| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
NEPPs, prostaglandin (PG) analogs with a cross-conjugated dienone structure, can suppress the death of neuronal cells induced by oxidative stress. We conducted a structure-activity relationship study on this activity with various derivatives and elaborated a potent analog, NEPP11, which revealed an enhanced activity and lower toxicity. NEPP11 was proved to be effective for the protection of brain neurons against ischemia in mice by a dose-dependent manner.,Analyses of the expression levels of intracellular proteins and messenger RNAs indicated that induction of heme oxygenase-1 (HO-1), a stress-induced protein, by NEPP was highly responsible for the neuroprotective activity. In order to identify the intracellular target molecule (receptor) of NEPP associated with the induction of HO-1, a molecular probe attaching a biotin moiety was designed and synthesized. Application of the probe to an affinity labeling experiment resulted in the detection of some binding proteins. Furthermore, seve
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ral novel J-type PG analogs were synthesized and their biological activities were assayed. The PGs exerted suppressive activities similar to but somewhat weaker than NEPPs against neuronal cell death. We also attempted to develop a PET tracer to' analyze the localization and dynamic ovement of NEPP in brain by positron emission tomography (PET) for in vivo brain researches. Some candidates incorporating 76Br, a positron emitting nucleus with relatively long half-life, were designed and the corresponding non-radio-labeled derivatives were prepared. The cold compounds exhibited similar effects to NEPPs in the protection of neuronal cells against oxidative stress. Moreover, a stannylated precursor of a PET tracer candidate was successfully synthesized and the methodology for the induction of bromine into the precursor was established under cold conditions. In addition, a structure-activity study on the inhibition of IKKβ, a kinase that regulates the activity of a transcription factor NF-κB, resulted in the elaboration of a promising NEPP analog with improved inhibitory activity. Less
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