Differential regulation of gonadotropin-releasing hormone (GnRH) receptor expression in the posterior mediobasal hypothalamus by steroid hormones: implication of GnRH neuronal activity

Seong, Jae Young; Kang, Sang Soo; Kam, Kyung-Yoon; Han, Young-Goo; Kwon, Ho; Ryu, Kyungza; Kim, Kyungjin

doi:10.1016/s0169-328x(97)00297-0

Cited by 34 publications

(29 citation statements)

References 35 publications

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“…Its actions appear to include the ultrashort feedback regulation of GnRH secretion, as indicated by the single-cell RT-PCR discovery of GnRH-R expression in GnRH neurones [41,42,43]. In the context of the present findings, it is noteworthy that previous studies involving ligand binding, immunohistochemistry, in situ hybridisation histochemistry or transgenic animals [44,45,46,47,48] have identified GnRH-R-expressing neurones in the rodent RP3V and Arc, sites which contain very few GnRH neurones in those animals; a neurotransmitter phenotype for these GnRH-R-positive cells remains to be determined.…”

Section: Discussionsupporting

confidence: 50%

Gonadotropin-Releasing Hormone Neurones Innervate Kisspeptin Neurones in the Female Mouse Brain

Kalló

Vida²,

Bardóczi³

et al. 2013

Neuroendocrinology

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Kisspeptin (KP) neurones in the rostral periventricular area of the third ventricle (RP3V) and arcuate nucleus (Arc) are important elements in the neuronal circuitry regulating gonadotropin-releasing hormone (GnRH) secretion. KP and co-synthesised neuropeptides/neurotransmitters act directly on GnRH perikarya and processes. GnRH neurones not only form the final output pathway regulating the reproductive functions of the anterior pituitary gland, but also provide neuronal input to sites within the hypothalamus. The current double-label immunohistochemical studies investigated whether GnRH-immunoreactive (IR) projections to the RP3V and/or Arc establish morphological connections with KP-IR neurones at these sites. To optimise visualisation of KP immunoreactivity in, respectively, the RP3V and Arc, ovariectomised (OVX) oestrogen-treated and OVX oil-treated female mice were studied. Confocal laser microscopic analysis of immunofluorescent specimens revealed GnRH-IR axon varicosities in apposition to approximately 25% of the KP-IR neurones in the RP3V and 50% of the KP-IR neurones in the Arc. At the ultrastructural level, GnRH-IR neurones were seen to establish asymmetric synaptic contacts, which usually reflect excitatory neurotransmission, with KP-IR neurones in both the RP3V and Arc. Together with previous data, these findings indicate reciprocal connectivity between both of the KP cell populations and the GnRH neuronal system. The functional significance of the GnRH-IR input to the two separate KP cell populations requires electrophysiological investigation.

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Section: Discussionsupporting

confidence: 50%

Gonadotropin-Releasing Hormone Neurones Innervate Kisspeptin Neurones in the Female Mouse Brain

Kalló

Vida²,

Bardóczi³

et al. 2013

Neuroendocrinology

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“…To determine whether the deslorelindocetaxel conjugate is indeed effective via LHRH-R, LNCaP and PC-3 cells were treated with deslorelin-docetaxel conjugate following pretreatment with AON against the LHRH-R. Previous studies from our laboratory have used the AON approach to selectively reduce LHRH-R expression (29). Using this AON, previous studies have shown a decrease in the LHRH-R mRNA expression by ∼73 ± 10.2% and LHRH-R protein expression by 42 ± 4.8% in a lung cancer cell line (23).…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorothioated antisense oligonucleotide (AON) and sense oligonucleotide (SON) directed against the LHRH-R, previously validated by Koushik et al (23) for reducing LHRH-R expression, were synthesized for this purpose (29). Briefly, both LNCaP and PC-3 cells plated in six-well plates were treated with 10 μmol/L AON or SON and Lipofectin (10 μg/mL) in serum-free medium for 24 h, after which the cells were placed in 2% serum-containing medium for 12 h. Cells that were not pretreated were used as controls.…”

Section: Molecular Cancer Therapeuticsmentioning

confidence: 99%

Luteinizing hormone-releasing hormone receptor–targeted deslorelin-docetaxel conjugate enhances efficacy of docetaxel in prostate cancer therapy

Sundaram

Durairaj

Kadam

et al. 2009

Molecular Cancer Therapeutics

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Docetaxel, a chemotherapeutic agent currently used for improving survival of prostate cancer patients, suffers from low therapeutic index. The objective of this study was to prepare a new docetaxel derivative conjugated to deslorelin, a luteinizing hormone-releasing hormone (LHRH) superagonist, and to determine whether it enhances docetaxel potency in vitro and in vivo. Because docetaxel is not amenable for conjugation with peptides, we introduced a -COOH group in docetaxel, forming docetaxel-hemiglutarate, and subsequently conjugated this to serine in deslorelin, forming deslorelin-docetaxel. Fouriertransform IR, 1 H-nuclear magnetic resonance, and liquid chromatography-mass spectrometry analyses confirmed deslorelin-docetaxel formation. Antiproliferative efficacy in LNCaP and PC-3 cell lines over 24, 48, and 72 hours exhibited the order deslorelin-docetaxel > docetaxel, whereas deslorelin alone had no effect, with deslorelindocetaxel potency being 15-fold greater than docetaxel at 72 h. Further, cells pretreated with antisense oligonucleotide against LHRH receptor exhibited decreased deslorelin-docetaxel efficacy, without any change in docetaxel efficacy. Thus, deslorelin-docetaxel efficacy is likely mediated via LHRH receptor. Cell cycle analysis showed that docetaxel treatment led to arrest in G 2 -M phase, whereas deslorelin-docetaxel treatment allowed greater progression to apoptosis in both cell lines, with deslorelin-docetaxel exerting 5-fold greater apoptosis compared with docetaxel in prostate cancer cell lines. Antitumor efficacy studies in PC-3 prostate xenograft-bearing mice indicated the efficacy order deslorelin-docetaxel > docetaxel ≫ deslorelin > PBS, with deslorelin-docetaxel exerting 5.5-fold greater tumor growth inhibition than docetaxel alone. Thus, deslorelin-docetaxel prepared in this study retains pharmacologic effects of both docetaxel and deslorelin while enhancing the antiproliferative, apoptotic, and antitumor efficacy of docetaxel by several folds in prostate cancer therapy.

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“…Other studies have shown that GnRH receptors are widely distributed throughout the brain, and that their density and mRNA levels fluctuate during the estrous cycle (40,41). Considerable overlapping of the brain areas that contain GnRH-producing cells, and those that exhibit expression of GnRH receptor mRNA, has been reported (42).…”

Section: Discussionmentioning

confidence: 99%

Autocrine Regulation of Gonadotropin-Releasing Hormone Secretion in Cultured Hypothalamic Neurons

et al. 1999

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Episodic hormone secretion is a characteristic feature of the hypothalamo-pituitary-gonadal system, in which the profile of gonadotropin release from pituitary gonadotrophs reflects the pulsatile secretory activity of GnRH-producing neurons in the hypothalamus. Pulsatile release of GnRH is also evident in vitro during perifusion of immortalized GnRH neurons (GT1-7 cells) and cultured fetal hypothalamic cells, which continue to produce bioactive GnRH for up to 2 months. Such cultures, as well as hypothalamic tissue from adult rats, express GnRH receptors as evidenced by the presence of high-affinity GnRH binding sites and GnRH receptor transcripts. ]GnRH caused a prominent increase in GnRH release. In perifused hypothalamic cells and GT1-7 cells, treatment with the GnRH receptor agonist, des-Gly 10 -[D-Ala 6 ]GnRH N-ethylamide, reduced the frequency and increased the amplitude of pulsatile GnRH release, as previously observed in GT1-7 cells. In contrast, exposure to the GnRH antagonist analogs abolished pulsatile secretion and caused a sustained and progressive increase in GnRH release. These findings have demonstrated that GnRH receptors are expressed in hypothalamic GnRH neurons, and that receptor activation is required for pulsatile GnRH release in vitro. The effects of GnRH agonist and antagonist analogs on neuropeptide release are consistent with the operation of an ultrashort-loop autocrine feedback mechanism that exerts both positive and negative actions that are necessary for the integrated control of GnRH secretion from the hypothalamus.

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Differential regulation of gonadotropin-releasing hormone (GnRH) receptor expression in the posterior mediobasal hypothalamus by steroid hormones: implication of GnRH neuronal activity

Cited by 34 publications

References 35 publications

Gonadotropin-Releasing Hormone Neurones Innervate Kisspeptin Neurones in the Female Mouse Brain

Gonadotropin-Releasing Hormone Neurones Innervate Kisspeptin Neurones in the Female Mouse Brain

Luteinizing hormone-releasing hormone receptor–targeted deslorelin-docetaxel conjugate enhances efficacy of docetaxel in prostate cancer therapy

Autocrine Regulation of Gonadotropin-Releasing Hormone Secretion in Cultured Hypothalamic Neurons

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