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A Saria

Publications and source records attributed to A Saria.

At least 37 records · Page 2Linked to original sources
PubMed1998

Levels and proteolytic processing of chromogranin A and B and secretogranin II in cerebrospinal fluid in neurological diseases.

Human cerebrospinal fluid (CSF) contains chromogranin A and B and secretogranin II which represent peptides secreted from neuronal large dense core vesicles. Within these vesicles these precursor peptides are at least partly processed to smaller peptides. We analysed the CSF levels of chromogranins/secretogranin by radioimmunoassay using specific antisera. The degree of their processing was characterized by molecular sieve column chromatography followed by radioimmunoassay. As previously shown secretogranin II is fully processed to smaller peptides including the peptide secretoneurin, whereas processing of chromogranin A was more limited. For chromogranin B we found in this study a high degree of processing comparable to that of secretogranin II. An analysis of CSF from patients with multiple sclerosis, essential tremor, Alzheimer and Parkinson disease, did not reveal any differences in proteolytic processing of chromogranins/secretogranin when compared to control CSF. We conclude that in the four diseases investigated there is no change in the proteolytic processing of the chromogranins/secretogranin within the large dense core vesicles. The absolute levels of chromogranins/secretogranin varied in CSF collected in different hospitals, however their relative ratios were remarkable constant. We suggest to use this ratio as a parameter to standardise CSF levels of other peptides, e.g. neuropeptides. In Parkinson patients the chromogranin A/secretogranin II ratio was significantly increased whereas in Alzheimer patients and those with essential tremor and multiple sclerosis no change of the ratios was observed. Apparently there are only limited changes in the biosynthesis, processing, secretion and CSF clearance of these peptides in pathological conditions.

Adult↗
PubMed1998

Secretoneurin, a novel neuropeptide, in the human dental pulp.

Secretoneurin is a neuropeptide that is stored in and released from primary afferent neurones. By radioimmunoassay and immunohistochemistry, secretoneurin was here demonstrated in the human dental pulp and localized in varicose nerve fibres that were frequently associated with blood vessels. No significant correlation was found between the levels of immunoreactive secretoneurin and immunoreactive calcitonin-gene related peptide. The results suggest that primary afferent neurones of the human dental pulp contain secretoneurin, which may influence local inflammatory responses if it is released together with other neuropeptides.

Adolescent↗
PubMed1998

NGF but not GDNF or neurturin enhance acetylcholine tissue levels in striatal organotypic brain slices.

Trophic factors play important roles in survival and nerve fiber growth of cholinergic interneurons in the striatum in vivo and in vitro. In this study an organotypic slice model was used to investigate the effects of nerve growth factor and the novel factors glial cell line-derived neurotrophic factor and neurturin as well as other trophic factors on the striatal acetylcholine tissue levels: During culturing over 2 weeks acetylcholine tissue levels markedly decreased, representing degeneration of cholinergic neurons. When striatal slices were cultured for 2 weeks in the presence of 100 ng/ml nerve growth factor tissue levels of acetylcholine and the expression of choline acetyltransferase-like immunoreactivity and mRNA, as well as the muscarinic M2 autoreceptor mRNA were markedly enhanced compared to slices cultured without or with 10 ng/ml nerve growth factor. A single administration of nerve growth factor had no effect on acetylcholine tissue levels suggesting that nerve growth factor does not directly increase acetylcholine synthesis. All other trophic factors (glial cell line-derived neurotrophic factor, neurturin, brain-derived neurotrophic factor, neurotrophin-3 and -4/5, fibroblast growth factor-2, insulin like growth factor-I) had no effects on acetylcholine tissue levels. Thus, the organotypic slice model is a suitable system to study the effects of trophic factors and it is concluded that nerve growth factor selectively enhances acetylcholine tissue levels, indicating protection of cholinergic interneurons in the dorsal striatum.

Acetylcholine↗
PubMed1998

Long-term pharmacokinetics of clozapine.

BACKGROUND: Previous studies of clozapine pharmacokinetics have shown a wide intra- and inter-individual variability of plasma levels in patients on stable clozapine doses. We investigated dose-plasma level relationships and intra-individual variability of plasma levels during maintenance treatment with clozapine. METHOD: Forty-one patients on clozapine were followed for 26 weeks with repeated plasma level measurements and assessments of co-medication and clinical symptoms. In a second step, 15 patients on stable clozapine doses between treatment Weeks 12 and 52 were followed in the same way. Coefficient of variation was used as a parameter of plasma level deviation. RESULTS: Dose-plasma level correlations stayed significant from Week 6 to Week 26 (n = 41). The group of patients followed up to Week 52 showed a mean intra-individual coefficient of variation of 52.8% (s.d. = 20.6), and remained stable psychopathologically. CONCLUSIONS: Even though clozapine plasma levels may show a significant degree of variation, this is not necessarily reflected in a change in psychopathology.

Adult↗
PubMed1997

Opioid-related changes in nociceptive threshold and in tissue levels of enkephalins after target disruption of the gene for neutral endopeptidase (EC 3.4.24.11) in mice.

Neutral endopeptidase EC 3.4.24.11 (NEP) is localized in peptidergic neurons and various colocalized peptides or other humoral mediators may serve as substrates. Target disruption of the NEP gene was reported to enhance the lethal response to endotoxin shock in mice. We examined thermonociceptive thresholds and enkephalin (ENK) tissue levels in transgenic NEP (-/-) and control wild type NEP (+/+) mice. Hot plate (52 degrees C) latency was 13.1 +/- 1.4 s in NEP (+/+) mice (n = 16) while latency increased significantly (P = 0.031) to 17.7 +/- 1.6 s in NEP (-/-) mice. Naloxone (10 mg/kg) had no effect on hot plate latency in NEP (+/+) mice (12.5 s, n = 8), but significantly decreased the latency in NEP (-/-) mice compared to untreated NEP (-/-) deficient mice (10.5 s, n = 8). Morphine (3 or 10 mg/kg) analgesic response was similar in knockout mice and wild type mice. Methionine-ENK (MET-ENK) and leucine-ENK (LEU-ENK) levels were determined in extracts from cortex, brain stem, hypothalamus, striatum, spinal cord, trigeminal ganglion and heart in treated and untreated mice. ENK-levels varied in a regionally-dependent manner and were significantly decreased in hypothalamus and spinal cord. We conclude that deletion of the NEP gene results in an opioid-related increase in thermonociceptive threshold. Regional differences in opioid metabolism indicate that NEP evokes tissue-specific patterns of ENK-regulation. NEP selectively controls opioid biosynthesis in hypothalamus and spinal cord presumably by feedback regulation.

Analgesics, Opioid↗
PubMed1997

Secretoneurin-like immunoreactivity in rat sympathetic, enteric and sensory ganglia.

Distribution of secretoneurin-like immunoreactivity (SN-LI) was studied in the rat sympathetic ganglia/adrenal gland, enteric and sensory ganglia by immunohistochemical methods. SN-LI nerve fibers formed basket-like terminals surrounding many of the postganglionic neurons of the superior cervical, stellate, paravertebral chain ganglia, coeliac/superior mesenteric and inferior mesenteric ganglia. Postganglionic neurons of the superior cervical and other sympathetic ganglia exhibited low-to-moderate levels of SN-LI. In all these sympathetic ganglia, clusters of small diameter (< 10 microm) cells, which may correspond to the small intensely fluorescent (SIF) cells, were found to be intensely labeled. Surgical sectioning or ligation of the cervical sympathetic trunk for 7-10 days resulted in a nearly total loss of SN-LI fibers in the superior cervical ganglia, whereas immunoreactivity in the postganglionic neurons and small diameter cells remained essentially unchanged. In the thoracolumbar and sacral segments of the spinal cord, SN-LI nerve fibers were detected in the superficial layers of the dorsal horn as well as in the intermediolateral cell column (ILp). Occasionally, SN-LI somata were noted in the ILp. SN-LI nerve fibers formed a delicate plexus underneath the capsule of the adrenal gland, some of which traversed the adrenal cortex and reached the adrenal medulla. While heavily invested with SN-LI nerve terminals, chromaffin cells seemed to express a low level of SN-LI. In the enteric plexus, varicose SN-LI nerve fibers and terminals formed a pericellular network around many myenteric and submucous ganglion cells; the ganglionic neurons were lightly to moderately labeled. A population of ganglion cells in the dorsal root, nodose and trigeminal ganglia exhibited moderate-to-strong SN-LI. The detection of SN-LI in nerve fibers and somata of various sympathetic ganglia, enteric plexus and adrenal medulla and in somata of the sensory ganglia implies an extensive involvement of this peptide in sympathetic, enteric and sensory signal processing.

Animals↗
PubMed1997

Ontogenic development of secretogranin II and of its processing to secretoneurin in rat brain.

The ontogenic development of secretogranin II was studied by immunochemistry and immunohistochemistry. Extracts of brains from various developmental stages were analyzed by a radioimmunoassay for secretoneurin, a peptide derived from secretogranin II. From gestational day 13 to adulthood the levels increased from 0.1 to 94 fmol/mg wet weight. Characterization of the immunoreactivity by molecular sieve chromatography revealed that throughout all developmental stages the proprotein secretogranin II was fully processed to the free peptide secretoneurin. In immunohistochemistry secretoneurin-IR was first detected at embryonic day 13. Between embryonic days 14 and 18 a strong increase in the number of secretoneurin immunopositive cells was observed in many brain areas, notably in the amygdala, hypothalamus, olfactory bulb and several brainstem nuclei. The pattern of staining during development is quite similar to that in the adult. The present paper demonstrates that secretoneurin immunoreactivity appears early in embryonic life. Processing of the proprotein secretogranin II starts when the protein is first synthesized apparently at about the same time when the prohormone convertase PC1 and PC2 can be demonstrated.

Animals↗
PubMed1997

Neurochemical compartments in the human forebrain: evidence for a high density of secretoneurin-like immunoreactivity in the extended amygdala.

Secretoneurin is a 33-amino acid neuropeptide produced by endoproteolytic processing from secretogranin II, which is a member of the chromogranin/ secretogranin family. In this immunocytochemical study we investigated the localization of secretoneurin-like immunoreactivity in the human substantia innominata in relation to the ventral striatopallidal system, the bed nucleus-amygdala complex and the basal nucleus of Meynert. A high density of secretoneurin immunostaining was found in the medial part of the nucleus accumbens. All subdivisions of the bed nucleus of the stria terminalis displayed a very prominent immunostaining for secretoneurin, whereas substance P and enkephalin showed a more restricted distribution. A high concentration of secretoneurin immunoreactivity was also observed in the central and medial amygdaloid nuclei. In the lateral bed nucleus of the stria terminalis and the sublenticular substantia innominata, the appearance of secretoneurin immunoreactivity was very similar to that of enkephalin-like immunoreactivity, exhibiting mostly peridendritic and perisomatic staining. The ventral pallidum and the inner pallidal segment displayed strong secretoneurin immunostaining. Secretoneurin did not label cholinergic neurons in the basal forebrain. This study demonstrates that secretoneurin-like immunoreactivity is prominent in the bed nucleus-amygdala complex, referred to as extended amygdala. The distribution of secretoneurin-like immunoreactivity in comparison with that of other neuroanatomical markers suggests that this forebrain system is a discret compartment in the human forebrain.

Adult↗
PubMed1997

Obstructive ileus of large bowel is associated with low tissue levels of neuropeptides in prestenotic bowel segment.

The neuropeptides substance P, vasoactive intestinal polypeptide, and the recently discovered peptide secretoneurin are neurotransmitters of the intrinsic nervous system of the gut and effect gut motility. The aim of this study was to investigate whether these neuropeptides are involved in the pathophysiology of large bowel ileus. Five patients underwent colonic resections for obstructive cancer of the colon. Full-thickness specimens of the resected colon were taken 10 cm proximal and 10 cm distal to the site of tumor obstruction. Substance P-, vasoactive intestinal polypeptide-, and secretoneurin-like immunoreactivities were measured in the specimens by radioimmunoassay. In addition immunocytochemistry was performed. Tissue levels of substance P, vasoactive intestinal polypeptide, and secretoneurin were lower in the prestenotic than in the poststenotic bowel segment. In accordance, immunocytochemistry revealed a denser staining of ganglion cells and fibers for all three neuropeptides in the poststenotic bowel. The decreased tissue levels of substance P, vasoactive intestinal polypeptide, and secretoneurin in the prestenotic bowel segment may contribute to the final decompensation of obstructive ileus.

Aged↗
PubMed1996

Induction of tachykinin gene and peptide expression in guinea pig nodose primary afferent neurons by allergic airway inflammation.

Substance P (SP), neurokinin A (NKA), and calcitonin gene-related peptide (CGRP) have potent proinflammatory effects in the airways. They are released from sensory nerve endings originating in jugular and dorsal root ganglia. However, the major sensory supply to the airways originates from the nodose ganglion. In this study, we evaluated changes in neuropeptide biosynthesis in the sensory airway innervation of ovalbumin-sensitized and -challenged guinea pigs at the mRNA and peptide level. In the airways, a three- to fourfold increase of SP, NKA, and CGRP, was seen 24 h following allergen challenge. Whereas no evidence of local tachykinin biosynthesis was found 12 h after challenge, increased levels of preprotachykinin (PPT)-A mRNA (encoding SP and NKA) were found in nodose ganglia. Quantitative in situ hybridization indicated that this increase could be accounted for by de novo induction of PPT-A mRNA in nodose ganglion neurons. Quantitative immunohistochemistry showed that 24 h after challenge, the number of tachykinin-immunoreactive nodose ganglion neurons had increased by 25%. Their projection to the airways was shown. Changes in other sensory ganglia innervating the airways were not evident. These findings suggest that an induction of sensory neuropeptides in nodose ganglion neurons is crucially involved in the increase of airway hyperreactivity in the late response to allergen challenge.

Animals↗
PubMed1996

CSF of neuroleptic-naive first-episode schizophrenic patients: levels of biogenic amines, substance P, and peptides derived from chromogranin A (GE-25) and secretogranin II (secretoneurin).

Lumbar cerebrospinal fluid (CSF) was collected from controls and neuroleptic-naive patients with their first acute schizophrenic episode. The CSF was analyzed for several biogenic amines and their metabolites [dopamine,dihydroxyphenylacetic acid (DOPAC), noradrenaline, 5-hydroxytryptamine (5-HT), 5-hydroxyindolacetic acid (5-HIAA)]. For these transmitters, which are stored and secreted from synaptic vesicles, there was no significant difference between controls and schizophrenic patients. As constituents of large dense-core vesicles substance P (SP) and GE-25 (derived from chromogranin A)-and secretoneurin (derived from secretogranin 11)-immunoreactivities were determined. SP-like immunoreactivity levels did not differ between controls and patients; however, GE-25 was elevated and especially the GE-25/secretoneurin ratio was significantly (p < .001) higher in patients. Characterization of the immunoreactivities by high-performance liquid chromatography did not reveal any difference between patients (n = 3) and controls in the processing of the two proproteins chromogranin A and secretogranin II. These data indicate that proteolytic processing of the two widespread constituents of large dense-core vesicles, i.e., chromogranin A and secretogranin II, is not altered in schizophrenic patients. The increase in the chromogranin A /secretoneurin ratio in schizophrenic patients deserves further investigation in order to elucidate its possible pathogenetic significance.

Adult↗
PubMed1996

Striatal efferents preferentially innervate neurons in the ventral pallidum containing GABAA receptor alpha 1 subunit-like immunoreactivity.

The gamma-aminobutyric acid-A receptor consists of several subunits. In this immunohistochemical study we investigated the regional distribution of the alpha 1 and alpha 2 subunits with subunit-specific antibodies in the ventral pallidum, and compared the staining patterns to those of substance P (SP). alpha 1 subunit antigenic sites were found to be localized to pallidal neurons, varicosities, and varicose fibers. alpha 1 immunopositive fibers mainly appeared "tubulus-like" due to the intense staining of the membranes of the long pallidal dendrites. Double labelling of alpha 1 subunit and substance P revealed that alpha 1 subunit-like immunoreactive (IR) dendrites and somata of the pallidal neurons were often invested by SP-IR striatal efferents. Subcellularly, the dendritic and somatic membranes of pallidal neurons were strongly immunopositive for the alpha 1 subunit, whereas only a few axon terminals exhibited alpha 1-IR. alpha 2-IR was restricted to a low number of ventral pallidal neurons. The distributional patterns obtained for the alpha 1 and alpha 2 subunits suggest that striatal efferent neurons directly influence pallidal neurons displaying a distinct GABAA subunit composition, which may be of pharmacological importance since the alpha 1 beta x gamma 2-subunits containing receptors have mainly a benzodiazepine type I pharmacology.

Animals↗
PubMed1996

Effects of secretogranin II-derived peptides on the release of neurotransmitters monitored in the basal ganglia of the rat with in vivo microdialysis.

In vivo microdialysis was used to study the effect of secretogranin II-derived peptides on dynorphin B (Dyn B), dopamine, gamma-aminobutyric acid (GABA), glutamate and aspartate release in the substantia nigra and neostriatum of halothane-anaesthesized rats. In the substantia nigra, local infusion of secretoneurin (secretogranin II 154-186) (1-50 microM) increased, in a concentration-dependent manner, extracellular aspartate, glutamate, Dyn B, dopamine and GABA levels. The effect was particularly prominent on aspartate and glutamate levels which, following 50 microM of secretoneurin, were increased by > 20 and > 10 fold, respectively. However, the effect of secretoneurin on Dyn B release appeared to be more specific, since a significant increase (> 20 fold) was already observed following 1 microM of secretoneurin. In the neostriatum, Dyn B, glutamate, aspartate and GABA levels were also increased by local secretoneurin infusion, but the effect was less prominent than in the substantia nigra. In the substantia nigra, only Dyn B levels were significantly increased following infusion of 10 microM of the secretoneurin-C terminal (secretoneurin-15C), whereas Dyn B and GABA levels were increased by the same concentration of the secretogranin II C terminus (YM). Only glutamate and aspartate levels were increased by local infusion of 10 microM of secretogranin II 133-151 (LF), a peptide adjacent to secretoneurin in the primary amino acid sequence. In the neostriatum, Dyn B and GABA levels were increased by 10 microM of secretoneurin-15C. Dyn B levels were also increased by 10 microM of YM, and glutamate and aspartate levels were increased by 10 microM of both YM and LF. Thus secretogranin II-derived peptides affect extracellular levels of several putative neurotransmitter systems monitored in the basal ganglia of the rat with in vivo microdialysis. The effect of Dyn B appears to be specific and related to a physiological role of secretoneurin, since (i) it occurs in an area where secretoneurin-immunocytochemistry has been observed, (ii) is exerted at comparatively low concentrations, and (iii) is mimicked by secretoneurin-15C. The increases in excitatory amino acid levels produced by high concentrations of secretoneurin and other secretogranin II-derived peptides reflect, perhaps, a potential neurotoxicity produced by abnormal accumulation of these peptides.

Animals↗
PubMed1996

Glial-cell-line-derived neurotrophic factor enhances biosynthesis of substance P in striatal neurons in vitro.

Glial-cell-line-derived neurotrophic factor (GDNF) is a novel trophic factor with potent trophic effects on several neuron populations in the central and peripheral nervous system. In the present study, we have investigated and compared the potential of dopamine and metamphetamine with that of the two striatal neurotrophic factors, viz., GDNF and neurotrophin-(NT)-4/5, to regulate substance P and its preprotachykinin-A mRNA in organotypic striatal slices from postnatal (day 10) rats. Incubation for 2 weeks with 10 ng/ml GDNF significantly increased substance-P-like immunoreactivity determined by radioimmunoassay. Similarly, the corresponding preprotachykinin-A mRNA increased after 1 and 2 weeks of incubation, as analyzed by in situ hybridization. NT-4/5 exhibited similar effects. The dopamine-releasing agent metamphetamine stimulated substance-P-containing neurons in 1-week-old striatal slices, whereas dopamine stimulated substance-P-like immunoreactivity in 1- and 2-week old striatal cultures. The effects of dopamine and GDNF were not additive. We conclude that substance-P-containing medium-sized spiny neurons in the striatum are under both dopaminergic and growth factor control by GDNF and NT-4/5, which are both synthesized in the striatum. This adds a previously unknown role to those that have been established for GDNF in the nigrostriatal system.

Animals↗
PubMed1996

Presence and distribution of a new neuropeptide, secretoneurin, in human retina.

Secretoneurin (SN) is a neuropeptide formed by endoproteolytic processing of secretogranin II (chromogranin C). Chromatographic analysis revealed that the human retina contains significant concentrations (14.2 fmol/mg wet weight) of this peptide. Its cellular localization in the retina was characterized by immunohistochemistry. SN-immunoreactive (IR) fibers showed a distinct distribution in central and peripheral retinal regions. Immunopositive somata were found in the ganglion cell layer and in the inner nuclear layer. The localization was similar to that of substance P. The physiological role of SN in the human retina is at present unknown. However, its presence in ganglion cells and/or amacrine cells suggests that it may play a role in visual processing.

Aged↗
PubMed1996

Acute and chronic noradrenergic regulation of neurotrophin messenger RNA expression in rat hippocampus: evidence from lesions and organotypic cultures.

Noradrenergic neurons from the locus coeruleus innervate several brain regions, such as hippocampus and cortex. The hippocampus exhibits the highest concentration of the neurotrophins nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 in the brain. To study the role of the noradrenergic system in the chronic regulation of neurotrophin messenger RNA expression, chemical [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, 6-hydroxydopamine] and mechanical (knife-cut axotomy) lesions were performed, in the rat, and neurotrophin messenger RNAs analysed after 14 and 35 days. The intensity of the lesion was verified by characterization of the noradrenergic system using immunohistochemistry and in situ hybridization for dopamine-beta-hydroxylase and the measurement of noradrenaline tissue levels. To study the acute regulation, hippocampal organotypic slice cultures were prepared and neurotrophin messenger RNAs analysed after incubation in different concentrations of noradrenaline. We report that the noradrenergic N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine depletion significantly increased nerve growth factor and brain-derived neurotrophic factor messenger RNAs but not neurotrophin-3 messenger RNA in hippocampal areas 35 days after the lesion, while the knife-cut axotomy had a less pronounced effect and the 6-hydroxydopamine lesion did not change the neurotrophins. When incubating the organotypic hippocampal cultures with different concentrations of noradrenaline, nerve growth factor and brain-derived neurotrophic factor messenger RNAs but not neurotrophin-3 messenger RNA were significantly reduced in the dentate gyrus. We conclude that nerve growth factor and brain-derived neurotrophic factor but not neurotrophin-3 expression are inhibited by noradrenaline, arising from the locus coeruleus.

Animals↗
PubMed1995

Distribution of secretoneurin-like immunoreactivity in comparison with that of substance P in the human spinal cord.

Secretoneurin (SN), a neuropeptide of 33 amino acids, was determined in comparison with substance P (SP) by immunocytochemistry in normal human spinal cord. The density of secretoneurin-like immunoreactivity (SN-IR) was high in the superficial dorsal horn and in the lateral column of autonomic arcs. The ventral horn displayed low to moderate density of SN-IR and prominently outlined motoneurons. The congruent distribution of SN and SP to the termination of primary afferents may indicate that SN is involved in modulation of pain.

Ganglia, Parasympathetic↗