Basic research on the diagnosis and therapy for abnormal brain aging caused by oxidative stress.

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As a marker of increased oxidative stressin the brain of Senescence Accerelated Model mice P8 prone (SAMP8), mitochnodrial DNA deletion was evaluatedusing polymerase chain reaction (PCR). In addition, responsible site in mitochondrial electron transport chain was identified using mitochondrial fraction isolated from SAMP8 brain. In SAMP8 brain, significant increase in mitochondrial DNA deletion was found when compared with resistant prone (SAMR1) brain, even in pre-symptomatic young age. In SAMP8 brain, hyper activity of mitohcondrial respiration with lower respiration control ration than SAMR1. Thus, it can be said that an inefficient hyperactive state exists in the mitochondrial electron transport chain before the age-associated dysfunction develops.Using SAMP8 and SAMR1, the possibility of oxidative stress diagnosis in the brain was clarified using positron emitting radiopharmaceutical, Cu-ATSM.In SAMP8 brain, a novel hypoxia marker Cu-ATSM, which can detect the failure of electron transport using positron emission tomography (PET), highly retained than in SAMR1.Base on these finding, pre-clinical studies were started under the guide line of the Ethical Committee of our university. In normal volunteers, Cu-ATSM showed no significant accumulation in normal tissues, except for metabolic excretion organs, as well as no apparent side-effect. Then, as a first clinical trial, ischemic heart disease and tumor patients were diagnosed and clear image of unstable angina and lung tumor could be obtained.Independent from these findings, we found the interpatient differences in the brain accumulation of Cu-PTSM, a derivative of Cu-ATSM in various brain diseases. Possible relationship between mental levels and Cu-ATSM accumulation will be a next focus of the study.