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Biomedical subjects

R Quirion

Publications and source records attributed to R Quirion.

At least 109 records · Page 6Linked to original sources
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

Differential binding profile and internalization process of neurotensin via neuronal and glial receptors.

Two G-protein-coupled receptors for the tridecapeptide neurotensin (NT) have been identified and cloned in mammalian brain: a high-affinity (Kd = 0.3 nM) receptor, sensitive to the antagonist SR 48692 but insensitive to levocabastine, and a lower-affinity (Kd = 2-4 nM) receptor, sensitive to levocabastine but with poor affinity for SR 48692. Although there is good evidence that the high-affinity site is predominantly expressed in neurons, little is known of the cellular localization of the low-affinity receptor. In the present study, we identify by confocal microscopy selective levocabastine-sensitive, SR 48692-resistant binding of a fluorescent derivative of NT (fluo-NT) to a subpopulation of glial fibrillary acidic protein-immunoreactive glial cells grown in culture from the midbrain and cerebral cortex of embryonic and neonatal rats, respectively. We also demonstrate, by combining fluo-NT detection with tyrosine hydroxylase immunofluorescence, that these glial binding sites are differentially regulated from the SR 48692-sensitive NT receptor expressed in the same cultures by mesencephalic dopamine neurons. Whereas the latter undergoes rapid ligand-induced internalization followed by centripetal mobilization of ligand-receptor complexes from processes to perikarya and from perikaryal periphery to cell center, the former induces the formation of cell-surface clusters that fail to internalize. It is concluded that NT may exert its effects on both neurons and astrocytes in the CNS. Whereas NT neural signaling is exerted through high-affinity receptors and may be partly effected through internalization of receptor-ligand complexes, glial signaling is exerted through low-affinity NT receptors and appears to be transduced exclusively at the level of the plasma membrane.

Animals↗
PubMed1997

Interleukin-2 increases choline acetyltransferase activity in septal-cell cultures.

Interleukin-2 (IL-2) is a potent modulator of in vitro acetylcholine release in hippocampal slices [Hanisch et al. (1993) J. Neurosci., 13:3368]. In order to further investigate the cellular nature of this effect, we used embryonic septal-cell cultures (E17), known to be enriched with the cholinergic phenotype. Septal cells were grown at different plating densities under serum-free conditions. The effect of IL-2 on the expression of the cholinergic phenotype was determined using choline acetyltransferase (ChAT) activity and acetylcholinesterase (AChE) cytochemistry. IL-2 significantly enhanced ChAT activity in 5-day-old cultures (5 days in vitro). The amplitude of increases correlated with plating density. At 5 x 10(5) cells/well, the increase in ChAT activity was 35-55% greater than control values in the presence of 10(-14)-10(-10) M IL-2, whereas at 7.5 x 10(5) cells/well, this increase was substantially lower (20%) and only observed at concentrations between 10(-13)-10(-11) M. At 10(6) cells/well, IL-2 had no effect on ChAT activity. The IL-2-induced increase in ChAT activity was significantly inhibited in the presence of an IL-2 receptor antibody. Moreover, this increase was not dependent upon trophic actions, as the number of AChE-positive cells or their morphological characteristics were not altered by IL-2. Taken together, these results suggest that IL-2 can stimulate, at pM concentrations, ChAT activity by acting via its own receptors expressed by septal neurons.

Animals↗
PubMed1997

Reduction in p140-TrkA receptor protein within the nucleus basalis and cortex in Alzheimer's disease.

It has been hypothesized that the diminished transport of nerve growth factor (NGF) seen within cholinergic basal forebrain (CBF) neurons in Alzheimer's disease (AD) results from a defect in the expression of its high-affinity trkA receptor. The present study used an anti-human trkA-specific monoclonal antibody (mAb 5C3) that recognizes the NGF docking site, combined with quantitative optical densitometry, to evaluate whether expression of the trkA protein is altered within the nucleus basalis and its cortical projection sites in AD. In normal aged humans, trkA immunoreactivity revealed a continuum of positive neurons extending throughout all CBF subfields. In addition, trkA-positive neurons were scattered throughout the olfactory tubercle and striatum. These regions also displayed intense trkA neuropil staining. Although fewer in total number, remaining CBF perikarya in AD displayed a significant decrease in trkA levels relative to aged controls. Biochemical analysis revealed a significant reduction in trkA protein within both the nucleus basalis and the frontal cortex in AD relative to aged controls. In contrast, trkA levels in the caudate nucleus were unaffected. The decrease in trkA protein in conjunction with our recent observations that the message for trkA is reduced within individual CBF neurons in AD supports the concept that defects in the production and/or utilization of the trkA receptor may be a key event mediating degeneration of NGF-responsive CBF neurons in this disease.

Aged↗
PubMed1997

Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors.

Calcitonin generelated peptide (CGRP) is a neuropeptide discovered by a molecular approach over 10 years ago. More recently, islet amyloid polypeptide or amylin, and adrenomedullin were isolated from human insulinoma and pheochromocytoma respectively, and revealed between 25 and 50% sequence homology with CGRP. This review discusses findings on the anatomical distributions of CGRP mRNA, CGRP-like immunoreactivity and receptors in the central nervous system, as well as the potential physiological roles for CGRP. The anatomical distribution and biological activities of amylin and adrenomedullin are also presented. Based upon the differential biological activity of various CGRP analogs, the CGRP receptors have been classified in two major classes, namely the CGRP1 and CGRP2 subtypes. A third subtype has also been proposed (e.g. in the nucleus accumbens) as it does not share the pharmacological properties of the other two classes. The anatomical distribution and the pharmacological characteristics of amylin binding sites in the rat brain are different from those reported for CGRP but share several similarities with the salmon calcitonin receptors. The receptors identified thus far for CGRP and related peptides belong to the G protein-coupled receptor superfamily. Indeed, modulation of adenylate cyclase activity following receptor activation has been reported for CGRP, amylin and adrenomedullin. Furthermore, the binding affinity of CGRP and related peptides is modulated by nucleotides such as GTP. The cloning of various calcitonin and most recently of CGRP1 and adrenomedullin receptors was reported and revealed structural similarities but also significant differences to other members of the G protein-coupled receptors. They may thus form a new subfamily. The cloning of the amylin receptor(s) as well as of the other putative CGRP receptor subtype(s) are still awaited. Finally, a broad variety of biological activities has been described for CGRP-like peptides. These include vasodilation, nociception, glucose uptake and the stimulation of glycolysis in skeletal muscles. These effects may thus suggest their potential role and therapeutic applications in migraine, subarachnoid haemorrhage, diabetes and pain-related mechanisms, among other disorders.

Amino Acid Sequence↗
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

L-Deprenyl and MDL72974 do not improve the recovery of dopaminergic cells following systemic administration of MPTP in mouse.

L-Deprenyl, a monoamine oxidase B (MAO-B) inhibitor, administered prior to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) protects dopaminergic neurons against degeneration in several animal species including mice. L-Deprenyl inhibits MPP+ formation, the mediator of MPTP toxicity. In addition, L-deprenyl, administered 72 h following MPTP, improves the recovery of tyrosine hydroxylase (TH) immunopositive neurons in the substantia nigra (SN) of mice. This observation lead to the proposal that L-deprenyl exerts a 'neurorescue' effect. However, clinical trials failed to demonstrate that L-deprenyl can effectively 'rescues' degenerating dopaminergic neurons in early untreated Parkinson's disease (PD) patients. These observations prompted us to reevaluate the long-term impact of L-deprenyl on MPTP-induced dopaminergic cell loss in mice. In addition, we made use of another MAO-B inhibitor, MDL72974, to assess MAO-B participation in this paradigm. Our results suggest that L-deprenyl does not improve the recovery of TH immunopositive neurons in MPTP-treated mice. An apparent reduction in TH+ neurons is observed in the SN of MDL72974 and L-deprenyl/MPTP-treated mice at 30 days post-treatment. The possible implication of these findings in relation to the used of MAO-B inhibitors in PD is discussed.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1997

Comparative developmental profile of the neuropeptide Y Y1 receptor gene and protein in the rat brain.

Neuropeptide Y (NPY) is one of the most abundant peptides found in the mammalian central nervous system (CNS) and plays several important roles in regulating brain function. Physiological roles of NPY in the brain are mediated by at least six receptor subtypes (Y1 to Y6). In the present study, a rat Y1 receptor cRNA probe was used for in in situ hybridization experiments in order to determine the developmental profile of this receptor mRNA and to compare it with its translated protein using receptor autoradiography with the radiolabelled ligand [125I][Leu31,Pro34]PYY. The NPY Y1 receptor mRNA is expressed as early as by the 12th day of gestation while specific [125I][Leu31,Pro34]PYY binding is observed by day 14 of gestation. Thereafter, both signals steadily increased, with Y1 receptor mRNA increasing faster than its translated protein during fetal life. The in situ hybridization signals reached a plateau around birth and remained high during the first 2 post-natal weeks to display the adult distribution by the end of the 3rd post-natal week. Similarly, specific [125I][Leu31,Pro34]PYY binding constantly increased during brain maturation and reached a plateau by the end of the 3rd post-natal week. In some brain areas, such as the cerebral cortex, specific binding declined slightly before attaining its adulthood pattern. Throughout ontogenesis, the profile of both the Y1 receptor mRNA and protein was well-matched except in hypothalamic areas where relatively higher mRNA signals were observed. Taken together, these results along with previous reports describing NPY-like immunoreactivity in the early developmental rat brain, suggest that the NPY Y1 receptor may play an important role in early brain development and maturation on the basis of its very early pattern of embryonic expression.

Animals↗
PubMed1997

Cloning and in situ hybridization analysis of the expression of polysialyltransferase mRNA in the developing and adult rat brain.

Polysialyltransferase (PST) is an enzyme that catalyzes the addition of polysialic acid (PSA), a homopolymer of alpha-2,8-linked sialic acid residues, onto neural cell adhesion molecule (NCAM). The expression of PSA-NCAM in the brain is developmentally regulated and is of critical importance; however, the temporal and spatial developmental expression of brain PST, a potential key player in the control of PSA-NCAM levels, remains unclear. In the present study, we have cloned the coding region of rat PST cDNA by reverse transcription-polymerase chain reaction, using primers based on the hamster PST-1 cDNA sequence. A 39-mer oligonucleotide complementary to rat PST cDNA was synthesized to investigate the distribution of its mRNA in the developing and adult rat brain by Northern blot and in situ hybridization. In the embryonic rat brain, PST mRNA was detected abundantly throughout the neuroepithelia of most brain regions. At post-natal days 1 and 14, PST was detected throughout the neocortex, in the pyramidal cells (PC) of the hippocampus proper, the granule cell layer (GCL) of the dentate gyrus, the anterior ventral nucleus of the thalamus (AVNT) and the GCL and external germinal layer of the cerebellum. Finally, from PD21 until adulthood, expression of PST mRNA was restricted to the PC layer of the hippocampus proper, the GCL of the dentate gyrus, the AVNT, the GCL of the cerebellum and the dorsal and lateral nucleus of the anterior olfactory bulb. The developmental profile of PST mRNA is paralleled in some structures by that of the PSA-NCAM, there are, however, notable exceptions. Therefore, our results demonstrate that expression of rat PST mRNA is developmentally regulated, is present in the adult rat brain in restricted areas and may be involved in regulating temporal and spatial expression of PSA-NCAM.

Aging↗
PubMed1997

[3H]1,3-di(2-tolyl)guanidine and [3H](+)pentazocine binding sites in the rat brain: autoradiographic visualization of the putative sigma1 and sigma2 receptor subtypes.

Sigma (sigma) receptors have generated a great deal of interest on the basis of their possible role in psychosis and on locomotor behaviors. The effects of sigma drugs on these various functions are apparently mediated by different sigma receptor subtypes (sigma1 and sigma2). However, little information is currently available on the discrete anatomical distribution of these putative sigma receptor subtypes in the rat brain. The aim of the present study was to investigate, by quantitative autoradiography, the respective distribution of purported sigma1 and sigma2 receptor subtypes in the rat brain using [3H]1,3-di(2-tolyl)guanidine, a universal sigma ligand, and [3H](+)pentazocine, a selective sigma1 ligand. Putative sigma2 receptor sites were visualized using [3H]1,3-di(2-tolyl)guanidine in presence of a saturating concentration of (+)pentazocine. Specific [3H]1,3-di(tolyl)guanidine and [3H](+)pentazocine binding sites were found to be widely but discretely distributed in the rat brain. The highest densities of specific labeling were seen in various cranial nerve nuclei, followed by certain hippocampal sub-fields and laminae, the red nucleus, the interpeduncular nucleus and mid-layers of primary and secondary motor cortices. Lower amounts of specific binding were present in various other structures including most thalamic and hypothalamic nuclei, and the cerebellum. Interestingly, [3H]1,3-di(2-tolyl)guanidine binding in the motor cortex was found to be particularly resistant to a saturating concentration of (+)pentazocine suggesting an enrichment in the putative sigma2 receptor subtype. This also applies for a few other structures such as the nucleus accumbens, substantia nigra pars reticulata, central gray matter, occulomotor nucleus and cerebellum. On the other hand, the sigma1 subtype is more abundant in most other regions with the highest densities seen in the dentate gyrus of the hippocampal formation, facial nucleus, and various thalamic and hypothalamic nuclei. The comparative localization of the sigma1 and sigma2 receptor binding sites probably relates to the differential effects of sigma1 and sigma2 drugs in the rat brain.

Analgesics, Opioid↗
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↗
PubMed1997

Characterization of neuropeptide Y receptor subtypes in the normal human brain, including the hypothalamus.

The aim of the present study was to investigate the existence and distribution of neuropeptide Y receptor subtypes in various regions of the normal human brain using the peptide YY derivative receptor probes, [125I][Leu31,Pro34]polypeptide YY/Y1 and [125I]polypeptide YY(3-36)/Y2, in addition to the non-selective ligand [125I]polypeptide YY. Membrane binding assays performed with post mortem frontal cortex homogenates revealed that [125I]polypeptide YY and [125I]polypeptide YY(3-36) bound in a time- and protein concentration-dependent manner. Very low amounts of specific [125I][Leu31,Pro34]polypeptide YY binding could be detected even in the presence of high amounts of protein, contrasting with results obtained with [125I]polypeptide YY and [125I]polypeptide YY(3-36), a preferential Y2 receptor probe. Analysis of saturation isotherms revealed that [125I]polypeptide YY(3-36) bound to a single class of high-affinity sites (0.5-2 nM). Significantly higher binding capacities were evident for [125I]polypeptide YY(3-36) as compared to [125I][Leu31,Pro34]polypeptide YY, suggesting that the human frontal cortex, in contrast to the rat, is mostly enriched with Y2 receptors. Ligand selectivity profile confirmed the hypothesis that polypeptide YY(3-36), neuropeptide Y and polypeptide YY but not the [Leu31,Pro34] derivatives are potent competitors of [125I]polypeptide YY and [125I]polypeptide YY(3-36) binding sites. Autoradiographic studies demonstrated further that cortical areas, as well as most other regions of the human brain, are particularly enriched with Y2/[125I]polypeptide YY(3-36) sites, while only low to very low amounts of Y1 binding were detected except in the dentate gyrus of the hippocampal formation. In the human hypothalamus, a preponderance of Y2 binding sites was also noted. Taken together, these results clearly establish that the distribution of the Y1 and Y2 receptor subtypes in human is different from the rodent brain, the Y2 subtype being most abundant in the human brain.

Aged↗
PubMed1997

Neurotoxic consequences of central long-term administration of interleukin-2 in rats.

Interleukin-2 is an immunoregulatory cytokine with several recently established CNS activities. Central effects of interleukin-2 include growth promotion for neuronal and glial cells as well as modulatory influences on neurotransmission and hormone release. However, little is known about the consequences in the CNS of chronically elevated levels of interleukin-2. Alterations in the interleukin-2/interleukin-2 receptor system are not only associated with CNS trauma, inflammation and certain neuropathologies; elevated interleukin-2 concentrations are especially induced during the therapeutic use of interleukin-2 in cancer treatments. In the present study, intracerebroventricular (i.c.v.) interleukin-2 infusions (5 15 U/h) were performed in Sprague Dawley rats for up to 14 days. Interleukin-2-treated animals showed significantly increased plasma levels of corticosterone indicating an hyperfunctioning of the hypothalamic-pituitary-adrenocortical axis that lasted over the 14 day infusion period. Moreover, the performance of interleukin-2-treated animals in the Morris swim maze task was transiently impaired. Quantitative receptor autoradiographic analyses revealed changes in the binding levels of cholinergic M1 and M2 as well as dopaminergic D1 and D2 receptors in selected brain areas in which interleukin-2 was shown to modulate neurotransmission and which are enriched with interleukin-2 receptor expression. Decreased receptor binding levels were observed in the frontoparietal cortex (M2, D1, D2), hippocampal CA1 region (M1, M2) and the nucleus accumbens (D2). Histological and immunohistochemical examination of the brains of interleukin-2-treated animals revealed multiple alterations. Interleukin-2 treatment resulted in an intracranial accumulation of non-neural, MHC class II-positive cells as well as T and B lymphocytes within the infused brain hemisphere. Cellular infiltrates were associated with angiogenesis and the deposition of extracellular matrix material, such as fibronectin. Adjacent brain regions that were partly invaded and dislodged by the cellular masses were characterized by reactive astrogliosis, microglial activation, endothelial upregulation of adhesion molecules, myelin damage and neuronal loss. Together the data suggest that persistently elevated central levels of interleukin-2 can interfere with several CNS functions and may lead to nervous tissue injury. These findings could be relevant to CNS pathologies characterized by abnormal interleukin-2 production and to central responses to interleukin-2 treatments.

Animals↗
PubMed1997

Distribution and levels of [125I]IGF-I, [125I]IGF-II and [125I]insulin receptor binding sites in the hippocampus of aged memory-unimpaired and -impaired rats.

The insulin-like growth factors (IGF-I and IGF-II) and insulin are localized within distinct brain regions and their respective functions are mediated by specific membrane receptors. High densities of binding sites for these growth factors are discretely and differentially distributed throughout the brain, with prominent levels localized to the hippocampal formation. IGFs and insulin, in addition to their growth promoting actions, are considered to play important roles in the development and maintenance of normal cell functions throughout life. We compared the anatomical distribution and levels of IGF and insulin receptors in young (five month) and aged (25 month) memory-impaired and memory-unimpaired male Long Evans rats as determined in the Morris water maze task in order to determine if alterations in IGF and insulin activity may be related to the emergence of cognitive deficits in the aged memory-impaired rat. In the hippocampus, [125I]IGF-I receptors are concentrated primarily in the dentate gyrus (DG) and the CA3 sub-field while high amounts of [125I]IGF-II binding sites are localized to the pyramidal cell layer, and the granular cell layer of the DG. [125I]insulin binding sites are mostly found in the molecular layer of the DG and the CA1 sub-field. No significant differences were found in [125I]IGF-I. [125I]IGF-II or [125I]insulin binding levels in any regions or laminae of the hippocampus of young vs aged rats. and deficits in cognitive performance did not relate to altered levels of these receptors in aged memory-impaired vs aged memory-unimpaired rats. Other regions. including various cortical areas, were also examined and failed to reveal any significant differences between the three groups studied. It thus appears that IGF-I, IGF-II and insulin receptor sites are not markedly altered during the normal ageing process in the Long Evans rat, in spite of significant learning deficits in a sub-group (memory-impaired) of aged animals. Hence. recently reported changes in IGF-I receptor messenger RNA levels in aged memory-impaired rats are apparently not reflected at the level of the translated protein.

Aging↗
PubMed1997

Systemic administration of kainic acid induces selective time dependent decrease in [125I]insulin-like growth factor I, [125I]insulin-like growth factor II and [125I]insulin receptor binding sites in adult rat hippocampal formation.

Administration of kainic acid evokes acute seizure in hippocampal pathways that results in a complex sequence of functional and structural alterations resembling human temporal lobe epilepsy. The structural alterations induced by kainic acid include selective loss of neurones in CA1-CA3 subfields and the hilar region of the dentate gyrus followed by sprouting and permanent reorganization of the synaptic connections of the mossy fibre pathways. Although the neuronal degeneration and process of reactive synaptogenesis have been extensively studied, at present little is known about means to prevent pathological conditions leading to kainate-induced cell death. In the present study, to address the role of insulin-like growth factors I and II, and insulin in neuronal survival as well as synaptic reorganization following kainate-induced seizure, the time course alterations of the corresponding receptors were evaluated. Additionally, using histological preparations, the temporal profile of neuronal degeneration and hypertrophy of resident astroglial cells were also studied. [125I]Insulin-like growth factor I binding was found to be decreased transiently in almost all regions of the hippocampal formation at 12 h following treatment with kainic acid. The dentate hilar region however, exhibited protracted decreases in [125I]insulin-like growth factor I receptor sites throughout (i.e. 30 days) the study. [125I]Insulin-like growth factor II receptor binding sites in the hippocampal formation were found to be differentially altered following systemic administration of kainic acid. A significant decrease in [125I]insulin-like growth factor II receptor sites was observed in CA1 subfield and the pyramidal cell layer of the Ammon's horn at all time points studied whereas the hilar region and the stratum radiatum did not exhibit alteration at any time. A kainate-induced decrease in [125I]insulin receptor binding was noted at all time points in the molecular layer of the dentate gyrus whereas binding in CA1-CA3 subfields and discrete layers of the Ammon's horn was found to be affected only after 12 h of treatment. These results, when analysed with reference to the observed histological changes and established neurotrophic/protective roles of insulin-like growth factors and insulin, suggest possible involvement of these growth factors in the cascade of neurotrophic events that is associated with the reorganization of the hippocampal formation observed following kainate-induced seizures.

Animals↗
PubMed1997

Evidence for direct and indirect mechanisms in the potent modulatory action of interleukin-2 on the release of acetylcholine in rat hippocampal slices.

1. The biphasic nature of the potent modulatory action of interleukin-2 (IL-2) on hippocampal acetylcholine (ACh) release was investigated by use of brain slice superfusion. 2. Both the potentiating (10(-13) M) and inhibitory (10(-9) M) effects of IL-2 on hippocampal ACh release were stimulation-dependent and were blocked by a neutralizing IL-2 receptor antibody, suggesting the activation of typical IL-2 receptors in both cases. 3. Tetrodotoxin (TTX: 10 microM) failed to block the potentiation of ACh release induced by a very low concentration of IL-2 (10(-13) M) suggesting a direct effect on cholinergic nerve terminals. 4. In contrast, the inhibitory effect seen at a higher concentration (10(-9) M) was TTX-sensitive, and hence indicative of an indirect action. 5. To establish the nature of this intermediate mediator, blockers of nitric oxide synthesis, and of opioid and gamma-aminobutyric acid (GABA) receptors were used. Only GABAA and GABAB receptor antagonists altered the inhibitory action of IL-2, suggesting the participation of GABA as mediator. 6. Taken together, these results provide further evidence for the potent role of IL-2 in the modulation of cholinergic function in the rat hippocampus.

Acetylcholine↗
PubMed1997

Endogenous neurotensin regulates hypothalamic-pituitary-adrenal axis activity and peptidergic neurons in the rat hypothalamic paraventricular nucleus.

Adrenocorticotropin (ACTH) secretion depends primarily on hypophysiotrophic factors released from neurons of the paraventricular nucleus of the hypothalamus. However, the neurochemical factors controlling these neurons, in particular neuropeptides, have had little investigation. In this study, we have investigated the role of neurotensin in the regulation of the different components of the hypothalamo-pituitary-adrenal (HPA) axis under basal and stress conditions in rats. For this purpose, animals were implanted with bilateral cannulae filled with crystals of the neurotensin antagonist, SR 48692, and which were located above the paraventricular nucleus. Five days after surgery, the effects of SR 48692 implants were studied on basal and stress-induced secretion of ACTH and corticosterone. Such treatment did not modify plasma levels of ACTH and corticosterone in basal conditions but reduced ACTH but not corticosterone levels after tail cut procedure. After an exposure to a novel environment for 30 min, both ACTH and corticosterone plasma levels were reduced in the SR 48692-treated group. In situ hybridization studies revealed that chronic administration of SR 48692 induced a significant reduction of CRF mRNA levels in the parvocellular division of the paraventricular nucleus of the hypothalamus. In addition, a 2-fold increase in basal levels of plasma vasopressin associated with an increase in vasopressin mRNA levels in the magnocellular neurons of the paraventricular nucleus was also detected. Finally, the basal plasma levels of oxytocin were not affected by the same treatment. Taken together, these findings strongly suggest that endogenous neurotensin in the paraventricular nucleus plays a tonic stimulatory role on HPA axis activity and an inhibitory effect on vasopressin secretion.

Adrenal Glands↗