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Effects of Kisspeptin1 on Electrical Activity of an Extrahypothalamic Population of Gonadotropin-Releasing Hormone Neurons in Medaka (Oryzias latipes)  [PDF]
Yali Zhao, Nancy L. Wayne
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0037909
Abstract: Kisspeptin (product of the kiss1 gene) is the most potent known activator of the hypothalamo-pituitary-gonadal axis. Both kiss1 and the kisspeptin receptor are highly expressed in the hypothalamus of vertebrates, and low doses of kisspeptin have a robust and long-lasting stimulatory effect on the rate of action potential firing of hypophysiotropic gonadotropin releasing hormone-1 (GnRH1) neurons in mice. Fish have multiple populations of GnRH neurons distinguished by their location in the brain and the GnRH gene that they express. GnRH3 neurons located in the terminal nerve (TN) associated with the olfactory bulb are neuromodulatory and do not play a direct role in regulating pituitary-gonadal function. In medaka fish, the electrical activity of TN-GnRH3 neurons is modulated by visual cues from conspecifics, and is thought to act as a transmitter of information from the external environment to the central nervous system. TN-GnRH3 neurons also play a role in sexual motivation and arousal states, making them an important population of neurons to study for understanding coordination of complex behaviors. We investigated the role of kisspeptin in regulating electrical activity of TN-GnRH3 neurons in adult medaka. Using electrophysiology in an intact brain preparation, we show that a relatively brief treatment with 100 nM of kisspeptin had a long-lasting stimulatory effect on the electrical activity of an extrahypothalamic population of GnRH neurons. Dose-response analysis suggests a relatively narrow activational range of this neuropeptide. Further, blocking action potential firing with tetrodotoxin and blocking synaptic transmission with a low Ca2+/high Mg2+ solution inhibited the stimulatory action of kisspeptin on electrical activity, indicating that kisspeptin is acting indirectly through synaptic regulation to excite TN-GnRH3 neurons. Our findings provide a new perspective on kisspeptin's broader functions within the central nervous system, through its regulation of an extrahypothalamic population of GnRH neurons involved in multiple neuromodulatory functions.
Effects of the Hormone Kisspeptin on Reproductive Hormone Release in Humans  [PDF]
Joanne L. Calley,Waljit S. Dhillo
Advances in Biology , 2014, DOI: 10.1155/2014/512650
Abstract: The kisspeptins are a family of neuropeptides which act as upstream stimulators of gonadotrophin releasing hormone (GnRH) neurons. Kisspeptin signalling is prerequisite to establishing the normal human reproductive phenotype; loss of function mutations in the KISS1 or KISS1R gene produces normosmic hypogonadotrophic hypogonadism in humans and mice, whilst increased activation of KISS1R causes precocious puberty. Administration of exogenous kisspeptin to human subjects stimulates an acute gonadotrophin rise. Serum kisspeptin levels also markedly increase during pregnancy. The identification of kisspeptin has been one of the biggest discoveries in the field of reproductive endocrinology, since the isolation and sequencing of GnRH in 1977, and has generated a novel research avenue which has received much attention over the past decade. This research has delineated many properties of the KISS1-KISS1R system, but there is still further work to do. Understanding kisspeptin’s role throughout our reproductive lifetime should help us better understand—and therefore treat—disorders of reproductive function. Promisingly, the current data supports the potential to develop kisspeptin based therapies. As an outlook article this paper focusses predominantly on our groups recent investigations into the effects of kisspeptin administration to humans and the potential therapeutic role of kisspeptin. 1. Introduction 1.1. Molecular Structure, Function, and Neuroanatomy of Kisspeptin Kisspeptins are coded for by the KISS1 gene and act via binding with the G-protein coupled receptor 54 (GPR54) also known as the KISS1 receptor (KISS1R). The initial protein product of the KISS1 gene is a 145-amino-acid peptide, a member of the arginine phenylalanine (RF) amide group. It is cleaved into shorter, biologically active peptides known as kisspeptin-54, kisspeptin-14, kisspeptin-13, and kisspeptin-10, where each number corresponds to the number of amino acids and with kisspeptin-10 representing the common C-terminal decapeptide sequence shared by all [1]. Kisspeptin expression has been identified in multiple tissues, including pancreas, adipose tissue, gonads, and placenta [1–3]; however, its main functional role is mediated by its expression within the central nervous system. Kisspeptin is produced by neurones in the infundibular (arcuate) nucleus of the hypothalamus. These neurons have been shown to have direct afferent connections onto GnRH neurons of the mediobasal hypothalamus in humans, and kisspeptin activity has been shown to induce upregulation of KISS1R within these GnRH
Inotropic Action of the Puberty Hormone Kisspeptin in Rat, Mouse and Human: Cardiovascular Distribution and Characteristics of the Kisspeptin Receptor  [PDF]
Janet J. Maguire, Helen R. Kirby, Emma J. Mead, Rhoda E. Kuc, Xavier d'Anglemont de Tassigny, William H. Colledge, Anthony P. Davenport
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027601
Abstract: Kisspeptins, the ligands of the kisspeptin receptor known for its roles in reproduction and cancer, are also vasoconstrictor peptides in atherosclerosis-prone human aorta and coronary artery. The aim of this study was to further investigate the cardiovascular localisation and function of the kisspeptins and their receptor in human compared to rat and mouse heart. Immunohistochemistry and radioligand binding techniques were employed to investigate kisspeptin receptor localisation, density and pharmacological characteristics in cardiac tissues from all three species. Radioimmunoassay was used to detect kisspeptin peptide levels in human normal heart and to identify any pathological changes in myocardium from patients transplanted for cardiomyopathy or ischaemic heart disease. The cardiac function of kisspeptin receptor was studied in isolated human, rat and mouse paced atria, with a role for the receptor confirmed using mice with targeted disruption of Kiss1r. The data demonstrated that kisspeptin receptor-like immunoreactivity localised to endothelial and smooth muscle cells of intramyocardial blood vessels and to myocytes in human and rodent tissue. [125I]KP-14 bound saturably, with subnanomolar affinity to human and rodent myocardium (KD = 0.12 nM, human; KD = 0.44 nM, rat). Positive inotropic effects of kisspeptin were observed in rat, human and mouse. No response was observed in mice with targeted disruption of Kiss1r. In human heart a decrease in cardiac kisspeptin level was detected in ischaemic heart disease. Kisspeptin and its receptor are expressed in the human, rat and mouse heart and kisspeptins possess potent positive inotropic activity. The cardiovascular actions of the kisspeptins may contribute to the role of these peptides in pregnancy but the consequences of receptor activation must be considered if kisspeptin receptor agonists are developed for use in the treatment of reproductive disorders or cancer.
Reproductive Hormone-Dependent and -Independent Contributions to Developmental Changes in Kisspeptin in GnRH-Deficient Hypogonadal Mice  [PDF]
John C. Gill,Oulu Wang,Shelley Kakar,Enzo Martinelli,Rona S. Carroll,Ursula B. Kaiser
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011911
Abstract: Kisspeptin is a potent activator of GnRH-induced gonadotropin secretion and is a proposed central regulator of pubertal onset. In mice, there is a neuroanatomical separation of two discrete kisspeptin neuronal populations, which are sexually dimorphic and are believed to make distinct contributions to reproductive physiology. Within these kisspeptin neuron populations, Kiss1 expression is directly regulated by sex hormones, thereby confounding the roles of sex differences and early activational events that drive the establishment of kisspeptin neurons. In order to better understand sex steroid hormone-dependent and -independent effects on the maturation of kisspeptin neurons, hypogonadal (hpg) mice deficient in GnRH and its downstream effectors were used to determine changes in the developmental kisspeptin expression. In hpg mice, sex differences in Kiss1 mRNA levels and kisspeptin immunoreactivity, typically present at 30 days of age, were absent in the anteroventral periventricular nucleus (AVPV). Although immunoreactive kisspeptin increased from 10 to 30 days of age to levels intermediate between wild type (WT) females and males, corresponding increases in Kiss1 mRNA were not detected. In contrast, the hpg arcuate nucleus (ARC) demonstrated a 10-fold increase in Kiss1 mRNA between 10 and 30 days in both females and males, suggesting that the ARC is a significant center for sex steroid-independent pubertal kisspeptin expression. Interestingly, the normal positive feedback response of AVPV kisspeptin neurons to estrogen observed in WT mice was lost in hpg females, suggesting that exposure to reproductive hormones during development may contribute to the establishment of the ovulatory gonadotropin surge mechanism. Overall, these studies suggest that the onset of pubertal kisspeptin expression is not dependent on reproductive hormones, but that gonadal sex steroids critically shape the hypothalamic kisspeptin neuronal subpopulations to make distinct contributions to the activation and control of the reproductive hormone cascade at the time of puberty.
Does Kisspeptin Signaling have a Role in the Testes?  [PDF]
Victoria Kyle,Shel-Hwa Yeo,William H. Colledge
Frontiers in Endocrinology , 2013, DOI: 10.3389/fendo.2013.00198
Abstract: Kisspeptins are a family of overlapping neuropeptides encoded by the Kiss1 gene that regulate the mammalian reproductive axis by a central action in the hypothalamus to stimulate GnRH release. Kisspeptins and their receptor (GPR54 also called KISS1R) are also expressed in the testes but a functional role in this tissue has not been confirmed. We examined which cell types in the testes expressed kisspeptin and its receptor by staining for β-galactosidase activity using tissue from transgenic mice with LacZ targeted to either the Kiss1 or the Gpr54 genes. Expression of both genes appeared to be restricted to haploid spermatids and this was confirmed by a temporal expression analysis, which showed expression appearing with the first wave of haploid spermatid cells at puberty. We could not detect any kisspeptin protein in spermatids however, suggesting that the Kiss1 mRNA may be translationally repressed. We tested whether kisspeptin could act on Leydig cells by examining the effects of kisspeptin on the immortalized Leydig cell line MA-10. Although MA-10 cells were shown to express Gpr54 by RT-PCR, they did not respond to kisspeptin stimulation. We also tested whether kisspeptin could stimulate testosterone release by a direct action on the testes using explants of seminiferous tubules. The explants did not show any response to kisspeptin. The functional integrity of the MA-10 cells and the seminiferous tubule explants was confirmed by showing appropriate responses to the LH analog, human chorionic gonadotropin. These data suggest that kisspeptin signaling does not have a significant role in testes function in the mouse.
The Vasoactive Potential of Kisspeptin-10 in the Peripheral Vasculature  [PDF]
Iain Sawyer,Sarah-Jane Smillie,Jennifer V. Bodkin,Elizabeth Fernandes,Kevin T. O'Byrne,Susan D. Brain
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0014671
Abstract: Splice products of the Kiss1 protein (kisspeptins) have been shown to be involved in a diverse range of functions, including puberty, metastasis and vasoconstriction in large human arteries. Circulating Kisspeptin-10 (Kp-10) plasma levels are low in normal individuals but are elevated during various disease states as well as pregnancy. Here, we investigated the potential of Kp-10, the shortest biologically active kisspeptin, to influence microvascular effects, concentrating on the cutaneous vasculature. Kp-10 caused a dose-dependent increase in oedema formation (0.3–10nmol/injection site), assessed by Evans Blue albumin dye extravasation, in the dorsal skin of CD1 mice. Oedema formation was shown to be inhibited by the histamine H1 receptor antagonist mepyramine. The response was characterised by a ring of pallor at the injection site in keeping with vasoconstrictor activity. Therefore, changes in dorsal skin blood flow were assessed by clearance of intradermally injected 99mtechnetium. Kp-10 was found to significantly reduce clearance, in keeping with decreased blood flow and providing further evidence for vasoconstrictor activity. The decreased clearance was partially inhibited by co-treatment with the cyclo-oxygenase inhibitor indomethacin. Finally evidence for the kisspeptin receptor gene (Kiss1R), but not the kisspeptin peptide gene (Kiss1), mRNA expression was observed in heart, aorta and kidney samples from normal and angiotensin II induced hypertensive mice, with similar mRNA levels observed in each. We have evidence for two peripheral vasoactive roles for kisspeptin-10. Firstly, plasma extravasation indicative of ability to induce oedema formation and secondly decreased peripheral blood flow, indicating microvascular constriction. Thus Kp-10 has vasoactive properties in the peripheral microvasculature.
Variety of functions and effects of kisspeptin
Matvienko M. G.,Pustovalov A. S.,Dzerzhinsky N. E.
Biopolymers and Cell , 2013, DOI: 10.7124/bc.000801
Abstract: A brief review of the literature on the properties and efficacy of kisspeptin, in particular, for the regulation of en- docrine functions. The results of numerous experiments with kisspeptin in molecular biology, reproductive medicine and endocrinology, as well as the development of vaccines against malignant tumors, are analyzed. Kisspeptin is known to initiate a cascade of changes leading to the puberty. According to the reports, this peptide modifies the activity of glands that produce sex hormones, so it can be used in the treatment of diseases associated with the violation of puberty, especially amenorrhea in adolescent girls. The effect of this peptide is related to the activation of hypothalamic cells that produce GnRH, which regulates a level of gonadotropin-releasing hormone. Thus, kisspeptin can activate the reproductive system without violating the protective mechanisms of orga- nism. The in-depth research of kisspeptin effects on all parts of the hypothalamic-pituitary-gonadal axis is promising, as well as the investigation of neuron-glial interactions in the central nervous system under the influence of this peptide.
Expression and Function of Kisspeptin during Mouse Decidualization  [PDF]
Peng Zhang, Min Tang, Ting Zhong, Yan Lin, Teng Zong, Chengxue Zhong, BaoPing Zhang, Min Ren, HaiBin Kuang
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0097647
Abstract: Background Plasma kisspeptin levels dramatically increased during the first trimester of human pregnancy, which is similar to pregnancy specific glycoprotein-human chorionic gonadotropin. However, its particular role in the implantation and decidualization has not been fully unraveled. Here, the study was conducted to investigate the expression and function of kisspeptin in mouse uterus during early pregnancy and decidualization. Methodology/Principal Findings Quantitative PCR results demonstrated that Kiss1 and GPR54 mRNA levels showed dynamic increase in the mouse uterus during early pregnancy and artificially induced decidualization in vivo. KISS-1 and GPR54 proteins were spatiotemporally expressed in decidualizing stromal cells in intact pregnant females, as well as in pseudopregnant mice undergoing artificially induced decidualization. In the ovariectomized mouse uterus, the expression of Kiss1 mRNA was upregulated after progesterone or/and estradiol treatment. Moreover, in a stromal cell culture model, the expression of Kiss1 and GPR54 mRNA gradually rise with the progression of stromal cell decidualization, whereas the attenuated expression of Kiss1 using small interfering RNA approaches significantly blocked the progression of stromal cell decidualization. Conclusion our results demonstrated that Kiss1/GPR54 system was involved in promoting uterine decidualization during early pregnancy in mice.
Quantification of Rat Kisspeptin Using a Novel Radioimmunoassay  [PDF]
James S. Kinsey-Jones, Kylie E. Beale, Joy Cuenco, Xiao Feng Li, Stephen R. Bloom, Kevin T. O’Byrne, Kevin G. Murphy
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0097611
Abstract: Kisspeptin is a hypothalamic peptide hormone that plays a pivotal role in pubertal onset and reproductive function. Previous studies have examined hypothalamic kisspeptin mRNA expression, either through in situ hybridisation or real-time RT-PCR, as a means quantifying kisspeptin gene expression. However, mRNA expression levels are not always reflected in levels of the translated protein. Kisspeptin-immunoreactivity (IR) has been extensively examined using immunohistochemistry, enabling detection and localisation of kisspeptin perikaya in the arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV). However, quantification of kisspeptin-IR remains challenging. We developed a specific rodent radioimmunoassay assay (RIA) capable of detecting and quantifying kisspeptin-IR in rodent tissues. The RIA uses kisspeptin-10 as a standard and radioactive tracer, combined with a commercially available antibody raised to the kisspeptin-10 fragment. Adult female wistar rat brain samples were sectioned at 300 μm and the ARC and AVPV punch micro-dissected. Brain punches were homogenised in extraction buffer and assayed with rodent kisspeptin-RIA. In accord with the pattern of kisspeptin mRNA expression, kisspeptin-IR was detected in both the ARC (47.1±6.2 fmol/punch, mean±SEM n = 15) and AVPV (7.6±1.3 fmol/punch, mean±SEM n = 15). Kisspeptin-IR was also detectable in rat placenta (1.26±0.15 fmol/mg). Reverse phase high pressure liquid chromatography analysis showed that hypothalamic kisspeptin-IR had the same elution profile as a synthetic rodent kisspeptin standard. A specific rodent kisspeptin-RIA will allow accurate quantification of kisspeptin peptide levels within specific tissues in rodent experimental models.
Evaluation of antidepressant activity of tramadol in mice  [cached]
Tayal Vandana,Kalra Bhupinder,Chawla Shalini
Indian Journal of Pharmacology , 2008,
Abstract: Objective: To evaluate antidepressant like effect of tramadol in mice. Materials and Methods: Tramadol was administered at three different doses (10,20 and 40 mg/kg,i.p) once daily for 7 days to Swiss albino mice of either sex. The immobility period of control and drug treated mice were recorded in tail suspension test (TST).The antidepressant effect of tramadol was compared to that of fluoxetine (20 mg/kg, i.p), administered for seven days. Results: Tramadol produced significant antidepressant effect at all the doses, as indicated by reduction in immobility times as compared to control. The efficacy of tramadol at doses of 20 and 40 mg/kg was comparable with that of fluoxetine. Tramadol at 10 mg/kg dose showed significantly less antidepressant activity compared to fluoxetine. Conclusion: The results of the present study indicate antidepressant like activity of tramadol.
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