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At least 217 records · Page 12Linked to original sources

PubMed1983

Clinical studies of monoamine receptors in the affective disorders and receptor changes with antidepressant treatment.

Pre-clinical and clinical studies suggest that the responsiveness of monoamine and cholinergic receptors may be altered in the affective disorders and that antidepressants may modify the sensitivity of these receptors. The growth hormone response to clonidine is reduced in depressed patients compared to controls according to several independent studies, suggesting that post-synaptic alpha 2-adrenergic receptors may be less responsive in depressed patients. The cortisol response to clonidine is enhanced in depressed patients compared to controls in our study raising the possibility that cortisol hypersecretion in depressed patients may be related to noradrenergic dysfunction. The hypotensive response to clonidine is blunted in patients on chronic antidepressant treatment with either clorgyline or desipramine suggesting that pre-synaptic alpha 2-adrenergic receptors may subsensitize with chronic antidepressant treatment. The prolactin increase in response to fenfluramine is less in depressed patients compared to controls suggesting decreased functional activity of the serotonergic system in depression. Platelet alpha 2-adrenergic receptor number as measured by tritiated dihydroergocriptine (3H-DHE) binding is increased in depressed patients compared to controls, while cyclic 3'-5' adenosine monophosphate (cAMP) production in response to prostaglandin E1 (PGE1) and norepinephrine (NE) inhibition of PGE1-stimulated cAMP production are reduced in the platelets of depressed patients. Thus, it is not clear that increased 3H-DHE binding reflects increased functional responsiveness and might in fact be compensatory to decreases in functional responses of alpha 2-adrenergic receptors.

Clonidine↗

PubMed1995

Lead inhibits Ca(2+)-stimulated nitric oxide synthase activity from rat cerebellum.

Pb2+ is reported to cause cognitive dysfunctions in children and to inhibit long-term potentiation (LTP), a model form of synaptic plasticity that involves nitric oxide (NO). Since Pb2+ interacts with Ca(2+)-calmodulin, and brain nitric oxide synthase (NOS) is Ca(2+)-calmodulin regulated, we examined the effects of Pb2+ on NOS activity prepared from rat cerebellum. NOS required NADPH and was inhibited by monomethylarginine. Full NOS activity required 0.6 microM free Ca2+ and was inhibited 50% by 17 nM and 100% by 80 nM free Pb2+. NOS inhibition by Pb2+ was reversible by increasing free Ca2+ concentrations. Evaluation of other divalent cations resulted in the following ranked order of potencies: Cu2+ > Pb2+ >> Zn2+; Fe2+, Ba2+, Mg2+, Mn2+, and Sr2+ were ineffective. These results suggest that Pb2+ inhibition of brain NOS activity may account for some of the effects of Pb2+ on the CNS.

Animals↗

PubMed2025

Biological roles of nonsense-mediated RNA decay: insights from the nervous system.

Nonsense-mediated RNA decay (NMD) is a highly selective and conserved RNA turnover pathway. The discovery that NMD is not only a quality control pathway that degrades aberrant mRNAs but also degrades subsets of normal mRNAs has led to the hypothesis that NMD influences and controls normal biological events. In this review, we lay out the support for this hypothesis, with a focus on NMD's roles in the nervous system. Studies have demonstrated roles for NMD in several aspects of nervous system development, including neural cell generation and differentiation. Studies in mice have provided evidence that NMD inhibits neural inflammation and promotes mature neuron functions, including dendritic spine maturation and synaptic plasticity, providing a potential explanation for why NMD deficiency leads to cognitive and behavioral dysfunction in mice and humans.

Nonsense Mediated mRNA Decay↗

PubMed1992

Early neurochemical changes in the autonomic neuropathy of the gut in experimental diabetes.

Some neurochemical changes in the gut of rats after five weeks of alloxan-induced diabetes were investigated. It was found that at this stage of diabetes the changes were restricted mainly to the small intestine with a special selectivity for the duodenum. No changes were found in the most part of the large intestine and rectum. The methionine-enkephalin content was markedly reduced throughout the small intestine, while vasoactive intestinal polypeptide was increased in duodenum, ileum and caecum. Substance P content was unaffected, while at later stages of the disease it was significantly reduced in the entire small intestine. Sympathetic noradrenaline and intrinsic serotonin contents were significantly increased in the duodenum and unchanged throughout the rest of the intestine. These data suggest that the small intestine and caecum might be the early target of diabetic autonomic neuropathy, that might involve progressively the rest of the large intestine at later stages as recent results have suggested. It is likely that the gastrointestinal dysfunctions, often present in diabetic patients, might also be due to the combined pre-synaptic alterations, and to the functional imbalance between Gs and Gi/Go transduction proteins recently reported. Insulin therapy, begun seven days after alloxan treatment, reduced drastically the hyperglycaemia, restored normal body growth and prevented all the gut neurochemical changes associated with alloxan-induced diabetes.

Animals↗

PubMed2001

CSF studies in violent offenders. II. Blood-brain barrier dysfunction without concurrent inflammation or structure degeneration.

Cerebral dysfunction without corresponding structural pathology has been reported in brain imaging studies of violent offenders. Biochemical markers in the CSF reflect various types of CNS pathology, such as blood-brain barrier dysfunction (CSF/S albumin ratio), infectious or inflammatory processes (IgG and IgM indices), neuronal or axonal degeneration (CSF-tau protein) and synaptic de- or regeneration (CSF-growth associated protein-43 (GAP-43)). We compared these CSF markers in 19 non-psychotic perpetrators of severe violent crimes undergoing pretrial forensic psychiatric investigation and 19 age- and sex-matched controls. Index subjects had significantly higher albumin ratios (p = 0.002), indicating abnormal vascular permeability as part of the complex CNS dysfunction previously reported in violent offenders. Axis I disorders, including substance abuse or current medication, did not explain this finding. Since Ig-indices, CSF-tau protein or CSF-GAP-43 were not increased, there was no support for inflammation or neuronal/synaptic degeneration as etiological factors to CNS dysfunction in this category of subjects.

Adolescent↗

PubMed2001

Synaptic deprivation and age-related vulnerability to hypoxic-ischemic neuronal injury. A hypothesis.

Advanced age is associated with physiological changes, such as cerebral autoregulation dysfunction, atrial fibrillation, reduced cerebral blood flow, elevated blood pressure, and other changes. Stroke-related dementia is associated with brain loss principally due to strokes, and neuropathological examination of the brains of old people shows a direct correlation between the extent of brain loss and dementia. However, the exact mechanism of the age related vulnerability to hypoxic-ischemic neuronal injury remains unknown. The majority of synapses in the brain use excitatory amino acids as their neurotransmitter. Glutamate, a major endogenous excitatory amino acid required for normal physiological excitation, is also involved in the pathophysiology of hypoxic-ischemic neuronal injury. The N-methyl-D-aspartate (NMDA) glutamate receptor subtype plays a major role in mediating hypoxic-ischemic neuronal injury. NMDA receptors also mediate adaptive responses important for synaptic plasticity. This report explores the possible role of synaptic activity as a protective mechanism against neuronal cell death. Specifically, the role of NMDA receptors in neuronal plasticity by upregulating a survival pathway is discussed. Loss of a neuronal population that uses glutamate as its neurotransmitter leads to a loss of activity on the postsynaptic neurons or synaptic deprivation. Deprivation of excitatory amino acids on the postsynaptic neurons results in the failure of activity-dependent induced intrinsic survival pathways induced by NMDA receptors. The loss of neuroprotective intrinsic survival pathways increases the vulnerability of these neurons to more hypoxic-ischemic neuronal damage. Since cerebral infarction is also age related, this hypothesis provides a plausible explanation of how we become more vulnerable to hypoxic-ischemic neuronal injury as a function of age.

Age Factors↗

PubMed1996

Systematic screening for mutations in the coding region of the human serotonin transporter (5-HTT) gene using PCR and DGGE.

Dysfunctions in serotonergic pathways may underlie several psychiatric disorders. The reuptake of serotonin (5-HT) from synaptic terminals is mediated by a specific transporter (5-HTT). Genetic variation in the gene coding for the 5-HTT protein might be involved in the predisposition to psychiatric disorders. A systematic screening of the whole coding sequence of the 5-HTT gene in mood disorder (MD) and obsessive-compulsive disorder (OCD) patients, as well as in healthy controls, using PCR and denaturing gradient gel electrophoresis (DGGE) revealed the presence of two mutations. The first was in intron 4, and the second was a C-->A transversion leading to an amino-acid exchange (Leu-->Met) in position 255 of the deduced protein sequence. No further occurrence of this substitution was found in an extended sample of patients and controls. Therefore, structural modifications of the 5-HTT gene do not seem to play either a major or minor role in the genetic predisposition to MD or OCD.

Adult↗

PubMed1995

Loss of [3H]kainate and of NMDA-displaceable [3H]glutamate binding sites in brain in thiamine deficiency: results of a quantitative autoradiographic study.

Previous studies suggest that alterations of brain glutamate synthesis and release occur in experimental thiamine deficiency. In order to assess the integrity of post-synaptic glutamatergic receptors in thiamine deficiency, binding sites for [3H]glutamate (displaced by NMDA), [3H]-kainate, and [3H]quisqualate (AMPA sites) were evaluated using Quantitative Receptor Autoradiography in rat brain following 14 days of treatment with the central thiamine antagonist pyrithiamine. Compared to pair-fed controls, brains of symptomatic thiamine-deficient animals contained significantly fewer NMDA-displaceable binding sites in cerebral cortex, medial septum and hippocampus. It has been suggested that NMDA-receptor mediated glutamate excitotoxicity plays a role in the pathogenesis of neuronal loss in thiamine deficiency. If such is the case, the selective loss of NMDA binding sites in cerebral cortex and hippocampus offers a possible explanation for the relative nonvulnerability of these brain regions to pyrithiamine-induced thiamine deficiency. [3H]quisqualate (AMPA) binding sites were unchanged in all brain regions of pyrithiamine-treated rats whereas [3H]kainate sites were significantly reduced in density in medial and lateral thalamus. The decline in these binding sites may be due to neuronal loss in pyrithiamine-induced thiamine deficiency. Alterations of glutamatergic synaptic function involving both NMDA and kainate receptor subclasses could contribute to the pathogenesis of neurological dysfunction in Wernicke's Encephalopathy in humans.

Animals↗

PubMed1994

Cognitive functions of cortical ACh: lessons from studies on trans-synaptic modulation of activated efflux.

Trans-synaptic modulation of cortical ACh efflux is a useful approach for determining the functions of cortical ACh. Bilateral modulation of basal forebrain GABAergic transmission by benzodiazepine-receptor agonists and inverse agonists decreases and increases, respectively, activated cortical ACh efflux. The determination of behavioral functions which are mediated via activated cortical ACh efflux, and therefore subject to the effects of basal forebrain GABA-cholinergic manipulations, should promote analyses of the functions of cortical ACh. Trans-synaptic approaches to enhance activated cortical ACh efflux offer some potential for the treatment of cognitive dysfunctions associated with impaired cortical cholinergic transmission.

Acetylcholine↗

PubMed1998

Etiology and pathogenesis of Alzheimer's disease.

The diagnosis, genetics, risk factors, neuropathology, and pathogenesis of Alzheimer's disease (AD) are discussed. AD is a degenerative brain disorder and is the leading cause of dementia. Clinical manifestations of AD are primarily the progressive loss of memory and language. Other signs and symptoms of the disease include psychiatric and behavioral disturbances and impairments in the performance of activities of daily living (ADL). To diagnose AD, other causes of dementia-- some of which may be reversible--must be ruled out by laboratory testing and neuroimaging. The pathogenic process that causes AD has not been fully delineated; however, it clearly leads to neuropathology characterized by neuritic plaques, neurofibrillary tangles, and loss of cholinergic neurons in the nucleus basalis of Meynert. Genetic factors, including mutations in the amyloid precursor protein and the two presenilin genes, appear important in the development of early-onset familial AD, whereas the apolipoprotein E genotype influences the timing of disease onset after age 65. Genetic factors may promote or accelerate deposition of beta-amyloid protein to form plaques, as well as abnormal phosphorylation of tau protein to form neurofibrillary tangles. Several biochemical factors, such as inflammation, oxidative stress, and hormonal deficiency (estrogen), and other unmodifiable risk factors, notably aging, also play a role in the pathogenic process. The loss of neurons and synaptic connections is selective and causes deficiencies in cholinergic and other neurotransmitter systems, leading to cognitive dysfunction, psychiatric and behavioral disturbances, and eventual loss of ability to perform ADL. The etiology and pathogenesis of AD are highly complex; more effective therapeutic approaches than those currently available will be needed to address these underlying factors more specifically.

Alzheimer Disease↗

PubMed2000

Heparin blocks functional innervation of cultured human muscle by rat motor nerve.

In vitro innervated human muscle is the only experimental model to study synaptogenesis of the neuromuscular junction in humans. Cultured human muscle never contracts spontaneously but will if innervated and therefore is a suitable model to study the effects of specific neural factors on the formation of functional neuromuscular contacts. Here, we tested the hypothesis that nerve derived factor agrin is essential for the formation of functional synapses between human myotubes and motoneurons growing from the explant of embryonic rat spinal cord. Agrin actions were blocked by heparin and the formation of functional neuromuscular contacts was quantitated. At a heparin concentration of 25 microg/ml, the number of functional contacts was significantly reduced. At higher concentrations, formation of such contacts was blocked completely. Except at the highest heparin concentrations (150 microg/ml) neuronal outgrowth was normal indicating that blockade of neuromuscular junction formation was not due to neuronal dysfunction. Our results are in accord with the concept that binding of neural agrin to the synaptic basal lamina is essential for the formation of functional neuromuscular junctions in the human muscle.

Agrin↗

PubMed1999

Postsynaptic expression of Ca2+-permeable AMPA-type glutamate receptor channels by viral-mediated gene transfer.

The ability to artificially express a particular receptor protein in the postsynaptic sites of neurons in the central nervous system (CNS) would be useful for the study of synaptic function of cloned receptor genes as well as for gene therapy of neurological disorders caused by dysfunction of postsynaptic receptors. In this study, we aimed to express the cDNA of unedited GluR2 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor that forms inwardly rectifying and Ca2+-permeable channel in CNS neurons by using adenoviral-mediated gene transfer. For this purpose, we have constructed a recombinant adenovirus bearing an expression-switching unit, where the unedited GluR2 cDNA can be activated by the Cre recombinase-mediated excisional deletion of a stuffer DNA interposed between the promotor and the coding region. When PC12 cells were infected with this recombinant adenovirus together with an adenovirus expressing Cre recombinase, the inwardly rectifying and Ca2+-permeable AMPA receptor channels were expressed in nearly 100% of infected cells. Two days after co-infection of cultured rat hippocampal neurons with these adenoviruses, fast excitatory neurotransmission in the glutamatergic synapse was mediated predominantly by the inwardly rectifying and Ca2+-permeable AMPA receptor channels. This indicates that the native AMPA receptors in the postsynaptic sites of the glutamatergic synapse are replaced rapidly with recombinant receptors newly produced by the viral-mediated gene transfer.

2-Amino-5-phosphonovalerate↗

PubMed1978

On the possible mode of action of serotonin in neurotransmission and brain dysfunction.

Criteria necessary to classify a substance as neurotransmitter are used to determine whether disturbances in neurotransmitter function are involved in brain disorders. Six rather stringent criteria for a neurotransmitter are satisfied by the biogenic amine 5-hydroxytryptamine (5-HT): 1. the availability of 5-HT within the CNS is proved by its synthesis and transport, 2. it is stored within the presynaptic bouton, 3. presynaptic stimulation releases 5-HT, 4. it reacts with receptors of the synaptic membranes. 5. a functional equivalence of presynaptic stimulation and subsynaptic 5-HT action can be demonstrated, 6. the transmission is terminated by a retrieval mechanism.--On the basis of this transmitter concept brain dysfunctions as described in the literature are discussed in the light of results obtained using in vitro techniques with isolated synaptic structures. In renal and hepatic insufficiency the transport of the 5-HT precursor tryptophan is affected at the site of the blood-brain barrier. Tryptophan-5-hydroxylase, the rate-limiting enzyme in 5-HT synthesis, is inhibited in hypoxia. The antiparkinson drug 1-aminoadamantane and its 3.5-dimethyl derivative, D 145, inhibit 5-HT catabolism as well as 5-HT storage in synaptic vesicles and reuptake into isolated nerve endings. Since 1-aminoadamantanes enhance the electrically stimulated 5-HT and DA release from nerve endings spatial shifts of transmitter substances within the synaptic area as well as direct receptor stimulation by the drugs may be the cause for the ameliorating effect.

Adenosine Triphosphate↗

PubMed2000

Movement of zinc and its functional significance in the brain.

Zinc, an essential nutrient, is supplied to the brain via both the blood-brain and blood-cerebrospinal fluid barriers. Zinc is most concentrated in the limbic system, i.e. the hippocampus and amygdala, zinc-containing glutaminergic neuron-rich areas. A large portion of zinc serves the function of zinc metalloproteins in neurons and glial cells. In zinc-containing glutaminergic neurons, vesicular zinc, probably ionic zinc, may serve as an endogenous neuromodulator in synaptic neurotransmission. Vesicular zinc is dynamically coupled to the electrophysiological activity of zinc-containing glutaminergic neurons. Dietary zinc deprivation may influence zinc homeostasis in the brain, resulting in brain dysfunction such as learning impairment. Excessive excitation of zinc-containing glutaminergic neurons causes a decrease in vesicular zinc, and the decrease might be associated with the susceptibility to seizure. Alteration of zinc levels released into the synaptic cleft may influence neurotransmission in zinc-containing glutaminergic synapses. Therefore, zinc homeostasis in the presynaptic vesicle is important for the function of zinc-containing glutaminergic neurons.

Animals↗

PubMed1991

Non-synaptic mechanisms of Ca(2+)-mediated injury in CNS white matter.

Clinical deficits after injury to the CNS are due, in large part, to dysfunction of white matter (myelinated fiber tracts), including descending and ascending tracts in the spinal cord. A crucial set of questions, in the search for strategies that will preserve or restore function after CNS injury, centers on the pathophysiology of, and mechanisms underlying recovery of conduction in, CNS white matter. These questions are relevant both to spinal cord injury, and to brain infarction, which frequently affects white matter.

Animals↗

PubMed2000

Localization of metabotropic glutamate receptor type 2 in the human brain.

Metabotropic glutamate receptors are a heterogeneous family of G-protein-coupled receptors that are linked to multiple second messenger systems to regulate neuronal excitability and synaptic transmission. To elucidate the physiological role of these receptors in human central nervous system function and dysfunction at the receptor protein level requires the use of selective antibodies to determine the phenotype of cells expressing particular receptor subtypes. To this end the present study has examined the regional and cellular localization of the metabotropic glutamate type 2 receptor protein in selected human brain regions. After epitope prediction, antibodies have been generated against a short synthetic peptide corresponding to amino acid residues located in the putative intracellular carboxy-terminus and subsequently applied to an immunohistochemical investigation. Antibodies specifically detected the type 2 receptor in transfected mammalian cells and also recognized a major band of 98,000 mol. wt in western blots of human brain tissue membranes. At the light microscope level immunohistochemical studies have demonstrated that type 2-like immunoreactivity was widely distributed in the human brain, being characterized by the presence of a strong immunoreaction in multiple cortical regions, and in structures comprising the basal ganglia, to include the caudate nucleus, putamen, globus pallidus, substantia nigra and subthalamic nucleus. In the hippocampal formation, immunoreactivity was predominant in selective cell layers of both the dentate gyrus and cornu ammonis, the subicular complex and entorhinal cortex. In the thalamus, multiple subnuclei showed reaction product. In the cerebellar cortex, immunoreactivity was expressed in a number of cell layers and cell types. Furthermore, using double immunofluorescence we confirmed that the type 2 receptor is a product of normal resting astrocytes in the cerebral cortex in particular. This antibody provides a new immunological tool with the potential to evaluate the distribution of human metabotropic glutamate receptor 2 protein in other brain regions and in human central nervous system diseases.

Animals↗

PubMedDate not supplied

[Synaptic zinc in the central nervous system].

Apart from iron, zinc is the most abundant oligoelement in the nervous tissue. Although the majority of zinc constitutes a stable fraction that is tightly bound to molecules and molecular complexes (structural or metabolic zinc), a small proportion (10 15% of cerebral zinc) remains as an ion and it is stored inside membranous compartments (ionic vesicular zinc). In neurons, most of this ionic zinc can be found inside synaptic vesicles and it is released outside the neuron during synaptic transmission: this is the synaptic zinc. In the surroundings of the synapse, zinc acts over a variety of neuronal receptors and ionic channels, playing a modulatory role that is not yet fully understood. The prolonged presence of zinc in the vicinity of the synapse allows its translocation to postsynaptic neurons, which lack the defensive mechanisms (membrane transporters that store zinc into vesicles). In this case, zinc acts as a neurotoxic and it can induce neuronal cell death. Neurons and glial cells have very efficient, although not well known, cleaning mechanisms that eliminate synaptic zinc from the extracellular space; it probably is simultaneous with glutamate clearance. It is feasible that dysfunction of these zinc cleaning systems could induce compensatory mechanisms (precipitation induced by amyloid precursor protein) which in turn could potentiate ethiologic factors of Alzheimer s disease.

Alzheimer Disease↗

PubMed2000

Glutamatergic components underlying lead-induced impairments in hippocampal synaptic plasticity.

Epidemiological investigations have established the relationship between chronic developmental lead (Pb) exposure and cognitive impairments in young children, defining Pb neurotoxicity as a significant pediatric health problem. Exposed animals have proven to be effective models of this condition, exhibiting similar sensitivity to the actions of Pb and replicating abnormal learning behaviors in exposed children. Research has extended these observations in animals to identifying the processes underlying the cognitive dysfunction, utilizing the long-term potentiation (LTP) paradigm as a correlate of learning ability. Results from these studies have been in widespread agreement in reporting impairments in synaptic plasticity. Exposure-related changes consist of increases in LTP induction threshold, decreases in magnitude of potentiation, and shortened LTP duration. Furthermore, while LTP may be more readily affected by Pb during early development, exposure initiated after weaning also potently affects synaptic plasticity. Biphasic dose-effect relationships also appear in which impaired LTP is observed at intermediate exposure levels (27-62 microg/100 ml), but not at higher exposures. Investigation of the synaptic processes underlying LTP has provided additional insight into the bases of the impaired potentiation and diminished cognitive ability. Biochemical and neurophysiological approaches have found stimulated glutamate release to be diminished in hippocampus at blood Pb values where deficits in LTP have been observed. Multiple actions of Pb may be involved at this exposure level since animals exposed postweaning exhibited similar decrements in evoked glutamate release to those exposed continuously from conception, similar to the observations in measures of LTP. A biphasic dose-effect relationship was also found in which stimulated glutamate release in hippocampus was decreased at intermediate exposures, but not at higher levels. A direct inhibitory effect of Pb2+ on NMDA receptor function does not appear to occur at environmentally relevant exposure levels, but both exposure-induced increases and decreases in receptor density have been reported by different workers. Evidence from behavioral and neurophysiological investigations can be explained by increased NMDA receptor density on the bases of increased sensitivity to agonists and decreased sensitivity to antagonists. From this body of findings it is apparent that decreases in stimulated glutamate release are a significant contributing factor to the exposure-related changes seen in LTP. Furthermore, despite general agreement on the actions of Pb on synaptic plasticity, reports of exposure effects on NMDA receptor function have been relatively variable, suggesting either that the nature of the receptor changes are dependent on exposure conditions or that the receptors are secondarily affected by Pb actions produced at signal transduction or cellular loci.

Animals↗