LPS-treated group, prenatal maternal EPO-treated group (5,000 U/kg, intraperitoneally given to pregnant rats at 18 and 19 days of gestation), and postnatal EPO-treated group (5,000 U/kg, intraperitoneally given to 1-day-old rat pups). Cytokine induction in the postnatal 7-day-old (P7) rat brain after maternal administration of LPS was determined by the ELISA method. The proinflammatory cytokine levels (IL-1 beta, TNF-alpha, and IL-6) in P7 rat pup brains were significantly increased in the LPS-treated group as compared with the control group. Prenatal maternal EPO treatment significantly reduced the concentration of TNF-alpha and IL-6 in the newborn rat brain following LPS injection. The concentration of IL-1 beta was decreased in the intrauterine EPO treatment group. Postnatal EPO treatment significantly decreased only the IL-6 concentration in the newborn rat brain following LPS injection. The concentration of cytokines, IL-1 beta and TNF-alpha, was reduced in the postnatal EPO treatment group. We demonstrated here that LPS administration in pregnant rats at gestational day 18 and 19 induced WM injury in P7 progeny characterized by apoptosis. Prenatal maternal and postnatal EPO treatment significantly reduced the number of apoptotic cells in the periventricular WM. Using immunohistochemistry techniques, we investigated the effects of maternal administration of LPS on myelin basic protein (MBP) staining, as a marker of myelination in the periventricular area in the neonatal rat brain. MBP staining was significantly less and weaker in the brains of the LPS-treated group as compared with the prenatal maternal EPO-treated group. However, the postnatal EPO treatment did not prevent LPS-stimulated loss of MBP-positive staining. In conclusion, especially prenatal maternal EPO treatment attenuates LPS-induced injury by reducing the expression of inflammatory cytokines and sparing MBP in the neonatal rat brain. While the postnatal EPO treatment prevented LPS-induced brain injury this effect was partial. To our knowledge, this is the first study that demonstrates a protective effect of EPO on LPS-induced WM injury in the developing brain. Regarding the wide use of EPO in premature newborns, this agent maybe potentially beneficial in treating LPS-induced brain injury in the perinatal period.
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PMID:Erythropoietin attenuates lipopolysaccharide-induced white matter injury in the neonatal rat brain. 1762 93

Periventricular leukomalacia (PVL), the dominant form of brain injury in premature infants, is characterized by white matter injury (WMI) and is associated with cerebral palsy. The pathogenesis of PVL is complex and likely involves ischemia/reperfusion, free radical formation, excitotoxicity, impaired regulation of cerebral blood flow, a procoagulant state, and inflammatory mechanisms associated with maternal and/or fetal infection. Using an established animal model of human PVL, we investigated whether activated protein C (APC), an anti-coagulant factor with anti-inflammatory, anti-apoptotic, anti-oxidant, and cytoprotective activities, could reduce endotoxin-induced WMI in the developing rat brain. Intraperitoneal injections of lipopolysaccharide (LPS) (0.5 mg/kg body weight) were given at embryonic days 18 (E18) and 19 (E19) to pregnant Sprague-Dawley rats; control rats were injected with sterile saline. A single intravenous injection of recombinant human (rh) APC (0.2 mg /kg body weight) was given to pregnant rats following the second LPS dose on embryonic day 19 (E19). Reduced cell death in white matter and hypomyelination were shown on TUNEL and myelin basic protein (MBP) staining, respectively, on late postnatal days (P7) in APC-treated groups. There were significantly fewer TUNEL+nuclei in the periventricular WM in the APC+LPS group than in the untreated LPS group. Compared to the APC+LPS and control group, MBP expression was weak in the LPS group on P7, indicating endotoxin-induced hypomyelination in the developing rat brain. APC attenuated the LPS-induced protein expression of inflammatory cytokines, tumor necrosis factor-alpha, and interleukin-6, as evaluated by ELISA in neonatal rat brains. A single intraperitoneal injection of rhAPC (0.2 mg/kg body weight) to neonatal rats on P1 also had similar protective and anti-inflammatory effects against maternally administered LPS. Collectively, these data support the hypothesis that APC may provide protection against an endotoxin-evoked inflammatory response and WMI in the developing rat brain. Moreover, our results suggest that the possible use of APC in treatment of preterm infants and pregnant women with maternal or placental infection may minimize the risk of PVL and cerebral palsy.
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PMID:Activated protein C reduces endotoxin-induced white matter injury in the developing rat brain. 1764 74

Operative neuromodulation is the field of altering electrically or chemically the signal transmission in the nervous system by implanted devices in order to excite, inhibit or tune the activities of neurons or neural networks and produce therapeutic effects. It is a rapidly evolving biomedical and high-technology field on the cutting-edge of developments across a wide range of scientific disciplines. The authors review relevant literature on the neuromodulation procedures that are performed in the spinal cord or peripheral nerves in order to treat a considerable number of conditions such as (a) chronic pain (craniofacial, somatic, pelvic, limb, or due to failed back surgery), (b) spasticity (due to spinal trauma, multiple sclerosis, upper motor neuron disease, dystonia, cerebral palsy, cerebrovascular disease or head trauma), (c) respiratory disorders, (d) cardiovascular ischemia, (e) neuropathic bladder, and (f) bowel dysfunction of neural cause. Functional neuroprosthetics, a field of operative neuromodulation, encompasses the design, construction and implantation of artificial devices capable of generating electrical stimuli, thereby, replacing the function of damaged parts of the nervous system. The present article also reviews important literature on functional neuroprostheses, functional electrical stimulation (FES), and various emerging applications based on microsystems devices, neural engineering, neuroaugmentation, neurostimulation, and assistive technologies. The authors highlight promising lines of research such as endoneural prostheses for peripheral nerve stimulation, closed-loop systems for responsive neurostimulation or implanted microwires for microstimulation of the spinal cord to enable movements of paralyzed limbs. The above growing scientific fields, in combination with biological regenerative methods, are certainly going to enhance the practice of neuromodulation. The range of neuromodulatory procedures in the spine and peripheral nerves and the dynamics of the biomedical and technological domains which are reviewed in this article indicate that new breakthroughs are likely to improve substantially the quality of life of patients who are severely disabled by neurological disorders.
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PMID:An introduction to operative neuromodulation and functional neuroprosthetics, the new frontiers of clinical neuroscience and biotechnology. 1769 51

The possibility that hypothermia started during or after resuscitation at birth might reduce brain damage and cerebral palsy has tantalized clinicians for a long time. The key insight was that transient severe hypoxia-ischemia can precipitate a complex biochemical cascade leading to delayed neuronal loss. There is now strong experimental and clinical evidence that mild to moderate cooling can interrupt this cascade, and improve the number of infants surviving without disability in the medium term. The key remaining issues are to finding better ways of identifying babies who are most likely to benefit, to define the optimal mode and conditions of hypothermia and to find ways to further improve the effectiveness of treatment.
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PMID:Head cooling for neonatal encephalopathy: the state of the art. 1776 15

This study was an investigation of a possible correlation between either the gestational age (GA) and type of brain injury or between the gestational age and type, distribution and severity of cerebral palsy (CP). Four hundred sixty-one children with a birthweight > or = 1250 g and GA > or = 30 weeks with a complicated neonatal period and/or brain injury on serial cerebral ultrasound were selectively followed at the regional Center for Developmental Disorders. The children were divided into a preterm and term group. There were 40 children with cerebral palsy in the preterm group and 38 children with cerebral palsy in the term group. Various types of brain injury diagnosed by echography were nosologically classified. The type, distribution and severity of cerebral palsy were also registered. The type of brain injury most frequently occurring in the term group was hypoxic-ischemic injury to the basal ganglia (39%), focal ischemia (18%), subcortical hemorrhage (13%) and parasagittal cerebral injury (10%). In the preterm group 39% of the children with cerebral palsy had periventricular leukomalacia, 24% intraventricular hemorrhage and 18% persistent flares. There was a significant correlation between the GA and type of brain injury (P < 0.001; Cramer's V = 0.76) and between the GA and type (P = 0.004; Cramer's V = 0.47) and distribution (P < 0.001; Cramer's V = 0.55) of CP. There was no significant correlation between the GA and severity of CP. The type of brain injury detected by serial ultrasound during the neonatal period, as well as the type and location of CP detected during later childhood, are all GA-dependent in at-risk newborn infants with a birthweight of > or = 1,250 g and GA > or = 30 weeks.
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PMID:Influence of gestational age on the type of brain injury and neuromotor outcome in high-risk neonates. 1802 51

Hypoxia/ischemia (H/I) brain injury at birth is an important cause of cerebral palsy, mental retardation, and epilepsy. The H/I insult also causes energy failure, oxidative stress, and unbalanced ion fluxes, leading to high induction of autopahgy in brain neurons. Since the mice unable to execute autophagy (due to brain-specific deletion of Atg7 or Atg5) die by massive loss of cerebral and cerebellar neurons with accumulation of ubiquitin aggregates, induction of neuronal autophagy after H/I injury is generally considered neuroprotective by maintaining cellular homeostasis. However, our recent results show that hippocampal pyramidal neurons undergoing caspase-dependent or -independent death following neonatal H/I injury possess abundant LC3-positive granules, and such H/I neuronal death is largely prevented by Atg7 deficiency. In the present review we discuss the roles of autophagy and other forms of programmed cell death in the neonatal H/I brain insult.
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PMID:Autophagic neuron death in neonatal brain ischemia/hypoxia. 1821 31


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