The satiety effect of growth hormone-releasing factor in rats

The effect of growth hormone-releasing factor (GRF) on feeding behavior in rats was examined. Starvation-induced feeding was suppressed by intraventricular administration of 1 nmol and 4 nmol of synthetic human GRF (hGRF). Food intake was not affected when the peptide was administered by intraperitoneal injection. Furthermore, centrally administered hGRF also suppressed feeding in hypophysectomized rats. These results suggest that GRF suppression of food intake is mediated through the central nervous system independent of its effect on pituitary growth hormone secretion.     

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.     

Effect of hypothalamic ventromedial lesions on plasma growth hormone response to growth hormone-releasing factor in rats

The effect of ventromedial-arcuate (VMH-ARC) nuclei lesions on plasma growth hormone (GH) response to human growth hormone-releasing factor (GRF, 1 microgram/kg b.wt., i.v.) was studied in conscious rats after they had received chlorpromazine (CPZ) or CPZ plus antiserum against somatostatin (ASS). When rats were pretreated with CPZ alone, there was no difference in basal plasma GH level between VMH-ARC lesioned rats and controls. The magnitude of plasma GH response to GRF in 5 out of 6 VMH-ARC lesioned rats exceeded that of controls. When the same observation was repeated using the same rats after they had received ASS and CPZ, basal plasma GH levels of controls were significantly higher than those of VMH-ARC lesioned rats, and the magnitude of the plasma GH response to GRF was augmented in both groups of rats. The plasma GH response to GRF was comparable between two groups, though the peak plasma GH response to GRF was slightly but significantly lower in VMH-ARC lesioned rats as compared to controls. Pituitary GH content was reduced significantly in VMH-ARC lesioned rats as compared to controls. The results demonstrate that the pituitary responsiveness to GRF does not appear to be altered significantly in rats bearing bilateral VMH-ARC lesions. In addition, the placement of electrolytic lesions in VMH-ARC regions causes reduced SS secretion into the hypophyseal portal vessels and leads to an augmentation of plasma GH response to GRF.     

Effect of enhancement of cholinergic tone on the growth hormone response to acute hyperglycaemia or thyrotropin-releasing hormone in dogs

The effect of enhancement of cholinergic tone by pyridostigmine on the growth hormone (GH) response to thyrotropin-releasing hormone (TRH) or glucose-induced acute hyperglycaemia was tested in six adult unanaesthetized beagle dogs. Both TRH (5μg/ kg iv) and glucose (2 g/kg orally) did not significantly alter baseline GH levels but reduced the GH response to GH-releasing hormone (GHRH) (2 μg/kg iv), although this effect was more clear-cut with TRH than with glucose. Pretreatment with pyridostigmine (2 mg/kg orally) counteracted the inhibitory effect of hyperglycaemia on the GHRH-induced GH release, but had no effect on the inhibition induced by TRH. In summary, these results indicate that: 1) acute hyperglycaemia and TRH play an inhibitory role on GHRH-stimulated GH secretion in dogs; 2) the inhibitory effect of acute hyperglycaemia is mediated via hypothalamic cholinergic neurotransmission, whereas other neurotransmitter pathways would be. involved in the effect of TRH.     

Effects of neonatal administration of monosodium glutamate on plasma growth hormone (GH) response to GH-releasing factor in adult male and female rats

Female and male rats were treated with monosodium glutamate (MSG; 4 mg/g b.wt.) as neonates and the capability of the pituitary gland to secrete growth hormone (GH) in response to an intravenous injection of human GH-releasing factor (GRF) was evaluated under pentobarbital anesthesia on 109 days of life. Immunoreactive GRF content in the pituitary stalk-median eminence tissue in MSG-treated rats was less than 20% of that of control. A significant dose-dependent plasma GH response was observed after the administration of two doses of human GRF (0.25 and 1 μg/kg b.wt.,i.v.) in both control and MSG-treated rats. The responses between MSG-treated and control rats were comparable in female rats, but they were significantly reduced in male MSG-treated rats. These results show that the pituitary's responsiveness to exogenous GRF is well preserved in MSG-treated rats despite prolonged and severe depletion of endogenous GRF and there exists a sex difference in the effect of MSG on GH secretion elicited by GRF.     

GHRP-6-induced changes in electrical activity of single cells in the arcuate, ventromedial and periventricular nucleus neurones [correction of nuclei] of a hypothalamic slice preparation in vitro

Previously, we demonstrated that systemic injection of the growth hormone secretagogue, growth hormone-releasing peptide (GHRP)-6, selectively activated cells in the hypothalamic arcuate nucleus, as reflected by increased electrical activity and induction of the immediate early gene c-fos. The growth hormone secretagogue receptor distribution is not confined to the arcuate nucleus, suggesting that additional sites of action may exist. In the present study we characterized the electrophysiological responses of cells in the arcuate nucleus, ventromedial nucleus and periventricular nucleus in an in-vitro hypothalamic slice preparation, following bath application of GHRP-6. Additionally, since central somatostatin administration has been shown to attenuate the induction of the c-fos gene by GHRP-6, we sought to determine whether the arcuate cells activated by GHRP-6 are also somatostatin-sensitive. Male Wistar rats (100-150 g body weight (BW)) were anaesthetized (urethane; 1.2 g/kg BW) and the brains removed. Coronal sections (400 microm thickness) were cut through a block of hypothalamus and were transferred to a slice chamber perfused with artificial cerebrospinal fluid. Forty-one arcuate nucleus cells were tested with bath application of 15 microm GHRP-6 for 10 min, 16 of which were tested subsequently (>30 min later) with application of 10 microM somatostatin. Following GHRP-6 administration, 19 cells (46. 3%) showed a significant increase in firing rate during the 15-min period after GHRP-6 application (P<0.001), 17 cells (41.5%) did not respond and the remaining five cells (12.2%) were significantly inhibited. Six of the eight arcuate nucleus cells that were excited by GHRP-6 were significantly inhibited by somatostatin. By contrast, five of the six arcuate nucleus cells that were unresponsive to GHRP-6 were also unresponsive to somatostatin. In the ventromedial nucleus, of 19 cells tested, eight cells (42.1%) were excited by GHRP-6, eight cells (42.1%) were unresponsive and the remaining three cells (15.8%) were significantly inhibited. Of 19 cells recorded in the periventricular nucleus, 13 (68.4%) were unresponsive to GHRP-6 and six (31.6%) were significantly inhibited. Thus, electrophysiological studies in vitro suggest that: (1) neurones in the hypothalamic arcuate nucleus, ventromedial nucleus and periventricular nucleus show changes in electrical activity in response to GHRP-6; and (2) the arcuate nucleus cells excited by GHRP-6 are also subject to inhibitory control by somatostatin.     

Growth hormone releasing factor increases growth hormone release from MtTW15 pituitary tumors

The MtTW15 pituitary tumor secretes growth hormone and prolactin. Perifusion of these dispersed MtTW15 tumor cells with 10 nM growth hormone releasing factor (GRF) increases growth hormone release without affecting prolactin release. This effect is dose-dependent between 0.001 and 0.1 nM and is blocked by 100 nM somatostatin. These findings suggest that this tumor and clones derived from it may be valuable tools in studying the cellular mechanisms of action of GRF and somatostatin.     

Gonadotropin response to synthetic gonadotropin hormone-releasing hormone (GnRH) in chronic schizophrenia

GnRH stimulation tests were performed in 15 adult male chronic hebephrenic schizophrenics and 15 oligophrenic controls, matched for age and length of hospitalization. GnRH was given at doses of 50, 100 and 150 gamma to five subjects of each type, and FSH and LH levels in the blood were assayed at 0, 10, 20, 30, 60, and 90 minutes. The tests were performed twice in schizophrenics off therapy and after 10, 20 and 30 days of chlorpromazine therapy (4 mg/kg body weight/day, peros). The controls were not given chlorpromazine and were tested only twice. Schizophrenics showed relative increases in both FSH and LH which were greater than those of the controls, and the response persisted longer. Chlorpromazine had no effect on the test.     

The luteinizing hormone-releasing hormone (LHRH) system in normal and estrogenized neonatal rats

LHRH perikarya and processes were compared in 6, 9, and 11 day old normal and estrogenized male and female rats. Estradiol benzoate was administered SC in 1 or 1000 μg amounts when the animals were 2 days old. Control animals received either an equivalent amount of the oil vehicle or no injection. After perfusion with Bouin's solution, brains were embedded in paraffin and sectioned 6 μ coronally through the entire brain. The peroxidase-antiperoxidase immunocytochemical technique was used to assess the development of LHRH cells and fibers. The primary antiserum to LHRH was Arimura's antiserum #743. LHRH immunopositive perikarya were present in the septal-preoptic but not in the arcuate-median eminence regions. No immunopositive reaction product was present following treatment with antiserum #743 absorbed with LHRH. At each of the three ages, the amount of detectable LHRH cell bodies was considerably greater in normal males than in females. The high dose of estrogen reduced the quantity of LHRH perikarya localized in the male and increased it in the female. LHRH processes formed a “rostral” pathway in proximity with the organum vasculosm of the lamina terminalis (OVLT) in the vicinity of the rostral preoptic area and a “caudal” one extending through the arcuate-median eminence region. Many more LHRH immunopositive processes were visualized in normal males than in female siblings on days 9 and 11. The high dosage of estrogen also reduced the amount of LHRH immunoreactive material in 9 and 11 day old males but not in equivalent age females. The data are consistent with the findings that the hypothalamic-pituitary-gonadal inhibitory system functions earlier in the male than in the female and that the LHRH system can be modified by estrogen circulating during the period of sexual differentiation.     

Corticotropin-releasing factor (CRF) inhibits gonadotropin-releasing hormone (GnRH) release from superfused rat hypothalami in vitro

A dose-dependent suppression of basal gonadotropin-releasing hormone (GnRH) release was observed when rat hypothalamic slices were superfused with human/rat corticotropin-releasing factor (CRF) (10(-12) to 10(-8) M). CRF was also found to significantly reduce the amount of GnRH released in response to 56 mM KCl. These in vitro results demonstrate that the CRF inhibition of GnRH secretion observed in vivo occurs within the hypothalamus and independently of the CRF activation of the pituitary-adrenal-gonadal axis.     

Characterization and Localization of Mouse Hypothalamic Growth Hormone-Releasing Factor and Effect of Gold Thioglucose-Induced Hypothalamic Lesions

Hypothalamic growth hormone-releasing factor (GRF) in higher mammals, including human GRF, is a 44 amino acid residue peptide and is highly homologous in structure. By contrast, mouse GRF (mGRF) recently deduced by cDNA cloning consists of only 42 residues and shows relatively low homology to the GRFs of higher mammals and the same rodent species, rat. To characterize and localize the predicted mature mGRF peptide in the hypothalamus, we have generated its antiserum and developed a homologous radioimmunoassay. Immunoreactive mGRF in the acid hypothalamic extract was eluted as a single peak at a position identical to that of synthetic peptide on both gel filtration chromatography and reverse-phase high-performance liquid chromatography (HPLC). Secretion of immunoreactive mGRF from incubated hypothalami increased several fold in response to 50 mM K⁺, and this rise was abolished in the absence of medium Ca²⁺. Only a single peak of immunoreactive mGRF that coeluted with synthetic replicate was observed after the K⁺ -stimulated medium was extracted on Bond Elut C18 cartridges and applied on reverse-phase HPLC. Immunohistochemistry identified many mGRF-positive cell bodies in the arcuate nucleus and dense bundles of immunoreactive fibers in the median eminence. Treatment of mice with gold thioglucose (GTG), a chemical agent known to cause hypothalamic lesions, markedly depleted both content and in vitro secretion of immunoreactive mGRF. The decline in mGRF secretion was greater in GTG obese than in nonobese mice, whereas somatostatin secretion was not affected by GTG treatment. As compared to the previous findings obtained on rat GRF, mouse had approximately the same content of hypothalamic GRF, but retained only one third the capacity to release GRF in response to the same depolarizing stimulus. These findings demonstrate that mouse hypothalamus contains and secretes a mGRF-like molecule which has immunological and chromatographic characteristics identical to that predicted by molecular cloning. The depolarization-evoked, Ca²⁺-dependent release of immunoreactive mGRF and its neuronal localization in the arcuate nucleus-median eminence region indicate that it functions as a hypophysiotropic hormone of physiological importance. GTG produces hypothalamic GRF deficiency, probably sparing hypophysiotropic somatostatin neurons, and could be used to generate a mouse model for human GRF-deficient dwarfism.     

Caloric Intake Stimulates Growth Hormone Secretion in Food-Deprived Rats with Anterolateral Deafferentation of the Medial Basal Hypothalamus or Administered Antiserum to Somatostatin

In rats, food deprivation inhibits episodic growth hormone (GH) secretion. On the basis of previous studies, we hypothesized that during a recovery from prolonged fasting, caloric intake stimulates the release of GH-releasing factor (GRF) and this process does not depend on the specific macronutrients in the meal, while protein in the meal acts to restore characteristic ultradian rhythmicity of GH secretion. To test this hypothesis, the effect of caloric intake on GH secretion was examined in fasted adult male Wistar rats devoid of somatostatin (SS) influence on GH secretion either by anterolateral deafferentation (ALC) of the medial basal hypothalamus (MBH) or administration of anti–SS goat serum (ASS). Rats were provided with an indwelling right atrial cannula and were deprived of food for 72 h. ALC was performed 2 weeks prior to the study. ASS was given i.v. 8 h and 7 h prior to refeeding, respectively. Serial blood specimens were collected every 10 min. fn rats with ALC (ALC rats) or rats given ASS (ASS rats), the blood GH level revealed irregularly occurring small fluctuations, instead of the usual high bursts and low trough level. The baseline GH level and the mean GH level of fasted ALC rats or fasted ASS rats were significantly lower than those of fed ALC rats or fed ASS rats. Feeding the isocaloric mixed meal, the protein meal or the protein-deficient meal increased the GH pulse frequency, the pulse amplitude, the baseline GH level and the mean GH level in 72–h fasted ALC rats. These changes in GH secretory pattern persisted during the period of observation and were independent of the type of meal ingested. Following feeding the mixed meal, similar changes in the GH secretory pattern demonstrated in 72-h fasted ALC rats were also observed in 72–h fasted ASS rats, suggesting that the stimulation of GH secretion following caloric intake is not limited to ALC rats. Since the influence of SS on GH secretion has been largely eliminated in ALC or ASS rats, it is highly unlikely that the augmentation of GH secretion following feeding after prolonged food deprivation was the consequence of inhibition of SS secretion. Although GRF measurement was not performed, it is conceivable that the signal of caloric intake is conveyed to the MBH and acts to stimulate GRF release.     

Dibutyryl cyclic adenosine monophosphate stimulates in vitro luteinizing hormone-releasing hormone release only from median eminence derived from ovariectomized, estradiol-primed rats

The present study examined the effect of intermittent infusion of dibutyryl cyclic AMP (dbcAMP; 10(-7) M; 10 min on, 20 min off) on in vitro luteinizing hormone-releasing hormone (LH-RH) release from the rat median eminence (ME) derived from immature rats: intact females, intact males, ovariectomized (OVX) females, castrated (CAST) males, ovariectomized, estradiol primed (OVX + E2) females and castrated, estradiol primed (CAST + E2) males. In intact, OVX and CAST conditions, spontaneous LH-RH release from MEs was not modified by dbcAMP infusion. However, E2 implants in OVX and CAST rats selectively affected the responsiveness of MEs to dbcAMP: ME from OVX + E2 were highly responsive to dbcAMP; contrarily, MEs from CAST + E2 were unresponsive to this nucleotide. Therefore, these differences in MEs responsiveness to dbcAMP-induced LH-RH release appear to be dependent upon a critical effect of E2 priming on this tissue in female but not in male rats.     

No nerve growth factor response to treatment with memantine in adult rats

Summary. Nerve growth factor (NGF) is the most widely examined neurotrophin in the experimental models of Alzheimers disease (AD) and has been shown to prevent the retrograde degeneration of cholinergic neurons. In this study we examined NGF and cholineacetyltransferase (ChAT) changes in several rat brain regions after excitotoxic lesion of the entorhinal cortex with quinolinic acid and tested the effect of memantine on spatial learning in the radial maze after lesion. We observed a significant increase (+26%, p=0.02) of NGF concentrations in the hippocampus of the lesioned rats when compared to sham-lesioned rats. Chronic treatment with memantine showed no significant effect on the NGF increase in the hippocampus (p=0.72). The ChAT activity was significantly increased in the lesioned rats when compared to controls (+16%, p<0.05) and did not depend on treatment with memantine. In spite of this, memantine improved performance of the radial maze. This indicates that memory improving effects of memantine observed in experimental animals and in clinical studies are probably not related to changes in brain NGF content, whereas the observed NGF increase in the denervated hippocampus is probably trauma-related reflecting impaired retrograde transport of hippocampal NGF.Present address: Solvay Pharmaceuticals BV, Weesp, NiederlandePresent address: Institute of Pharmacology PAN, Cracow, Poland     

The Effect of Growth Hormone Secretagogues and Neuropeptide Y on Hypothalamic Hormone Release from Acute Rat Hypothalamic Explants

Growth hormone (GH) secretagogues (GH-releasing peptides and their non-peptide analogues) stimulate growth hormone release via specific G-protein coupled receptors both directly from the pituitary gland and through stimulation of the hypothalamus. The exact mechanism of action in the hypothalamus is not known. The presence of endogenous GH releasing hormone (GHRH) seems to be necessary for the in-vivo actions of growth hormone secretagogues (GHSs), but data suggest that further factors must be involved as well. The effect of GHSs is not entirely specific for the GH axis; they release prolactin and stimulate the hypothalamo-pituitary-adrenal axis causing elevations in circulating ACTH and cortisol levels in both animal and human studies. Recently, it has also been suggested that GHSs stimulate hypothalamic neuropeptide Y (NPY) neurones. In the present study, we have therefore investigated the direct effect of several GHSs (GHRP-6, hexarelin and the non-peptide analogues L-692, 429 and L-692, 585) on GHRH, somatostatin (SS), corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) release in vitro in an acute rat hypothalamic incubation system. We also assessed the effect of NPY on GHRH, SS and AVP release. Freshly removed hypothalami were incubated in control media for 20 min and then in 1-4 consecutive 20-min periods in each of the test substances at different concentrations. There was no significant change in either the basal or potassium-stimulated release of GHRH or SS at low concentrations of any of the secretagogues; however, at millimolar doses a paradoxical inhibition of GHRH was observed with GHRP-6, hexarelin and L-692 585 (data are expressed as the ratio of treated to preceding basal release; at 20 min control group: 0.97+/-0.02, GHRP-6: 0.55+/-0.04, P<0.001 compared to control group; hexarelin: 0. 56+/-0.06, P<0.001, L-692,585: 0.70+/-0.03, P<0.001), while SS was stimulated after 60 or 80 min (at 80 min control: 0.80+/-0.03, hexarelin: 1.23+/-0.07, P<0.05 and L-692,585: 1.37+/-0.11, P<0.05). GHSs stimulated hypothalamic AVP release (at 20 min control: 0. 99+/-0.06 ratio to basal release, 10-4 M concentration of GHRP-6: 6. 31+/-1, P<0.001, hexarelin: 1.88+/-0.4, P<0.01, L-692,429: 1.90+/-0. 5, P<0.05 and L-692,585: 2.34+/-0.96, P<0.01), while no stimulatory effect was found on CRH release. NPY significantly stimulated SS and inhibited basal and potassium-stimulated GHRH release, while potentiating potassium-evoked AVP secretion. The Y1 receptor antagonist BIBP 3226 did not inhibit the effects of NPY on SS, GHRH or AVP release. We therefore conclude that, in this in-vitro rat hypothalamic incubation model, growth hormone secretagogues stimulate the release of AVP but have no effect on either GHRH, SS or CRH at low doses; at high doses paradoxically they inhibit the hypothalamic GH axis similar to in-vivo data in the rat. We speculate that these effects might be mediated by NPY.     

Differential contribution of nitric oxide and cGMP to the stimulatory effects of growth hormone-releasing hormone and low-concentration somatostatin on growth hormone release from somatotrophs

There is increasing evidence that nitric oxide (NO) produced by NO synthase (NOS), and their signalling partners, guanylyl cyclase and cGMP, play a relevant role in growth hormone (GH) secretion from somatotrophs. We previously demonstrated that both GH-releasing hormone (GHRH; 10(-8) M) and low concentrations of somatostatin (10(-15) M) stimulate pig GH release in vitro, whereas a high somatostatin concentration (10(-7) M) inhibits GHRH-induced GH secretion. To ascertain the possible contribution of the NOS-NO and guanylyl cyclase-cGMP routes to these responses, cultures of pituitary cells from prepubertal female pigs were treated (30 min) with GHRH (10(-8) M) or somatostatin (10(-7) or 10(-15) M) in the absence or presence of activators or blockers of key steps of these signalling cascades, and GH release was measured. Two distinct activators of NO route, SNAP (5x10(-4) M) or L-AME (10(-3) M), similarly stimulated GH release when applied alone (with this effect being blocked by 10(-7) M somatostatin), but did not alter the stimulatory effect of GHRH or 10(-15) M somatostatin. Conversely, two NO pathway inhibitors, NAME (10(-5) M) or haemoglobin (20 microg/ml) similarly blocked GHRH- or 10(-15) M somatostatin-stimulated GH release. 8-Br-cGMP (10(-8) to 10(-4) M) strongly stimulated GH release, suggesting that cGMP may function as a subsequent step in the NO pathway in this system. Interestingly, 10(-7) M somatostatin did not inhibit the stimulatory effect of 8-Br-cGMP. Moreover, although 8-Br-cGMP did not modify the effect of GHRH, it enhanced GH release stimulated by 10(-15) M somatostatin. Accordingly, a specific guanylyl cyclase inhibitor, LY-83, 583 (10(-5) M) did not alter 10(-15) M somatostatin-induced GH release, whereas it blocked GHRH-induced GH secretion. These results demonstrate for the first time that the NOS/NO signalling pathway contributes critically to the stimulatory effects of both GHRH and low-concentration somatostatin on GH release, and that, conversely, the subsequent guanylyl cyclase/cGMP step only mediates GHRH- and not low-concentration somatostatin-induced GH secretion from somatotrophs.     

Effect of sericin on diabetic hippocampal growth hormone/insulin-like growth factor 1 axis

Previous studies have shown that sericin extracted from silk cocoon significantly reduces blood glucose levels and protects the nervous system against diabetes mellitus. In this study, a rat type 2 diabetes mellitus model was established by intraperitoneal injection of 25 mg/kg streptozotocin for 3 successive days, following which the rats were treated with sericin for 35 days. After treatment, the blood glucose levels of the diabetic rats decreased significantly, the growth hormone level in serum and its expression in the hippocampus decreased significantly, while the insulin-like growth factor-1 level in serum and insulin-like growth factor-1 and growth hormone receptor expression in the hippocampus increased significantly. The experimental findings indicate that sericin improves disorders of the growth hormone/insulin-like growth factor 1 axis to alleviate hippocampal damage in diabetic rats.     

Resistance of Growth Hormone Secretion to Hypoglycemia in the Mouse

Although previous studies have demonstrated that acute hypoglycemia inhibits growth hormone (GH) secretion due to stimulation (hypothalamic somatostatin (SS) neurones in the rat, the effect of hypoglycemia on GH secretion has not yet been elucidated in the mouse In this study, the effects of insulin-induced hypoglycemia on mouse GH secretion, hypothalamic c-fos expression, GH-releasing hormon (GRH) and SS mRNA levels were investigated in conscious male mice. Seven days after implantation of chronic atrial catheters, bloo samples were taken every 20 min from 1200–1600 h under unrestrained conditions. Insulin was administered iv every 20 min fro1 1200-1240 h to induce moderate hypoglycemia (MH) and severe hypoglycemia (SH), respectively. Expression of hypothalamic c-fos protei was examined 30 min and 60 min after induction of hypoglycemia by immunohistochemistry. Hypothalamic GRH and SS mRNA level were examined 1 h and 3 h after induction of hypoglycemia by Northern blot analysis. The lowest mean plasma glucose levels after insuli injections were 49.1 ± 4.1 mg/dl and 34.2 ± 5.6 mg/dl in conscious mice, respectively. However, pulsatile GH secretion was no significantly altered in either group. Although both MH and SH markedly stimulated c-fos expression in specific hypothalamic nuclc including the paraventricular nucleus, they did not induce c-fos protein in the periventricular nucleus. Neither MH nor SH altere hypothalamic GRH or SS mRNA levels. These results suggest that hypoglycemia does not activate SS neurons which inhibit GH secretio in the mouse.     

Effects of lesions in the periventricular nucleus of the preoptic-anterior hypothalamus on growth hormone and thyrotropin secretion and brain somatostatin

Two experiments were performed to study the role of somatostatin (SRIF) neurons of the preoptic-anterior hypothalamic area (PO-AHA) in regulating growth hormone (GH) and thyrotropin (TSH) secretion in rats. Small lesions were placed in the periventricular (PV) zone and blood was collected at 24 h and 15 days after surgery. Blood samples were obtained at 3 min and at 15 min after ether exposure for assessing non-stress levels, respectively, of plasma GH and TSH. Non-stress blood samples were also collected at decapitation at 4 weeks. The brains from the first experiment were dissected and processed for measuring SRIF content in several regions. At 24 h and 15 days, non-stress GH and TSH levels were significantly elevated in rats with PV lesions. Stress-induced decrements in GH levels persisted in all groups. Although non-stress plasma GH and TSH levels returned to normal in lesioned rats at 4 weeks, SRIF content was decreased 83% in the median eminence and 33% in the hypothalamus. These results show that discrete lesions in the PV zone of the PO-AHA cause transient elevations in non-stress secretion of GH and TSH and that normal levels of such secretion can be reinstated despite reductions of SRIF in the median eminence and hypothalamus.     

The effect of intravenous growth hormone infusion on cerebrospinal fluid somatostatin levels in the rhesus monkey

CSF was continuously withdrawn over 13 days from the cervical subarachnoid space of two rhesus monkeys during the intravenous infusion of saline or human growth hormone (GH) and samples collected during sequential 2 h periods were assayed for somatostatin (SRIF). SRIF-like immunoreactivity (SRIF-LI) concentrations were decreased during GH infusion as compared to saline infusion (P less than 0.005) and the maximal effect occurred during the hours of darkness (18.00-06.00 h). Since in vivo GH administration stimulates hypothalamic SRIF-LI release, CSF SRIF-LI does not appear to be derived primarily from the hypothalamus but rather from extrahypothalamic brain by a mechanism inhibited by GH.