| Co-Investigator(Kenkyū-buntansha) |
YOSHIOKA Mitsuhiro Hokkaido Univ., Neuropharmacology, Professor, 大学院・医学研究科, 教授 (40182729)
SAKUMA Ichiro Hokkaido Univ., Cardiovascular Med., Assistant Professor, 医学部附属病院, 講師 (40260393)
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| Budget Amount *help |
¥10,000,000 (Direct Cost: ¥10,000,000)
Fiscal Year 2004: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2003: ¥6,900,000 (Direct Cost: ¥6,900,000)
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| Research Abstract |
Attention-deficit/hyperactivity disorder (AD/HD) is the most common cognitive disorder among children characterized by inattention, hyperactivity and impulsivity. Its pathogenesis is implicated with gender and vascular dysfunction, since reduction of cerebral blood flow in the frontal cortex/striatum and male preponderance are common, however, mechanism(s) that underlie abnormalities of cerebral blood flow and its relationship with male predominance have not been studied. Thus, we measured levels of key angiogenic factors [vascular endothelial growth factor (VEGF), VEGF receptors (KDR, Fit-1), endothelial nitric oxide synthase (eNOS)], sex steroid receptors [Estrogen receptors (ER) alpha and beta, androgen receptor (AR)] and aromatase P450 (aromatase) in the frontal cortex of male juvenile (6 week-old) stroke-prone spontaneously hypertensive rats (SHRSP), which manifests behavioral abnormalities similar to AD/HD patients, using Western blotting and immunohistochemistry. Aged-matched Wi
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star-Kyoto rats (WKY) were used as genetic controls. The effects of gonadectomy and hormone replacement (HR) on these molecules and cognitive behavior (Y-maze alternation behavior) were also studied. Levels of VEGF, VEGF receptors (KDR and Fit-1), eNOS, ERα and aromatase were significantly down-regulated in sham SHRSP compared to age-matched WKY, effects which were attenuated by administration of either exogenous estrogen, testosterone, AR antagonist (flutamide) or gonadectomy. In contrast, AR levels were up-regulated in sham SHRSP and castrated SHRSP treated with DHT, but down-regulated by castration and sham SHRSP treated with estrogen. Gonadectomy also ameliorated alternation behavior in sham SHRSP. We postulate that high DHT levels in the frontal cortex of juvenile SHRSP leads to the down-regulation of VEGF and the associated molecules (KDR, Fit-1, eNOS), and distortion in expression of sex steroid receptors (ER, AR) and aromatase in male SHRSP. Thus, alternations in gonadal hormone metabolism and VEGF angiogenic signaling cascade could consequently lead to a reduction in cerebral blood flow, which in turn may impair cognition. Less
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