Biomedical subjects
J C Reubi
Publications and source records attributed to J C Reubi.
Brain somatostatin receptor subpopulation visualized by autoradiography.
[125I-Tyr11]somatostatin-14 as well as iodinated D-Tyr1 and Tyr3 derivatives of the cyclic octapeptide somatostatin analog, SMS 201-995 (H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol) have been used as radioligands for somatostatin receptor autoradiography in rat brain. Although the cyclic octapeptide ligands label the majority of the regions labeled with [125I-Tyr11]somatostatin, in the cortex and hippocampus only a subpopulation of somatostatin receptors is labeled. Cyclic octapeptide ligands have improved resolution due to their very low non-specific binding.
Autoradiographic mapping of somatostatin receptors in the rat central nervous system and pituitary.
Somatostatin receptor-binding sites have been visualized by autoradiography in the rat central nervous system and the pituitary using the [Tyr3] derivative of the stable octapeptide somatostatin analogue SMS 201-995, code named 204-090 (sequence in text), which has been shown to label specifically high-affinity somatostatin receptors in brain homogenates. Receptors are particularly concentrated in the deeper layers of the cerebral cortex and large areas of the limbic system are rich in somatostatin receptors, in particular the hippocampus (CA1, CA2, dentate gyrus), most amygdaloid nuclei, the medial habenula and the septum. Parts of the olfactory, visual and auditory, as well as visceral and somatic sensory systems are heavily labelled, in particular the anterior olfactory nucleus and tubercle, the superior and inferior colliculi, the nucleus of the solitary tract, the substantia gelatinosa of the spinal cord and the spinal trigeminal nucleus. It is of interest that the central grey and locus coeruleus are also substantially labelled with [125I]204-090. Striatum has moderate amounts of somatostatin receptors, distributed in a patchy and heterogeneous way. Cerebellum and substantia nigra are virtually devoid of somatostatin receptors. The described receptors are likely to represent the molecular target for a variety of pharmacological actions of somatostatin in the central nervous system and they emphasize the role played by somatostatin as a neuropeptide in this organ.
A somatostatin analogue inhibits chondrosarcoma and insulinoma tumour growth.
The in vivo effects on tumour growth of a potent somatostatin analogue, SMS 201-995 [H-(D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr-(ol)], were measured in two characterised transplantable tumours: a) the Swarm rat chondrosarcoma, known to be insulin-, growth hormone (GH)-, somatomedin- and corticosteroid-dependent, b) a hamster insulinoma, bearing specific high affinity somatostatin receptors. SMS 201-995 (1.25 mg/kg/day) given for 25 days to rats bearing freshly transplanted chondrosarcomas inhibited tumour volume by 48%. A significant tumour growth inhibition was measured also in well developed tumours treated with high doses of SMS 201-995 (1.25mg/kg/day) for 7 days. In the treated animals, GH was significantly inhibited. In hamsters bearing a freshly transplanted insulinoma, the daily application of SMS 201-995 (200 micrograms/kg/day, sc) for 33 days could significantly inhibit the growth (as measured by tumour volume) of the tumour. A moderate inhibitory effect of SMS 201-995 on the growth of well grown insulinomas could also be observed. This study shows that SMS 201-995 under the present experimental conditions has a moderate but significant growth inhibitory effect in two different transplantable tumour models. In the rat chondrosarcoma, the effect of SMS 201-995 is probably indirect, due to inhibition of GH, somatomedin and insulin. In the hamster insulinoma, the effect is possibly due to a more direct action of SMS 201-995 on specific somatostatin receptors present in this tumour.
Central nervous system-mediated growth inhibition of a rat prostate carcinoma by an opioid.
Long-term treatment for more than 3 months with a central nervous system (CNS)-active drug, the opioid agonist bremazocine, at a dose of 1 mg/kg per day elicited an 80% inhibition of the volume of the subcutaneously transplanted rat prostate adenocarcinoma Dunning R3327H. Whereas, under this therapy, prostate tumour and prostatic weights were decreased, testes and pituitary weights remained normal. Bremazocine inhibited not only the growth of freshly transplanted tumours but also that of well-grown Dunning prostate carcinomas since, after 41 days of treatment, such tumours showed a volume inhibition of 52%. In these experiments bremazocine decreased LH and testosterone plasma levels significantly. Bremazocine, therefore, probably acts mainly through suprapituitary CNS-opiate receptor sites, which indirectly, rather than locally, mediate LH inhibition. Indeed, no specific receptors for bremazocine could be found in the Dunning tumour, which makes a local action of bremazocine in this tissue unlikely. the efficient tumour growth inhibition through the supra-pituitary action of bremazocine makes such opiate drugs, which lack respiratory and side effects due to improper use, of potential interest for treatment of prostatic tumours.
Visualization of LHRH receptors in the rat brain.
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Evidence for two somatostatin-14 receptor types in rat brain cortex.
The binding characteristics of a stable somatostatin analogue, SMS 201-995, have been evaluated in a somatostatin receptor binding assay using [125I-Tyr11]somatostatin, and cortical, pituitary or pancreatic membranes. High affinity binding sites for somatostatin-14 and for SMS 201-995 were identified in rat cortex (Kd = 0.60 nM) as well as in pituitary (Kd = 0.74 nM) and pancreatic beta-cells (Kd = 0.18 nM). In the cortex, in contrary to the two other tissues, SMS 201-995 only labels a part (approximately 75%) of the receptors recognized by somatostatin-14. This suggests the presence in the cortex of more than one population of somatostatin receptors. In conclusion, SMS 201-995 appears as a valuable tool for differentiating the two somatostatin receptor types.
High density of somatostatin receptors in pituitary tumors from acromegalic patients.
Using a SRIH receptor-binding assay previously developed for rat pituitary tissue, we measured SRIH-binding sites in human pituitary adenomas obtained from five acromegalic patients. Saturable and high affinity-binding sites for SRIH were found, with respective dissociation constants (Kd) of 0.57, 1.48, 1.04, 0.24, and 1.04 nM for the different adenomas, which is comparable with the Kd of 0.95 nM for SRIH in normal rat pituitary. In adenomas of most patients, however, the number of sites was much higher than in rat pituitary (100 fmol/mg protein), being, respectively, 757, 800, 441, 103, and 1058 fmol/mg protein. The pharmacological characteristics of these sites were similar in both species, [Des-Trp8]SRIH being inactive but the stable SRIH analog SMS 201-995 [H-(D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr(ol)] being slightly more potent than SRIH. This is the first description of specific SRIH-binding sites in human pituitary tissue and in particular in human pituitary adenomas. These results suggest that the development of GH-secreting pituitary adenomas is not due to the absence of SRIH receptors or to a decrease in their affinity for SRIH. The large number of sites with high affinity for SMS 201-995 suggests that the use of SRIH analogs could be of potential benefit in reducing GH levels in patients with acromegaly.
High affinity binding sites for somatostatin to rat pituitary.
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Pituitary somatostatin receptors: dissociation at the pituitary level of receptor affinity and biological activity for selective somatostatin analogs.
High affinity and saturable binding of [125I-Tyr11]somatostatin (SS) is described in membrane homogenates from a pituitary transplantable tumor (GH4C1) rich in somatotrophs (KD for SS = 0.67 nM; Bmax = 30 fmol/mg protein). Binding characteristics and pharmacology are similar to those measured on normal pituitary membranes. The potency of various SS analogs highly correlates with that measured in in vitro bioassay for growth hormone. This suggests that those GH4C1 membranes are a good model for SS receptors on somatotrophs. Interestingly however, analogs in which the Asn5 is deleted (Des-Asn5) or D-Ser replaces Ser13 show dissociated potencies between the various assays: [D-Ser13] analogs are more potent in pituitary than in GH4C1 membranes binding assay. Des-Asn5-modified analogs are much more potent in both pituitary binding assays than in the bioassay. This could reflect a multiplicity of SS receptor subtypes in pituitary.
Specific high affinity binding sites for somatostatin-28 on pancreatic beta-cells: differences with brain somatostatin receptors.
Saturable and high affinity binding sites have been obtained for an iodinated somatostatin-28 (SS-28) analog, [Leu8,D-Trp22,125I-Tyr25] SS-28, in a membrane preparation from hamster insulinoma, mainly composed of pancreatic beta-cells. Specific binding is maximal after 1 hour incubation at 22C and represents 65% of the total binding. KD for [Leu8,D-Trp22,Tyr25] SS-28 is 0.25 nM with the number of sites corresponding to 68 fmol/mg protein. The KD for SS-28 (1nM) is more than 5 times lower than that for SS-14. SS-28 analogs, such as [D-Trp22] SS-28 and analogs which selectively inhibit insulin release in vivo (Des-Asn5[D-Trp8,D-Ser13] SS-14 and Des-Asn19[D-Trp22,D-Ser27] SS-28), are the most potent compounds in this assay. C-terminal replacement of L-cysteine by D-cysteine reduces the apparent affinity of SS analogs. Unrelated peptides and the inactive analog Des-Trp8-SS-14 have no affinity for insulinoma binding sites. There are differences between the insulinoma SS binding sites and those monitored under similar conditions from rat cerebral cortex. In cerebral cortex, SS-14 and SS-28 have similar affinity for the binding sites, and the insulin selective analogs are less potent than SS-14. It is concluded that pancreatic beta-cells, as well as brain, possess high affinity binding sites for SS, but that they differ in some of their pharmacological properties.
Mass fragmentographic determination of endogenous glycine and glutamic acid released in vivo from the pigeon optic tectum. Effect of electric stimulation of a midbrain nucleus.
Various investigations suggest glycine to be an inhibitory transmitter in the pigeon optic lobe in a pathway originating in the nucleus isthmi, pars parvocellularis (Ipc) terminating in the optic tectum. In order to obtain additional evidence for this hypothesis the in vivo release of endogenous glycine in the optic tectum upon electrical stimulation of Ipc was investigated. By perfusing the upper strata of the optic tectum with Ringer solution using a push-pull cannula endogenous amino acids released from the surrounding tissue were collected. Concentration of glycine and glutamic acid in the perfusates were determined by mass fragmentography of their N-pentafluoropropionyl hexafluoroisopropyl esters. Deuterium-labeled glycine and glutamic acid were used as internal standards for quantitative measurements. The resting release of glycine and glutamic acid was 2.9 pmol/min and 1.4 pmol/min, respectively. Electrical stimulation of Ipc was found to induce a 2--40-fold increase of the glycine efflux into the perfusate whereas the efflux of glutamic acid remained at a constant level. These findings strongly support the hypothesis that glycine is a transmitter in Ipc-tectal neurons.
High affinity binding sites for a somatostatin-28 analog in rat brain.
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Selective bidirectional transport of [3H]d-aspartate in the pigeon retino-tectal pathway.
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Diurnal variation in the release of alpha-MSH from rat hypothalamus and pituitary.
Release of alpha-MSH from rat hypothalamic slices was characterized with respect to ionic requirements and possible diurnal variations using a sensitive radioimmunoassay. Addition of 47 mM KCl to the superfusion medium resulted in a twofold increase in alpha-MSH functions as a neurotransmitter or neuromodulator in the hypothalamus. Both spontaneous and potassium-induced alpha-MSH release compared to spontaneous release. Removal of calcium from the superfusion medium abolished the potassium-evoked release of alpha-MSH. This supports the concept that alpha-MSH release were related to diurnal variation. Marked release from the slices was observed at 10.10 h, corresponding to a peak in the alpha-MSH concentration in the hypothalamus [18] and to a lower levels of alpha-MSH in the blood. Contrarily, no significant release from the hypothalamus was obtained at 17.00 h when hypothalamic alpha-MSH content was low, but blood levels exhibited a peak. These findings suggest that there are differences in the regulation of the alpha-MSH from the pituitary and that in the hypothalamus.
Glutamatergic pathways in the pigeon and the rat brain.
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The effect of cochlear nerve lesion on the release of glutamate, aspartate, and GABA from cat cochlear nucleus, in vitro.
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In vitro release of 5-[3H]hydroxytryptamine from rat spinal trigeminal nucleus.
A potassium-evoked release of 5-[3H]hydroxytryptamine (5-HT), newly synthesized from [3H]tryptophan, was obtained from slices of the subnucleus caudalis of rat spinal trigeminal nucleus by means of an in vitro perfusion system. This release was dose-dependent and calcium-sensitive and quantitatively comparable to the 5-HT release in substantia nigra. The putative transmitter of the primary sensory afferents, substance P, stimulates the spontaneous 5-HT release, whereas another peptide, neurotensin, has no effect.