| Abstract | Attention-deficit/hyperactivity disorder (AD/HD) is a common pediatric behavioral disorder associated, in part, with male preponderance and reduced regional cerebral blood flow (rCBF). However, mechanism(s) underlying male preponderance and reduced rCBF in AD/HD are unclear. The present study profiles the expression of angiogenic and hormonal factors likely to underlie these symptoms using a recently characterized AD/HD animal model, juvenile male stroke-prone spontaneously hypertensive rats (SHRSP). Because vascular endothelial growth factor (VEGF) signaling cascade and gonadal steroids are key regulators of angiogenesis and gender-based behavior, respectively, we profiled their patterns of expression in the frontal cortex of SHRSP to elucidate their roles in the genesis of AD/HD male preponderance and rCBF. Interestingly, levels of VEGF, VEGF receptors (KDR, Flt-1), endothelial nitric oxide synthase, phosphorylated Akt (pAkt), estrogen receptor-alpha, aromatase, and capillary density in sham-operated SHRSP were remarkably down-regulated, whereas androgen receptor levels were up-regulated, compared with age-matched genetic control, Wistar-Kyoto rats. Castration, estrogen, and androgen receptor antagonist (flutamide) counteracted these effects. Dihydrotestosterone, but not testosterone, reversed the beneficiary effects of castration. Estrogen receptor-beta levels remained unchanged in all groups examined. We postulate that changes in androgen metabolism that tend to up-regulate local dihydrotestosterone concentration and diminish estrogen synthesis, in the frontal cortex of juvenile male SHRSP, may lower levels and/or activity of VEGF and its signaling cascade and, subsequently, reduce rCBF. These findings could, in part, help explain the pathogenesis of reduced rCBF and male preponderance in AD/HD. |
| Authors | Subrina Jesmin, Hiroko Togashi, Ichiro Sakuma, Chishimba N Mowa, Ken-Ichi Ueno, Taku Yamaguchi, Mitsuhiro Yoshioka, Akira Kitabatake
(Affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.)
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| Journal | Endocrinology
(Endocrinology)
Vol. 145
Issue 9
Pg. 4330-43
(Sep 2004)
ISSN: 0013-7227 United States |
| PMID | 15178644
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Estrogen Receptor alpha
- Estrogen Receptor beta
- Estrogens
- Gonadal Steroid Hormones
- Proto-Oncogene Proteins
- Receptors, Androgen
- Receptors, Estrogen
- Vascular Endothelial Growth Factor A
- Nitric Oxide
- Dihydrotestosterone
- Testosterone
- Nitric Oxide Synthase
- Nitric Oxide Synthase Type III
- Nos3 protein, rat
- Aromatase
- Vascular Endothelial Growth Factor Receptor-1
- Vascular Endothelial Growth Factor Receptor-2
- Akt1 protein, rat
- Proto-Oncogene Proteins c-akt
- Protein-Serine-Threonine Kinases
|
| Topics |
- Animals
- Aromatase
(genetics)
- Attention Deficit Disorder with Hyperactivity
(physiopathology)
- Capillaries
(physiology)
- Cerebrovascular Circulation
(physiology)
- Dihydrotestosterone
(blood)
- Disease Models, Animal
- Estrogen Receptor alpha
- Estrogen Receptor beta
- Estrogens
(blood)
- Frontal Lobe
(blood supply)
- Gonadal Steroid Hormones
(blood)
- Hypertension
(physiopathology)
- Male
- Nitric Oxide
(metabolism)
- Nitric Oxide Synthase
(genetics)
- Nitric Oxide Synthase Type III
- Protein-Serine-Threonine Kinases
(genetics)
- Proto-Oncogene Proteins
(genetics)
- Proto-Oncogene Proteins c-akt
- Rats
- Rats, Inbred SHR
- Rats, Inbred WKY
- Receptors, Androgen
(genetics)
- Receptors, Estrogen
(genetics)
- Signal Transduction
(physiology)
- Stroke
(physiopathology)
- Testosterone
(blood)
- Vascular Endothelial Growth Factor A
(genetics)
- Vascular Endothelial Growth Factor Receptor-1
(genetics)
- Vascular Endothelial Growth Factor Receptor-2
(genetics)
|
