scholarly journals Hypothalamic IGF-I Gene Therapy Prolongs Estrous Cyclicity and Protects Ovarian Structure in Middle-Aged Female Rats

Endocrinology ◽  
2013 ◽  
Vol 154 (6) ◽  
pp. 2166-2173 ◽  
Author(s):  
Silvia S. Rodríguez ◽  
José I. Schwerdt ◽  
Claudio G. Barbeito ◽  
Mirta A. Flamini ◽  
Ye Han ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Positive Feedback ◽  
Female Rats ◽  
Middle Aged ◽  
Ovarian Histology ◽  
Igf I ◽  
Estrous Cyclicity ◽  
Ovarian Structure ◽  
I Gene ◽  
Estrogen Positive Feedback

Abstract There is substantial evidence that age-related ovarian failure in rats is preceded by abnormal responsiveness of the neuroendocrine axis to estrogen positive feedback. Because IGF-I seems to act as a permissive factor for proper GnRH neuronal response to estrogen positive feedback and considering that the hypothalamic content of IGF-I declines in middle-aged (M-A) rats, we assessed the effectiveness of long-term IGF-I gene therapy in the mediobasal hypothalamus (MBH) of M-A female rats to extend regular cyclicity and preserve ovarian structure. We used 3 groups of M-A rats: 1 group of intact animals and 2 groups injected, at 36.2 weeks of age, in the MBH with either a bicistronic recombinant adeno-associated virus (rAAV) harboring the genes for IGF-I and the red fluorescent protein DsRed2, or a control rAAV expressing only DsRed2. Daily vaginal smears were taken throughout the study, which ended at 49.5 weeks of age. We measured serum levels of reproductive hormones and assessed ovarian histology at the end of the study. Although most of the rats injected with the IGF-I rAAV had, on the average, well-preserved estrous cyclicity as well as a generally normal ovarian histology, the intact and control rAAV groups showed a high percentage of acyclic rats at the end of the study and ovaries with numerous enlarged cysts and scarce corpora lutea. Serum LH was higher and hyperprolactinemia lower in the treated animals. These results suggest that overexpression of IGF-I in the MBH prolongs normal ovarian function in M-A female rats.

scholarly journals IGF-I Gene Therapy in Aging Rats Modulates Hippocampal Genes Relevant to Memory Function

2017 ◽  
Vol 73 (4) ◽  
pp. 459-467 ◽  
Author(s):  
Joaquín Pardo ◽  
Martin C Abba ◽  
Ezequiel Lacunza ◽  
Olalekan M Ogundele ◽  
Isabel Paiva ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Memory Function ◽  
Aging Rats ◽  
Igf I ◽  
I Gene

scholarly journals The Excitatory Peptide Kisspeptin Restores the Luteinizing Hormone Surge and Modulates Amino Acid Neurotransmission in the Medial Preoptic Area of Middle-Aged Rats

Endocrinology ◽  
2009 ◽  
Vol 150 (8) ◽  
pp. 3699-3708 ◽  
Author(s):  
Genevieve Neal-Perry ◽  
Diane Lebesgue ◽  
Matthew Lederman ◽  
Jun Shu ◽  
Gail D. Zeevalk ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Preoptic Area ◽  
Gaba Release ◽  
Medial Preoptic Area ◽  
Aged Rats ◽  
Middle Aged ◽  
Lh Surge ◽  
Age Related ◽  
Lh Release ◽  
Estrogen Positive Feedback

Reproductive success depends on a robust and appropriately timed preovulatory LH surge. The LH surge, in turn, requires ovarian steroid modulation of GnRH neuron activation by the neuropeptide kisspeptin and glutamate and γ-aminobutyric acid (GABA) neurotransmission in the medial preoptic area (mPOA). Middle-aged females exhibit reduced excitation of GnRH neurons and attenuated LH surges under estrogen-positive feedback conditions, in part, due to increased GABA and decreased glutamate neurotransmission in the mPOA. This study tested the hypothesis that altered kisspeptin regulation by ovarian steroids plays a role in age-related LH surge dysfunction. We demonstrate that middle-aged rats exhibiting delayed and attenuated LH surges have reduced levels of Kiss1 mRNA in the anterior hypothalamus under estrogen-positive feedback conditions. Kisspeptin application directly into the mPOA rescues total LH release and the LH surge amplitude in middle-aged rats and increases glutamate and decreases GABA release to levels seen in the mPOA of young females. Moreover, the N-methyl-d-aspartate receptor antagonist MK801 blocks kisspeptin reinstatement of the LH surge. These observations suggest that age-related LH surge dysfunction results, in part, from reduced kisspeptin drive under estrogen-positive feedback conditions and that kisspeptin regulates GnRH/LH release, in part, through modulation of mPOA glutamate and GABA release.

Effects of IGF-I gene therapy on the injured rat pudendal nerve

2003 ◽  
Vol 14 (1) ◽  
pp. 2-8 ◽  
Author(s):  
J. M. Kerns ◽  
S. Shott ◽  
L. Brubaker ◽  
K. Sakamoto ◽  
J. T. Benson ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Pudendal Nerve ◽  
Igf I ◽  
I Gene

scholarly journals IGF-I: from diagnostic to triple-helix gene therapy of solid tumors.

2002 ◽  
Vol 49 (4) ◽  
pp. 979-990 ◽  
Author(s):  
Ladislas A Trojan ◽  
Piotr Kopinski ◽  
Ming X Wei ◽  
Adama Ly ◽  
Aleksandra Glogowska ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Growth Factor ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Triple Helix ◽  
Human Tumor ◽  
Igf I ◽  
I Gene

Alterations in the expression of growth factors and their receptors are associated with the growth and development of human tumors. One such growth factor is IGF-I (insulin-like growth factor I ), a 70-amino-acid polypeptide expressed in many tissues, including brain. IGF-I is also expressed at high levels in some nervous system-derived tumors, especially in glioblastoma. When using IGF-I as a diagnostic marker, 17 different tumors are considered as expressing the IGF-I gene. Malignant glioma, the most common human brain cancer, is usually fatal. Average survival is less than one year. Our strategy of gene therapy for the treatment of gliomas and other solid tumors is based on: 1) diagnostic using IGF-I gene expression as a differential marker, and 2) application of "triple-helix anti-IGF-I" therapy. In the latter approach, tumor cells are transfected with a vector, which encodes an oligoribonucleotide--an RNA strand containing oligopurine sequence which might be capable of forming a triple helix with an oligopurine and/or oligopyrimidine sequence of the promotor of IGF-I gene (RNA-IGF-I DNA triple helix). Human tumor cells transfected in vitro become down-regulated in the production of IGF-I and present immunogenic (MHC-I and B7 expression) and apoptotic characteristics. Similar results were obtained when IGF-I antisense strategy was applied. In both strategies the transfected cells reimplanted in vivo lose tumorigenicity and elicit tumor specific immunity which leads to elimination of established tumors.

scholarly journals Insulin-Like Growth Factor (IGF)-I Modulates Endothelial Blood-Brain Barrier Function in Ischemic Middle-Aged Female Rats

Endocrinology ◽  
2016 ◽  
Vol 157 (1) ◽  
pp. 61-69 ◽  
Author(s):  
Shameena Bake ◽  
Andre K. Okoreeh ◽  
Robert C. Alaniz ◽  
Farida Sohrabji
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Barrier Function ◽  
Female Rats ◽  
Brain Barrier ◽  
Blue Dye ◽  
Middle Aged ◽  
Blood Brain ◽  
Age Related ◽  
Igf I

Abstract In comparison with young females, middle-aged female rats sustain greater cerebral infarction and worse functional recovery after stroke. These poorer stroke outcomes in middle-aged females are associated with an age-related reduction in IGF-I levels. Poststroke IGF-I treatment decreases infarct volume in older females and lowers the expression of cytokines in the ischemic hemisphere. IGF-I also reduces transfer of Evans blue dye to the brain, suggesting that this peptide may also promote blood-brain barrier function. To test the hypothesis that IGF-I may act at the blood-brain barrier in ischemic stroke, 2 approaches were used. In the first approach, middle-aged female rats were subjected to middle cerebral artery occlusion and treated with IGF-I after reperfusion. Mononuclear cells from the ischemic hemisphere were stained for CD4 or triple-labeled for CD4/CD25/FoxP3 and subjected to flow analyses. Both cohorts of cells were significantly reduced in IGF-I–treated animals compared with those in vehicle controls. Reduced trafficking of immune cells to the ischemic site suggests that blood-brain barrier integrity is better maintained in IGF-I–treated animals. The second approach directly tested the effect of IGF-I on barrier function of aging endothelial cells. Accordingly, brain microvascular endothelial cells from middle-aged female rats were cultured ex vivo and subjected to ischemic conditions (oxygen-glucose deprivation). IGF-I treatment significantly reduced the transfer of fluorescently labeled BSA across the endothelial monolayer as well as cellular internalization of fluorescein isothiocyanate–BSA compared with those in vehicle-treated cultures, Collectively, these data support the hypothesis that IGF-I improves blood-brain barrier function in middle-aged females.

scholarly journals Hypothalamic Insulin-Like Growth Factor-I Receptors Are Necessary for Hormone-Dependent Luteinizing Hormone Surges: Implications for Female Reproductive Aging

Endocrinology ◽  
2010 ◽  
Vol 151 (3) ◽  
pp. 1356-1366 ◽  
Author(s):  
Brigitte J. Todd ◽  
Zaher O. Merhi ◽  
Jun Shu ◽  
Anne M. Etgen ◽  
Genevieve S. Neal-Perry
Keyword(s):  
Young Adult ◽  
Third Ventricle ◽  
Female Rats ◽  
Aged Rats ◽  
Gnrh Neuron ◽  
Middle Aged ◽  
Reproductive Senescence ◽  
Lh Surge ◽  
Neuron Activation ◽  
Igf I

Brain IGF-I receptors are required for maintenance of estrous cycles in young adult female rats. Circulating and hypothalamic IGF-I levels decrease with aging, suggesting a role for IGF-I in the onset of reproductive senescence. Therefore, the present study investigated potential mechanisms of action of brain IGF-I receptors in the regulation of LH surges in young adult and middle-aged rats. We continuously infused IGF-I, the selective IGF-I receptor antagonist JB-1, or vehicle into the third ventricle of ovariectomized young adult and middle-aged female rats primed with estradiol and progesterone. Pharmacological blockade of IGF-I receptors attenuated and delayed the LH surge in young adult rats, reminiscent of the LH surge pattern that heralds the onset of reproductive senescence in middle-aged female rats. Infusion of IGF-I alone had no effect on the LH surge but reversed JB-1 attenuation of the surge in young females. In middle-aged rats, infusion of low doses of IGF-I partially restored LH surge amplitude, and infusion of JB-1 completely obliterated the surge. Intraventricular infusion of IGF-I or JB-1 did not modify pituitary sensitivity to exogenous GnRH or GnRH peptide content in the anterior or mediobasal hypothalamus in either young or middle-aged rats. These findings support the hypothesis that brain IGF-I receptor signaling is necessary for GnRH neuron activation under estrogen-positive feedback conditions and that decreased brain IGF-I signaling in middle-aged females contributes, in part, to LH surge dysfunction by disrupting estradiol-sensitive processes that affect GnRH neuron activation and/or GnRH release.

scholarly journals Sensitivity to exogenous GH and reversibility of the reduced IGF-I gene expression in aging rats

2001 ◽  
pp. 73-85 ◽  
Author(s):  
B Velasco ◽  
L Cacicedo ◽  
E Melian ◽  
G Fernandez-Vazquez ◽  
F Sanchez-Franco
Keyword(s):  
Gene Expression ◽  
Young Adult ◽  
Mrna Level ◽  
Young Group ◽  
Male Rats ◽  
Middle Aged ◽  
Igf I ◽  
Old Rats ◽  
Rhgh Treatment ◽  
I Gene

BACKGROUND: IGF-I gene expression and IGF-I plasma concentration decline with age. A decreased sensitivity to GH has been suggested to be a contributory mechanism to this, in addition to attenuated GH secretion. OBJECTIVE: This study focuses on the sensitivity to exogenous GH and the reversibility of the reduced IGF-I gene expression in aging male rats. DESIGN: Three groups of male Wistar rats aged 3 months (young adult), 11 months (middle-aged) and 27 months (old), received recombinant human GH (rhGH) (150 microg/12 h s.c.) for seven consecutive days. RESULTS: This rhGH treatment completely reversed plasma immunoreactive IGF-I (IR-IGF-I) and hepatic IGF-I mRNA levels in 11-month-old and 27-month-old animals to the levels of the young group of animals. The sensitivity in the old group (percentage of increment after the same or lower dose of rhGH per body weight) was increased for both parameters; serum IGF-I increment: 15% in 3-month-old, 42.6% in 11-month-old and 119.1% in 27-month-old rats; and hepatic IGF-Ib mRNA increase: 45% in 3-month-old, 27.8% in 11-month-old and 64.3% in 27-month-old rats. IGF binding protein-3 (IGFBP-3) mRNA level in the liver was significantly decreased in the old group and only a partial reversion occurred in this group after rhGH treatment; the percentage of increment was also higher in the old group of rats. In extrahepatic tissues IGF-I mRNA was not significantly different in the kidney and the testis of the three groups, and the rhGH treatment produced a significant and similar increase of IGF-I mRNA level in the kidney of the three groups of rats and in the testis of the 27-month-old animals. The GHr/GHBP mRNA remained unchanged in the liver and in the kidney or the testis of the three groups, and was not influenced by the rhGH treatment. Exogenous rhGH decreased pituitary GH mRNA accumulation in a more intense manner in the old group versus control of each group: young adult, 25%; middle-aged, 41.2%; and old rats, 55%. The action of rhGH on pituitary immunoreactive GH (IR-GH) content was only significantly evident in the young group. CONCLUSIONS: These results establish that exogenous rhGH recovers the attenuated liver IGF-I gene expression and the diminished plasma IR-IGF-I in old rats to the levels of young adult animals. They also indicate that the hepatic and extrahepatic (kidney and testis) sensitivity to one established dose per weight of exogenous rhGH is not altered in old animals, or could be potentially increased in some tissues.

Chronic blockade of brain IGF-I receptors suppresses food intake and estrous cyclicity in female rats

2006 ◽  
Vol 27 (1) ◽  
pp. 7
Author(s):  
Brigitte J. Todd ◽  
Gary J. Schwartz ◽  
Anne M. Etgen
Keyword(s):  
Food Intake ◽  
Female Rats ◽  
Igf I ◽  
Estrous Cyclicity
Sign in / Sign up

Export Citation Format

Share Document