title: Insulin-like growth factor-I regulates LH release by modulation of kisspeptin and NMDA-mediated neurotransmission in young and middle-aged female rats.
abstract: This study investigated potential mechanisms by which age and IGF-I receptor (IGF-Ir) signaling in the neuroendocrine hypothalamus affect estradiol-positive feedback effects on GnRH neuronal activation and on kisspeptin and N-methyl-D-aspartate (NMDA)-induced LH release and on the abundance of NMDA receptor subunits Nr1 and Nr2b and Kiss1r transcript and protein in the hypothalamus of young and middle-aged female rats. We infused vehicle, IGF-I, or JB-1, a selective antagonist of IGF-Ir, into the third ventricle of ovariectomized female rats primed with estradiol or vehicle and injected with vehicle, kisspeptin (3 or 30 nmol/kg), or NMDA (15 or 30 mg/kg). Regardless of dose, NMDA and kisspeptin resulted in significantly more LH release, GnRH/c-Fos colabeling, and c-Fos immunoreative cells in young than in middle-aged females. Estradiol priming significantly increased Kiss1r, Nr1, and Nr2b receptor transcript and protein abundance in young but not middle-aged female hypothalamus. JB-1 attenuated kisspeptin and NMDA-induced LH release, numbers of GnRH/c-Fos and c-Fos cells, and Kiss1r, Nr1, and Nr2b transcript and protein abundance in young females to levels observed in middle-aged females. IGF-I significantly enhanced NMDA and kisspeptin-induced LH release in middle-aged females without increasing numbers of GnRH/c-Fos or c-Fos immunoreactive cells. IGF-I infusion in middle-aged females also increased Kiss1r, Nr1, and Nr2b protein and transcript to levels that were equivalent to young estradiol-primed females. These findings indicate that age-related changes in estradiol-regulated responsiveness to excitatory input from glutamate and kisspeptin reflect reduced IGF-Ir signaling.
authors.affiliation: Department of Obstetrics and Gynecology (G.N.-P., J.S., Y.S., A.M.E.) and the Dominick P. Purpura Department of Neuroscience (G.N.-P., A.M.E.), Albert Einstein College of Medicine, Bronx, New York 10461; and Internal Medicine of Tongji Hospital (D.Y.), Huazhong University of Science and Technology, Wuhan 430030, R.P. China.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Neal-Perry
authors.forename: Dachun
authors.initials: D
authors.lastname: Yao
authors.forename: Jun
authors.initials: J
authors.lastname: Shu
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.forename: Anne M
authors.initials: AM
authors.lastname: Etgen
mesh_terms: D000375:Aging; D000818:Animals; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007030:Hypothalamo-Hypophyseal System / Q000254:growth & development / Q000378:metabolism; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D057967:Infusions, Intraventricular; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059648:Kisspeptins / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000378:metabolism*; D016202:N-Methylaspartate / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D055099:Neuroendocrine Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000074502:Receptors, Kisspeptin-1; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: C491406:Kiss1 protein, rat; C492247:Kiss1r protein, rat; D059648:Kisspeptins; D009419:Nerve Tissue Proteins; D009842:Oligopeptides; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D016194:Receptors, N-Methyl-D-Aspartate; C548904:insulin-like growth factor-1, rat; C411572:H 1356; D016202:N-Methylaspartate; D007334:Insulin-Like Growth Factor I; D007986:Luteinizing Hormone; D017526:Receptor, IGF Type 1