2002 Fiscal Year Final Research Report Summary
Treatment of neonatal brain damage through regulation of protease-activatred receptor-1.
| Project/Area Number |
13671137
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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 |
Embryonic/Neonatal medicine
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| Research Institution | Kobe University Hospital |
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Principal Investigator |
TSUNEISHI Syuichi Kobe University, University Hospital Assistant Professor, 医学部附属病院, 助手 (10271040)
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| Co-Investigator(Kenkyū-buntansha) |
YOKOYAMA Naoki Kobe University, University Hospital Assistant Professor, 医学部附属病院, 助手 (20314487)
YONETANI Masahiko Kobe University, Graduate School of Medicine Associate Professor, 大学院・医学系研究科, 助教授 (60221678)
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| Project Period (FY) |
2001 – 2002
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| Keywords | hypoxic-ischemic encephalopathy / thrombin / protease-activated receptor-1 / PAR-1 / necrosis / apoptosis / neonatl rat |
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| Research Abstract |
The aim of this study is to determine the efficacy of regulation of thrombin protease-activated receptor-1 against neonatal hypoxic-ischemic (HI) brain damage.
Protease-activated receptor-1 (PAR-1) is a key structure in the balance between serine proteases and its inhibitors, and plays an important role in development and plasticity of the developing brain. A unique artificial peptide, TRAP (thrombin receptor activating peptide), which has an amino acid sequence of SFLLRN, can directly activate PAR-1, We investigated the usefulness of TRAP to prevent neuronal cells from the hypoxic-ischemic (HI) insult in the developing rats. The ontogeny of PAR-1 in the developing rat brain showed that PAR-1 is expressed much at birth- P10, which means significant role on the neurogenesis and glial proliferation.
P7 Sprague-Dawley rats were introduced to the HI loading by the combination of left common carotid artery ligation and the exposure to 8% O_2 for 2 hrs. Low dose TRAP (0.5 μg) administration intracerebroventricularly at 2 hrs before HI insult rescued the CA1 hippocampal nerve cells significantly at P14. High dose TRAP (50 μg) did not rescue the viability of CA1 nerve cells hi contrast. Both the saline and TRAP-50μg groups showed clear DNA ladder formation and positive immunostaining against single-stranded DNA in their hippocampal tissue, suggesting the significant presence of apoptotic nerve cell death.
Adequate activation of PAR-1 using TRAP can inhibit the nerve cell loss against the HI insult in the developing rat brain. This effect is in part dependent on anti-apoptotic function of PAR-1 activation. Regulation of PAR-1 in the developing brain can protect nerve and glial cells through modificating their differentiation.
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