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Biomedical subjects

E Costa

Publications and source records attributed to E Costa.

At least 163 records · Page 9Linked to original sources
PubMed1993

[Differentiated thyroid carcinoma in childhood: multicenter review of the club of pediatric oncology].

The club of paediatric oncology of the Sociedad Española de Cirugía Pediátria conducted a retrospective and multicentric study on differentiated thyroid carcinoma in children. Seventeen cases from four hospitals were reviewed. Initial surgery in all cases consisted of partial or total thyroidectomy, associated in 76% of cases by cervical node removal. In 6 patients (35%) tumoral mass relapsed and 13 cases (76%) hypothyroidism was observed as a post-surgical sequela (in one patient, furthermore dysphonia and hypoparathyroidism persisted). Total survival rate in the series is 100%; one patient is currently diagnosed of node relapsed and remaining patients are disease-free. A diagnostic protocol based on echography, gammagraphy and biopsy is proposed. Oncology surgery i.e. tumoral and healthy tissue resection with node removal in one operation is recommended. With this approach, although we tend to place the patient in hypothyroidism and therefore susceptible to substitutive therapy, the multiple relapses observed in the review would be avoided. Prolonged follow-up guarantees early diagnosis of possible tumoral recurrence.

Adolescent↗
PubMed1993

Semisynthetic sphingolipids prevent protein kinase C translocation and neuronal damage in the perifocal area following a photochemically induced thrombotic brain cortical lesion.

A vascular thrombotic lesion localized to the rat sensorimotor cortex was produced following intravenous injection of the photosensitive dye rose bengal, and its activation with a small beam of high-intensity white light focused to the skull overlaying the sensorimotor cortex. In the sensorimotor cortex at various times after the triggering event, two contiguous brain regions with different degree(s) of neuronal damage can be distinguished: (1) a primary thrombotic ischemic core where the majority of cells are dead and (2) a penumbra region surrounding the core lesion in which a slower progressive neuronal degeneration is occurring. Importantly, in both brain regions the neuronal degeneration is associated with the activation and persistent translocation of protein kinase C (PKC) as indicated by an increase in 4-beta-3H-phorbol-12,13-dibutyrate (3H-PDBu) binding. Moreover, the demonstration that in the area penumbra the neuronal degeneration and the persistent translocation of PKC can be inhibited by a pretreatment with dizocilpine (i.e., MK-801) indicates that the dynamics of the progression of the neuronal degeneration are maintained by glutamate accumulating in the extraneuronal fluids. MK-801 additionally prevents the transcriptional activation of several immediate-early genes (IEGs) (e.g., c-fos) and their cognate third nuclear messenger (i.e., c-Fos) expression present in the hemisphere ipsilateral to the lesion. On the other hand, LIGA4 and LIGA20 derivatives of GM1 lysoganglioside reduce the membrane translocation of PKC and the neuronal damage in the penumbra area, but fail to change the increase of IEG expression in the cortex ipsilateral to the lesion.

Animals↗
PubMed1992

Diazepam-binding inhibitor (DBI)-processing products, acting at the mitochondrial DBI receptor, mediate adrenocorticotropic hormone-induced steroidogenesis in rat adrenal gland.

Diazepam-binding inhibitor (DBI) is a 9-kDa polypeptide that colocalizes in glial, adrenocortical, and Leydig cells with the mitochondrial DBI receptor (MDR). By binding with high affinity to the MDR, DBI and one of its processing products--DBI-(17-50)--regulate pregnenolone synthesis and have been suggested to participate in the immediate activation of adrenal steroidogenesis by adrenocorticotropic hormone (ACTH). In adrenals of hypophysectomized rats (1 day after surgery), ACTH failed to acutely affect the amount of adrenal DBI and the density of MDR but increased the rate of DBI processing, as determined by the HPLC profile of DBI-(17-50)-like immunoreactivity. The similar latency times for this effect and for ACTH stimulation of adrenal steroidogenesis suggest that the two processes are related. The ACTH-induced increase in both adrenal steroidogenesis and rate of DBI processing were completely inhibited by cycloheximide; this result suggests the requirement for the de novo synthesis of a protein with a short half-life, probably an endopeptidase. This enzyme, under the influence of ACTH, may activate formation of a DBI-processing product that stimulates steroidogenesis via the MDR. In support of this hypothesis is the demonstration that in hypophysectomized rats the MDR antagonist PK 11195 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxam ide completely inhibited the adrenal steroidogenesis stimulated by ACTH and by the high-affinity MDR ligand 4'-chlorodiazepam.

Adrenal Glands↗
PubMed1992

Expression patterns of gamma-aminobutyric acid type A receptor subunit mRNAs in primary cultures of granule neurons and astrocytes from neonatal rat cerebella.

Using a competitive polymerase chain reaction assay, we have quantitated the absolute amounts of mRNA encoding 14 distinct subunits of the gamma-aminobutyric acid type A (GABAA) receptor in primary cultures of rat cerebellar granule neurons and cerebellar astrocytes. We found that the total amount of GABAA receptor subunit mRNA in astrocytes was 2 orders of magnitude lower than in neuronal cells. Furthermore, granule cell cultures expressed all 14 different GABAA subunit mRNAs, while the astroglial cultures contained detectable amounts of all the subunits expressed by granule cells except the alpha 6 and the gamma 2L subunits. Of the alpha subunit family members, the alpha 1, alpha 5, and alpha 6 mRNAs were prominent in granule cells, while the alpha 1 and alpha 2 mRNAs were abundant in astrocytes. Of the beta receptor subunit mRNAs, the beta 1 and beta 3 mRNAs were abundantly expressed in both cultures. The gamma 2S and gamma 2L mRNAs constituted the great majority of gamma subunit mRNAs in neurons, while the gamma 1 subunit mRNA was the most abundant gamma subunit mRNA in astrocytes. When various allosteric modulators of GABAA receptors were tested electrophysiologically, methyl 6,7-dimethoxy-4-ethyl-beta-carboline- 3-carboxylate (DMCM) was the only one to modulate chloride currents elicited by GABA in a significantly different manner in granule cells (negative modulation) compared with astrocytes (positive modulation). The latter effect was previously observed in transiently expressed recombinant GABAA receptors containing a gamma 1 instead of a gamma 2 subunit. Our quantitative mRNA results suggest that an important molecular determinant responsible for the DMCM-positive modulatory effect on astroglial native GABAA receptors is the presence of the gamma 1 subunit in the receptor assembly.

Animals↗
PubMed1992

Release of endogenous benzodiazepine receptor ligands (endozepines) from cultured neurons.

Endozepines are naturally occurring small organic molecules, devoid of peptidic bonds and halogens, that act as allosteric modulators of the GABAA receptor through their actions at the benzodiazepine binding site. Endozepines are present in physiologically significant amounts in the brain and can act as potent positive allosteric modulators of the GABAA receptor. In this study, 3 endozepines present in cultured cerebellar granule cells were found to be released from neurons in a potassium-stimulated, calcium-dependent fashion. This release could also be mimicked by increasing concentrations of veratridine. Although endozepines were also found in cultured astrocytes, they could not be released in significant amounts by potassium depolarization. Differential release under depolarizing conditions and granule cell content of the various endozepines suggested a possible metabolic relationship between these two processes.

Animals↗
PubMed1992

Pregnenolone biosynthesis in C6-2B glioma cell mitochondria: regulation by a mitochondrial diazepam binding inhibitor receptor.

The C6-2B glioma cell line, rich in mitochondrial receptors that bind with high affinity to benzodiazepines, imidazopyridines, and isoquinolinecarboxamides (previously called peripheral-type benzodiazepine receptors), was investigated as a model to study the significance of the polypeptide diazepam binding inhibitor (DBI) and the putative DBI processing products on mitochondrial receptor-regulated steroidogenesis. DBI and its naturally occurring fragments have been found to be present in high concentrations in C6-2B glioma cells, to compete against specific isoquinolinecarboxamide or 4'-chlorodiazepam binding to mitochondrial recognition sites with high affinity, and to stimulate mitochondrial pregnenolone formation. These data suggest that this cell type may express both the receptor and the putative agonist ligand to regulate steroidogenesis. Therefore, we propose to term this mitochondrial receptor MDR (mitochondrial DBI receptor) to indicate its responsiveness to DBI in steroid biosynthesis. In the present work, we show that mitochondria of C6-2B cells convert (22R)-22-hydroxycholesterol to pregnenolone by a mechanism blocked by aminoglutethimide. Immunoblotting confirmed the presence of relatively high levels of cytochrome P-450 cholesterol side-chain-cleavage enzyme in C6-2B cell mitochondria. Furthermore, isoquinolinecarboxamide binding sites associated with the 18-kDa mitochondrial polypeptide subunit of the MDR are abundant in C6-2B glioma cell mitochondria (Bmax approximately 30 pmol/mg protein) and are coupled to the regulation of steroid biosynthesis. Occupancy of MDRs with nanomolar concentrations of the naturally occurring polypeptide, DBI, as well as its naturally occurring processing product tetratriacontaneuropeptide [DBI-(17-50)] increases pregnenolone formation. Clonazepam and octadecaneuropeptide [DBI-(33-50)], which exhibit a higher affinity for gamma-aminobutyric acid type A receptors but a low affinity for MDR, were ineffective in stimulating pregnenolone synthesis. These findings provide evidence that C6-2B cells exhibit a significant steroidogenic activity which resembles that found in peripheral endocrine organs and they suggest that MDRs and DBI are involved in the regulation of glial cell steroidogenesis.

Animals↗
PubMed1992

Regulation of pregnenolone synthesis in C6-2B glioma cells by 4'-chlorodiazepam.

An experimental model to study synthesis of cholesterol and pregnenolone from the precursor mevalonolactone (MVA) was developed in C6-2B glioma cells. The steroidogenic capability of this cell line and the regulation of pregnenolone production by 4'-chlorodiazepam (4'CD), a specific ligand for the mitochondrial diazepam binding inhibitor (DBI) receptor (MDR), were investigated. Cells maintained in serum-free media were incubated with lovastatin (20 microM) and two inhibitors of pregnenolone metabolism, trilostane (25 microM) and 1,2,3,4-tetrahydro-4-oxo-7-chloro-2-naphthylpyridine (10 microM). Under these conditions the incorporation of [3H]MVA into cholesterol and pregnenolone formation was biphasic, with an initial rapid phase (within 1 min) followed by a slower phase. Cholesterol and pregnenolone were identified by coelution with authentic steroids from a Si 60 Lichrosorb column and gas chromatography/mass spectrometry. Pregnenolone synthesis in intact C6-2B glioma cells was stimulated by nanomolar concentrations of 4'CD after 5 min of incubation with MVA. The stimulatory effect was dependent on drug concentration and the maximal effect was achieved at 10 nM. The time course showed that the incorporation of MVA into pregnenolone is accelerated by the MDR ligand. Cholesterol synthesis is only slightly and not significantly affected by 4'CD. These results support the view that steroid synthesis occurs in a glioma cell line. Moreover, we provide evidence for a rapid steroid synthesis in C6-2B glioma cells, which in turn appears to be accelerated by 1-100 nM 4'CD, a MDR ligand.

Animals↗
PubMed1992

Molecular mechanisms of the partial allosteric modulatory effects of bretazenil at gamma-aminobutyric acid type A receptor.

In central nervous system gamma-aminobutyric acid (GABA) inhibits neuronal activity by acting on GABA type A (GABAA) receptors. These heterooligomeric integral membrane proteins include a GABA-gated Cl- channel and various allosteric modulatory sites where endogenous modulators and anxiolytic drugs act to regulate GABA action. In vivo, various anxiolytic drugs exhibit a wide range of variability in their modulatory efficacy and potency of GABA action. For instance, bretazenil modulatory efficacy is much lower than that of diazepam. Such low efficacy could be due either to a preferential modulation of specific GABAA receptor subtypes or to a low modulatory efficacy at every GABAA receptor subtype. To address these questions we studied drug-induced modifications of GABA-activated Cl- currents in native GABAA receptors of cortical neurons in primary cultures and in recombinant GABAA receptors transiently expressed in transformed human embryonic kidney cells (293) after transfection with cDNAs encoding different molecular forms of alpha, beta, and gamma subunits of GABAA receptors. In cortical neurons the efficacy of bretazenil was lower than that of diazepam, whereas the potency of the two drugs was similar. In cells transfected with gamma 2 subunits and various molecular forms of alpha and beta subunits bretazenil efficacy was always lower than that of diazepam. However, in cells transfected with gamma 1 or gamma 3 subunits and various forms of alpha and beta subunits the efficacy of both diazepam and bretazenil was lower and always of similar magnitude. When bretazenil and diazepam were applied together to GABAA receptors including a gamma 2 subunit, the action of diazepam was curtailed in a manner related to the dose of bretazenil.

Allosteric Regulation↗
PubMed1992

In vitro interaction between cerebellar astrocytes and granule cells: a putative role for nitric oxide.

In primary cultures of astrocytes and granule cells from neonatal rat cerebellum, the activity and function of nitric oxide (NO) synthase were measured by the conversion of [3H]arginine to [3H]citrulline and the accumulation of cyclic guanosine monophosphate (cGMP), respectively. The glutamate receptor agonist N-methyl-D-aspartate (NMDA) and the Ca2+ ionophore A23187 stimulated NO synthase activity in cerebellar granule cells but not in astrocytes. In granule cells, NMDA, A23187, and sodium nitroprusside (SNP) elicited an accumulation of cGMP, whereas only SNP was active in astrocytes. However, in astrocytes that were incubated together with granule cells, NMDA induced a more than 3-fold increase in the concentration of cGMP; this increase was blocked by both the NO synthase inhibitor NG-monomethyl-L-arginine (MeArg) and the allosteric NMDA receptor antagonist (+)5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate (MK-801). Thus, cerebellar astrocytes do not appear to express NO synthase but do contain guanylate cyclase, which can be activated by an NO-like factor produced by cerebellar granule cells after stimulation by NMDA.

Amino Acid Oxidoreductases↗
PubMed1992

Building a bridge between neurobiology and mental illness.

GABA (gamma amino butyric acid) is the most abundant and important inhibitory transmitter in mammalian CNS. It counterbalances the glutamate mediated neuronal excitation. Abnormalities of the interaction of these two transmitters might change the mechanisms of neuronal group selection that according to Edelman [Neural Darwinism. Basic Books, New York] play a role in mediating several brain functions including cognition processes. Indeed imbalances in GABAergic functions were shown to elicit psychoses. They can be obtained by administration of drugs that affect synthesis, metabolism and uptake of GABA and thereby cause a persistent stimulation of GABAA receptors or perhaps by genetic abnormalities in DNA transcription, pre-mRNA splicing, mRNA translation and posttranslation modifications of GABAA receptor subunits. The complexities in the regulation of GABAA receptor subunit structure, synthesis, assembly and the brain location of specific mRNA encoding for these subunits are investigated with in situ mRNA hybridization specific for subunits of GABAA receptors. The role of the variability resulting from the complexities in the regulation of GABAA receptor allosteric modulation by drugs and putative endogenous allosteric modulators of GABA action at GABAA receptors is discussed. This discussion gives relevance to the possibility that genetic abnormalities in the expression of proteins participating in GABAergic function are to be considered as a possible target of the genetic defects operative in psychoses. In line with this thinking, it is suggested that partial allosteric modulators (partial agonists) of GABAA receptors and the phosphothioate or methylphosphonate analogs antisense to specific mRNA oligonucleotides that mediate the expression of genetic information concerning GABAA and glutamate receptor subunits may become valuable tools in psychiatric research. Perhaps in the future these studies might generate new ideas useful in the therapy of genetically determined psychiatric illness.

Bipolar Disorder↗
PubMed1992

Pharmacological characterization of regulation of phosphoinositide metabolism by recombinant 5-HT2 receptors of the rat.

Transfection of 5-HT2 receptor cDNA in 293 cells induced the expression of a protein binding domain, exhibiting the classical 5-HT2 receptor transduction mechanism. Both [3H]DOB and [3H]spiperone high affinity binding sites were present in membranes of sense but not of antisense, 5-HT2 receptor cDNA transfected cells. Addition of 1 microM 5-HT induced a time-dependent increase of phosphoinositide (PI) metabolism in sense but not in antisense, 5-HT2 receptor cDNA transfected cells. Graded concentrations of 5-HT and of different serotonergic agonists showed different potencies (DOI greater than 5-HT greater than quipazine greater than DOM greater than alpha-methyl-5-HT greater than 8-OH-DPAT greater than 2-methyl-5-HT greater than CGS-12066B) in stimulating turnover of PI in cells transfected with cDNA encoding for 5-HT2 receptors of the rat. The ability of different antagonists to inhibit 5-HT-stimulated turnover of PI bore a direct relationship with their potency to inhibit 5-HT2 receptor binding in cells transfected with 5-HT2 receptor cDNA (spiperone greater than ketanserin greater than ritanserin greater than mianserin greater than haloperidol). Preincubation of transfected 293 cells with pertussis toxin failed to modify either 5-HT- or DOI-induced activation of metabolism of PI. Pretreatment of transfected 293 cells with DOI (100 nM) for 2 hr or more, significantly reduced activation of turnover of PI elicited by graded doses of 5-HT. When the transfected 293 cells were exposed to DOI (100 nM) for 12 hr and the challenge was performed after a 2-hr wash-out period, the desensitization of the response to 5-HT was virtually abolished.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Distinct developmental patterns of expression of rat alpha 1, alpha 5, gamma 2S, and gamma 2L gamma-aminobutyric acidA receptor subunit mRNAs in vivo and in vitro.

We have quantitated the alpha 1, alpha 5, gamma 2S, and gamma 2L gamma-aminobutyric acidA (GABAA) receptor subunit mRNAs in the maturing cerebellum in vivo and in cerebellar granule neurons differentiating in vitro. Absolute amounts of mRNA were measured by reverse transcription and competitive polymerase chain reaction (PCR) analysis with appropriate internal standards. The alpha 1 and gamma 2L mRNA content increased continuously during postnatal cerebellar maturation and their changes with time matched very closely those of the cerebellar granule cells differentiating in vitro. The gamma 2S subunit mRNA showed a relatively constant pattern of expression both in vivo and in vitro, with comparable absolute concentrations in both developmental paradigms. The alpha 5 mRNA was initially high in vivo and decreased (eight-fold) to adult levels as postnatal cerebellar development progressed. In vitro the amount of alpha 5 GABAA receptor subunit mRNA was higher than in vivo at 3 days, increased by more than twofold by 8 days, and declined to approximately the initial values at 23 and 28 days in vitro. Collectively, the results indicate that the alpha 1, alpha 5, gamma 2S, and gamma 2L GABAA receptor subunit mRNAs are regulated differentially in a temporal manner during in vivo and in vitro maturation. Moreover, a comparison of the ontogenetic profiles of the gamma 2S and gamma 2L mRNAs indicates that alternative splicing of the gamma 2 primary RNA transcript is regulated developmentally during postnatal maturation of the rat cerebellum.

Animals↗
PubMed1992

Glutamate receptor agonists stimulate nitric oxide synthase in primary cultures of cerebellar granule cells.

The glutamate receptor agonist N-methyl-D-aspartate (NMDA) stimulated a rapid, extracellular Ca(2+)-dependent conversion of [3H]arginine to [3H]citrulline in primary cultures of cerebellar granule cells, indicating receptor-mediated activation of nitric oxide (NO) synthase. The NMDA-induced formation of [3H]citrulline reached a plateau within 10 min. Subsequent addition of unlabeled L-arginine resulted in the disappearance of 3H from the citrulline pool, indicating a persistent activation of NO synthase after NMDA receptor stimulation. Glutamate, NMDA, and kainate, but not quisqualate, stimulated both the conversion of [3H]arginine to [3H]citrulline and cyclic GMP accumulation in a dose-dependent manner. Glutamate and NMDA showed similar potencies for the stimulation of [3H]citrulline formation and cyclic GMP synthesis, respectively, whereas kainate was more potent at inducing cyclic GMP accumulation than at stimulating [3H]citrulline formation. Both the [3H]arginine to [3H]citrulline conversion and cyclic GMP synthesis stimulated by NMDA were inhibited by the NMDA receptor antagonist MK-801 and by the inhibitors of NO synthase, NG-monomethyl-L-arginine (MeArg) and NG-nitro-L-arginine (NOArg). However, MeArg, in contrast to NOArg, also potently inhibited [3H]arginine uptake. Kainate (300 microM) stimulated 45Ca2+ influx to the same extent as 100 microM NMDA, but stimulated [3H]citrulline formation to a much lesser extent, which suggests that NO synthase is localized in subcellular compartments where the Ca2+ concentration is regulated mainly by the NMDA receptor.

Amino Acid Oxidoreductases↗
PubMed1992

Purification and characterization of naturally occurring benzodiazepine receptor ligands in rat and human brain.

Chemicals that are active at the benzodiazepine receptor (endozepines) are naturally present in the CNS. These substances are present in tissue from humans and animals and in plants and fungi. Using selective extraction protocols, HPLC purification, receptor binding displacement studies, and selective anti-benzodiazepine antibodies, we have identified six or seven peaks of endozepines in rat and human brain. All material could competitively displace [3H]flunitrazepam binding to cerebellar benzodiazepine binding sites. Two peaks also competitively displaced Ro 5-4864 binding to the mitochondrial benzodiazepine binding site. Total amounts of brain endozepines were estimated to be present in potentially physiological concentrations, based on their ability to displace [3H]flunitrazepam binding. Although endozepine peaks 1 and 2 had HPLC retention profiles similar to those of nordiazepam and diazepam, respectively, gas chromatography-mass spectrometry as well as high-performance TLC revealed biologically insignificant amounts of diazepam (less than 0.02 pg/g) and nordiazepam (less than 0.02 pg/g) in the purified material. Electrophysiologically, some purified endozepines positively modulated gamma-aminobutyric acid (GABA) action on Cl- conductance, monitored in patch-clamped cultured cortical neurons or in mammalian cells transfected with cDNA encoding various GABAA receptor subunits. These studies demonstrate that mammalian brains contain endozepines that could serve as potent endogenous positive allosteric modulators of GABAA receptors.

Allosteric Regulation↗
PubMed1992

[Primary cardiac rhabdomyosarcoma involving the mitral valve].

Primary cardiac rhabdomyosarcoma is rare and its extension to the mitral valve even rarer. We report a case of left atrial rhabdomyosarcoma involving the mitral valve. The patient was a 62-year-old man who complained of recurrent pre-syncopal episodes, dyspnoea often sudden in onset, asthenia and major weight loss (10 kg in one month). 2-D echocardiography revealed a 4.9 cm2 wide mass attached to the atrial side of the anterior mitral leaflet and to the adjacent inferior interatrial septum, where it seemed to have origin. CT scan and scintigraphy revealed bone, kidney and spleen metastases. The patient underwent emergency cardiac surgery because of increasing pre-syncopal and dyspnoeic episodes due to obstruction by the intracardiac mass. At surgery a tumor was found infiltrating the left atrial wall, the interatrial septum, the mitral anulus and the anterior mitral leaflet up to its tip. Invasion of mitral anulus did not allow mitral valve replacement, so that an excision of the intracardiac mass was performed as extensively as possible. Histology revealed a rhabdomyosarcoma. A post-operative chemotherapy cycle had to be stopped due to onset of atrial fibrillation and dyspnoea. 2-D echo monitoring revealed rapid new growth of the tumor across the basal portion of mitral valve leaflet to the atrioventricular orifice. After several episodes of increasing dyspnoea, the patient had a pulmonary oedema and died.

Dyspnea↗
PubMed1992

Sodium nitroprusside inhibits N-methyl-D-aspartate-evoked calcium influx via a nitric oxide- and cGMP-independent mechanism.

In primary cultures of rat cerebellar granule cells, sodium nitroprusside (SNP), a vasodilator that generates nitric oxide (NO), potently inhibited N-methyl-D-aspartate (NMDA)-evoked 45Ca2+ influx (IC50 = 6.6 microM). This inhibition was time dependent and was complete when SNP was applied 10 min before NMDA stimulation. The effect of SNP was transient and the ability of NMDA to stimulate 45Ca2+ influx was restored after SNP withdrawal. The effect of SNP was selective for the NMDA-sensitive glutamate receptor, because SNP failed to antagonize kainate-stimulated 45Ca2+ influx. The action of SNP was independent of the ability of this agent to generate NO; S-nitroso-N-acetylpenicillamine, an NO-containing compound that was 100 times more potent than SNP in stimulating cGMP accumulation, failed to inhibit NMDA-evoked 45Ca2+ influx. In contrast, K4Fe(CN)6, a compound structurally similar to SNP but devoid of NO, inhibited both 45Ca2+ influx (IC50 = 27 microM) and cGMP accumulation evoked by NMDA; K3Fe(CN)6 was inactive. Thus, in cerebellar granule cells, SNP and K4Fe(CN)6 interfere with the function of NMDA receptors, possibly at the level of the receptor recognition site. The resulting blockade of Ca2+ influx through NMDA receptor channels accounts for the reported ability of these compounds to protect granule cells from NMDA-induced neurotoxicity. This protection is not mediated by an NO-dependent mechanism but depends on the action of the ferrocyanide portion of the SNP molecule.

Animals↗
PubMed1992

2-Aryl-3-indoleacetamides (FGIN-1): a new class of potent and specific ligands for the mitochondrial DBI receptor (MDR).

The 2 aryl-3-indoleacetamides (FGIN-1) are a new class of compounds that potently (nM) and selectively bind to glial mitochondrial diazepam binding inhibitor (DBI) receptors (MDR), previously called peripheral benzodiazepine receptors, and increase mitochondrial steroidogenesis. The high-affinity binding of FGIN-1 to MDR derivatives depends on the following chemical characteristics: 1) the dialkylation of the amide; 2) the chain length of this alkyl substitution; and 3) the halogenation of aryl groups appended to the indole nucleus. FGIN-1 derivatives do not bind to gamma-aminobutyric acid (GABAA), GABAB, glycine, glutamate, dopamine, serotonin, opiate, cholecystokinin, beta adrenergic, cannabinoid or sigma receptors. FGIN-1-27 [N, N-di-n-hexyl 2-(4-fluorophenyl)indole-3-acetamide] enters the brain, and for this reason, this FGIN-1 compound is potent and efficacious behaviorally. Like the neurosteroid 3 alpha-5 alpha tetrahydrodeoxycorticosterone (THDOC), FGIN-1-27 delays the onset of isoniazid-induced convulsions, but fails to delay the onset of bicuculline-induced convulsions. However, differently from THDOC, the FGIN-1-27 anticonvulsant action is blocked by the isoquinoline carboxamide PK 11195. In the elevated plus maze test, FGIN-1-27 inhibits neophobia manner that is antagonized by PK 11195 but not by flumazenil. Because FGIN-1-27 binds to MDR and does not bind to the GABAA receptors, it is inferred that FGIN-1-27 may act on GABAA receptors indirectly, presumably via a stimulation of neurosteroid synthesis and release from glial cells.

Acetamides↗