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S Kar

Publications and source records attributed to S Kar.

At least 55 records · Page 3Linked to original sources
PubMed2000

Effects of voluntary ethanol drinking on [125I]insulin-like growth factor-I, [125I]insulin-like growth factor-II and [125I]insulin receptor binding in the mouse hippocampus and cerebellum.

Chronic exposure to ethanol can induce widespread cell loss in the brain, in some cases even causing dementia. Although the underlying mechanism associated with ethanol toxicity has not yet been established, it is suggested that one of the ways in which ethanol disrupts neuronal functioning/survival is by targeting the actions of mitogenic growth factors. Insulin-like growth factors-I and -II and insulin are structurally related polypeptides with potent mitogenic and metabolic effects on the central and peripheral nervous systems. These growth factors and their respective receptors are widely distributed throughout the brain, including the hippocampus and cerebellum. Evidence indicates that ethanol can decrease plasma levels of insulin-like growth factors and can also inhibit the growth-promoting and cell survival effects of these growth factors under in vitro conditions. The present study was designed to determine if voluntary ethanol consumption over a 21-day period could alter [125I]insulin-like growth factor-I, [125I]insulin-like growth factor-II and [125I]insulin receptor-binding sites in the hippocampus and cerebellum-areas known to be severely affected following chronic exposure to ethanol. C57BL/6 mice were presented with either water only or a choice of water and a 10% v/v ethanol solution. Mice with access to the ethanol solution drank an average of 5.35+/-0.77 g of ethanol/kg body weight per day. [125I]Insulin-like growth factor-I receptor-binding sites were found to be significantly increased in all subfields of the hippocampal formation, but not in the cerebellum, of ethanol-treated mice compared to controls. [125I]Insulin-like growth factor-II and [125I]insulin receptor-binding sites, on the other hand, did not exhibit any alterations either in the hippocampus or cerebellum following chronic exposure to ethanol. These results, in keeping with earlier reports, suggest that hippocampal insulin-like growth factor-I is more sensitive to ethanol treatment than either insulin-like growth factor-II or insulin, and the observed increase in the [125I]insulin-like growth factor-I receptor levels possibly reflects an activity-dependent response to prevent/slow down neuronal degeneration and/or to regulate subtle functional alterations that follow chronic exposure to ethanol.

Alcohol Drinking↗
PubMed2000

Morphine treatment induced calcitonin gene-related peptide and substance P increases in cultured dorsal root ganglion neurons.

The mechanism of spinal tolerance to the analgesic effects of opiates is unclear at present. We have reported previously that calcitonin gene-related peptide-like immunoreactivity was significantly increased in primary afferents of the spinal dorsal horn during the development of morphine tolerance, suggesting that changes in the level of pain-related neuropeptides in dorsal root ganglion neurons may be involved [Menard D. P. et al. (1996) J. Neurosci. 16, 2342-2351]. In this study, we investigated if in vitro treatment with morphine can mimic the in vivo findings and induce increases in calcitonin gene-related peptide-like immunostaining in cultured dorsal root ganglion neurons from young (three-month-old) and middle-aged (10-month-old) adult rats. Following a repetitive exposure to morphine sulfate (1, 5, 10 microM) for six days, the number of calcitonin gene-related peptide- and substance P-immunoreactive neurons in cultured dorsal root ganglia from three- and 10-month-old rats was significantly increased. A lower concentration (0.5 microM) of morphine induced these increases only in dorsal root ganglion neurons from middle-aged rats. Morphine treatment was also found to increase the number of calcitonin gene-related peptide-immunoreactive neurons possessing multiple, long branches (i.e. with at least one branch >0.5mm). This apparent increase in the number of calcitonin gene-related peptide- and substance P-immunoreactive neurons observed following morphine treatment was blocked by naloxone, an opiate antagonist, indicating the involvement of genuine opioid receptors. No significant change in the number of neuropeptide Y- or galanin-immunoreactive neurons in cultured dorsal root ganglia was detected following any of these treatments. These data suggest that repeated exposure to morphine rather selectively increases calcitonin gene-related peptide- and substance P-like immunoreactivity in cultured dorsal root ganglion neurons. Moreover, the sensitivity to morphine-induced changes is greater in cultured dorsal root ganglion neurons from 10- compared to three-month-old rats. Hence, cultured dorsal root ganglion neurons can provide a model to investigate the cellular and molecular mechanisms underlying alterations in neuropeptide levels following repeated exposure to opiates and their relevance to the development of opioid tolerance.

Age Factors↗
PubMed2000

Ashy dermatosis.

Explore the source record for details and available documents.

Biopsy, Needle↗
PubMed1999

Impact of neonatal kainate treatment on hippocampal insulin-like growth factor receptors.

The insulin-like growth factors-I and -II have neurotrophic properties and act through specific membrane receptors. High levels of binding sites for these growth factors are distributed discretely throughout the brain, being concentrated in the hippocampal formation. Functionally, the insulin-like growth factors, in addition to their growth-promoting actions, are considered to play important roles in normal cell functions, as well as in response to pharmacological or surgical manipulations. In adult rats, we have previously shown that systemic injection of kainate produces an overall decrease, in a time-dependent manner, in insulin-like growth factor-I and -II receptor binding sites in the hippocampus [Kar S. et al. (1997) Neuroscience 80, 1041-1055]. Given the evidence that insulin-like growth factors play a critical role during the early stages of brain development, the present study is a logical extension of this earlier report and established the effect of neonatal kainate injection on the developmental profile of insulin-like growth factor receptors. We have evaluated the time-course alteration of these receptors following systemic injection of kainate to newborn rats. After injection of a sublethal dose of kainate (5 mg/kg, i.p.) to postnatal one-day-old pups, [125I]insulin-like growth factor-I, [125I]insulin-like growth factor-II and [125I]insulin binding sites were studied at different postnatal days (7, 14, 21, 28 and 35) using receptor autoradiography. In the developing hippocampus, insulin-like growth factor-I and insulin binding sites are concentrated primarily in the dentate gyrus and the CA2/CA3 subfields, whereas insulin-like growth factor-II binding is discretely localized to the pyramidal layer and the granular layer of the dentate gyrus. Following kainate injection, we observed a slight increase in insulin-like growth factor-I binding sites in given hippocampal subfields starting at postnatal day 14, being significant at day 21. At later days, a progressive decrease was noted. This transient increase may represent an attempt for neuronal plasticity by up-regulating receptor levels. In contrast, insulin-like growth factor-II and insulin receptor binding sites are found to be decreased in various regions of the hippocampus in kainate-treated pups. Taken together, these results provide further evidence for the existence and differential alterations of insulin-like growth factor-I, insulin-like growth factor-II and insulin receptors in the developing rat hippocampus following kainate-induced lesion, suggesting possible involvement of these growth factors in brain plasticity.

Aging↗
PubMed1999

Cholinergic systems and long-term potentiation in memory-impaired apolipoprotein E-deficient mice.

Impairments in cholinergic neurotransmitter systems of the basal forebrain are a hallmark of Alzheimer's disease pathophysiology. The presence of the epsilon4 allele of apolipoprotein E was recently implicated as a major risk factor in both familial and sporadic Alzheimer's disease. The present study examined the integrity of cholinergic and non-cholinergic systems in apolipoprotein E-deficient, memory-impaired mice. Choline acetyltransferase activity, hippocampal acetylcholine release, nicotinic and muscarinic (M1 and M2) receptor binding sites and acetylcholinesterase cell or terminal density showed no signs of alteration in either three-month or 9.5-month-old apolipoprotein E-deficient mice compared to controls. In contrast, long-term potentiation was found to be markedly reduced in these mice, but increases in the strength of stimulation induced the same level of long-term potentiation as that observed in controls. These alterations did not appear to be the consequence of modifications in the binding properties of glutamatergic receptors (N-methyl-D-aspartate and [RS]-alpha-amino-3-hydroxy-5-methylisoxazole propionic acid) but from defective regulation of the (RS)-alpha-amino-3-hydroxy-5-methylisoxazole propionic acid receptor by phospholipase A2 activity. These results support the notion that apolipoprotein E plays a fundamental role in neuronal plasticity, which could in turn affect cognitive performance through imbalances in extra- and intracellular lipid homeostasis.

Acetylcholine↗
PubMed1999

Protective and rescuing abilities of IGF-I and some putative free radical scavengers against beta-amyloid-inducing toxicity in neurons.

beta-Amyloid (A beta) peptides are most likely involved in the neurodegenerative process occurring in Alzheimer's Disease (AD) and are enriched in senile plaques. The mechanisms of A beta toxicity are not clear but likely involve free radicals and apoptosis. Much interest is currently aiming at developing effective approaches to block A beta toxicity in order to slow down disease progression. In that context, we are particularly interested in studying the role of insulin-like growth factors, particularly IGF-I and purported free radical scavengers including a Gingko biloba extract (EGb761) as blocker of A beta toxicity in a simple in vitro model of hippocampal primary cultures. We observed that both IGF-I and EGb761 are unique in that they are able not only to protect but even to rescue neurons against A beta toxicity. These results are summarized here and possible mechanisms of action are discussed to explain the protective properties of these two classes of agents.

Adjuvants, Immunologic↗
PubMed1999

Relationship of flow and cross-sectional area to frictional stress in airway models of asthma.

Frictional stress from air flowing through narrowed airways may damage the airway mucosa and thereby increase airway inflammation and airway obstruction. To investigate the levels of frictional stress that might occur in the airway, we measured the frictional stress in three physical airway models (model 1: normal state; models 2 and 3: narrowed states with cross-sectional area half and one-fourth of model 1, respectively) at tracheal expiratory flow rates of 1, 2, 3, 4, 5, 6, 7, and 8 L/sec. Frictional stress measured at stations in the trachea (A), two each in the left (B and C) and right (D and E) major bronchi, and one in the right secondary bronchus (F) indicated that at higher flow rates, high values of the frictional stress seen in model 3 (highest value being 139.2 N/m2 at 8 L/sec at station) could well damage the airway wall, especially during episodes of cough, and particularly when the mucosa is inflamed and friable as it is in asthmatic patients. Conversely, control of cough may have anti-inflammatory benefits in asthmatic patients.

Adult↗
PubMed1998

Structural and kinetic studies of phosphorylation-dependent regulation in smooth muscle myosin.

In this study, we have examined the mechanism of phosphorylation-dependent regulation in smooth muscle myosin through the use of structural and kinetic methodologies applied to several myosin fragments. Fluorescence anisotropy decay measurements demonstrate that regulatory light chain phosphorylation significantly reduces the rotational correlation time of regulatable myosin preparations, whereas minimally regulated ones show little effect in this assay. Sedimentation equilibrium studies show that the regulatory domain can dimerize with a dissociation constant that is unaffected by regulatory light chain phosphorylation. Finally, kinetic studies on the interactions of myosin-ADP constructs with actin are also consistent with a model in which interactions occur between the two heads, which are lost with regulatory light chain phosphorylation. We propose that in the absence of regulatory light chain phosphorylation, the two heads of myosin interact with each other, due to a weak intrinsic dimerization of the regulatory domains that is significantly stabilized by the proximal rod. Regulatory light chain phosphorylation abolishes the stabilizing effect of the proximal rod, leading to a loss of this interaction.

Actins↗
PubMed1998

Beta-amyloid peptides as direct cholinergic neuromodulators: a missing link?

Beta-Amyloid peptide (Abeta) is found in diffuse and focal deposits throughout the brain from Alzheimer's disease (AD) patients. Another feature of AD is the widespread degeneration and dysfunction of the basal-forebrain cholinergic system. Until now, it has been unclear how these features of AD might be related. Recent reports, however, suggest that Abeta can potently inhibit various cholinergic neurotransmitter functions independently of apparent neurotoxicity. This capacity of Abeta might contribute to the vulnerability of selected cholinergic neuronal populations in AD. Moreover, the high potency (picomolar to nanomolar concentrations) of these effects and the secretion of Abeta by brain cells indicate that Abeta-induced cholinergic hypoactivity might have physiological in addition to pathological significance.

Alzheimer Disease↗
PubMed1998

Amyloid beta-peptide inhibits high-affinity choline uptake and acetylcholine release in rat hippocampal slices.

The characteristic pathological features of the postmortem brain of Alzheimer's disease (AD) patients include, among other features, the presence of neuritic plaques composed of amyloid beta-peptide (A beta) and the loss of basal forebrain cholinergic neurons, which innervate the hippocampus and the cortex. Studies of the pathological changes that characterize AD and several other lines of evidence indicate that A beta accumulation in vivo may initiate and/or contribute to the process of neurodegeneration and thereby the development of AD. However, the mechanisms by which A beta peptide influences/causes degeneration of the basal forebrain cholinergic neurons and/or the cognitive impairment characteristic of AD remain obscure. Using in vitro slice preparations, we have recently reported that A beta-related peptides, under acute conditions, potently inhibit K+-evoked endogenous acetylcholine (ACh) release from hippocampus and cortex but not from striatum. In the present study, we have further characterized A beta-mediated inhibition of ACh release and also measured the effects of these peptides on choline acetyltransferase (ChAT) activity and high-affinity choline uptake (HACU) in hippocampal, cortical, and striatal regions of the rat brain. A beta(1-40) (10(-8) M) potently inhibited veratridine-evoked endogenous ACh release from rat hippocampal slices and also decreased the K+-evoked release potentiated by the nitric oxide-generating agent, sodium nitroprusside (SNP). It is interesting that the endogenous cyclic GMP level induced by SNP was found to be unaltered in the presence of A beta(1-40). The activity of the enzyme ChAT was not altered by A beta peptides in hippocampus, cortex, or striatum. HACU was reduced significantly by various A beta peptides (10(-14) to 10(-6) M) in hippocampal and cortical synaptosomes. However, the uptake of choline by striatal synaptosomes was altered only at high concentration of A beta (10(-6) M). Taken together, these results indicate that A beta peptides, under acute conditions, can decrease endogenous ACh release and the uptake of choline but exhibit no effect on ChAT activity. In addition, the evidence that A beta peptides target primarily the hippocampus and cortex provides a potential mechanistic framework suggesting that the preferential vulnerability of basal forebrain cholinergic neurons and their projections in AD could relate, at least in part, to their sensitivity to A beta peptides.

Acetylcholine↗
PubMed1998

Vibrio cholerae O139 Bengal: combined physical and genetic map and comparative analysis with the genome of V. cholerae O1.

A combined physical and genetic map of the genome of strain SG24 of Vibrio cholerae O139 Bengal, a novel non-O1 strain having epidemic potential, has been constructed by using the enzymes NotI, SfiI, and CeuI. The genome of SG24 is circular, and the genome size is about 3. 57 Mb. The linkages between 47 NotI and 32 SfiI fragments of V. cholerae SG24 genomic DNA were determined by combining two approaches: (i) identification of fragments produced by enzyme I in fragments produced by enzyme II by the method of fragment excision, redigestion, and end labeling and (ii) use of the linking clone libraries generated from the genome of classical O1 strain 569B. The linkages between nine CeuI fragments were determined primarily by analyses of partial fragments of the CeuI-digested genome. More than 80 cloned homologous and heterologous genes, including several operons, have been positioned on the physical map. The map of the SG24 genome represents the second map of a V. cholerae genome, and a comparison of this map with that of classical O1 strain 569B revealed considerable diversity in DNA restriction sites and allowed identification of hypervariable regions. Several genetic markers, including virulence determinant genes, are in different positions in the SG24 and 569B genomes.

Chromosome Mapping↗
PubMed1997

Insulin-like growth factors-I and -II differentially regulate endogenous acetylcholine release from the rat hippocampal formation.

Insulin-like growth factors-I and -II (IGF-I and -II) are structurally related mitogenic polypeptides with potent growth promoting effects. These peptides and their corresponding IGF-I and -II receptors are selectively localized in the brain. To date, most of the effects of IGFs are believed to be mediated by IGF-I receptors whereas the significance of IGF-II receptor in mediating biological responses remains unclear. In the present study, we characterized the distribution of IGF-I and IGF-II receptor sites and investigated the effects of both factors on endogenous acetylcholine (ACh) release in adult rat hippocampus. [125I]IGF-I receptor binding sites are recognized by IGF-I> IGF-II> insulin, whereas [125I]IGF-II binding was competed potently by IGF-II> IGF-I but not by insulin. At the cellular level, IGF-I receptor sites were primarily noted in the molecular layer of the dentate gyrus and the CA2-CA3 subfields of the Ammon's horn whereas IGF-II sites were localized predominantly in the pyramidal cell layer of the CA1-CA3 subfields and in the granular cell layer of the dentate gyrus. IGF-I (10(-14)-10(-8) M) and des(1-3) IGF-I (10(-10)-10(-8) M) were found to inhibit whereas IGF-II (10(-14)-10(-8) M) potentiated K+-evoked ACh release from hippocampal slices. Tetrodotoxin altered the effects of IGF-I but not those of IGF-II suggesting that IGF-I acts indirectly via the release of other modulators whereas IGF-II acts directly on or in close proximity to the cholinergic terminals. The inhibitory effects of IGF-I were also observed in the frontal cortex but not in the striatum. In contrast, the stimulatory effects of IGF-II were evident both in the frontal cortex and striatum. Taken together, these results reveal the differential localization of IGF-I and IGF-II receptor sites in the hippocampal formation and the opposite role for these growth factors in the acute regulation of ACh release likely via two distinct mechanisms. Additionally, these data provide the first evidence for a direct role for IGF-II and its receptors in the regulation of transmitter release in the central nervous system.

Acetylcholine↗
PubMed1997

Insulin-like growth factor I protects and rescues hippocampal neurons against beta-amyloid- and human amylin-induced toxicity.

Insulin-like growth factors (IGF-I and IGF-II) are well known trophic factors and their specific receptors are uniquely distributed throughout the brain, being especially concentrated in the hippocampal formation. IGFs possess neurotrophic activities in the hippocampus, an area severely affected in Alzheimer disease. These data, together with the evidence that beta-amyloid (Abeta)-derived peptides likely play an important role in the neurodegenerative process observed in Alzheimer disease, led us to investigate if IGFs could be neuroprotective to hippocampal neurons against toxicity induced by amyloidogenic derivatives. Exposure of rat primary hippocampal neurons to different concentrations of Abeta25-35, Abeta1-40, Abeta1-42, and human amylin produced marked toxicity, while similar concentrations of two control Abeta peptides-reverse (Abeta40-1) and scrambled sequence (Abeta25-35)-and rat amylin failed to exhibit any significant effect on neuronal survival. IGF-I (10-100 nM) significantly protected hippocampal neurons against neurotoxicity induced by Abeta derivatives and human amylin. The homolog IGF-II was also effective although less potent than IGF-I suggesting the involvement of a typical IGF-I receptor in the observed neuroprotective effect. Most interestingly, IGF-I (10-100 nM) was even able to rescue neurons pre-exposed (up to 4 days) to amyloidogenic peptides. Other neurotrophic factors are reported to lack such rescuing abilities. These results suggest that IGF-I may have unique properties as a potent neuroprotective and neurorescuing agent against amyloid-related neurotoxicity.

Amyloid↗
PubMed1997

Inhibition of spermidine synthase gene expression by transforming growth factor-beta 1 in hepatoma cells.

We screened genes responsive to transforming growth factor-beta (TGF-beta 1) protein in a human hepatoma cell line (Hep3B) using a PCR-mediated differential display technique, in order to investigate the mechanisms involved in TGF-beta-induced growth suppression. We found a gene that was down-regulated by TGF-beta 1 to be completely identical in an approx. 620 bp segment to the gene for the enzyme spermidine synthase, which mediates the conversion of putrescine into spermidine. Both spermidine synthase mRNA expression and its enzyme activity were decreased after TGF-beta 1 treatment of Hep3B cells. The inhibition of spermidine synthase gene expression by TGF-beta 1 protein was also observed in other hepatoma cell lines. The expression of genes for other biosynthetic enzymes in polyamine metabolism (ornithine decarboxylase and S-adenosylmethionine decarboxylase) was also inhibited to the same extent as for spermidine synthase, while the gene expression of spermidine/spermine N1-acetyltransferase, a catabolic enzyme, was relatively resistant to TGF-beta 1. Spermine levels in Hep3B cells were decreased by TGF-beta 1 treatment, although the levels of spermidine and putrescine were unchanged, probably due to compensation by remaining spermidine/spermine N1-acetyltransferase activity. Exogenously added spermidine or spermine, but not putrescine, partially antagonized the growth-inhibitor effects of TGF-beta 1 on Hep3B cells. Our data suggest that down-regulation of gene expression of the enzymes involved in polyamine metabolism, including spermidine synthase, may be associated with the mechanism of TGF-beta-induced growth suppression.

Carcinoma, Hepatocellular↗
PubMed1997

Rediscovering an old friend, IGF-I: potential use in the treatment of neurodegenerative diseases.

Insulin-like growth factor-I (IGF-I) is a pleiotropic protein that acts on many tissues and organs. As it is one of the major trophic factors in the circulation, its actions in peripheral tissues are well established. It has been used for the treatment of several diseases, including growth deficiency, osteoporosis, catabolic disorders and diabetes. Recent evidence supports the significance of IGF-I in the maintenance of the integrity and homeostasis of the nervous system. The widespread distribution of its receptor allows IGF-I to affect the survival of numerous populations of neurones and glial cells in both the CNS and the PNS. Most recently, a clinical trial has revealed the beneficial effects of IGF-I in amyotrophic lateral-sclerosis (ALS), a degenerative disease of the motoneurones. We review briefly here experimental and clinical information that suggests the potential usefulness of IGF-I in the treatment of certain neurodegenerative diseases, including ALS, Alzheimer's disease, various neuropathies and brain trauma. The rather unique propensity of IGF-I to act on a variety of neuronal cells might provide a general means of reducing or slowing down neuronal losses that occur following various brain insults.

Humans↗
PubMed1997

Presence and differential internalization of two distinct insulin-like growth factor receptors in rat hippocampal neurons.

The pharmacological characteristics, localization and process of internalization of the insulin-like growth factor I and II receptors were studied in rat primary hippocampal cultured neurons grown under serum-free conditions. [125I]insulin-like growth factor-I binding was specific with an apparent affinity (Kd) of 0.1 nM and IC50 values of 0.1, 2.9 and 99.7 nM for insulin-like growth factor-I, insulin-like growth factor-II and insulin, respectively. The competition by insulin suggests the presence of genuine insulin-like growth factor-I receptors and not insulin-like growth factor binding proteins. In contrast, [125I]insulin-like growth factor-II binding showed a Kd of 0.1 nM and IC50 values of 0.2 and 20.5 nM for insulin-like growth factor-II and insulin-like growth factor-I while insulin was inactive, a well established characteristic of the insulin-like growth factor-II receptor. Using emulsion autoradiography, specific binding sites for [125I]insulin-like growth factor-I and -II were over the whole cultured neurons. The use of selective insulin-like growth factor-I and -II receptor antibodies further confirmed the existence of these receptors in rat hippocampal cultured neurons. To investigate the respective internalization profile of [125I]insulin-like growth factor-I and [125I]insulin-like growth factor-II receptor-ligand complexes in neurons, a technique of acid stripping was used. The apparent rate of endocytosis was found to be greater for the insulin-like growth factor-II than for the insulin-like growth factor-I receptor complexes. The internalization of [125I]insulin-like growth factor-I and [125I]insulin-like growth factor-II ligand-receptor complexes was confirmed using phenylarsine oxide which significantly blocked both internalization processes. In order to eliminate possible receptor recycling, monensin was used and shown to have no effect on the internalization of either ligand. Since the insulin-like growth factor-I receptor is coupled to tyrosine kinase activity, tyrphostin 47, a specific tyrosine kinase inhibitor. was used and shown to decrease [125I]insulin-like growth factor-I but not the [125I]insulin-like growth factor-II receptor internalization profile. Accordingly, insulin-like growth factor-I is apparently internalized mostly via the insulin-like growth factor-I tyrosine kinase type receptor, while insulin-like growth factor-II is not. The insulin-like growth factor-II receptor ligand complex is likely internalized via a pathway possibly related to mannose-phosphorylated residues as the insulin-like growth factor-II/mannose-6-phosphate receptor has been implicated in the intracellular targeting of lysosomal proteins containing glycosylated residues. Taken together, our results indicate that primary hippocampal cultured neurons represent a unique model for investigating the differential role and intracellular trafficking of both insulin-like growth factor-I and insulin-like growth factor-II receptor ligand complexes and their relevance to the respective functional role of these two-related trophic factors in the central nervous system.

Animals↗