Gonadal Hormones And Frontocortical Expression Of Vascular Endothelial Growth Factor In Male Stroke-prone, Spontaneously Hypertensive Rats, A Model For Attention-deficit/hyperactivity Disorder
aged female rats; animal-model; central-nervous-system; cerebral-blood-flow; computed tomography; deficit-hyperactivity-disorder; emission; Endocrinology & Metabolism; estrogen-receptor-alpha; in-situ hybridization; insulin-resistant; messenger-ribonucleic-acid; stage
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.
Jesmin S; Togashi H; Sakuma I; Mowa C N; Ueno K I; Yamaguchi T; Yoshioka M; Kitabatake A
Endocrinology
2004
2004-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1210/en.2004-0487" target="_blank" rel="noreferrer noopener">10.1210/en.2004-0487</a>
Characterization Of Regional Cerebral Blood Flow And Expression Of Angiogenic Growth Factors In The Frontal Cortex Of Juvenile Male Shrsp And Shr
abnormalities; AD/HD; angiogemic factor; animal-model; attention-deficit/hyperactivity; brain; children; deficit-hyperactivity-disorder; disorder; frontal cortex; Neurosciences & Neurology; nitric-oxide; NOS isoform; regional cerebral blood flow; spontaneously hypertensive-rats; stroke-prone; vegf
Attention-deficit/hyperactivity disorder (AD/HD) is a common pediatric behavioral disorder associated with male preponderance and reduction of regional cerebral blood flow (rCBF). However, lack of an appropriate animal model exhibiting appropriate AD/HD symptoms stands in the way of studying mechanism(s) underlying reduced rCBF and male preponderance. Our group has been investigating the suitability of juvenile male stroke-prone spontaneously hypertensive rats (SHRSP), a substrain of the commonly used AD/HD animal model SHR, as a model for AD/HD because, unlike SHR, SHRSP displays cognitive impairment and male preponderance. Our more recent studies revealed alterations in the synthesis of sex steroid hormones and angiogenic factors in the frontal cortex of male SHRSP compared to the genetic control WKY. Based on these observations, the present study utilizes laser-Doppler flowmetry, histochemistry, enzyme immunoassay, immunoblotting, and real-time PCR to characterize and compare the patterns of regional cerebral blood flow and synthesis of angiogenic molecules [basic fibroblast growth factor; nitric oxide synthase isoforms (endothelial, neuronal and inducible); vascular endothelial growth factor (VEGF) and its signaling molecules VEGF receptors, phosphorylated Akt, endothelial nitric oxide synthase eNOS] between male SHRSP and SHR. Overall, consistent with our previous data showing alteration in VEGF/Akt/NO signaling, there was a marked reduction in the profile of rCBF (35%) and angiogenic factors of SHRSP, compared to age-matched genetic control Wistar-Kyoto rats (WKY) and SHR. We conclude that, unlike SHR, the profiles of rCBF and angiogenic factors in SHRSP are altered in juvenile male. Thus, SHRSP appears to be a more suitable animal model for studying changes in rCBF in AD/HD. (C) 2004 Elsevier B.V. All rights reserved.
Jesmin S; Togashi H; Mowa C N; Ueno K; Yamaguchi T; Shibayama A; Miyauchi T; Sakuma I; Yoshioka M
Brain Research
2004
2004-12
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.brainres.2004.10.004" target="_blank" rel="noreferrer noopener">10.1016/j.brainres.2004.10.004</a>