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Biomedical subjects

L M García-Segura

Publications and source records attributed to L M García-Segura.

At least 19 recordsLinked to original sources
PubMed2003

Facial nerve regeneration through progesterone-loaded chitosan prosthesis. A preliminary report.

Biodegradable nerve guides have represented new treatment alternatives for nerve repairing. They are gradually biodegradable, exert biological effects directly to the injured nerve, and act as drug- or cell-delivery devices. Furthermore, progesterone (PROG) has been demonstrated to promote injured peripheral nerve regeneration. In this study, it was hypothesized that PROG delivered from chitosan prostheses provides better facial nerve regenerative response than chitosan prostheses with no PROG. As there are no reports on the use of the former as nerve-guide material in the regeneration of injured nerves, this is the main objective of the present work. Chitosan prostheses containing PROG were used to bridge 10-mm gaps in rabbit facial nerves. The regenerated nerves were evaluated 45 days after implantation in animals with the use of light microscopy and morphometric analysis. Gas chromatography was used in order to quantify PROG content in prosthesis prior to and after implantation in subcutaneous tissue at different periods of up to 60 days. In addition, the prosthesis walls were evaluated with histological techniques in order to assess their integrity and the surrounding tissue reaction. Chitosan prostheses allowed PROG release during the time needed for nerve regeneration. At 45 days myelinated nerve fibers were observed in both the proximal and distal stumps. This parameter and the N ratio were higher in the progesterone-treated group when compared to that of the vehicle control. Findings indicate that chitosan prostheses were useful in nerve regeneration, acting as a long-lasting PROG delivery device a faster nerve regeneration.

Animals↗
PubMed2003

Neurogenesis in explants from the walls of the lateral ventricle of adult bovine brain: role of endogenous IGF-1 as a survival factor.

Previous studies have shown the existence of proliferating cells in explants from bovine (Bos Taurus) lateral ventricle walls that were maintained for several days in vitro in the absence of serum and growth factors. In this study we have characterized the nature of new cells and have assessed whether the insulin-like growth factor-1 (IGF-1) receptor regulates their survival and/or proliferation. The explants were composed of the ependymal layer and attached subependymal cells. Ependymal cells in culture were labelled with glial markers (S-100, vimentin, GFAP, BLBP, 3A7 and 3CB2) and did not incorporate bromodeoxiuridine when this molecule was added to the culture media. Most subependymal cells were immunoreactive for beta III-tubulin, a neuronal marker, and did incorporate bromodeoxiuridine. Subependymal neurons displayed immunoreactivity for IGF-1 and its receptor and expressed IGF-1 mRNA, indicating that IGF-1 is produced in the explants and may act on new neurons. Addition to the culture media of an IGF-1 receptor antagonist, the peptide JB1, did not affect the incorporation of bromodeoxiuridine to proliferating subependymal cells. However, JB1 significantly increased the number of TUNEL positive cells in the subependymal zone, suggesting that IGF-1 receptor is involved in the survival of subependymal neurons. In conclusion, these findings indicate that neurogenesis is maintained in explants from the lateral cerebral ventricle of adult bovine brains and that IGF-1 is locally produced in the explants and may regulate the survival of the proliferating neurons.

Age Factors↗
PubMed2002

Effects of early undernutrition on the brain insulin-like growth factor-I system.

Undernutrition reduces circulating concentrations of insulin-like growth factor (IGF)-I, but how it affects the brain IGF system, especially during development, is largely unknown. We have studied IGF-I, IGF-II, IGF receptor and IGF binding protein (BP)-2 mRNA expression in the hypothalamus, cerebellum and cerebral cortex of neonatal rats that were food restricted beginning on gestational day 16. One group was refed starting on postnatal day 14. Rats were killed on postnatal day 8 or 22. Undernutrition did not produce an overall reduction in brain weight at either age but, at 22 days, both the cerebellum and hypothalamus weighed significantly less. At 8 days, no change was detected in the central IGF axis in response to undernutrition. However, in 22-day-old undernourished rats, IGF-I and IGF receptor mRNA expression were increased in both the hypothalamus and cerebellum, while IGFBP-2 was decreased, but only in the hypothalamus. Refeeding had no effect on any of these parameters. These results suggest that the hypothalamus and cerebellum respond to malnutrition and the decrease in circulating IGF-I, a peptide fundamental for growth and development, by increasing the local production of both the growth factor and its receptor in attempt to maintain normal development.

Animals↗
PubMed2001

Space flight affects magnocellular supraoptic neurons of young prepuberal rats: transient and permanent effects.

Effects of microgravity on postural control and volume of extracellular fluids as well as stress associated with space flight may affect the function of hypothalamic neurosecretory neurons. Since environmental modifications in young animals may result in permanent alterations in neuroendocrine function, the present study was designed to determine the effect of a space flight on oxytocinergic and vasopressinergic magnocellular hypothalamic neurons of prepuberal rats. Fifteen-day-old Sprague-Dawley female rats were flown aboard the Space Shuttle Columbia (STS-90, Neurolab mission, experiment 150) for 16 days. Age-matched litters remained on the ground in cages similar to those of the flight animals. Six animals from each group were killed on the day of landing and eight animals from each group were maintained under standard vivarium conditions and killed 18 weeks after landing. Several signs of enhanced transcriptional and biosynthetic activity were observed in magnocellular supraoptic neurons of flight animals on the day of landing compared to control animals. These include increased c-Fos expression, larger nucleoli and cytoplasm, and higher volume occupied in the neuronal perikaryon by mitochondriae, endoplasmic reticulum, Golgi apparatus, lysosomes and cytoplasmic inclusions known as nematosomes. In contrast, the volume occupied by neurosecretory vesicles in the supraoptic neuronal perikarya was significantly decreased in flight rats. This decrease was associated with a significant decrease in oxytocin and vasopressin immunoreactive levels, suggestive of an increased hormonal release. Vasopressin levels, cytoplasmic volume and c-Fos expression returned to control levels by 18 weeks after landing. These reversible effects were probably associated to osmotic stimuli resulting from modifications in the volume and distribution of extracellular fluids and plasma during flight and landing. However, oxytocin levels were still reduced at 18 weeks after landing in flight animals compared to controls. This indicates that space flight during prepuberal age may induce irreversible modifications in the regulation of oxytocinergic neurons, which in turn may result in permanent endocrine and behavioral impairments.

Age Factors↗
PubMed2001

Role of the endogenous cannabinoid system as a modulator of dopamine transmission: implications for Parkinson's disease and schizophrenia.

The endogenous cannabinoid system is a new signaling system composed by the central (CB1) and the peripheral (CB2) receptors, and several lipid transmitters including anandamide and 2-arachidonylglycerol. This system is the target of natural cannabinoids, the psychoactive constituents of Cannabis sativa preparations (marijuana, hashish). Acute and chronic cannabis exposure has been associated with subjective feelings of pleasure and relaxation, but also to the onset of psychiatric syndromes, a decrease of the efficacy of neuroleptics and alterations in the extrapyramidal system regulation of motor activity. These actions point to a tight association of the cannabinoid system with the brain dopaminergic circuits involved in addiction, the clinical manifestation of positive symptoms of schizophrenia and Parkinson's disease. The present work discusses anatomical, biochemical and pharmacological evidences supporting a role for the endogenous cannabinoid system in the modulation of dopaminergic transmission. Cannabinoid CB1 receptors are present in dopamine projecting brain areas. In primates and certain rat strains it is also located in dopamine cells of the A8, A9 and A10 mesencephalic cell groups, as well as in hypothalamic dopaminergic neurons controlling prolactin secretion. CB1 receptors co-localize with dopamine D1/D2 receptors in dopamine projecting fields. Manipulation of dopaminergic transmission is able to alter the synthesis and release of anandamide as well as the expression of CB1 receptors. Additionally, CB1 receptors can switch its transduction mechanism to oppose to the ongoing dopamine signaling. Acute blockade of CB1 receptor potentiates the facilitatory role of dopamine D2 receptor agonists on movement. CB1 stimulation results in sensitization to the motor effects of indirect dopaminergic agonists. The dynamics of these changes indicate that the cannabinoid system is an activity-dependent modulator of dopaminergic transmission, an hypothesis relevant for the design of new therapeutic strategies for dopamine-related diseases such as the psychosis and Parkinson's disease.

Journal Article↗
PubMed2000

Oligodendrocytes in brain and optic nerve express the beta3 subunit isoform of Na,K-ATPase.

The Na,K-ATPase, which catalyzes the active transport of Na(+) and K(+), has two principal subunits (alpha and beta) that have several genetically distinct isoforms. Most of these isoforms are expressed in the nervous system, but certain ones are preferentially expressed in glia and others in neurons. Of the beta isoforms, beta1 predominates in neurons and beta2 in astrocytes, although there are some exceptions. Here we demonstrate that beta3 is expressed in rat and mouse white matter oligodendrocytes. Immunofluorescence microscopy identified beta3 in oligodendrocytes of rat brain white matter in typical linear arrays of cell bodies between fascicles of axons. The intensity of stain peaked at 20 postnatal days. beta3 was identified in cortical oligodendrocytes grown in culture, where it was expressed in processes and colocalized with antibody to galactocerebroside. In the mouse and rat optic nerve, beta3 stain was seen in oligodendrocytes, where it colocalized with carbonic anhydrase II. For comparison, optic nerve was stained for the beta1 and beta2 subunits, showing distinct patterns of labelling of axons (beta1) and astrocytes (beta2). The C6 glioma cell line was also found to express the beta3 isoform preferentially. Since beta3 was not found at detectable levels in astrocytes, this suggests that C6 is closer to oligodendrocytes than astrocytes in the glial cell lineage.

Animals↗
PubMed2000

Anatomically specific changes in the expression of somatostatin, growth hormone-releasing hormone and growth hormone receptor mRNA in diabetic rats.

Growth hormone (GH) secretion is altered in poorly controlled diabetic animals. However, modifications in the hypothalamic neuropeptides that control GH secretion, somatostatin and GH-releasing hormone (GHRH), as well as changes in the sensitivity of the hypothalamus and pituitary to the feedback effects of GH, are less clear. We have used RNase protection assays and in-situ hybridization to address whether the mRNA expression of GH, somatostatin and GHRH, as well as of the GH receptor (GHR) in the hypothalamus and anterior pituitary, are altered in streptozotocin-induced diabetic rats. After induction of diabetes, rats were treated with insulin twice daily for 3 weeks to obtain either poorly controlled (mean plasma glucose >300 mg/dl) or well-controlled diabetic rats. Although no significant change in pituitary GH mRNA expression was found, the hypothalamic expression of GHRH and somatostatin mRNA was reduced in poorly-controlled diabetic rats and returned to control values with normalisation of plasma glucose concentrations (P<0.0001 and P<0.002, respectively). Somatostatin mRNA expression was reduced only in the central portion of the periventricular nucleus, with no change being seen in the other areas of the periventricular nucleus or in the arcuate, suprachiasmatic or paraventricular nuclei. A significant decline in GHRH mRNA expression was observed in both the arcuate nucleus and ventromedial hypothalamus. Anterior pituitary GHR mRNA expression was significantly reduced in both well and poorly-controlled diabetic rats, while there was no change in the hypothalamus. To examine whether the evolution time of the diabetes influences these parameters, in a subsequent experiment, diabetic rats received no insulin for 2 months. A significant decline in GHRH and somatostatin mRNA expression was also observed in these rats. In addition, pituitary GH mRNA expression declined significantly in long-term diabetic rats. These results demonstrate that: (1) the expression of both GHRH and somatostatin declines specifically in anatomical areas involved in anterior pituitary hormone control; (2) GHR mRNA expression is decreased in the pituitary of diabetic rats, but not in the hypothalamus, and does not return to control values with normalisation of mean blood glucose concentrations; and (3) the evolution time of the diabetes is important for detecting some changes, including the decrease in pituitary GH mRNA expression.

Animals↗
PubMed2000

Effect of neonatal and adult testosterone treatment on the cellular composition of the adult female rat anterior pituitary.

The adult female pituitary has significantly more lactotrophs than that of the male, while the later has a higher percent of somatotrophs. It is clear that GH and prolactin (PRL) gene expression and somatotroph and lactotroph proliferation are modulated by the postpubertal hormone environment; however, the role of the neonatal steroid environment in this process is not known. We have used in situ hybridization to determine the number of GH and PRL mRNA-containing cells, as well as the level of expression of these two hormones, in response to neonatal and adult testosterone treatment. Female rats exposed to testosterone during the neonatal period, adulthood or both periods, as well as normal females and males were used. Exposure to testosterone during the neonatal period significantly increased the percentage of somatotrophs (ANOVA: P<0. 005) and decreased that of lactotrophs in the adult female rat (ANOVA: P<0.001). Adult testosterone treatment had no significant effect on the percentage of somatotrophs. The percentage of lactotrophs was significantly increased by adult testosterone only in those rats also exposed to neonatal testosterone. PRL mRNA concentrations, as reflected by silver grains/cell, were reduced by neonatal testosterone and increased by adult testosterone treatment (ANOVA: P<0.0001). Overall PRL mRNA levels, measured by densitometry, were also reduced by neonatal testosterone exposure, but adult testosterone had no effect (ANOVA: P<0.001). GH mRNA levels per cell, as reflected by silver grains/cell, were increased by adult testosterone, while neonatal testosterone treatment had no effect. Overall GH mRNA levels per unit area, determined by densitometry measurements, were increased by both neonatal and adult testosterone treatment, with the combination of these two treatments resulting in adult females having levels indistinguishable from intact males (ANOVA: P<0.003). These results suggest that, in combination with postpubertal sex steroids, the neonatal gonadal steroid environment plays an important role in determining anterior pituitary hormone synthesis and cellular composition.

Analysis of Variance↗
PubMed1999

Insertion of Escherichia coli alpha-haemolysin in lipid bilayers as a non-transmembrane integral protein: prediction and experiment.

alpha-Haemolysin is an extracellular protein toxin (approximately 107 kDa) secreted by Escherichia coli that acts at the level of the plasma membranes of target eukaryotic cells. The nature of the toxin interaction with the membrane is not known at present, although it has been established that receptor-mediated binding is not essential. In this work, we have studied the perturbation produced by purified alpha-haemolysin on pure phosphatidylcholine bilayers in the form of large unilamellar vesicles, under conditions in which the toxin has been shown to induce vesicle leakage. The bilayer systems containing bound protein have been examined by differential scanning calorimetry, fluorescence spectroscopy, differential solubilization by Triton X-114, and freeze-fracture electron microscopy. All the data concur in indicating that alpha-haemolysin, under conditions leading to cell lysis, becomes inserted in the target membrane in the way of intrinsic or integral proteins. In addition, the experimental results support the idea that inserted alpha-haemolysin occupies only one of the membrane phospholipid monolayers, i.e. it is not a transmembrane protein. The experimental data are complemented by structure prediction studies according to which as many as ten amphipathic alpha-helices, appropriate for protein-lipid interaction, but no hydrophobic transmembrane helices are predicted in alpha-haemolysin. These observations and predictions have important consequences for the mechanism of cell lysis by alpha-haemolysin; in particular, a non-transmembrane arrangement of the toxin in the target membrane is not compatible with the concept of alpha-haemolysin as a pore-forming toxin.

Amino Acid Sequence↗
PubMed1999

Increased glucagon-like peptide-1 receptor expression in glia after mechanical lesion of the rat brain.

Glucagon-like peptide-1 (GLP-1)(7-36) amide, a member of the glucagon and related peptides family, and its receptor have an anatomically specific expression in the brain. Furthermore, the GLP-1 receptor is expressed in both neurons and glia. Because after a penetrating injury a large population of astrocytes become activated and augment their expression of numerous substances, we have used in situ hybridization to determine whether the expression of the GLP-1 receptor increases in response to a penetrating injury. We have found that GLP-1 receptor expression increases dramatically along the border of the injury. Furthermore, this expression can be colocalized to glial fibrillary acidic protein (GFAP) and non-GFAP mRNA containing cells, suggesting that at least part of this increase is due to an increase in GLP-1 receptor expression in glial cells.

Animals↗
PubMed1998

Sexually dimorphic interaction of insulin-like growth factor (IGF)-I and sex steroids in lactotrophs.

Anterior pituitary hormone secretion is sexually dimorphic due partially to gender differences in the postpubertal hormone environment; however, differences in the pituitary's responsiveness to these signals may also play a role. We have used simple and double in situ hybridization to determine whether lactotrophs and somatotrophs from male and female rats respond differently in vitro to growth hormone-releasing hormone (GHRH), somatostatin (SS) or insulin-like growth factor (IGF)-I and whether sex steroids modulate these responses. Cultures were treated with either 17 beta-estradiol (E; 10(-9)M), testosterone (T; 10(-7)M), dihydrotestosterone (DHT; 10(-7) M) or vehicle in combination with either GHRH (10(-7)M), SS (10(-7)M), IGF-I (10(-7)M) or vehicle. Basal mRNA levels of GH, prolactin (PRL) and pituitary transcription factor-1 (Pit-1) did not differ between the sexes. The responses to peptide hormones alone were similar between the sexes, but not in the presence of gonadal steroids. In females, DHT reduced and E increased the stimulatory effect of GHRH and inhibitory effect of SS on GH mRNA levels (two-way ANOVA: P < 0.05), while having no effect in males. An additive effect of E and GHRH on PRL mRNA levels was seen only in males. The E induced rise in PRL mRNA levels was completely inhibited by SS in females, but only partially so in males (two-way ANOVA: P < 0.001). IGF-I inhibited the E induced rise in PRL and lactotroph Pit-1 mRNA levels only in females. These results suggest that sex steroids modulate the pituitary's response to hypothalamic and circulating factors differently in males and females and that this may play a role in generating the sexually dimorphic patterns of pituitary hormone secretion.

Animals↗
PubMed1998

Cellular composition of the adult rat anterior pituitary is influenced by the neonatal sex steroid environment.

Growth hormone (GH) and prolactin (PRL) secretion differ significantly between adult males and females and this is due, at least in part, to the postpubertal hormone environment which affects GH and PRL gene expression, as well as somatotrope and lactotrope proliferation. However, the role of the neonatal steroid environment in this phenomenon is less well understood. We have used in situ hybridization to determine the number of GH and PRL mRNA containing cells, as well as the level of expression of these two hormones and of the pituitary transcription factor 1 (Pit-1). Neonatally castrated male rats that had been exposed to testosterone during the neonatal period, adulthood or during both periods, males castrated as adults, normal adult males and normal proestrous females were used. Orchidectomy of adult rats had no effect on the number of somatotropes or lactotropes, but significantly reduced GH and PRL mRNA levels. Neonatal castration significantly reduced the percentage of somatotropes and increased that of lactotropes in the adult male. In addition, GH and Pit-1 mRNA levels were reduced significantly, but PRL mRNA levels were not modified. Treatment of neonatally castrated males with testosterone during the neonatal period significantly increased the percentage of somatotropes and decreased the percentage of lactotropes compared to vehicle-treated animals. It also increased GH and Pit-1 mRNA levels, but did not affect PRL mRNA levels. Adult testosterone treatment significantly increased the percentage of both somatotropes and lactotropes, as well as GH, PRL and Pit-1 mRNA levels. Treatment of neonatally castrated males with testosterone during both the neonatal and adult periods returned the percentage of somatotropes and lactotropes, as well as GH, PRL and Pit-1 mRNA levels, to that of the intact male. These results suggest that, although the postpubertal steroid environment is important in determining anterior pituitary hormone synthesis and cellular composition, the neonatal steroid environment also plays an important role in this phenomenon.

Animals↗
PubMed1996

Sex steroid effects on the development and functioning of the growth hormone axis.

1. The secretory pattern of growth hormone (GH) is sexually dimorphic in the adult rat. However, this difference between the sexes does not become apparent until after the onset of puberty, suggesting that pubertal sex steroids play an important role in the manifestation of this phenomenon. 2. We have addressed the question as to whether there exists a sexual dimorphism in the hypothalamic neuropeptides that regulate GH release from the anterior pituitary, i.e., somatostatin (SS) and growth hormone-releasing hormone (GHRH). In addition, we have investigated whether the developmental changes in the GH secretory pattern are correlated with changes in these neuropeptides. The effect of testosterone treatment on SS and GHRH neurons during both the neonatal period and adulthood have also been studied. 3. We have found that the synthetic capacity, as reflected in relative messenger RNA (mRNA) levels, of both SS and GHRH neurons changes throughout development in both male and female rats. These mRNA levels are sexually dimorphic at certain times during maturation and can be modulated by changes in testosterone levels, suggesting that sex steroid modulation of these two neuropeptide systems could at least partially account for the sexual dimorphism seen in the adult GH secretory pattern. 4. The neonatal steroid environment has also been suggested to be involved in the generation of the final adult GH secretory pattern, although the mechanisms underlying this effect are even less well understood. In support of the hypothesis that the neonatal steroid environment plays an important role in organizing the GH axis, we have found that the number of GHRH neurons in the adult brain, as well as their sensitivity to adult steroids, is modulated by neonatal testosterone treatment. The number of SS neurons in the periventricular and paraventricular nuclei were not modulated by neonatal steroids; however, the synthetic capacity of these neurons does appear to be influenced by the neonatal steroid environment. 5. These studies suggest that both the neonatal and adult sex steroid environments influence the adult GH secretory pattern by modulating GHRH and SS neurons.

Animals↗
PubMed1996

Expression of the beta 1 and beta 2(AMOG) subunits of the Na,K-ATPase in neural tissues: cellular and developmental distribution patterns.

We have used isoform-specific antisera against the Na,K-ATPase beta 1 (SpETb1) and beta 2(AMOG) (SpETb2) subunit isoforms in order to establish their specific cellular and subcellular localization in several developmental stages of the rat central nervous system. Immunocytochemical preparations revealed beta 1 Isoform protein in most neural cells, being predominantly located in the soma of neurons and astrocytes, with no appreciable developmental variations. In the newborn rat, beta 2(AMOG) immunoreactivity was present in cellular processes of astroglia and in the somas of neurons and decreasing in intensity with maturation until adulthood, where no beta 2 isoform was detected in neurons. The differential location of these isoforms, both developmentally and at the cellular level suggest a complex regulation of their genes expression and mechanisms of subcellular distribution, as well as functional differences.

Adenosine Triphosphatases↗
PubMed1996

In vivo and in vitro regulation of pituitary transcription factor-1 (Pit-1) by changes in the hormone environment.

Pituitary transcription factor-1 (Pit-1 or GHF-1) is a transcription factor specific to the anterior pituitary and is involved in the expression and regulation of the growth hormone (GH), prolactin (PRL) and thyroid-stimulating hormone (TSH) beta-subunit genes. The expression of these three genes can be modulated by changes in the hormone environment and it is thought that some of these effects are mediated through Pit-1, but little is known about the physiological regulation of this transcription factor. Therefore, we first asked whether Pit-1 gene expression is modified as a result of changes in the in vivo gonadal steroid environment and if this could be correlated with changes in GH and/or PRL mRNA levels. Secondly, we sought to determine if sex steroids affect the mRNA levels of these three peptides by acting at the level of the pituitary and whether these effects are androgen or estrogen mediated. Finally, how sex steroids modulate the response of these three genes to the hypothalamic neuropeptides growth hormone-releasing hormone (GHRH) and somatostatin (SS) was analyzed. To this end, we compared Pit-1, GH and PRL mRNA levels in the anterior pituitary of intact, castrated, and castrated testosterone-replaced adult male rats. In addition, primary cultures of adult male pituitaries were used to study the direct effects of both androgens and estrogens on Pit-1, GH, and PRL mRNA levels. In situ hybridization histochemistry was used to compare relative levels of Pit-1, GH and PRL mRNA. Densitometric analysis of the in vivo studies showed that castration resulted in a 57, 40 and 55% decline in Pit-1, GH and PRL mRNA signal levels, respectively. Furthermore, replacement with testosterone (T) at the time of castration completely prevented the decline in all three mRNA species (ANOVA: Pit-1 mRNA, p < 0.0001; GH mRNA, p < 0.0001; PRL mRNA, p < 0.0001). In vivo, both T (10(-7) M) and estradiol (10(-9) M) were capable of stimulating Pit-1 mRNA and PRL mRNA levels, while dihydrotestosterone (DHT; 10(-7) M) had no effect. There was no effect of any of these steroid treatments on GH mRNA levels in vitro. Addition of GHRH to the cultures increased GH mRNA levels, as well as those of Pit-1 and PRL, and SS had the opposite effect on GH mRNA levels. Whereas the GH response to GHRH was not significantly modified by exposure to sex steroids, the effect of SS was. The presence of sex steroids was capable of modifying the Pit-1 and PRL responses to both GHRH and SS. These results clearly indicate that changes in circulating levels of sex steroids modulate the expression of Pit-1 in the anterior pituitary and that these changes can be correlated with commensurate modifications in GH and PRL mRNA levels. Furthermore, the effect on both Pit-1 and PRL mRNA levels occurs, at least in part, at the level of the anterior pituitary and is an estrogen-receptor-mediated event. In contrast, the effects of gonadal steroids on GH mRNA levels are less direct and are most likely mediated at the level of the hypothalamus, as well as through modulation of the response of the somatotroph to hypothalamic factors. We conclude that the transcription factor Pit-1 is actively regulated physiologically and may be involved in mediating some of the effects of sex steroids and hypothalamic factors on the synthesis of certain anterior pituitary hormones.

Animals↗
PubMed1996

Growth hormone-releasing peptides: clinical and basic aspects.

Growth hormone (GH)-releasing peptides (GHRPs), a family of synthetic oligopeptides which stimulate GH release, were identified more than a decade ago. The effects of these peptides on GH release have been described in vivo and in vitro, in both animals and humans, using various doses and administration routes. It is generally accepted that GHRPs stimulate the release of GH by acting at the level of the pituitary through a receptor different to that for the endogenous GH-releasing hormone (GHRH). In addition, it has been reported that there are specific binding sites for these peptides in the hypothalamus and that systemic administration of GHRPs increases the expression of the immediate early gene c-fos in a subpopulation of hypothalamic neurons. However, the identity of these hypothalamic neurons and the mechanism of action of GHRPs at both the hypothalamic and pituitary levels remain unknown. One interesting aspect of GHRPs is that they are orally active and this phenomenon has been demonstrated in both animals and humans. Furthermore, these drugs stimulate GH secretion in humans dose-dependently with the magnitude and duration of this response being comparable to that seen with an intravenous peptide bolus. We have studied the oral activity of GHRP-2 on GH release in normal children. In addition, we have analyzed the response to GHRP-2 of obese adolescents, as well as the effects of an intravenous bolus of GHRH alone and GHRH plus GHRP-2. Orally administered GHRP-2 stimulates GH secretion in normal children and, although it seems that this drug is more potent in girls, there were no statistical differences between the groups. Characteristically, GH levels started to increase by 15 min, peaked at 60 min and returned to basal concentrations by 180 min. The effect of GHRP-2 was synergistic with GHRH 1-29 NH2. In addition, obese subjects appeared to have a greater response to this peptide than did normal controls. To study the effects of GHRPs on hypothalamic GHRH and somatostatin neurons, female dwarf rats (dw/dw) were treated continuously with GHRP-6 (1 mg/kg per 24 h) for 14 days. In situ hybridization for GHRH and SS was performed. We found that GHRP-6 stimulated GHRH mRNA levels in the posterior arcuate nucleus (ARC), with no significant effect in the anterior ARC or ventromedial hypothalamic neurons. SS mRNA levels in the posterior periventricular nucleus (PeN) were decreased after GHRP-6 treatment, while no effect was seen in the anterior PeN, ARC, or lateral paraventricular nucleus. These results suggest that GHRP-6 treatment modulates hypothalamic neurons controlling GH secretion; however, whether this effect is direct or mediated through another factor remains to be elucidated.

Animals↗
PubMed1996

Interaction of the signalling pathways of insulin-like growth factor-I and sex steroids in the neuroendocrine hypothalamus.

Among the numerous endocrine signals that affect the central nervous system, sex steroids play an important role. It has been recently postulated that part of the effects of these hormones on the brain may be mediated by trophic factors, such as insulin-like growth factor I (IGF-I). Both estradiol and IGF-I increase the survival and differentiation of developing fetal rat hypothalamic neurons in culture. The effect of estradiol is blocked by the pure estrogen receptor antagonist ICI 182,780, by an antisense oligonucleotide to the estrogen receptor, and by an antisense oligonucleotide to IGF-I. In turn, the effect of IGF-I is blocked by ICI 182,780 and by the antisense oligonucleotide to the estrogen receptor. These findings indicate that estrogen-induced activation of the estrogen receptor in developing hypothalamic neurons requires the presence of IGF-I and that both estradiol and IGF-I use the estrogen receptor to mediate their trophic effects on hypothalamic cells. In vivo, sex steroids affect IGF-I levels in the endocrine hypothalamus. IGF-I levels in tanycytes, a specific subtype of glial cells present in the arcuate nucleus and median eminence, are sexually dimorphic in the rat, increase with the onset of puberty, and are regulated by perinatal and adult levels of sex steroids. These changes may be due to hormonal modifications of IGF-I uptake by tanycytes from blood or cerebrospinal fluid. Therefore, this type of glial cell appears to play a central role in the interaction of sex steroids and IGF-I in the hypothalamus.

Animals↗