2004 Fiscal Year Final Research Report Summary
Development of the Treatment of Amyotrophic Lateral Sclerosis (ALS) with Neural Stem Cells
| Project/Area Number |
14570598
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | Okayama University |
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Principal Investigator |
NAGANO Isao Okayama University, Hospital, Instructor, 医学部・歯学部附属病院, 講師 (80335603)
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| Co-Investigator(Kenkyū-buntansha) |
ABE Koji Okayama University, Graduate School of Medicine and Dentistry, Professor, 大学院・医歯学総合研究科, 教授 (20212540)
HONMOU Osamu Sapporo Medical University, Instructor, 医学部, 講師 (90285007)
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| Project Period (FY) |
2002 – 2004
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| Keywords | ALS / SOD1 / VEGF / hypoxia / Flk-1 / IGF-1 / neural precursor cell |
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| Research Abstract |
At first, we examined the induction of vascular endothelial growth factor (VEGF) in the G93A SOD1-mutant mice exposed to systemic hypoxia. Baseline expression of VEGF was increased in the SOD1-mutant mice compared with wild-type littermates. VEGF expression in the mutant mice was hardly induced by hypoxia, in contrast to the wild-type littermates where approximately nine-fold increase in VEGF expression was observed, indicating that the response of VEGF to hypoxia is impaired in the SOD1-mutant mice. We next investigated whether reduction of Flk-1, one of VEGF receptors, could induce motor neuron loss by inhibiting the Flk-1 expression using antisense oligodeoxynucleotides (AS-ODNs). Intrathecal infusion of AS-ODNs for 7 days suppressed almost completely Flk-1 expression in the lumbar segment, and was followed by a hypoxic challenge for 1 hour that was repeated for 7 more days. We observed that reduced Flk-1 expression and hypoxic challenge for 7 days resulted in 〜50% loss of motor neurons, in which the activation of Akt and ERK, that is increased levels of phosphorylated-Akt and of phosphorylated-ERK by hypoxia, was markedly inhibited. These results suggest that VEGF exerts its protective effect on motor neurons against hypoxia-induced toxicity by the Flk-1 receptor.
To examine the possible effectiveness of IGF-1 in a mouse model of familial ALS, the G93A SOD1-mutant mice were treated by continuous IGF-1 delivery into the intrathecal space of the lumbar spinal cord. We found that the intrathecal administration of IGF-1 improved motor performance, delayed the onset of clinical disease, and extended survival in the G93A transgenic mice. Next, we performed a double blind clinical trial to assess the effect of intrathecal administration of IGF-1 on disease progression in patients with ALS. We found that the intrathecal administration of IGF-1 had a modest but significant beneficial effect in ALS patients without any serious adverse effects.
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[Journal Article] Reduction of a VEGF receptor, Flk-1, by antisense oligonucleotides induces motor Neuron death in rat spinal cord exposed to hypoxia2005
Author(s)
Shiote M, Nagano I, Ilieva H, Murakami T, Narai H, Ohta Y, Nagata T, Shoji M, Abe K
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Journal Title
Neuroscience 132
Pages: 175-182
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Reduction of a VEGF receptor, Flk-1, by antisense oligonucleotides induces motor neuron death in rat spinal cord exposed to hypoxia.2005
Author(s)
Shiote M, Nagano I, Ilieva H, murakami T, Narai H, Ohta Y, Nagata T, Shoji M, Abe K.
-
Journal Title
Neuroscience 132
Pages: 175-182
Description
「研究成果報告書概要(欧文)」より
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