Víctor M. Arce

Activation of growth hormone receptor delivers an antiapoptotic signal: evidence for a role of Akt in this pathway.

A signaling pathway was delineated by which GH promotes cell survival. Experiments were performed in human leukemic cells (HL-60) and Chinese hamster ovary (CHO) cells. In HL-60 cells, GH treatment reduced starvation-induced cell death. In contrast, when HL-60 cells were treated with an anti-GH antibody, cell survival was sharply reduced. In CHO cells stably expressing either the wild-type (wtGHR) or a truncated form (Δ454GHR) of the GH receptor in which GH induces a sustained activation of the receptor-associated tyrosine kinase JAK2, we found that GH stimulation inhibited programmed cell death induced by withdrawal of survival factors. This effect was enhanced in cells expressing the truncated form. In contrast, GH did not affect cell survival in CHO cells transfected with either the empty vector or a mutated GHR unable to transduce the signal (4P/AGHR). We also showed that the inhibitory action of GH on apoptosis is probably mediated via stimulation of the serine-threonine kinase Akt, as 1) GH treatmen...

Activation of Human Somatostatin Receptor 2 Promotes Apoptosis Through a Mechanism that is Independent from Induction of p53

The ability of both somatostatin (SS) and its stable analogues to inhibit cell growth depends on the stimulation of specific membrane receptors (SSTR1-5), which belong to the G protein-coupled receptor family. Accumulating evidence suggests that the SSTR2 plays a major role in mediating cell cycle arrest, and it is also clear that SHP-1, a cytoplasmic phosphotyrosine phosphatase (PTP), is an essential component of the SSTR2-mediated cytostatic effect. In contrast, the possibility that SSTR2 activation may also lead to increased apoptosis is still beyond debate, despite SHP-1 activation is also able to promote cell death in several cell types. In the present work we have investigated the ability of SSTR2 to induce apoptosis in HL-60 cells. We have found that HL-60 cells uniquely express the SSTR2 subtype, and that stimulation of SSTR2 with the SS analogue SMS 201-995 results in an increased cell death. In all, these findings demonstrate that activation of SSTR2 promotes apoptosis in HL-60 cells. Moreover, in contrast with the proapoptotic mechanism previously reported for SSTR3, cell death induced by activation of SSTR2 is independent from accumulation of p53.

The role of sexual steroids in the modulation of growth hormone (GH) secretion in humans.

Sex steroids contribute to modulate GH secretion in man. However, both the exact locus and mechanism by which their actions are exerted still remain not clearly understood. We undertook a number of studies designed to ascertain: (1) whether or not sudden or chronic changes in circulating gonadal steroids may affect GH secretion in normal adults; and (2) the reason(s) for gender-related dimorphic pattern of GH release. The pituitary reserve of GH, as evaluated by means of a GHRH challenge, was similar in women with anorexia nervosa and in normally menstruating women. Estrogenic receptor blockade with tamoxifen (TMX) did not significantly change GHRH-induced GH response in these normal women. Therefore, acute or chronic hypoestrogenism apparently had no important effects at level of somatotrophs. In another group of normal women we tested the possibility that changes in circulating estrogens might induce changes in the hypothalamic-somatotroph rhythm (HSR). GHRH challenges were performed throughout a menstrual cycle, and again after having achieved functional ovarian blockade with a GnRH agonist treatment. Short-term ovarian blockade did not significantly affect the parameters of GH response to GHRH, although it was accompanied by an increase in the number of women in a refractory HSR phase at testing. This suggested a low potentiating effect on the basic pattern of somatostatin (SS) release occurring as a consequence of the decrease in circulating estrogens. In normal men, neither the GH response to GHRH nor the HSR were affected by functional testicular blockade (after GnRH agonist treatment). However, the administration of testosterone enanthate (250 mg) to another group of men increased both the GHRH-induced GH release and the number of subjects in a spontaneous secretory HSR phase at testing; these were reversed by estrogenic receptor blockade with TMS. In another group of normal men, the fraction of GH secreted in pulses (FGHP) during a nocturnal sampling period was significantly decreased by testicular blockade. Other parameters of GH secretion,such as the number of GH pulses and their mean amplitude (A), and the mean plasma GH concentration (MCGH), showed a slight, although not significant, decrease following the lack of androgens. The administration of testosterone enanthate (500 mg) reversed these parameters to values similar to those in the basal study. Interestingly, when tamoxifen was given after testosterone enanthate, A, MCGH and FGHP increased to values significantly higher than in any other experimental condition in that study.(ABSTRACT TRUNCATED AT 400 WORDS)

REASONS FOR THE VARIABILITY IN GROWTH HORMONE (GH) RESPONSES TO GHRH CHALLENGE: THE ENDOGENOUS HYPOTHALAMIC‐SOMATOTROPH RHYTHM (HSR)

The aims of this study were: (1) to test the possibility that pre‐GHRH plasma GH values could reflect the functional status of the hypothalamic‐somatotroph rhythm (HSR) at testing, and thus explain if it is responsible for the marked variability in GH responsiveness to GHRH challenge and (2) to see if exogenous somatostatin (SS) could disrupt this endogenous HSR and thus make the GH responses homogeneous.

Growth hormone (GH) and brain trauma

Growth hormone (GH) is a pleiotropic hormone with known neurotrophic effects. We aimed to study whether GH administration might be useful together with rehabilitation in the recovery of TBI patients. 13 TBI patients (8 M, 5 F; age: 6-53 years old) were studied. Time after TBI: 2.5 months to 11 years; 5 patients showed acquired GH-deficiency (GHD). Disabilities observed: cognitive disorders; motor plegias; neurogenic dysphagia (n=5), vegetative coma (n=2) and amaurosis (n=1). All but one TBI patient followed intense rehabilitation for years. Treatment consisted of GH administration (maximal dose 1 mg/day, 5 days/week, resting 15-days every 2-months, until a maximum of 8 months) and clinical rehabilitation according to the individual needs (3-4 h/day, 5 days/week, during 6-12 months). Informed consent was obtained before commencing GH administration. GH significantly increased plasma IGF-1 values (ng.mL(-1)) in both GHD and no GHD patients, being then similar between both groups (GHD: 275.6±35.6 [p<0.01 vs. baseline], no GHD: 270.2±64 [p<0.05 vs. baseline]). In all the cases clear significant improvements were observed during and at the end of the combined treatment. Cognitive improvements appeared earlier and were more important than motor improvements. Swallowing improved significantly in all TBI patients with neurogenic dysphagia (2 of them in a vegetative state). Visual performance was ameliorated in the patient with amaurosis. No undesirable side-effects were observed. Our data indicate that GH can be combined with rehabilitation for improving disabilities in TBI patients, regardless of whether or not they are GHD.

Interferon beta promotes survival in primary astrocytes through phosphatidylinositol 3-kinase

Although interferon-beta (IFN-beta) has been demonstrated to be effective in the treatment of multiple sclerosis (MS) patients, the mechanism(s) underlying its beneficial effects has not been uncovered yet. Until now, most of the effort in the study of the relevant mechanisms of IFN-beta has dealt with its ability to modulate the immune response. Only recently, it has been proposed that the beneficial effects of IFN-beta in MS patients could depend on its ability to modulate astrocyte function. In the present work, we have found that IFN-beta treatment promotes the survival of astrocytes through stimulation of the phosphatidylinositol 3-kinase (PI-3K)/Akt pathway. We propose that the beneficial effects of IFN-beta in MS therapy may depend, at least in part, on its capacity to protect astrocytes against the apoptotic cell death that occurs in the early steps of the pathogenesis of MS.

Growth hormone (GH) treatment may cooperate with locally-produced GH in increasing the proliferative response of hippocampal progenitors to kainate-induced injury

Primary objective: This study was designed to investigate the effect of growth hormone treatment on the proliferation of endogenous neural progenitor cells in the dentate gyrus (DG) of the brain stimulated by kainic acid (KA)-induced neurotoxicity. Research design: Neurotoxicity was induced by intraperitoneal injection of KA. GH treatment lasted 4 days, starting either immediately or after 10 days of administration of the neurotoxic insult. Methods and procedure: Proliferating cells were immunodetected after labelling by in vivo administration of 5-bromodeoxyuridine (BrdU). GH expression was detected by in situ hybridization and immunofluorescence. Main outcomes and results: KA administration stimulated the proliferation of hippocampal precursors and this effect was significantly enhanced by GH treatment. Hippocampal GH expression was also up-regulated in response to KA administration. Conclusions: The findings support the possibility that the proliferative response observed in the hippocampus of rats treated with KA and GH is a consequence of cooperation between the exogenous and the locally-produced hormone and their synergism with other mitogenic factors generated in response to the neurotoxic damage. Therefore, GH treatment could be used to cooperate with other physiological or pathological stimuli in order to promote cell proliferation.

Expression of growth hormone receptor in the human brain

This study was designed to investigate the presence of growth hormone receptor (GHR) expression in the human brain tissue, both normal and tumoral, as well as in the human glioblastoma cell line U87MG. Reverse transcription-polymerase chain reaction revealed the presence of GHR mRNA in all brain samples investigated and in U87MG cells. GHR immunoreactivity was also detected in this cell line using both immunocytochemistry and western blotting. All together, our data demonstrate the existence of GHR expression within the central nervous system (CNS), thus supporting a possible role for GH in the CNS physiology.

Role of growth hormone (GH) in the treatment on neural diseases: from neuroprotection to neural repair.

Growth hormone (GH) is a pleiotropic hormone that exerts important functions in the control of brain development as well as in the regulation neuronal differentiation and function, together with several behavioral and psychological effects that have been linked to its modulatory actions on brain neurotransmitters. In addition, the possibility that GH may play a role on brain repair after injury has been also envisaged, and a number of reports have shown that GH administration following injury confers neuroprotection and accelerates the recovery of some neural functions. In this review we have analyzed the state of the art of GH administration in several neural diseases. Though more studies are still necessary in order to completely understand the importance of GH in these processes, the promising results obtained so far, together with the absence of untoward effects during GH therapy, encourages the development of clinical assays in order to further support the use GH treatment in neural diseases in which neuroprotection and/or neuroregeneration are involved.

Regulation of hypothalamic somatostatin by glucocorticoids

Glucocorticoids (GCs) play a key role in the physiology of the hypothalamic-somatotroph axis, since these steroids enhance growth hormone (GH) gene transcription and increase GHRH receptor synthesis. However, GC excess inhibits normal growth in all species studied. This is mainly due to the impaired GH secretion observed during hypercortisolism, a situation in which GH responses to a number of stimuli, including GHRH, are blunted. The inhibitory effect of GCs on GH secretion seems to be dependent on enhanced hypothalamic SS secretion. Since SS release is stimulated by beta-adrenergic agonism we tested the possibility that GC inhibition of GH secretion would depend on increased beta-adrenoceptor activity in SS-producing neurons. The experimental design consisted in evaluating the GH response to GHRH in normal subjects after having induced hypercortisolism, with DEX, and blocking beta-adrenoceptors with propranolol (PRO). Moreover, to investigate the specificity of this mechanism, GHRH-induced GH release was tested after inducing hypercortisolism and enhancing alpha 2-adrenergic or muscarinic cholinergic tone, by giving clonidine (CLO) or pyridostigmine (PD), respectively. As expected, nocturnal DEX administration inhibited the GH response to GHRH. In this situation of hypercortisolism, both PRO and CLO, but not PD, were able to reverse the inhibitory effect of DEX on GHRH-elicited release. However, the potentiating effect of these drugs on the GHRH-induced GH secretion was only observed for PRO. These data confirm that GC excess inhibits GH release by increasing hypothalamic SS secretion, and that the mechanism is mediated by GC-induced enhanced beta-adrenergic responsiveness. Therefore, the defective GHRH secretion observed in chronic hypercortisolism must be a consequence of the continuous blockade that SS excess exerts on GHRH-producing neurons. Our postulate agrees with other data in the literature showing that GCs modulate the secretion of some hypothalamic peptides by changing the responsiveness of the producing neurons from alpha 2-adrenoceptors to that of beta-adrenoceptors.