Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are several indications for an involvement of neuroexcitatory mechanisms in ischemic neuron damage. Since we forwarded the hypothesis in 1982 that the transmitter glutamate is playing a key role, several lines of evidence have substantiated this: there is a pronounced transmitter release induced by ischemia and there is uptake of Ca++ via NMDA-operated calcium channels. Under certain circumstances postischemic neuron death can be impaired by administration of either NMDA-antagonists or calcium blockers. Further proof for the induction of harmful excitatory mechanisms by ischemia has been obtained by preischemic denervation of the vulnerable nerve cells. After transient cerebral ischemia in rats or gerbils, there are signs of irreversible damage (eosinophilia) of neurons in the dentate hilus (somatostatin-positive cells) after 2-3 hours and of hippocampal pyramidal neurons after 2-3 days (delayed neuron death). In the first case, removal of the (main) input to hilus cells by degranulation (colchicine selectively eliminates granule cells) protects these. In the case of pyramidal neurons removal of Schaffer collaterals/commisurals or input from the entorhinal cortex have a protective effect. Recently, we have measured glutamate and calcium in CA1 of denervated rats during 10 min of ischemia, and it turns out that there is almost no extracellular glutamate release or lowering of calcium in contrast to ischemic animals with intact innervation. Also in the postischemic period there are indications of a continuation of the damaging processes induced by ischemia. Besides the well known postischemic hypoperfusion, a prolonged release of glutamate has been reported, as well as burst firing in some models.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ischemia as an excitotoxic lesion: protection against hippocampal nerve cell loss by denervation. 838 Jun 75

The nicotinic cholinergic antagonist alpha-bungarotoxin (alpha-BT) binds throughout the rat hippocampal formation. The binding is displaceable by d-tubocurarine. The most heavily labeled cells are GABA-containing interneurons in the dentate and in Ammon's horn. These neurons have several different morphologies and contain several neuropeptides. alpha-BT-labeled interneurons in the dentate are small cells between the granular and molecular layers that often contain neuropeptide Y. alpha-BT-labeled interneurons in CA1 are medium-sized interneurons, occasionally found in stratum pyramidale, but more often found in stratum radiatum and stratum lacunosum moleculare. These neurons often contain cholecystokinin. The largest alpha-BT-labeled interneurons are found in CA3, in both stratum radiatum and stratum lucidum. These neurons are multipolar and frequently are autofluorescent. They often contain somatostatin or cholecystokinin. These large interneurons have been found to receive medial septal innervation and may also have projections that provide inhibitory feedback directly to the medial septal nucleus. The cholinergic innervation of the hippocampus from the medial septal nucleus is under the trophic regulation of NGF and brain-derived neurotrophic factor, even in adult life. Expression of mRNA for both these factors is increased in CA3 and the dentate after intraventricular administration of alpha-BT, but not after administration of the muscarinic antagonist atropine. alpha-BT-sensitive cholinergic receptors on inhibitory interneurons may be critical to medial septal regulation of the hippocampal activity, including the habituation of response to sensory input.
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PMID:Alpha-bungarotoxin binding to hippocampal interneurons: immunocytochemical characterization and effects on growth factor expression. 847 87

The distribution of somatostatin receptors (SRIF-R) was analyzed in the limbic system of the adult rat by in vitro autoradiography with [125I-Tyr0,DTrp 8]S14 as a radioligand. Precise quantification of the density of binding sites, at 0.2 mm intervals throughout the different areas revealed a marked heterogeneity of labeling in most structures. In particular, SRIF-R were concentrated in the basal (104.4 +/- 3.3 fmol/mg proteins) and basolateral amygdaloid nuclei (94.8 +/- 4.3 fmol/mg proteins), and in the nucleus of the lateral olfactory tract (121.6 +/- 2.4 fmol/mg proteins), whereas moderate densities were detected in the amygdalo-hippocampal nucleus (76.4 +/- 2.8 fmol/mg proteins). The medial (41.3 +/- 1.9 fmol/mg proteins) and the central (24.0 +/- 1.4 fmol/mg proteins) amygdaloid nuclei contained lower SRIF-R concentrations. It appears from these observations, in the light of the anatomical pathways of the amygdala, that intra-amygdalian SRIF-containing neurons project to the amygdalo-hippocampal nucleus, and that SRIF-R in the basolateral complex are the target of afferents from limbic cortical areas. SRIF-R were detected at different levels of the hippocampal formation but their distribution was more restricted than that of SRIF-containing fibers. The maximal density of sites was detected in the ventral and dorsal parts of the subiculum (115.0 +/- 3.4 and 87.0 +/- 2.8 fmol/mg proteins, respectively) and in the parasubiculum (100.1 +/- 5.4 fmol/mg proteins). In Ammon's horn, the stratum oriens and stratum radiatum of the CA1 field were the only sites enriched in SRIF-R (74.1 +/- 2.0 and 74.6 +/- 1.9 fmol/mg proteins, respectively). The apparent lack of receptors in the pyramidal cell layer indicated that, in Ammon's horn, SRIF is involved in intra-hippocampal communication. Low levels of receptors were found in the hippocampal CA2 and CA3 fields. SRIF-R in the dentate gyrus were mainly concentrated in the molecular layer (57.3 +/- 1.2 fmol/mg proteins). A very high density of sites was also observed in the entorhinal cortex (up to 123.1 +/- 1.5 fmol/mg proteins). A clear mismatch between SRIF and SRIF-R was detected in the septum and the habenula. In the profound layers of the cingulum and retrosplenial cortex, a heterogeneous distribution of SRIF-R was observed. High concentrations of sites were detected in the rostral zone of the cingulate cortex (93.4 +/- 2.0 fmol/mg proteins) while the posterior cingulate only exhibited moderate concentrations of sites (66.5 +/- 0.7 fmol/mg proteins).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Quantitative autoradiography of somatostatin receptors in the rat limbic system. 851 16

5-Lipoxygenase-activating protein (FLAP) is an 18-kDa integral membrane protein required, in peripheral cells, for the activation of 5-lipoxygenase (5-LO) and for the resulting synthesis of leukotrienes from arachidonic acid. In the brain, the leukotrienes have been implicated in several pathophysiological events and in the electrophysiological effect of somatostatin, yet the cellular origin and role of these messenger molecules are still poorly understood. In the present study, we used reverse transcriptase-polymerase chain reaction, in situ hybridization, and immunohistochemistry to demonstrate that 5-LO and FLAP are expressed in various regions of the rat brain, including hippocampus, cerebellum, primary olfactory cortex, superficial neocortex, thalamus, hypothalamus, and brainstem. Highest levels of expression were observed in cerebellum and hippocampus. In the latter we demonstrate the colocalization of 5-LO and FLAP in CA1 pyramidal neurons. Moreover, electrophysiological experiments show that selective inhibition of FLAP with the compound MK-886 (0.25-1 microM) prevents the somatostatin-induced augmentation of the hippocampal K+ M-current. Our results provide necessary evidence for the presence and signaling role of 5-LO and FLAP in central neurons and strongly support their proposed participation in somatostatin-receptor transmembrane signaling.
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PMID:Arachidonate 5-lipoxygenase and its activating protein: prominent hippocampal expression and role in somatostatin signaling. 852 47

The synaptic input of interneurons with horizontal dendrites in stratum oriens of the CA1 region was investigated, with particular attention to the portion of synapses originating from local pyramidal cells. Most of these GABAergic interneurons are known to contain somatostatin, and terminate on pyramidal dendrites in conjunction with entorhinal afferents in stratum lacunosum-moleculare. A smaller number of horizontal cells in this layer are immunoreactive for calbindin, and project to the medial septum. Selective ischaemic degeneration was used to label local axon collaterals of CA1 pyramidal cells, and immunostaining for mGluR1 or calbindin to visualise somatostatin- and calbindin-containing horizontal interneurons, respectively, at the stratum oriens-alveus border. The number of degenerating and intact synaptic boutons was counted on mGluR1- as well as on calbindin-positive dendrites and somata, whereas in another group of animals the proportion of GABA-immunoreactive synapses was estimated on calbindin-positive dendrites. On average, > 60% of the total presynaptic elements of both cell types were degenerating, i.e. originated from CA1 pyramidal cells, whereas GABA-positive boutons, which are known to survive ischaemia, are likely to account for a large proportion of non-degenerating boutons. Thus the vast majority of presumed excitatory synapses on somatostatin- and calbindin-containing horizontal neurons derives from local collaterals of CA1 pyramidal cells. The remaining GABA-negative synapses surviving ischaemia may also originate from CA1 pyramidal cells, e.g. from those in the ventral hippocampus, which are rarely damaged by global forebrain ischaemia. Alternative sources may include subcortical afferents known to innervate interneurons, or ipsi- and contralateral CA3 pyramidal cells, which, according to the present results, may account only for a negligible number of synapses on these interneurons types. We conclude that somatostatin-containing neurons at the oriens-alveus border of CA1, which are likely to mediate an inhibitory control of the efficacy and/or plasticity of entorhinal synapses on pyramidal cell dendrites, are driven primarily in a feed-back manner. The source of afferent excitation for calbindin-containing horizontal neurons in this region is very similar, suggesting that the GABAergic hippocamposeptal feed-back is also activated by local pyramidal cell collaterals.
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PMID:Synaptic input of horizontal interneurons in stratum oriens of the hippocampal CA1 subfield: structural basis of feed-back activation. 854 73

Somatostatin (SST) is one of the major peptide transmitters in the mammalian central nervous system and also seems to exert specific functions during brain development. In contrast to ligand binding experiments, by which two pharmacologically different binding sites were characterized, molecular cloning techniques have led to the identification of at least five different receptor subtypes (SSTR1-5), which according to RNA blot analyses seem to be differentially distributed and regulated in the developing brain. In order to provide more precise data on the distribution of SSTR1 during ontogenesis, we have performed an in situ hybridization analysis, using a 35S-labelled RNA probe, in the developing rat cortex between embryonic day (E)12 and adulthood. Within the cortical plate, expression of SSTR1 gene was first detected in parallel with the establishment of the deep laminae V/VI at E16, thereby following the characteristic morphogenetic gradients of cortical plate construction. Thus, with the subsequent addition of cells along the radial dimension, e.g. the deposition of the supragranular neurons beyond E18, the hybridization signal spreads as an uniform homogenous band through the entire cortical plate, whereby silver grains reach their peak density around birth. Similar developmental gradients were observed along the lateromedial and frontooccipital dimension, whereby SSTR1 transcripts were detected near the frontal pole and the lateral cortical areas roughly 2 days before they appeared in the occipital and medial cortical anlage, respectively. From the initially homogenous distribution, two distinct SSTR1 mRNA-positive bands coextensive with laminae V/VI and II/III, respectively, and sparing lamina IV evolved during the first postnatal week, the grain density of which decreased during further postnatal development. Within the hippocampal formation, SSTR1 transcripts were initially observed at E18 in the subicular complex, and after birth also extending into the neighboring CA1 region. During the 1st and 2nd postnatal week, silver grains were observed over the pyramidal cell layer of CA2 and CA3 and as a faint supragranular band in the dentate gyrus. Similar to the isocortex, grain density decreased thereafter. Hypothetically, the pronounced temporospatial regulation of SSTR1 gene expression during brain development can be correlated with (1) the establishment and eventual reduction of transient cortical SSTergic neuron populations described for late pregnancy and early postnatal development and (2) a receptor subtype exchange during maturation as evidenced by the late (from postnatal day 7 onward) appearance of e.g. SSTR3.
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PMID:Distribution of somatostatin receptor subtype 1 mRNA in the developing cerebral hemispheres of the rat. 857 44

Following transient global ischemia most of the neurons containing somatostatin in the fascia dentata of the dorsal hippocampal formation die, while somatostatinergic neurons in the CA1 region survive. The neurons react to ischemia with a transiently reduced expression of somatostatin mRNA and peptide. We have tested the hypothesis that this selective vulnerability is solely related to those somatostatinergic neurons which do not express the calcium-binding protein parvalbumin. Postischemic changes were studied in rat dorsal hippocampus at 2 and 16 days after 10 min of global cerebral ischemia using a four-vessel occlusion model. We performed a double-staining visualizing the mRNA coding for somatostatin by non-radioactive in situ hybridization and parvalbumin protein by immunocytochemistry. Only 5% of the somatostatinergic cells in the fascia dentata contained parvalbumin. The number of somatostatinergic cells was permanently reduced following ischemia. Among surviving neurons we found cells with and without parvalbumin expression. Thus, expression of parvalbumin is not predictive for survival of somatostatinergic cells in the fascia dentata. In contrast, in CA1, 37% of the somatostatinergic cells contained parvalbumin. These cells were unaffected by the transient ischemic period. The somatostatinergic cells lacking parvalbumin showed transiently reduced mRNA levels at day 2, but recovered to control values at the 16th postischemic day. Thus, expression of the calcium-buffering protein parvalbumin coincides with resistance of somatostatinergic neurons in CA1 to transient effects of ischemia. We conclude that the calcium-buffering capacity of parvalbumin may partially contribute to the protection of somatostatinergic neurons from ischemia in the dorsal hippocampus. However, the survival of somatostatinergic cells without parvalbumin indicates the importance of other factors as well.
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PMID:Co-localization of somatostatin mRNA and parvalbumin in the dorsal rat hippocampus after cerebral ischemia. 858 97

Sustained electrical stimulation of the perforant pathway was used to induce long-lasting hippocampal seizures in conscious rats. One hour prior to stimulation, rats were given i.p. injections of either saline or a commonly used antiepileptic drug, carbamazepine (5H-dibenz[b, f]azepine-5-carboxamide; CBZ; 20 mg/kg). When tested 2 weeks later in a water maze, both the saline- and the carbamazepine-pretreated rats showed similarly a severe impairment in spatial learning compared to non-stimulated controls. Histological evaluation revealed that the pyramidal cell damage was (P < 0.05) milder in the carbamazepine-pretreated group in the CA1, but not the CA3c subfield. However, the number of somatostatin-immunoreactive neurons in both stimulated groups was reduced equally. Thus, at the dose of 20 mg/kg, which is a usual anticonvulsive dose in humans, carbamazepine seems to offer only partial protection against pyramidal cell damage, but no protection against the hilar somatostatin-immunoreactive neuron loss or the spatial learning deficit after perforant pathway stimulation in rats. The result clearly differs from that obtained either with a GABA (gamma-aminobutyric acid)-enhancing drug and a novel antiepileptic, vigabatrin (4-amino-hex-5-enoic acid) or with a competitive NMDA (N-methyl-D-aspartate) receptor antagonist, CGP 39551 (DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid carboxyethylester) in the same test situation.
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PMID:Failure of carbamazepine to prevent behavioural and histopathological sequels of experimentally induced status epilepticus. 866 52

Biological actions of somatostatin are exerted via a family of receptors, for which five genes recently have been cloned. However, none of these receptor proteins has been visualized yet in the brain. In the present-study, the regional and cellular distribution of the somatostatin sst2A receptor was investigated via immunocytochemistry in the rat central nervous system by using an antibody generated against a unique sequence of the receptor protein. Specificity of the antiserum was demonstrated by immunoblot and immunocytochemistry on rat brain membranes and/or on cells transfected with cDNA encoding the different sst receptor subtypes. In rat brain sections, sst2A receptor immunoreactivity was concentrated either in perikarya and dendrites or in axon terminals distributed throughout the neuropil. Somatodendritic labeling was most prominent in the olfactory tubercle, layers II-III of the cerebral cortex, nucleus accumbens, pyramidal cells of CA1-CA2 subfields of the hippocampus, central and cortical amygdaloid nuclei, and locus coeruleus. Labeled terminals were detected mainly in the endopiriform nucleus, deep layers of the cortex, claustrum, substantia innominata, subiculum, basolateral amygdala, medial habenula, and periaqueductal gray. Electron microscopy confirmed the association of sst2A receptors with perikarya and dendrites in the former regions and with axon terminals in the latter. These results provide the first characterization of the cellular distribution of a somatostatin receptor in mammalian brain. The widespread distribution of the sst2A receptor in cerebral cortex and limbic structures suggests that it is involved in the transduction of both pre- and postsynaptic effects of somatostatin on cognition, learning, and memory.
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PMID:Localization of the somatostatin receptor SST2A in rat brain using a specific anti-peptide antibody. 869 57

The messenger RNA (mRNA) expression of somatostatin receptors sst1-5 was studied in human brain by in situ hybridization histochemistry using specific oligonucleotide probes. sst1 receptor mRNA was mainly found in the outer and intermediate layers of cerebral cortex, hippocampal formation (CA1, dentate gyrus, entorhinal cortex), hypothalamus, substantia nigra, medullary nuclei and dentate nucleus. sst2 transcripts were present in the deep layers of the cerebral cortex, amygdala, hippocampal formation (CA1, dentate gyrus, subiculum, entorhinal cortex), the granular layer of the cerebellum and pituitary. sst3 receptor mRNA was localized in the cerebral cortex, hippocampal formation (CA1, dentate gyrus), several medullary nuclei and the granule and possibly Purkinje cell layer of the cerebellum and at very low levels in the pituitary. sst4 receptor mRNA was absent in the cerebral cortex. Intermediate signals were observed in the dentate gyrus of the hippocampus and several medullary nuclei while an intense expression was found in the granule and Purkinje cell layer of cerebellum. sst5 transcripts were present in the pituitary and the granule layer of the cerebellum. The present results show that mRNAs of sst1-4 somatostatin receptors have distinct distribution patterns within the human brain, although there is overlap in several regions. sst5 receptor mRNA expression appears to be very low and restricted to the cerebellum and pituitary. The distribution pattern observed in the human brain was broadly similar to that reported previously in the rat brain. The high expression levels of at least two somatostatin receptor subtype mRNAs (sst2 and sst5) in the pituitary gland suggest that somatostatin may affect neuroendocrine functions via more than one receptor.
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PMID:Expression of five somatostatin receptor mRNAs in the human brain and pituitary. 889 42


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