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ABSTRACT: We report a rare case of anaplastic oligodendroglioma with extracranial metastasis, showing 1p19q co-deletion in both the brain tissue and the metastatic site. A 53-year-old man first presented with a left frontal tumor. The tumor was subtotally removed and irradiation was performed for the residual tumor and tumor bed. Two years after the initial treatment, several tumors appeared on his neck and one was resected. Histological examination revealed anaplastic oligodendroglioma, proved to be the same as the previous brain tumor. The patient refused further treatment, and died 30 months after the initial treatment. Autopsy demonstrated multiple extracranial metastases in the vertebrae, lymph nodes, spinal dura mater, thymus gland, and chest wall. We confirmed 1p19q loss of heterozygosity in both lesions, suggesting that 1p19q co-deletion might important to extracranial metastasis of oligodendroglioma.
Neurologia medico-chirurgica 01/2010; 50(2):161-4. · 0.61 Impact Factor
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ABSTRACT: The management of seven patients with choroid plexus tumors, 4 adults and 3 children (mean age 17.5 years) at our institution was reviewed. There were 4 cases of papilloma and 3 of carcinoma located in the lateral ventricle in 1 case, the third ventricle in 1 case, and the fourth ventricle in 5 cases. Total surgical excision was attempted in all patients. Total resection was achieved in three patients, resulting in no deficit in two and persistence of preoperative dysphagia in one. There was no recurrence after total resection. Subtotal resection was achieved in four patients, one of whom underwent second surgery resulting in total resection, and one patient died of respiratory disturbance after the third operation because of regrowth of the tumor. Complete excision could not be achieved in 3 of the 5 tumors located in the fourth ventricle because of extension to the brainstem. The median survival was 59.5 months for patients with papilloma, and 67.7 months for those with carcinoma. Adjuvant therapy was also required for carcinoma, one patient was treated by radiotherapy, and two by radiotherapy plus chemotherapy. Only one patient with papilloma was treated by radiotherapy plus chemotherapy postoperatively.
No shinkei geka. Neurological surgery 02/2006; 34(1):73-81. · 0.13 Impact Factor
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ABSTRACT: Oxidative stress after ischemia/reperfusion has been shown to induce DNA damage and subsequent DNA repair activity. Apurinic/apyrimidinic endonuclease (APE) is a multifunctional protein in the DNA base excision repair pathway which repairs apurinic/apyrimidinic sites in DNA. We investigated the involvement of oxidative stress and expression of APE in neurons after oxygen-glucose deprivation and after global cerebral ischemia. Our results suggest that overexpression of human copper/zinc-superoxide dismutase reduced oxidative stress with a subsequent decrease in APE expression. Production of oxygen free radicals and inhibition of the base excision repair pathway may play pivotal roles in the cell death pathway after ischemia.
Journal of Neurochemistry 05/2005; 93(2):351-8. · 4.06 Impact Factor
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ABSTRACT: Cumulative evidence suggests that apoptosis plays a pivotal role in cell death in vitro after hypoxia. Apoptotic cell death pathways have also been implicated in ischemic cerebral injury in in vivo ischemia models. Experimental ischemia and reperfusion models, such as transient focal/global ischemia in rodents, have been thoroughly studied and the numerous reports suggest the involvement of cell survival/death signaling pathways in the pathogenesis of apoptotic cell death in ischemic lesions. In these models, reoxygenation during reperfusion provides a substrate for numerous enzymatic oxidation reactions. Oxygen radicals damage cellular lipids, proteins and nucleic acids, and initiate cell signaling pathways after cerebral ischemia. Genetic manipulation of intrinsic antioxidants and factors in the signaling pathways has provided substantial understanding of the mechanisms involved in cell death/survival signaling pathways and the role of oxygen radicals in ischemic cerebral injury. Future studies of these pathways may provide novel therapeutic strategies in clinical stroke.
NeuroRx 02/2004; 1(1):17-25.
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ABSTRACT: The serine-threonine kinase Akt is activated by phosphorylation at serine-473. After phosphorylation, activated Akt inactivates BAD or caspase-9 or other apoptogenic components, thereby inhibiting cell death. In this study we examined the relationship between Akt phosphorylation and oxidative stress after transient focal cerebral ischemia (FCI) using copper-zinc superoxide dismutase (SOD1) transgenic (Tg) mice.
The mice were subjected to 60 minutes of middle cerebral artery occlusion by intraluminal suture blockade followed by 1, 4, and 24 hours of reperfusion. Phospho-Akt expression was examined by immunohistochemistry and Western blot analysis. Production of superoxide anion was assessed by the hydroethidine method in both wild-type mice and SOD1 Tg mice. DNA fragmentation was evaluated by terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling (TUNEL).
Immunohistochemistry demonstrated that phospho-Akt was constitutively expressed and was decreased in the ischemic core as early as 1 hour after reperfusion, whereas it was temporally increased in the cortex at 4 hours. Phospho-Akt expression was enhanced in the SOD1 Tg mice. Western blot analysis showed that phospho-Akt was maximized 4 hours after reperfusion in the wild-type mice, whereas phospho-Akt was increased as early as 1 hour after ischemia in the SOD1 Tg mice. There was a significant decrease in TUNEL-positive cells in the SOD1 Tg mice compared with the wild-type mice.
The present study suggests that SOD1 may contribute to the early activation of the Akt cell survival signaling pathway and may attenuate subsequent DNA damage after transient FCI.
Stroke 07/2003; 34(6):1513-8. · 5.73 Impact Factor
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ABSTRACT: Oxidative stress plays a pivotal role in ischemic-reperfusion cell injury. Oxygen-derived free radicals trigger DNA strand damage, which is responsible for the activation of poly(ADP-ribose) polymerase (PARP). Recent studies have shown that peroxynitrite is the primary mediator of DNA damage and, hence, PARP activation after ischemia. PARP activation depletes NAD and ATP pools, ultimately resulting in necrotic cell death by loss of energy stores. Our study shows that PARP is upregulated as early as 15 min after 1 h of transient focal cerebral ischemia and remains for 8 h. We also examined the role of superoxide in PARP induction using copper/zinc-superoxide dismutase transgenic mice. Immunohistochemical and Western blotting data showed that there was no increased induction in PARP expression in these mice, suggesting that one of the mechanisms by which ischemic injury is attenuated in these mice might be by the inhibition of PARP induction. Furthermore, double staining of ischemic tissue with a PARP antibody and terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling (TUNEL) indicated that most cells that are positive for TUNEL do not stain for the PARP antibody, confirming recent reports that PARP activation is involved in necrotic cell death rather than apoptosis during ischemic-reperfusion injury.
Molecular Brain Research 06/2003; 113(1-2):28-36. · 2.00 Impact Factor
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ABSTRACT: Angiogenesis is an intricately regulated phenomenon. Its mechanisms in the ischemic brain have not been clearly elucidated. The authors investigated expression of angiogenesis-related genes using a complementary DNA (cDNA) array method as well as Western blotting and immunohistochemistry, and compared these studies with a temporal profile of angiogenesis in mouse brains after ischemia. The number of vessels significantly increased 3 days after injury, and proliferating endothelial cells increased as early as 1 day. This means that angiogenesis occurs immediately after the injury. Ninety-six genes implicated in angiogenesis were investigated with a cDNA array study. It was found that 42, 29, and 13 genes were increased at 1 hour, 1 day, and 21 days, respectively. Most of the well-known angiogenic factors increased as early as 1 hour. Vessel-stabilizing factors such as thrombospondins also increased. At 1 day, however, thrombospondins decreased to lower levels than in the control, indicating a shift from vascular protection to angiogenesis. At 21 days, many genes were decreased, but some involved in tissue repair were newly increased. Western blotting and immunohistochemistry showed findings compatible with the cDNA array study. Many molecules act in an orchestrated fashion in the brain after ischemia and should be taken into account for therapeutic angiogenesis for stroke.
Journal of Cerebral Blood Flow & Metabolism 03/2003; 23(2):166-80. · 5.01 Impact Factor
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ABSTRACT: Recent studies have revealed that activation of extracellular signal-regulated kinase (ERK) may contribute to apoptosis, a cell death process involved in oxidative stress. We examined phosphorylation of ERK1/2 and oxidative stress after transient focal cerebral ischemia (FCI) using transgenic (Tg) mice that overexpress copper/zinc superoxide dismutase (SOD1). The mice were subjected to 60 min of middle cerebral artery (MCA) occlusion by intraluminal suture blockade followed by 1, 4, and 24 hr of reperfusion. Immunohistochemistry and Western blot analysis showed that phospho-ERK1 was markedly increased in the cortex within the MCA territory at 1 hr of reperfusion (p < 0.01), followed by a decrease at 24 hr in wild-type mice. Double staining with phospho-ERK1/2 and neuron-specific nuclear protein showed that phospho-ERK1/2 was primarily expressed in neurons. In SOD1 Tg mice, phospho-ERK1/2 was prominently reduced compared with nonischemic controls, shown by immunohistochemistry. Western blot analysis confirmed a significant decrease in phospho-ERK1/2 1 hr after FCI in the ischemic cortex (p < 0.005). Apoptotic-related DNA fragmentation was reduced in the ischemic cortex of SOD1 Tg mice compared with wild-type mice using a cell death assay. These results suggest that phosphorylation of ERK1/2 may be involved in apoptosis or cell death after transient FCI and that SOD1 may attenuate apoptotic cell death mediated by the mitogen-activated protein kinase/ERK pathway.
Journal of Neuroscience 09/2002; 22(18):7923-30. · 7.11 Impact Factor
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ABSTRACT: The serine-threonine kinase, Akt, is involved in the survival signaling pathways in many cell systems. The present study examined phosphorylation of Akt at serine-473 and DNA fragmentation after traumatic brain injury (TBI) in mice. Immunohistochemistry showed phospho-Akt was decreased in the injured cortex 1 h after TBI, whereas it was temporally increased at 4 h in the perifocal damaged cortex. In the CA1 region of the hippocampus, phospho-Akt was increased after TBI. Western blot analysis showed that Akt was significantly decreased as early as 1 h after trauma; however, the phosphorylation was accelerated at 4 h. Double staining with phospho-Akt and phospho-BAD or phospho-GSK-3beta revealed the colocalization of phospho-Akt and downstream elements. Double staining with phospho-Akt and terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling showed different cellular distributions after TBI. The present study implicates Akt phosphorylation in the signaling pathways that are involved in cell survival after TBI.
Neurobiology of Disease 05/2002; 9(3):294-304. · 5.40 Impact Factor
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ABSTRACT: Superoxide anion radicals (O2*-) are implicated in ischemia/reperfusion injury, although a direct relationship has not been elucidated. Recently, a specific method of hydroethidine (HEt) oxidation by O2*- was developed to detect O2*- production in a variety of experimental brain injury models. To clarify the role of O2*- in the mechanism of ischemia/reperfusion, we investigated O2*- production after ischemia/reperfusion and ischemia/reperfusion injury in mutant mice deficient in mitochondrial manganese superoxide dismutase (MnSOD) and in wild-type littermates.
Ischemia/reperfusion was performed for 60 minutes using intraluminal suture blockade of the middle cerebral artery in the mutant or wild-type mice. We evaluated fluorescent kinetics of HEt or ethidium, the oxidized form of HEt, in brains after an intravenous injection of HEt, followed by measurement of cellular O2*- production using specific HEt oxidation by O2*- before and after ischemia/reperfusion. Furthermore, we compared O2*- production and subsequent infarct volume in the mice using triphenyltetrazolium chloride after ischemia/reperfusion.
HEt oxidation to ethidium is primarily a result of mitochondrially produced O2*- under physiological conditions. Cerebral ischemia/reperfusion produced O2*- prominently in neurons shortly after reperfusion, followed by a delayed increase in endothelial cells. A deficiency in MnSOD in mutant mice increased mitochondrial O2*- production and exacerbated cerebral infarction, worsening neurological deficits after ischemia/reperfusion.
These results suggest that mitochondrial O2*- production may be a critical step underlying the mechanism of ischemia/reperfusion injury and that MnSOD may protect against ongoing oxidative cell death after ischemia/reperfusion.
Stroke 04/2002; 33(3):809-15. · 5.73 Impact Factor
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ABSTRACT: Mitochondria are known to be involved in the early stage of apoptosis by releasing cytochrome c, caspase-9, and the second mitochondria-derived activator of caspases (Smac). We have reported that overexpression of copper/zinc superoxide dismutase (SOD1) reduced superoxide production and ameliorated neuronal injury in the hippocampal CA1 subregion after global ischemia. However, the role of oxygen free radicals produced after ischemia/reperfusion in the mitochondrial signaling pathway has not been clarified. Five minutes of global ischemia was induced in male SOD1-transgenic (Tg) and wild-type (Wt) littermate rats. Cytosolic expression of cytochrome c and Smac and activation of caspases were evaluated by immunohistochemistry, Western blot, and caspase activity assay. Apoptotic cell death was characterized by DNA nick end and single-stranded DNA labeling. In the Wt animals, early superoxide production, mitochondrial release of cytochrome c, Smac, and cleaved caspase-9 were observed after ischemia. Active caspase-3 was subsequently increased, and 85% of the hippocampal CA1 neurons showed apoptotic DNA damage 3 d after ischemia. Tg animals showed less superoxide production and cytochrome c and Smac release. Subsequent active caspase-3 expression was not evident, and only 45% of the neurons showed apoptotic DNA damage. A caspase-3 inhibitor (N-benzyloxycarbonyl-val-ala-asp-fluoromethyl ketone) reduced cell death only in Wt animals. These results suggest that overexpression of SOD1 reduced oxidative stress, thereby attenuating the mitochondrial release of cytochrome c and Smac, resulting in less caspase activation and apoptotic cell death. Oxygen free radicals may play a pivotal role in the mitochondrial signaling pathway of apoptotic cell death in hippocampal CA1 neurons after global ischemia.
Journal of Neuroscience 02/2002; 22(1):209-17. · 7.11 Impact Factor
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ABSTRACT: The hippocampal CA1 neurons are selectively vulnerable to global ischemia, and neuronal death occurs in a delayed manner. The threshold of global ischemia duration that induces neuronal death has been studied, but the relationship between ischemia duration and glial death in the hippocampal CA1 area has not been fully studied. We examined neuronal/glial viability and morphological changes in the CA1 subregion after different durations of global ischemia. Global ischemia was induced in Sprague-Dawley rats by 10, 5, and 3 min of bilateral common carotid artery occlusion and hypotension. At 1-56 days after ischemia, the morphological reactions of neurons, astrocytes, oligodendrocytes, and microglia were immunohistochemically evaluated. Most of the hippocampal CA1 pyramidal neurons underwent delayed death at 3 days after 10/5 min of ischemia, but not after 3 min of ischemia. The number of astrocytes gradually declined after 10/5 min of ischemia, and viable astrocytes showed characteristic staged morphological reactions. Oligodendrocytes also showed morphological changes in their processes after 10/5 min of ischemia. Microglia transformed into a reactive form at 5 days only after 10/5 min of ischemia. These data suggest that some morphological changes in glial cells were not dependent on neuronal cell death, but their own reactions to the different severity of ischemia.
Journal of Neurotrauma 02/2002; 19(1):85-98. · 3.65 Impact Factor
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ABSTRACT: The X-ray repair cross-complementing group 1 (XRCC1) protein plays a central role in the DNA base excision repair pathway by interacting with DNA ligase III and DNA polymerase β. The present study examined the protein expression of XRCC1 and DNA fragmentation before and after cold injury-induced brain trauma (CIBT) in mice, in which apoptosis is assumed to participate. Immunohistochemistry showed the nuclear expression of XRCC1 in the entire region of the control brains. Fifteen minutes after CIBT, nuclear immunoreactivity was predominantly decreased in the inner boundary of the lesion, followed by a significant reduction of XRCC1 in the entire lesion 4 h after CIBT. A characteristic 70-kDa band was detected in the non-traumatic area, and was markedly decreased after CIBT as shown by Western blot analysis. DNA fragmentation was also observed after CIBT, and double staining with XRCC1 immunohistochemistry and terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end labeling showed a spatial relationship between XRCC1 loss and DNA fragmentation 24 h after CIBT. These data indicate that early decrease of XRCC1 and failure of the DNA repair mechanism may contribute to DNA-damaged neuronal cell death after CIBT.
Brain Research.
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ABSTRACT: Neuronal death in the hippocampal CA1 subregion has been shown to occur in a delayed manner after transient global ischemia. The 2-vessel occlusion model is one of the most frequently used global ischemia paradigms in rodents. Although researchers often fail to induce bilateral delayed CA1 neuronal death, the importance of hypotension severity has not been fully discussed. We induced 10 min of global ischemia with 2-vessel occlusion and various severities of hypotension in rats, and the subsequent neuronal damage and neurogenesis in the hippocampal CA1 pyramidal cell layer were immunohistochemically studied. Neuronal apoptosis after global ischemia was also characterized by terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end labeling (TUNEL). The mean arterial blood pressure of 31-35 mmHg was the most appropriate range of hypotension in this model because of low mortality and consistent bilateral CA1 injury. Most of the neurons in the CA1 pyramidal cell layer lost neuron specific nuclear protein and became TUNEL-positive 3 days after ischemia. There was no evidence of apoptosis or neurogenesis at 7-28 days. There were ischemia-tolerant neurons in the CA1 pyramidal cell layer that survived delayed neurodegeneration, however, further studies are necessary to characterize the property of these neurons.
Brain Research.
