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ABSTRACT: The authors report the case of a 65-year-old woman with atlantoaxial subluxation caused by rheumatoid arthritis. The patient had been hospitalized because of an infection after a total-knee replacement, when she suddenly lost consciousness and became apneic after an episode of intractable neck pain. Cranial computed tomography scanning demonstrated subarachnoid hemorrhage (SAH), and angiography revealed a dissecting aneurysm of the radiculomedullary artery that had originated from an extracranial vertebral artery dissection at the level of the atlantoaxial joint. Although coil embolization for the parent artery, including the dissecting aneurysm, was performed successfully, the patient died of worsening infection. The authors believe that the SAH occurred because of a ruptured dissecting aneurysm in the intradural portion of the radiculomedullary artery.
Journal of Neurosurgery Spine 01/2008; 7(6):660-3. · 1.53 Impact Factor
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ABSTRACT: Infarcts expand over a period of several days after focal cerebral ischemia. Inhibition of infarct expansion would be a promising strategy for the protection of the brain after ischemic insult. In this study, we examined the effect of statin treatment initiated 2 days after transient occlusion of the middle cerebral artery for 80 min. Treatment with continuous infusion of pravastatin with an osmotic minipump for 6 days resulted in a significantly smaller infarct volume and better recovery of motor function at 8 days after ischemia compared to vehicle treatment. These results suggest that statin treatment during the postischemic period may be effective in stroke patients.
Brain Research 12/2007; 1181:125-9. · 2.73 Impact Factor
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ABSTRACT: Brain ischemia stimulates neurogenesis. However, newborn neurons show a progressive decrease in number over time. Under normal conditions, the cAMP-cAMP responsive element binding protein (CREB) pathway regulates the survival of newborn neurons. Constitutive activation of CREB after brain ischemia also stimulates hippocampal neurogenesis. Thus, activation of cAMP-CREB signaling may provide a promising strategy for enhancing the survival of newborn neurons. We examined whether treatment of mice with the phosphodiesterase-4 inhibitor rolipram enhances hippocampal neurogenesis after ischemia.
Both common carotid arteries in mice were occluded for 12 minutes. Bromodeoxyuridine (BrdU) was used to label proliferating cells. Mice were perfused transcardially with 4% paraformaldehyde, and immunohistochemistry was performed. To evaluate the role of CREB in the survival of newborn neurons after ischemia, intrahippocampal injection of a CRE-decoy oligonucleotide was delivered for 1 week. We examined whether the activation of cAMP-CREB signaling by rolipram enhanced the proliferation and survival of newborn neurons.
Phospho-CREB immunostaining was markedly upregulated in immature neurons, decreasing to low levels in mature neurons. The number of BrdU-positive cells 30 days after ischemia was significantly less in the CRE-decoy treatment group than in the vehicle group. Rolipram enhanced the proliferation of newborn cells under physiologic conditions but not under ischemic conditions. Rolipram significantly increased the survival of nascent BrdU-positive neurons, accompanied by an enhancement of phospho-CREB staining and decreased newborn cell death after ischemia.
CREB phosphorylation regulates the survival of newborn neurons after ischemia. Chronic pharmacological activation of cAMP-CREB signaling may be therapeutically useful for the enhancement of neurogenesis after ischemia.
Stroke 06/2007; 38(5):1597-605. · 5.73 Impact Factor
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ABSTRACT: Neuronal progenitors in the adult hippocampus continually proliferate and differentiate to the neuronal lineage, and ischemic insult promotes hippocampal neurogenesis. However, newborn neurons show a progressive reduction in numbers during the initial few weeks, therefore, enhanced survival of newborn neurons seems to be essential for therapeutic strategy. Bcl-2 is a crucial regulator of programmed cell death in CNS development and in apoptotic and necrotic cell death. Therefore, we tested whether Bcl-2 overexpression enhances survival of newborn neurons in the adult mouse hippocampus under normal and ischemic conditions. Many newborn neurons in the hippocampal dentate gyrus undergo apoptosis. Human Bcl-2 expression in NSE-bcl-2 transgenic mice began at the immature neuronal stage and remained constant in surviving mature neurons. Bcl-2 significantly increased survival of newborn neurons under both conditions, but particularly after ischemia, with decreased cell death of newborn neurons in NSE-bcl-2 transgenic mice. We also clarified the effect by Bcl-2 overexpression of enhanced survival of newborn neurons in primary hippocampal cultures with BrdU labeling. These findings suggest that Bcl-2 plays a crucial role in adult hippocampal neurogenesis under normal and ischemic conditions.
Journal of Neuroscience Research 12/2006; 84(6):1187-96. · 2.74 Impact Factor
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ABSTRACT: Neurons acquire tolerance to ischemic stress when preconditioning ischemia occurs a few days beforehand. We focused on collateral development after mild reduction of perfusion pressure to find an endogenous response of the vascular system that contributes to development of ischemic tolerance.
After attachment of a probe, the left common carotid artery (CCA) of C57BL/6 mice was occluded. The left middle cerebral artery (MCA) was subsequently occluded permanently on days 0, 1, 4, 14, and 28 (n=8 each). The change in cortical perfusion during MCA occlusion was recorded. A sham group of mice received only exposure of the CCA and MCA occlusion 14 days later. In apoE-knockout mice, the MCA was occluded 14 days after CCA occlusion or sham surgery. Infarct size and neurologic deficit were determined 4 days after MCA occlusion.
Mice that had 45% to 65% of baseline perfusion after CCA occlusion were used. Cortical perfusion after MCA occlusion was significantly preserved in day 14 (47+/-16%) and day 28 (46+/-7%) groups compared with day 0 (28+/-8%), day 1 (33+/-19%), day 4 (29+/-16%), and sham groups (32+/-9%). Infarct size and neurologic deficits were also attenuated in day 14 and day 28 groups compared with other groups. In apoE-knockout mice, there was no significant difference in perfusion, neurologic deficits, or infarction size between groups with and without CCA occlusion.
Chronic mild reduction of perfusion pressure resulted in preservation of cortical perfusion and attenuation of infarct size after MCA occlusion. These responses of collaterals were impaired in apoE-knockout mice.
Stroke 11/2005; 36(10):2270-4. · 5.73 Impact Factor
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Journal of Cerebral Blood Flow & Metabolism 07/2005; · 5.01 Impact Factor
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Journal of Cerebral Blood Flow & Metabolism 07/2005; · 5.01 Impact Factor
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ABSTRACT: Recent studies have demonstrated that neurotrophic factors promote neurogenesis after cerebral ischemia. However, it remains unknown whether administration of genes encoding those factors could promote neural regeneration in the striatum and functional recovery. Here, we examined the efficacy of intraventricular injection of a recombinant adenovirus-expressing heparin-binding epidermal growth factor-like growth factor (HB-EGF) on neurogenesis, angiogenesis, and functional outcome after focal cerebral ischemia.
Transient focal ischemia was induced by middle cerebral artery occlusion (MCAO) for 80 minutes with a nylon filament in Wistar rats. Three days after MCAO, either adenovirus-expressing HB-EGF (Ad-HB-EGF) or Ad-LacZ, the control vector, was injected into the lateral ventricle on the ischemic side. Bromodeoxyuridine (BrdU) was injected intraperitoneally twice daily on the sixth and seventh days. On the eighth or 28th day after MCAO, we evaluated infarct volume, neurogenesis, and angiogenesis histologically. Neurological outcome was serially evaluated by the rotarod test after MCAO.
There was no significant difference in infarct volume between the 2 groups. Treatment with Ad-HB-EGF significantly increased the number of BrdU-positive cells in the subventricular zone on the 8th day. In addition, on the 28th day, BrdU-positive cells differentiated into mature neurons in the striatum on the ischemic side but seldom the cells given Ad-LacZ. Enhancement of angiogenesis at the peri-infarct striatum was also observed on the eighth day in Ad-HB-EGF-treated rats. Treatment with Ad-HB-EGF significantly enhanced functional recovery after MCAO.
Our data suggest that gene therapy using Ad-HB-EGF contributes to functional recovery after ischemic stroke by promoting neurogenesis and angiogenesis.
Stroke 05/2005; 36(4):859-64. · 5.73 Impact Factor
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ABSTRACT: Gene therapy may show promise for stroke patients, but invasive techniques such as intraventricular or intracerebral injection of therapeutic genes may have limited applicability. The purpose of this study is to develop systemic gene therapy using macrophages infiltrating the infarct to deliver and express the gene.
After permanent middle cerebral artery occlusion in rats, an enhanced green fluorescent protein (EGFP) plasmid conjugate in liposomes was injected via the femoral vein. We also constructed a bicistronic plasmid vector for fibroblast growth factor-2 (FGF-2) as well as EGFP, administering it in other rats with middle cerebral artery occlusion.
EGFP expression in normal brain was absent but was strong in macrophages accumulating along the infarct border. FGF-2 protein production was induced in macrophages along the infarct border after injection of bicistronic FGF-2 and EGFP plasmid vector; this stimulated proliferation of neural progenitors in the subventricular zone in the ischemic hemisphere compared with control plasmid vectors (61.7+/-5.2 versus 42.2+/-5.5 cells per mm2, n=4 each, P<0.01).
Systemic gene transfer by liposome to macrophages infiltrating an infarct may prove useful for gene therapy in stroke.
Stroke 08/2004; 35(8):1968-73. · 5.73 Impact Factor
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ABSTRACT: Cyclic AMP response element binding protein (CREB) is a transcription factor expressed constitutively primarily in neurons and is activated by phosphorylation at Ser(133) residue. CREB mediates expression of several neuroprotective proteins, including B-cell CLL/lymphoma 2 (BCL-2) and brain-derived neurotrophic factor (BDNF). Although phosphorylation of CREB after ischemia has been investigated extensively, CRE-mediated gene transcription after ischemia is not as well studied. We investigated temporal changes in CRE-mediated gene transcription in the cerebral cortex after focal ischemia in transgenic mice with a CRE-lacZ reporter gene. In the ischemic core, X-gal-positive cells, which reflected expression of the CRE-lacZ reporter gene, were observed rarely at any time point, though transient phosphorylation of CREB was detected. In contrast, the peri-infarct area showed a persistent increase in the number of X-gal-positive cells, of which more than half were positive for neuronal nuclei (NeuN). Our results suggest that CRE-mediated gene transcription, the pattern of which is not always consistent with that of CREB phosphorylation, occurs primarily in neurons in the peri-infarct area after focal cerebral ischemia and may be a neuroprotective response against ischemic insult.
Journal of Neuroscience Research 03/2004; 75(3):401-7. · 2.74 Impact Factor
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ABSTRACT: Several studies have suggested that cyclooxygenase-2 (COX-2) plays a role in ischemic neuronal death. Genetic disruption of COX-2 has been shown to reduce susceptibility to focal ischemic injury and N-methyl-d-aspartate-mediated neurotoxicity. The purpose of this study was to examine the effects of COX-2 deficiency on neuronal vulnerability after transient forebrain ischemia. Marked upregulation of COX-2 immunostaining in neurons was observed at the early stage and prominent COX-2 staining persisted in the CA1 medial sector and CA2 sector over 3 days after ischemia. The immunohistologic pattern of COX-2 staining in these sectors gradually condensed to a perinuclear location. The degree of hippocampal neuronal injury produced by global ischemia in COX-2-deficient mice was less than that in wild-type mice, coincident with attenuation of DNA fragmentation in the hippocampus. Also, treatment with a selective COX-2 inhibitor, nimesulide, after ischemia decreased hippocampal neuronal damages. These results of genetic disruption and chemical inhibition of cyclooxygenase-2 show that inhibition of COX-2 ameliorates selective neuronal death after transient forebrain ischemia in mice.
Journal of Cerebral Blood Flow & Metabolism 02/2004; 24(1):107-13. · 5.01 Impact Factor
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ABSTRACT: Global ischemia promotes neurogenesis in the dentate gyrus of the adult mouse hippocampus. Cyclooxygenase (COX)-2, the principal isoenzyme in the brain, modulates inflammation, glutamate-mediated cytotoxicity, and synaptic plasticity. We demonstrated that delayed treatment with different classes of COX inhibitor significantly blunted enhancement of dentate gyrus proliferation of neural progenitor cells after ischemia. COX-2 immunoreactivity was observed in both neurons and astrocytes in the dentate gyrus, but not in neural progenitor cells in the subgranular zone. Moreover, in the postischemic dentate gyrus of heterozygous and homozygous COX-2 knockout mice, proliferating bromodeoxyuridine-positive cells were significantly fewer than in wild-type littermates. These results demonstrate that COX-2 is an important modulator in enhancement of proliferation of neural progenitor cells after ischemia.
Journal of Neuroscience Research 06/2003; 72(4):461-71. · 2.74 Impact Factor
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ABSTRACT: Akt kinase is involved in growth factor-mediated neuronal protection. In the present study, we found in cultured neurons exposed to glutamate, that phosphorylation at Ser473 was transiently induced, but the level of phosphorylation at Thr308 and Akt activity were unchanged. Inhibition of phosphoinositide 3-kinase with LY294002 decreased phosphorylation and Akt activity, however, pretreatment with LY294002 did not affect glutamate toxicity. Our findings suggested that the endogenous Akt pathway does not play a crucial role in cell survival after exposure to glutamate.
Neuroscience Letters 12/2002; 333(3):187-90. · 2.11 Impact Factor
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ABSTRACT: Although accumulating evidence indicates that cAMP response element binding protein (CREB) phosphorylation is upregulated after cerebral ischemia, it remains uncertain whether CREB phosphorylation induced after ischemia leads to CRE-mediated gene transcription and is involved in cell survival or not. Using CRE-LacZ transgenic mice, we demonstrated that CRE-mediated gene expression was found in a subset of pCREB-positive neurons after transient global and focal cerebral ischemia and in cultured neurons after exposure to glutamate. Treatment with CRE-decoy oligonucleotide suppressed upregulation of BCL-2 expression and accelerated neuronal damage after exposure to glutamate. CRE-mediated gene expression occurs in neurons after metabolic stresses and exerts its neuroprotective action through production of survival-promoting molecules such as anti-apoptotic protein BCL-2.
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