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)

In addition to its functions as a neuronal messenger molecule, nitric oxide (NO) has also been implicated in playing a major role in ischemic damage and glutamate neurotoxicity. Using primary cortical cultures from transgenic neuronal NO synthase (NOS) null (nNOS-) mice, we definitively establish NO as a mediator of NMDA and hypoxic neurotoxicity. Neurotoxicity elicited by NMDA is markedly attenuated in nNOS- cortical cultures compared with wild-type cultures. The NOS inhibitor nitro-L-arginine is neuroprotective in wild-type but not nNOS-cultures, confirming the role of nNOS-derived NO in glutamate neurotoxicity. Confirming that the nNOS- cultures lack NMDA-stimulated nNOS activity, NMDA did not stimulate the formation of cGMP in nNOS- cultures, but markedly elevates cGMP in wild-type cultures. Both wild-type and nNOS- cultures are sensitive to toxicity induced by NO donors, indicating that pathways stimulated by NO that result in neuronal cell death are still intact in the transgenic mice. Superoxide dismutase is neuroprotective against NMDA and NO neurotoxicity in both wild-type and nNOS- cultures, highlighting the importance of superoxide anion in subsequent neuronal damage. The unknown cellular factors that endow differential resistance to NMDA neurotoxicity and differential susceptibility to quisqualate neurotoxicity remain intact in the nNOS- cultures, because the response of somatostatin-immunopositive neurons in nNOS- cultures to high-dose NMDA and low-dose quisqualate is identical to the response of NOS-immunopositive neurons in the wild-type cultures. There is no difference in susceptibility to kainate neurotoxicity between nNOS- and wild-type cultures and only a modest resistance to quisqualate neurotoxicity, confirming observations that NO-mediated neurotoxicity is associated primarily with activation of the NMDA receptor. The nNOS- cultures are markedly protected from 60 min of combined oxygen-glucose deprivation neurotoxicity compared with wild-type cultures. Wild-type cultures are protected from neuronal cell death by the NMDA receptor antagonist MK-801 and the NOS inhibitor L-nitroarginine methyl ester, but not its inactive stereoisomer D-nitroarginine methyl ester. nNOS- cultures were not additionally protected. These data confirm that activation of NMDA receptors and production of NO are primary mediators of neuronal damage after ischemic insult.
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PMID:Resistance to neurotoxicity in cortical cultures from neuronal nitric oxide synthase-deficient mice. 878 24

NMDA receptors are composed of proteins from two families: NMDAR1, which are required for channel activity, and NMDAR2, which modulate properties of the channels. The mRNA encoding the NMDAR2D subunit has a highly restricted pattern of expression: in the forebrain, it is found in only a small subset of cortical, neostriatal and hippocampal neurons. We have used a quantitative double-label in situ hybridization method to examine the expression of NMDAR2D mRNA in neurochemically defined populations of neurons. In the neostriatum, NMDAR2D was expressed by the interneuron populations marked by preprosomatostatin (SOM), the 67-kDa form of glutamic acid decarboxylase (GAD67), parvalbumin (PARV), and choline acetyltransferase (ChAT) mRNAs but not by the projection neurons expressing beta-preprotachykinin (SP) or preproenkephalin (ENK) mRNAs. In the neocortex, NMDAR2D expression was observed in only a small number of neurons, but these included almost all of the SOM-, GAD67-, and PARV-expressing interneurons. In the hippocampus, NMDAR2D was not present in pyramidal or granule cells, but was abundant in SOM-, GAD67-, and PARV-positive interneurons. NMDAR2D expression appears to be a property shared by interneurons in several regions of the brain. The unique electrophysiological characteristics conveyed by this subunit, which include resistance to blockade by magnesium ion and long channel offset latencies, may be important for the integrative functions of these neurons. NMDAR2D-containing receptor complexes may prove to be important therapeutic targets in human disorders of movement. In addition, the presence of NMDAR2D subunits may contribute to the differential vulnerability of interneurons to excitotoxic injury.
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PMID:Expression of NMDAR2D glutamate receptor subunit mRNA in neurochemically identified interneurons in the rat neostriatum, neocortex and hippocampus. 891 84

Somatostatin (SRIF) exerts a modulatory function on neuronal transmission in the CNS. It has been proposed that a reduction of calcium currents is the major determinant of the inhibitory activity of this peptide on synaptic transmission. Because the neurotoxicity induced by activation of the NMDA subtype of glutamate receptor is mediated through excessive Ca2+ influx, we investigated whether SRIF counteracted NMDA-induced neuronal cell death. Neurons from embryonic rat cerebral cortex were cultured for 7-10 days and then exposed to 0.5 and 1 mM NMDA for 24 h. The neuronal viability, as assessed by the colorimetric method, decreased by 40 and 60%, respectively, compared with the control condition. Morphological and biochemical evidence indicated that cell death occurred by necrosis and not through an apoptotic mechanism. SRIF (0.5-10 microM), simultaneously applied with excitatory amino acid, significantly reduced in a dose-dependent manner the neurotoxic effect of NMDA but not that of KA (0.25-0.5 mM). GABA (10 microM) partially protected neurons to a similar extent from NMDA- or KA-induced toxicity. SRIF type 2 receptor agonists, octreotide (SMS 201-995; 10 microM) and vapreotide (RC 160; 10 microM), did not influence the NMDA-dependent neurotoxicity. The intracellular mechanism involved in SRIF neuroprotection was investigated. Pertussin toxin (300 ng/ml), a G protein blocker, antagonized the protective effect of SRIF on NMDA neurotoxicity. Furthermore, the neuroprotective effect of SRIF was mimicked by dibutyryl-cyclic GMP (10 microM), a cyclic GMP analogue, whereas 8-(4-chlorphenylthio)-cyclic AMP (10 microM), a cyclic AMP analogue, was ineffective. The cyclic GMP content was increased in a dose-dependent manner by SRIF (2.5-10 microM). Finally, both specific (Rp-8-bromoguanosine 3',5'-monophosphate, 10 microM) and nonspecific [1-(5 isoquinolinylsulfonyl)-2-methylpiperazine (H7), 10 microM] cyclic GMP-dependent protein kinase (cGMP-PK) inhibitors did not interfere with NMDA toxicity but substantially reduced SRIF neuroprotection. Our data suggest a selective neuroprotective role of SRIF versus NMDA-induced nonapoptotic neuronal death in cortical cells. This effect is likely mediated by cGMP-PK presumably by regulation of the intracellular Ca2+ level.
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PMID:Neuroprotective effect of somatostatin on nonapoptotic NMDA-induced neuronal death: role of cyclic GMP. 897 41

Using immunohistochemical double-labeling with a specific antibody recognizing both NR2A and NR2B subunits, we studied the cellular distribution of the NMDA receptor subunit NR2A/2B on all major known striatal neuron types. Among striatal interneurons, our results showed that none of somatostatin interneurons was labeled for NR2A/2B subunits, 56% of parvalbumin interneurons were double-labeled for NR2A/2B, and all identified cholinergic interneurons were labeled for NR2A/2B. Among striatal projections neurons, 95% of striatonigral neurons, 96% of enkephalin-containing neurons, and 98% of calbindin-containing striatal matrix neurons were double-labeled for NR2A/2B. Our studies demonstrate that there is a differential distribution of the NMDA receptor NR2A/2B subunits on striatal neuron types. The paucity of NR2A/2B subunits on NMDA receptors on striatal somatostatin interneurons may confer resistance to NMDA receptor-mediated excitotoxicity on these neurons.
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PMID:Cellular distribution of the NMDA receptor NR2A/2B subunits in the rat striatum. 901 67

Certain types of cancer pain fail to respond well either to systemic drug therapy or to spinal opioids because of the occurrence of intolerable adverse effects. In addition to spinal opioids other drugs may produce an antinociceptive effect when administered by the spinal route, such as local anesthetics, NSAID, alpha 2-agonists, calcium-channel blockers, NMDA antagonists, cholinergic drugs, peptides such as somatostatin, octreotide or calcitonin, adenosine agonists, benzodiazepines, neurokinin and cholecystokinin antagonists, nitric oxide synthase inhibitors, corticosteroids, and enkephalinase inhibitors. All these drugs may be administered in combination between them, realising the so called balanced spinal analgesia. The aim of this study is to analyse: the available methods for the evaluation of pharmacological interactions, the types of interaction between different spinal antinociceptive drugs and the role of balanced spinal analgesia in the treatment of cancer pain. Analysis of the presented data shows that the spinal synergism between opioids-local anesthetics and opioids-alpha 2-agonists can be useful in the treatment of opioid refractory cancer pain. Furthermore, the use of cholinergic drugs combined with opioids and alpha 2-agonists may be promising. Finally, even if the synergism between NSAID or NMDA antagonists with opioids or alpha 2-agonists have been proved, at the moment their use in man by the spinal route is not advisable because of the absence of adequate studies on their neurotoxicity and adverse effects.
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PMID:[Balanced spinal analgesia in the treatment of oncologic pain. Review of the literature]. 910 86

Somatostatin is one of the major peptides in interneurons of the hippocampus. It is believed to play a role in memory formation and to reduce the susceptibility of the hippocampus to seizure-like activity. However, at the cellular level, the actions of somatostatin on hippocampal neurons are still controversial, ranging from inhibition to excitation. In the present study, we measured autaptic currents of hippocampal neurons isolated in single-neuron microcultures. Somatostatin and the analogous peptides seglitide and octreotide reduced glutamatergic, but not GABAergic, autaptic currents via pertussis toxin-sensitive G-proteins. This effect was observed whether autaptic currents were mediated by NMDA or non-NMDA glutamate receptors. Furthermore, somatostatin did not affect currents evoked by the direct application of glutamate, but reduced the frequency of spontaneously occurring excitatory autaptic currents. These results show that presynaptic somatostatin receptors of the SRIF1 family inhibit glutamate release at hippocampal synapses. Somatostatin, seglitide, and octreotide also reduced the frequency of miniature excitatory postsynaptic currents in mass cultures without affecting their amplitudes. In addition, all three agonists inhibited voltage-activated Ca2+ currents at neuronal somata, but failed to alter K+ currents, effects that were also abolished by pertussis toxin. Thus, presynaptic somatostatin receptors in the hippocampus selectively inhibit excitatory transmission via G-proteins of the Gi/Go family and through at least two separate mechanisms, the modulation of Ca2+ channels and an effect downstream of Ca2+ entry. This presynaptic inhibition by somatostatin may provide a basis for its reportedly anticonvulsive action.
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PMID:Somatostatin inhibits excitatory transmission at rat hippocampal synapses via presynaptic receptors. 915 23

Some authors have reported greater sparing of neurons containing somatostatin (SS)-neuropeptide Y (NPY)-NADPH-diaphorase (NADPHd) than projection neurons after intrastriatal injection of quinolinic acid (QA), an excitotoxin acting at NMDA receptors. Such findings have been used to support the NMDA receptor excitotoxin hypothesis of Huntington's disease (HD) and to claim that intrastriatal QA produces an animal model of HD. Other studies have, however, reported that SS/NPY/NADPHd interneurons are highly vulnerable to QA. We examined the influence of animal age (young versus mature), QA concentration (225 mM versus 50 mM), and injection speed (3 min versus 15 min) on the relative SS/NPY/NADPHd neuron survival in eight groups of rats that varied along these parameters to determine the basis of such prior discrepancies. Two weeks after QA injection, we analyzed the relative survival of neurons labeled by NADPHd histochemistry, SS/NPY immunohistochemistry, or cresyl violet staining (which stains all striatal neurons, the majority of which are projection neurons) in the so-called lesion transition zone (i.e., the zone of 40-60% neuronal survival). We found that age, and to a lesser extent injection speed, had a significant effect on relative SS/NPY/NADPHd interneuron survival. The NADPHd- and SS/NPY-labeled neurons typically survived better than projection neurons in young rats and more poorly in mature rats. This trend was greatly accentuated with fast QA injection. Age-related differences may be attributable to declines in projection neuron sensitivity to QA with age. Since rapid QA injections result in excitotoxin efflux, we interpret the effect of injection speed to suggest that brief exposure to a large dose of QA (with fast injection) may better accentuate the differential vulnerabilities of NADPHd/SS/NPY interneurons and projection neurons than does exposure to the same total amount of QA delivered more gradually (slow injection). These findings reconcile the discordant results found by previous authors and suggest that QA injected into rat striatum does reproduce the neurochemical traits of HD under some circumstances. These findings are consistent with a role of excitotoxicity in HD pathogenesis, and they also have implications for the basis of the more pernicious nature of striatal neuron loss in juvenile onset HD.
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PMID:Age-dependent differences in survival of striatal somatostatin-NPY-NADPH-diaphorase-containing interneurons versus striatal projection neurons after intrastriatal injection of quinolinic acid in rats. 927 55

Neurotrophin modulation of NMDA receptors in cultured murine and isolated rat neurons. J. Neurophysiol. 78: 2363-2371, 1997. Patch-clamp and calcium imaging techniques were used to assess the acute effects of the neurotrophins, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and nerve growth factor (NGF), on the responses of cultured and acutely isolated hippocampal and cultured striatal neurons to the glutamate receptor agonist N-methyl--aspartic acid (NMDA). The effects of BDNF on NMDA-activated currents were examined in greater detail. Currents evoked by NMDA, and the accompanying changes in intracellular calcium, were enhanced by low concentrations of the neurotrophins (1-20 ng/ml). The potentiation by the neurotrophins was rapid in onset and offset (<1 s). The neurotrophins also reduced desensitization of these currents in most cells. The enhancement of NMDA-activated currents by BDNF was observed using both perforated and whole cell patch recording techniques and could be demonstrated in outside-out patches. Furthermore, its effects were not attenuated by pretreatment with the protein kinase inhibitors genistein or 1-(5-isoquinolynesulfony)2-methylpiperazine (H7). Therefore, the actions of BDNF do not appear to be mediated by phosphorylation. Similar enhancements were observed with NT-3 and NT-4 and with NGF despite the fact that hippocampal neurons lack TrkA receptors. All together this evidence suggests that the enhancement of NMDA-evoked currents is unlikely to be mediated through the activation of growth factor receptors. Modulation of NMDA responses by BDNF was dependent on the concentration of extracellular glycine. The most pronounced potentiation by BDNF was observed at low concentrations, whereas no potentiation was observed in saturating concentrations of glycine, suggesting that BDNF may have increased the affinity of the NMDA receptor for glycine. However, the competitive glycine-site antagonist 7-chloro-kynurenic acid blocked the enhancement by BDNF without shifting the dose-inhibition relationship for this antagonist, and Mg2+ consistently depressed the potentiation of NMDA-evoked currents by BDNF, indicating that BDNF does not alter glycine affinity. BDNF also reversibly increased the probability of opening of NMDA channels recorded from outside-out patches taken from cultured hippocampal neurons. Other unrelated peptides including dynorphin and somatostatin also caused a glycine-dependent enhancement of NMDA currents and depressed the currents in saturating concentrations of glycine. In contrast, a shortened analogue dynorphin (6-17), which lacks N-terminus glycine residues, and another peptide met-enkephalin were without effects on NMDA currents recorded in low concentrations of glycine. Our results suggest that neurotrophins and other peptides can serve as glycine-like ligands for the NMDA receptor.
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PMID:Neurotrophin modulation of NMDA receptors in cultured murine and isolated rat neurons. 935 88

We studied the effect of various agonists of excitatory amino acid (EAA) receptor subtypes on somatostatin (SRIF) release from incubated rat hypothalamic slices. N-Methyl-D-aspartic acid (NMDA) and L-glutamate (1 x 10(-7) to 1 x 10(-3) M) stimulated, in a dose-dependent fashion, SRIF release. The maximal effect was obtained at a concentration of 1 x 10(-4) M for both drugs. The IC50 was 3.2 x 10(-5) M and 2.1 x 10(-5) M for NMDA and L-glutamate, respectively. Incubation with 2.5 x 10(-4) M D-2-amino-5-phosphonovalerate (a NMDA receptor antagonist) or 2-amino-4-phosphonobutyrate (a metabotropic receptor antagonist) was without significant effect on basal SRIF secretion and completely blocked the increase in SRIF release induced by 5 x 10(-5) M NMDA or L-glutamate, respectively. Incubation with 1 x 10(-4) M kainate or 0.5 x 10(-4) M alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) did not change basal SRIF secretion. Incubation with 2 x 10(-4) M gamma-D-glutamylglycine (a specific antagonist of kainate and AMPA receptors) had no effect under basal conditions or during exposure to kainate or AMPA. Our data demonstrate that EAAs stimulate SRIF secretion in vitro, by an action through NMDA and metabotropic receptors but not kainate or AMPA receptors.
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PMID:Effect of excitatory amino acids on rat hypothalamic somatostatin secretion in vitro. 935 63

In rat CA1 hippocampal pyramidal neurons (HPNs), somatostatin (SST) has inhibitory postsynaptic actions, including hyperpolarization of the membrane at rest and augmentation of the K+ M-current. However, the effects of SST on synaptic transmission in this brain region have not been well-characterized. Therefore we used intracellular voltage-clamp recordings in rat hippocampal slices to assess the effects of SST on pharmacologically isolated synaptic currents in HPNs. SST depressed both (R, S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate and N-methyl--aspartate (NMDA) receptor-mediated excitatory postsynaptic currents (EPSCs) in a reversible manner, with an apparent IC50 of 22 nM and a maximal effect at 100 nM. In contrast, SST at concentrations up to 5 microM had no direct effects on either gamma-aminobutyric acid-A (GABAA) or GABAB receptor-mediated inhibitory postsynaptic currents (IPSCs). The depression of EPSCs by SST was especially robust during hyperexcited states when polysynaptic EPSCs were present, suggesting that this peptide could play a compensatory role during seizurelike activity. SST effects were greatly attenuated by the alkylating agent N-ethylmaleimide, thus implicating a transduction mechanism involving the Gi/Go family of G-proteins. Use of 2 M Cs+ in the recording electrode blocked the postsynaptic modulation of K+ currents by SST, but did not alter the effects of SST on EPSCs, indicating that postsynaptic K+ currents are not involved in this action of SST. However, 2 mM external Ba2+ blocked the effect of SST on EPSCs, suggesting that presynaptic K+ channels or other presynaptic mechanisms may be involved. These findings and previous results from our laboratory show that SST has multiple inhibitory effects in hippocampus.
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PMID:Somatostatin depresses excitatory but not inhibitory neurotransmission in rat CA1 hippocampus. 940 20


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