• Nuclear Medicine and Molecular Imaging
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• v.41 no.2
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• pp.91-96
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• 2007

The measurement of pathologically low levels of tissue $pO_2$ is an important diagnostic goal for determining the prognosis of many clinically important diseases including cardiovascular insufficiency, stroke and cancer. The target tissues nowaday have mostly been tumors or the myocardium, with less attention centered on the brain. Radiolabelled nitroimidazole or derivatives may be useful in identifying the hypoxic cells in cerebrovascular disease or traumatic brain injury, and hypoxic-ischemic encephalopathy. In acute stroke, the target of therapy is the severely hypoxic but salvageable tissue. $^{18}F-MISO$ PET and $^{99}mTc-EC-metronidazole$ SPECT in patients with acute ischemic stroke identified hypoxic tissues and ischemic penumbra, and predicted its outcome. A study using $^{123}I-IAZA$ in patient with closed head injury detected the hypoxic tissues after head injury. Up till now these radiopharmaceuticals have drawbacks due to its relatively low concentration with hypoxic tissues associated with/without low blood-brain barrier permeability and the necessity to wait a long time to achieve acceptable target to background ratios for imaging in acute ischemic stroke. It is needed to develop new hypoxic marker exhibiting more rapid localization in the hypoxic region in the brain. And then, the hypoxic brain imaging with imidazoles or non-imidazoles may be very useful in detecting the hypoxic tissues, determining therapeutic strategies and developing therapeutic drugs in several neurological disease, especially, in acute ischemic stroke.

• Proceedings of the PSK Conference
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• 2003.10a
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• pp.104-105
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• 2003

Hypoxic-ischemic (H-I) encephalopathy in the prenatal and perinatal period is a major cause of morbidity and mortality and often results in cognitive impairment, seizures, and motor impairment (cerebral palsy). Many studies of neonatal H-I brain injury have utilized the well characterized Levine model in which unilateral carotid ligation is followed by exposure to hypoxia. (omitted)

• Clinical and Experimental Pediatrics
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• v.52 no.1
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• pp.105-110
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• 2009

Purpose : Perinatal asphyxia is an important cause of neonatal mortality and subsequent lifelong neurodevelopmental handicaps. Although many treatment strategies have been tested, there is currently no clinically effective treatment to prevent or reduce the harmful effects of hypoxia and ischemia in humans. Erythropoietin (Epo) has been shown to exert neuroprotective effects in various brain injury models although the exact mechanisms through which Epo functions are not completely understood. This study investigates the effect of Epo on hypoxic-ischemic (HI) brain injury and the possibility that its neuroprotective actions may be associated with iron-mediated metabolism. Methods : HI brain injury was produced in 7-day-old rats by unilateral carotid artery ligation followed by hypoxia with 8% oxygen for 2 h. At the end of HI brain injury, the rats received an intraperitoneal injection of 5,000 units/kg erythropoietin. Random premedication with iron, deferoxamine, iron-deferoxamine, or saline were performed 23 d before HI brain injury. The severity of the brain injury was assessed at 7 d after HI. Results : Single Epo treatment post-HI brain injury reduced the gross and histopathological findings of brain injury. Iron premedication did not increase the incidence or severity of the injury as measured by the damage score. Deferoxamine administration before HI brain injury improved the brain injury as compared to no treatment or Epo treatment. Conclusion : These findings indicate that Epo provides neuroprotective benefits after HI in the developing brain. These findings suggest that Epos neuroprotective actions may involve reducing iron in tissues that mediate the formation of free radicals.

• Clinical and Experimental Pediatrics
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• v.53 no.10
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• pp.898-908
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• 2010

Purpose: The neuroprotective effects of erythropoietin (EPO) have been recently shown in many animal models of brain injury, including hypoxic-ischemic (HI) encephalopathy, trauma, and excitotoxicity; however, limited data are available for such effects during the neonatal periods. Therefore, we investigated whether recombinant human EPO (rHuEPO) can protect against perinatal HI brain injury via an antiapoptotic mechanism. Methods: The left carotid artery was ligated in 7-day-old Sprague-Dawley (SD) rat pups ($in$ $vivo$ model). The animals were divided into 6 groups: normoxia control (NC), normoxia sham-operated (NS), hypoxia only (H), hypoxia+vehicle (HV), hypoxia+rHuEPO before a hypoxic insult (HE-B), and hypoxia+rHuEPO after a hypoxic insult (HE-A). Embryonic cortical neuronal cell culture of SD rats at 18 days gestation ($in$ $vitro$ model) was performed. The cultured cells were divided into 5 groups: normoxia (N), hypoxia (H), and 1, 10, and 100 IU/mL rHuEPO-treated groups. Results: In the $in$ $vivo$ model, Bcl-2 expressions in the H and HV groups were lower than those in the NC and NS groups, whereas those in the HE-A and HE-B groups were greater than those of the H and HV groups. The expressions of Bax and caspase-3 and the ratio of Bax/Bcl-2 were in contrast to those of Bcl-2. In the $in$ $vitro$ model, the patterns of Bcl-2, Bax, and caspase-3 expression and Bax/Bcl-2 ratio were similar to the results obtained in the in vivo model. Conclusion: rHuEPO exerts neuroprotective effect against perinatal HI brain injury via an antiapoptotic mechanism.

• Clinical and Experimental Pediatrics
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• v.62 no.12
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• pp.444-449
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• 2019

Background: Sixty percent of infants with severe neonatal hypoxic-ischemic encephalopathy die, while most survivors have permanent disabilities. Treatment for neonatal hypoxic-ischemic encephalopathy is limited to therapeutic hypothermia, but it does not offer complete protection. Here, we investigated whether hypoxia-inducible factor (HIF) promotes cell survival and suggested neuroprotective strategies. Purpose: HIF-1α deficient mice have increased brain injury after neonatal hypoxia-ischemia (HI), and the role of HIF-2α in HI is not well characterized. Copper-zinc superoxide dismutase (SOD)1 overexpression is not beneficial in neonatal HI. The expression of HIF-1α and HIF-2α was measured in SOD1 overexpressing mice and compared to wild-type littermates to see if alteration in expression explains this lack of benefit. Methods: On postnatal day 9, C57Bl/6 mice were subjected to HI, and protein expression was measured by western blotting in the ipsilateral cortex of wild-type and SOD1 overexpressing mice to quantify HIF-1α and HIF-2α. Spectrin expression was also measured to characterize the mechanism of cell death. Results: HIF-1α protein expression did not significantly change after HI injury in the SOD1 overexpressing or wild-type mouse cortex. However, HIF-2α protein expression increased 30 minutes after HI injury in the wild-type and SOD1 overexpressing mouse cortex and decreased to baseline value at 24 hours after HI injury. Spectrin 145/150 expression did not significantly change after HI injury in the SOD1 overexpressing or wild-type mouse cortex. However, spectrin 120 expression increased in both wild-type and SOD1 overexpressing mouse at 4 hours after HI, which decreased by 24 hours, indicating a greater role of apoptotic cell death. Conclusion: HIF-1α and HIF-2α may promote cell survival in neonatal HI in a cell-specific and regional fashion. Our findings suggest that early HIF-2α upregulation precedes apoptotic cell death and limits necrotic cell death. However, the influence of SOD was not clarified; it remains an intriguing factor in neonatal HI.

• Clinical and Experimental Pediatrics
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• v.64 no.8
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• pp.422-429
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• 2021

Background: Carnosine has antioxidative and neuroprotective properties against hypoxic-ischemic (HI) brain injury. Hypothermia is used as a therapeutic tool for HI encephalopathy in newborn infants with perinatal asphyxia. However, the combined effects of these therapies are unknown. Purpose: Here we investigated the effects of combined carnosine and hypothermia therapy on HI brain injury in neonatal rats. Methods: Postnatal day 7 (P7) rats were subjected to HI brain injury and randomly assigned to 4 groups: vehicle; carnosine alone; vehicle and hypothermia; and carnosine and hypothermia. Carnosine (250 mg/kg) was intraperitoneally administered at 3 points: immediately following HI injury, 24 hours later, and 48 hours later. Hypothermia was performed by placing the rats in a chamber maintained at 27℃ for 3 hours to induce whole-body cooling. Sham-treated rats were also included as a normal control. The rats were euthanized for experiments at P10, P14, and P35. Histological and morphological analyses, in situ zymography, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assays, and immunofluorescence studies were conducted to investigate the neuroprotective effects of the various interventional treatments. Results: Vehicle-treated P10 rats with HI injury showed an increased infarct volume compared to sham-treated rats during the triphenyltetrazolium chloride staining study. Hematoxylin and eosin staining revealed that vehicle-treated P35 rats with HI injury had decreased brain volume in the affected hemisphere. Compared to the vehicle group, carnosine and hypothermia alone did not result in any protective effects against HI brain injury. However, a combination of carnosine and hypothermia effectively reduced the extent of brain damage. The results of in situ zymography, TUNEL assays, and immunofluorescence studies showed that neuroprotective effects were achieved with combination therapy only. Conclusion: Carnosine and hypothermia may have synergistic neuroprotective effects against brain damage following HI injury.

• The Korean Journal of Physiology and Pharmacology
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• v.13 no.3
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• pp.257-263
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• 2009

This study aimed to investigate whether selective serotonin reuptake inhibitors (SSRIs) attenuate brain injury and facilitate recovery following photothrombotic cortical ischemia in mice. Male ICR mice were anesthetized and systemically administered Rose Bengal. Permanent focal ischemia was induced in the medial frontal and somatosensory cortices by irradiating the skull with cold light laser. The animals were treated with fluoxetine or sertraline once a day for 14 d starting 1 h after ischemic insult. Treatment with fluoxetine and sertraline significantly reduced the infarct size. The Evans blue extravasation indices of the fluoxetine- and sertraline-treated groups were significantly lower than that of the vehicle group. Treatment with fluoxetine and sertraline shifted the lower limit of the mean arterial blood pressure for cerebral blood flow autoregulation toward normal, and significantly increased the expression of heme oxygenase-1 (HO-1) and hypoxia-inducible factor-1 ${\alpha}$ (HIF-1 ${\alpha}$) proteins in the ischemic region. These results suggest that SSRIs, such as fluoxetine and sertraline, facilitate recovery following photothrombotic cortical ischemia via enhancement of HO-1 and HIF-1 ${\alpha}$ proteins expression, thereby providing a benefit in therapy of cerebral ischemia.

• Clinical and Experimental Pediatrics
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• v.49 no.2
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• pp.198-202
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• 2006

Purpose : Fas is a cell surface receptor that transduces apoptotic death signals. Interaction of extracelluar domain of Fas with Fas ligand(FasL) triggers the apoptotic process in many diseases. We investigated the expression of Fas and FasL in the hippocampus of 7-day-old newborn rat brains following hypoxia-ischemia injury. Methods : The 7-days-old newborn rats were exposed to 8 percent oxygen for two hours after the ligation of right common carotid arteries. The newborn rats were killed and their brains were removed at 12, 14 and 48 hours after hypoxic-ischemic injury. The expressions of Fas and FasL of the right hippocampus were observed by western blotting and immunofluorescent staining. Results : Fas and FasL were strongly expressed in the right hippocampus ipsilateral to the ligation of the common carotid artery by western blotting at 12 hours following hypoxic-ischemic injury, and then slowly decreased. The immunofluorescent expressions of Fas and FasL strongly increased in the CA1 area of the right hippocampus at 12 and 24 hours following hypoxic-ischemic injury. The immunofluorescent expression of Fas decreased at 48 hours, but the expression of FasL persisted strongly at 48 hours following hypoxic-ischemic injury. Conclusion : The interaction of Fas with FasL on the cell surface may be involved in neuronal injury following hypoxic-ischemic injury in the developing brain.

• The Journal of Korean Physical Therapy
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• v.15 no.4
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• pp.199-207
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• 2003

This review describes the neurophathological mechanisms that are implicated in perinatal brain injury. Perinatal brain injury is the most important cause of morbidity and mortality to infants, often leading to spastic motor deficits, mental retardation, seizures, and learning impairments. The immature brain injury is usually caused by cerebral hypoxia-ischemia, hemorrhage, or infection. The important form of perinatal brain injury is the hypoxic-ischemic injury and the cerebral hemorrhage. The pathology of hypoxic-ischemic injury include delayed energy failure by mitochondrial dysfunction, neuronal excitotoxicity and vulnerability of white matter in developing brain. The immature brain has the fragile vascular bed of germinal matrix and can not effectively centralize their circulation. Therefore, the cerebral hemorrhage process is considered to be involved in the periventricular leukomalacia.

• Neonatal Medicine
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• v.17 no.2
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• pp.181-192
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• 2010

Purpose: Current studies have demonstrated the neuroprotective effects of dizocilpine (MK-801) in many animal models of brain injury, including hypoxic-ischemic (HI) encephlopathy, trauma and excitotoxicity, but limited data are available for those during the neonatal periods. Here we investigated whether dizocilpine can protect the developing rat brain from HI injury via anti-apoptosis. Methods: In an in vitro model, embryonic cortical neuronal cell culture of Sprague-Dawley (SD) rats at 18-day gestation was done. The cultured cells were divided into three groups: normoxia (N), hypoxia (H), and hypoxia treated with dizocilpine (HD). The N group was prepared in 5% $CO_2$ incubators and the other groups were placed in 1% $O_2$ incubators (94% N2, 5% $CO_2$) for 16 hours. In an in vivo model, left carotid artery ligation was done in 7-day-old SD rat pups. The animals were divided into six groups; hypoxia (N), hypoxia (H), hypoxia with sham-operation (HS), hypoxia with operation (HO), HO treated with vehicle (HV), and HO treated with dizocilpine (HD). Hypoxia was made by exposure to a 2 hour period of hypoxic incubator (92% N2, 8% $O_2$). Results: In the in vitvo and in vivo models, the expressions of Bcl-2 in the hypoxia groups were reduced compared to the normoxia group. whereas those in the dizocilpine-treated group were increased compared to the hypoxia group. However. the expressions of Bax and caspase-3 and the ratio of Bax/Bcl-2 were revealed reversely. Conclusion: Dizocilpine has neuroprotective property over perinatal HI brain injury via anti-apoptosis.