| Co-Investigator(Kenkyū-buntansha) |
IWANAGA Rikako Department of Pediatrics and Child Health, Kurume University school of Medicine., 医学部, 助手 (20258396)
KOGA Atsuko Department of Pediatrics and Child Health, Kurume University school of Medicine., 医学部, 助手 (00140707)
TOKUNAGA Yasuyuki Department of Pediatrics and Child Health, Kurume University school of Medicine., 医学部, 助手 (60227585)
KOGA Hiroyasu Department of Pediatrics and Child Health, Kurume University school of Medicine., 医学部, 助手 (60312146)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1999: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Mitochondrial myopathy, which is a multisystem and a maternally inherted disorders, characterized by an abnormality in the human mitochondrial DNA, point mutation, deletion or duplication. Among those, a point mutation in the mitochondrial tRNALeu (UUR) gene is the most frequent genetical abnormality seen in the patient. MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) is characterized by stroke before 20 years old, is a maternally-inherited mitochondrial multisystem disorder. Mitochondrial angiopathy demonstrating degenerative change with increased abnormal mitochondria in the endothelial cells of intramuscular small arteries and arterioles have been reported in many MELAS patients. However, the primary cause of the young MELAS strokelike episodes, either mitochondrial cytopathy or angiopathy, or both is still controversial. Since abnormal mitochondria generates superoxide anion, we hypothesized that vascular complications in MELAS may be associ
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ated with endothelial dysfunction caused by oxidative stress. Nine patients were clinically, muscle-pathologically or genetically diagnosed as MELAS.Six patients have an A3243G mutation, one patient has a T3271C mutation in the mitochondrial tRNALeu (UUR) gene, and two patients have not been found their genetic abnormality. In this study, we examined flow-mediated vasodilatation, as a non-invasive measure of endothelial function, and effects of an antioxidant, vitamin *n patients with MELAS.We analyzed the correlationship between the amount of point mutation in the endothelial cell and the endothelial function by single-cell PCR analysis. We also studied the pharmacological effect on the clinical course, and biochemical parameters after administration of L-arginine to a patient in the acute phase of stroke on three separated occasions and, and on the functional aspects of the cerebral hemodynamics using single photon emission computed tomography (SPECT). Flow-mediated vasodilatation was significantly less (10% of the age-matched controls) in MELAS patients. Endothelium-dependent vasodilatation induced by glyceryl trinitrate was also impaired. Vitamin C administration significantly restored flow-mediated dilation and glyceryl trinitrate-induced vasodilatation to near-normal levels in MELAS but did not affect them in controls. After the administration of L-arginine, all the symptoms of the patient suggesting the strokelike episode were clinically improved. On SPECT using ECD, the intracranial hemodynamics were also improved in the ischemic area (in the left temporal lobe), but unchanged in the brain stem (thalamus). There are clear inverse correlationships between the amount of point mutation and the capacity of endothelial dependent-vasodilatation in the endothelial cells. Our data demonstrated that angiopathy seen in MELAS involved abnormality in the capacity of vasodilatation in the endothelial system, which may play an important role in causing strokelike episodes in this disorder. Less
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