Somatostatin alterations and brain diseases.
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Alzheimer Disease↗
Biomedical subjects
J Epelbaum
Publications and source records attributed to J Epelbaum.
Thyroidectomy abolishes pulsatile growth hormone secretion without affecting hypothalamic somatostatin.
The effects of thyroid hormone deprivation and of subsequent replacement therapy on growth hormone (GH) secretion were investigated in unrestrained unanesthetized rats. Male rats were thyroparathyroidectomized (TPTX) 5 weeks prior to plasma sampling for GH assay, or to decapitation for evaluation of hypothalamic somatostatin (SRIF) content and in vitro SRIF and GH release. Thyroid hormone deprivation suppressed pulsatile GH secretion as well as GH release induced by clonidine (150 micrograms/kg). Treatment of TPTX rats with small doses of triiodothyronine (T3) restored an episodic pattern of GH secretion, but with lower peak values than controls, as well as the GH response to clonidine. Thyroid deprivation induced a 92-fold decrease in GH release from the pituitary; however, the ratio between GH release and GH content was similar in TPTX and normal rats, and human pancreatic growth hormone-releasing factor (GRF) (3 X 10(-8) M) was still able to stimulate residual GH release by hemipituitaries from TPTX rats in a manner similar to that in euthyroid controls (295 and 254% stimulation, respectively). Thyroid deprivation or T3 replacement did not modify SRIF content in the hypothalamus or other brain structures tested. The capacity of K+ depolarization to release SRIF in vitro from the hypothalamus was not modified by TPTX. These findings indicate that thyroid hormones are necessary to maintain both pulsatile and induced GH secretion in unanesthetized rats. In addition they suggest that impairment of GH secretion in thyroidectomized rats does not depend upon changes in the hypothalamic SRIF regulation of the hormone but could be dependent on a defect in GRF release and/or, most probably, GH synthesis directly at the pituitary level.
Animals↗
Somatostatin receptors in human growth hormone and prolactin-secreting pituitary adenomas.
[125I-Tyr]Somatostatin [( 125I-Tyr]SRIH) binding was found in 11 GH-secreting pituitary adenomas [Kd = 0.46 +/- 0.15 (+/- SE) nM; maximum binding, 165 +/- 35 fmol/mg protein). This binding was specific, since it was displaced by somatostatin-14 (SRIH-14), N-Tyr-SRIH-14, and SRIH-28. In contrast, a number of peptides and drugs not structurally related to SRIH, such as bombesin, dopamine, LHRH, met-enkephalin, naloxone, neurotensin, secretin, substance P, TRH, or vasoactive intestinal peptide, did not affect [125I-Tyr]SRIH binding. [125I-Tyr]SRIH specific binding also was found in PRL-secreting pituitary adenomas. The kinetic characteristics of the specific binding were similar to those of GH-secreting adenomas. However, maximal binding was one quarter that of GH-secreting adenomas (37 +/- 9 fmol/mg protein). In contrast, nonsecreting (chromophobe) tumors were devoid of any specific binding. Finally, in acromegaly, the density of [125I-Tyr]SRIH-binding sites in the adenomas was negatively correlated with plasma GH levels before surgery (r = -0.80). This suggests that somatostatinergic control is involved in GH secretion in acromegalic patients.
Acromegaly↗
In vivo release of somatostatin from rat median eminence after local K+ infusion or delivery of nociceptive stress.
The effects of local infusion of a 16 mM K+ solution or of a nociceptive stress on the release of somatostatin (SRIF) from the hypothalamus was measured in unanesthetized male rats implanted with a push-pull cannula in the median eminence. Although the baseline secretion rate of SRIF was increased in animals displaying agitation as a result of handling stress, both treatments induced fast doubling of SRIF release lasting for 15-30 min. Neither an equimolar Na+ infusion into the median eminence nor a similar K+ infusion into the 3rd ventricle had any affect on this release. The possible role of SRIF release in the mechanism of growth hormone inhibition following nociceptive stress is discussed.
Animals↗
Subcellular distribution of somatostatin-14, somatostatin-28 and somatostatin-28 (1-12) in rat brain cortex and comparisons of their respective binding sites in brain and pituitary.
Subcellular distribution and binding characteristics of the three endogenous peptides somatostatin-14 (SRIF-14), somatostatin-28 (SRIF-28) and somatostatin-28(1-12) (SRIF-28(1-12] derived from preprosomatostatin were investigated in the rat brain cortex. The three peptides are predominantly recovered from a crude mitochondrial pellet (P2), containing the pinched off nerve endings. Specific high affinity binding sites for 125I-N-Tyr-SRIF-14 and 125I-N-Tyr-SRIF-28 are present on pituitary and brain membranes. Under the same conditions, 125I-N-Tyr-SRIF-28(1-12) binding is undetectable. Moreover, SRIF-28(1-12) does not displace 125I-N-Tyr-SRIF-14 or 125I-N-Tyr-SRIF-28 binding. SRIF-28 is more potent than SRIF-14 to displace 125I-N-Tyr-SRIF-28 binding to brain and pituitary membranes, while both peptides are equipotent to displace 125I-N-Tyr-SRIF-14 binding. Finally, the regional distribution of 125I-N-Tyr-SRIF-14 and 125I-N-Tyr-SRIF-28 binding sites in the brain is identical. In conclusion, the present results are consistent with a neurotransmitter and neurohormonal role for SRIF-14 and SRIF-28. The function of SRIF-28(1-12) in brain remains to be elucidated. Additionally, a differential role for SRIF-14 and SRIF-28 both in adenohypophysis and brain cannot be ascertained at the present time.
Animals↗
Calmodulin involvement on the Ca++-dependent release of LHRH and SRIF in vitro.
Mediobasal hypothalamic (MBH) slices of male adult rats were superfused at 37 degrees C with oxygenated Hepes-buffer Locke medium. Bacitracin (2 X 10(-5) M) was added to prevent enzymatic degradation of LHRH and SRIF. 6 min pulse of K+ (56 mM), veratridine (15 microM) or the ionophore A 23187 (10(-5) M), markedly stimulated the release of both neuropeptides. Trifluoperazine, a calmodulin inhibitor, decreased the K+-evoked LHRH and SRIF release in a dose-dependent manner; it was also effective in inhibiting the veratridine-induced neuropeptides release. Phenytoin, a calmodulin-dependent kinase inhibitor, also decreased in a dose-dependent manner the K+-induced LHRH and SRIF release; the basal release of both neuropeptides remained unaffected by either treatment. The ionophore-stimulated release of both neuropeptides was significantly inhibited as well. These data demonstrate that a Ca++-calmodulin kinase system may be involved in the mechanism of depolarization-induced LHRH and SRIF release from hypothalamic nerve terminals.
Animals↗
Biochemistry of the hypothalamus in Parkinson's disease.
We assayed the content of neurotransmitters (or their synthesizing enzymes) and neuropeptides in the hypothalamus of control and parkinsonian brains post mortem. Only dopamine concentrations were lower than normal in Parkinson's disease, suggesting that deficiency in hypothalamic dopamine transmission may play a role in the autonomic and endocrine abnormalities of this disorder.
Aged↗
Somatostatin and dementia in Parkinson's disease.
The concentrations of somatostatin in the cortex, hippocampus and caudate nucleus of subjects with Parkinson's disease were determined by radioimmunoassay. Somatostatin levels in the frontal cortex were significantly reduced in Parkinsonian subjects who were slightly or severely demented compared to controls and to non-demented Parkinsonians. Significant reductions were also observed in the hippocampus and entorhinal cortex of severely demented subjects.
Aged↗
[Demonstration of pulsatile secretion of somatostatin in the third cerebral ventricle of unanesthetized rats].
Using a specially designed push-pull cannula stereotaxically implanted into the 3rd ventricle, a pulsatile secretion of IR-SRIF with a circhoral periodicity was detected in male rats. At 30 min. to 1 h 1/2 intervals the secretion rate of the neuropeptide rose from a baseline rate of 14.5 +/- 0.5 pg/10 min., corresponding to a baseline concentration of 60 +/- 2 pg/ml to peaks of 50 +/- 5 pg/10 min. or 210 +/- 22 pg/ml, respectively. This pulsatile pattern was restricted to rats where histological examination showed no dilation pictures of the ventricle. The possible origin and function of intra-ventricular IR-SRIF are discussed.
Animals↗
Guanine nucleotide sensitivity of [125I]-Iodo NTyr somatostatin binding in rat adenohypophysis and cerebral cortex.
Specific [125I]-Iodo-NTyr somatostatin binding sites are present in adenohypophyseal and cerebral cortical membranes. Guanine nucleotides reduce the maximal binding capacity of adenohypophyseal binding sites without significantly affecting their apparent affinity. In pituitary as well as in cortex, GTP is the most potent nucleotide followed by GDP and guanylyl imidodiphosphate (GMP-PNP). The effect appears specific of guanine nucleotides since ATP, ADP and AMP are inactive on [125I]-Iodo-NTyr somatostatin binding. These results, showing the nucleotide sensitivity of [125I]-Iodo-NTyr somatostatin binding in pituitary and cerebral cortex, are compatible with a coupling of somatostatin receptors with adenylate cyclase.
Animals↗
Somatostatin connections between the hypothalamus and the limbic system of the rat brain.
Somatostatin (SRIF) content of several brain structures was evaluated by radioimmunoassay in rats bearing various types of hypothalamic transections, as well as lesions of the amygdala. Analysis of the regional changes in SRIF concentrations after surgery suggest the following conclusions: (1) hypothalamic somatostatinergic neurons project to the limbic system, with the exception of the amygdaloid nuclei; (2) the olfactory tubercle, the lateral septal nucleus, the habenula and probably the hippocampus receive somatostatin projections from periventricular SRIF-containing cells; (3) somatostatin-containing fibers take a lateral course after leaving periventricular cells and join the medial forebrain bundle; (4) somatostatin innervation of the amygdala seems to be intrinsic.
Amygdala↗
Somatostatin inhibits in vitro release of luteinizing hormone releasing hormone from rat mediobasal hypothalamic slices.
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Animals↗
Somatostatin in catecholamine-rich nuclei of the brainstem.
Somatostatin (SRIF) concentrations in catecholamine-rich nuclei of the rat brainstem were measured by radioimmunoassay. The study was performed both in control or sham operated animals and after transecting the major projections of hypothalamic SRIF-containing neurons. Concentrations of the peptide were found to be relatively high in the locus coeruleus, the parabrachial nucleus and the nucleus of the solitary tract; they were intermediate in the lateral reticular nucleus (A1 cell group) and low in the substantia nigra. Transection of hypothalamic periventricular efferents resulted in a 58% depletion of SRIF content in the locus coeruleus, while concentrations of the peptide in other areas were unaffected. Transection of the medial forebrain bundle at the level of the lateral hypothalamus decreased SRIF content by 55% in the substantia nigra, but not in the other nuclei tested. It is concluded that the hypothalamus contributes significantly to the somatostatinergic innervation of the locus coeruleus and the substantia nigra, whereas SRIF in the other nuclei is intrinsic or originates outside the hypothalamus.
Animals↗
Characterization, regional distribution, and subcellular distribution of 125I-Tyr1-somatostatin binding sites in rat brain.
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Animals↗
Somatostatin receptors on rat anterior pituitary membranes.
[125I]Iodo-Tyr1-somatostatin (SRIF) binds with high affinity to one class of sites in the rat anterior pituitary with a KD of 0.91 +/- 0.22 nM and a receptor concentration of 104.4 +/- 1.9 fmol/mg protein. This binding is saturable with respect to tissue concentration and is time-, temperature-, pH-, and calcium-dependent. It is also reversible as a function of time. The rates of association and dissociation were calculated to be 5.98 X 10(7) M-1 min-1 and 0.578 min-1, respectively. Binding of [125I]iodo-Tyr1-SRIF is not inhibited by morphine, beta-endorphin, [D-Ala2]Met-enkephalin, LHRH, TRH, histidylproline diketopiperazine, neurotensin, substance P, bombesin or vasoactive intestinal peptide. In contrast SRIF, [Tyr1]SRIF, and [D-Trp8,D-Cys14]SRIF displace [125I]iodo-Tyr1-SRIF binding with Ki values 0.10 +/- 0.05, 0.46 +/- 0.18, 0.05 +/- 0.01 nM, respectively. The constants of inhibition of a series of alanine monosubstituted analogs of SRIF are correlated (r = 0.89) with their biological potency on GH secretion. Furthermore, postnatal development patterns of [125I]iodo-Tyr1-SRIF binding sites follow the ability of SRIF to inhibit GH release. Thus, [125I]iodo-Tyr1-SRIF binding to adenohypophyseal membranes seems to reflect interaction with SRIF receptors on adenohypophyseal cells. Since biological effects of the peptide have been reported on GH, thyrotropin-stimulating hormone, and PRL secretion, further studies are required to determine the cell types upon which this binding occurs.
Animals↗
Reciprocal interactions of somatostatin with thyrotropin-releasing hormone and vasoactive intestinal peptide on prolactin and growth hormone secretion in vitro.
Reciprocal interactions of somatostatin (SRIF) and vasoactive intestinal peptide (VIP) or TRH on in vitro PRL and GH release from male rats hemipituitaries were investigated. SRIF did not modify basal PRL release, but TRH- or VIP-induced release was inhibited by SRIF in a dose-dependent manner [effective concentration-fifty (EC50) = 1.7 +/- 0.9 nM for SRIF inhibition of TRH stimulation and EC50 = 0.8 +/- 0.5 nM for SRIF inhibition of VIP stimulation]. VIP and TRH did not affect GH release by themselves, but reduced the inhibition of GH secretion elicited by SRIF (EC50 = 7.6 +/- 3.4 nM for TRH blockade of SRIF inhibition and EC50 = 4.6 +/- 3.1 nM for VIP blockade of SRIF inhibition). Secretin, a partial structural analog of VIP, also blocked SRIF-induced inhibition of GH and stimulated PRL release. Secretin stimulation of PRL release was also prevented by SRIF. [D-Trp8,D-Cys14]SRIF, a potent analog of SRIF, antagonized VIP stimulation of PRL secretion with the same apparent affinity as the native peptide. The maximal stimulation, but not the apparent affinity of VIP action on prolactin release was reduced by SRIF, suggesting that the interaction is of a noncompetitive nature. This conclusion as further substantiated by the observation that neither TRH nor VIP were able to displace specific 125I-labeled [Tyr1] SRIF high affinity binding to pituitary membranes. The three peptides tested thus appear to exhibit reciprocal interactions mediated by independent receptor sites on GH as well as on PRL-producing cells.
Animals↗
Topography of median eminence somatostatinergic innervation.
Somatostatin (SRIF) in the central nervous system is mostly concentrated in the median eminence (ME). Immunocytochemical methods have revealed high densities of SRIF-positive perikarya between the preoptic area and the periventricular nucleus of the hypothalamus (NPE). The aim of the present study was to define more precisely the specific pathways of SRIF neurons from NPE to the ME. SRIF levels were measured by radioimmunoassay, following various hypothalamic transections. Frontal periventricular sections decreased SRIF-ME content by 70% (P less than 0.01), when located at the anterior end of the ME but no diminution was observed when the cuts were located anteriorly or posteriorly. Parasaggital transections decreased SRIF-ME levels by 50% (P less than 0.05) when located at the outer border of the ventromedial and premammillary nucleus, but the decrease was not significant when cuts were located anteriorly. Taken together, our data indicate that most SRIF-containing neurons, originating in the NPE, do not reach the ME directly along the border of the 3rd ventricle; instead they form a loop across the medial forebrain bundle before re-entering the mediobasal hypothalamus at the ME level.
Afferent Pathways↗
Monosodium glutamate: acute and chronic effects on rhythmic growth hormone and prolactin secretion, and somatostatin in the undisturbed male rat.
The present in investigation was designed to determine the chronic effects of neonatal monosodium glutamate (MSG) administration (4 g/kg s.c.) and the acute effects of MSG (1 g/kg i.p.) on episodic growth hormone (GH) and prolactin (PRL) secretion and brain somatostatin (SRIF) in unanesthetized, chronically cannulated male rats. Adult rats showed the typical physical characteristics that result from neonatal MSG administration. Analysis of episodic GH secretion showed a significant reduction in : (1) the amplitude of GH secretory peaks. and (2) the mean 5.5-h plasma level of GH. Bursts of plasma PRL were inhibited by MSG, but the mean 5.5-h plasma levels were not affected. SRIF concentrations in the medial basal hypothalamus were reduced by 60% after neonatal MSG. Acute administration of MSG to adult rats caused an immediate, long-lasting suppression of rhythmic GH secretion and a rapid, transient release of PRL. These results suggest: (1) neonatally administered MSG causes a marked disturbance in episodic GH and PRL secretion in adult rats; (2) MSG induces a decrease in hypothalamic SRIF and possibly GH-releasing factor; and (3) the acute effects of MSG on GH and PRL may be due to the inhibition and/or excitation of a complex neuronal network involving monoaminergic and peptidergic systems.
Animals↗