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At least 145 records · Page 8Linked to original sources
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↗
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↗
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↗
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↗
PubMed1987

Dose-response relationship of clonidine in tetracaine spinal anesthesia.

The study was undertaken to define a dose-response relationship for clonidine in prolonging canine tetracaine spinal anesthesia. Using a randomized blind cross-over design, six mongrel dogs were given subarachnoid injections (1 ml) of the following solutions over an 8-week period: tetracaine 4 mg (control), or tetracaine 4 mg with clonidine in doses of 10, 25, 50, 100, 150, 200, and 300 micrograms. With clonidine doses equal to or exceeding 50 micrograms/ml, motor and sensory blockade were significantly (P less than 0.01) prolonged, when compared to the control times. Analysis of data by second order polynomial regression analysis produced a relationship defined by Y = 23.241 + 1.104(x) - 0.0023(x2) with r2 = 0.92 and P less than 0.001 for sensory blockade and Y = 38.7072 + 1.64425(x) - 0.004125(x2) with r2 = 0.90 and P less than 0.005 for motor blockade. From these curves, a plateau in clonidine dose-response for both sensory blockade and motor blockade occurred at 150 micrograms. The increase in duration of spinal anesthesia with clonidine may be related to a direct post-synaptic alpha 2 adrenoceptor arteriolar effect, a spinal cord pre- or post-synaptic alpha 2 antinociceptive action or supraspinal alpha 2 modulation of nociception. No animals showed evidence of neurologic dysfunction during the study. The authors conclude that a well-defined dose-response relationship exists for clonidine in canine tetracaine spinal anesthesia.

Anesthesia, Spinal↗
PubMed1994

Differential RNA editing efficiency of AMPA receptor subunit GluR-2 in human brain.

RNA editing in rat brain has been found to control a determinant of cation flow in alpha-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid (AMPA)-gated channels. Here we provide the first evidence that this RNA editing phenomenon occurs in human brain and is differentially regulated. Sequence analysis of human genomic DNA revealed a Q codon (CAG) in the putative channel-forming segment of human GluR-2, whereas in the majority of cDNA clones an R codon (CGG) was found. Examination of editing in various brain tissues revealed differences in the efficiency of this process. The hippocampus, cerebellum and temporal cortex harbour 100% edited GluR-2, whereas only 72% of substantia nigra, 89% of corpus striatum and 96% of fetal cDNAs have been found to be edited. This new discovery of differential efficiency of RNA editing has important implications in AMPA receptor channel-mediated calcium influx. AMPA receptors are thought to mediate the majority of the fast excitatory synaptic neurotransmission; the RNA editing process may therefore play a critical role in normal brain function and development. Dysfunction of this RNA editing process may have neuropathological consequences and could be related to certain neurodegenerative diseases.

Animals↗
PubMed1978

Tardive dyskinesia.

The movement disorder may appear after prolonged use of antipsychotic agents. Differential diagnosis includes hereditary, infectious, toxic and drug-induced causes of extrapyramidal dysfunction. Pathophysiology appears to be related to induced changes in dopamine neuronal function and may represent irreversible extrapyramidal synaptic modification. Treatment includes removing the offending agent when possible or using the lowest effective dose if the medication cannot be totally discontinued. Indiscriminate use of antipsychotic agents in nonpsychotic patients should be avoided.

Antipsychotic Agents↗
PubMed1994

Deviation in cerebral excitability: possible clinical implications.

Schizophrenia, a chemical signaling disorder in the brain, is also a deteriorating neurological disorder. The deficit in cerebral excitability, and associated reduced synaptic density, imply a risk of cortical breakdown of circuitry accompanied by an insufficient fill-in mechanism, and persistent silent spots, but no total loss of function, only dysfunction. This is subjectively experienced as deficiencies of cognition, perception and sensorimotor phenomena depending upon localization and connections of the disconnected circuitry. Considering the adversity inherent in this neural network, both the fast Hebbian pre-post form of learning and the slow pre-modulatory coincidence form of learning are probably impaired. The use of Feed Back Loops which usually govern our behaviour might also be impaired. In addition, we have to consider the daily problem of insufficient drive and motivation. Manic depressive psychosis, a chemical signaling disorder in the brain, is a true functional psychosis. The raised excitatory drive and raised synaptic density imply raised risk of uncoupling of circadian rhythms via the direct glutamatergic input to the suprachiasmatic nucleus of hypothalamus (SCN). This episodic brain stem dysfunction illustrates how a deficit in inhibition renders the brain unstable. The requirements of the fast Hebbian form of learning should easily be met, and neither should the slow forms of learning present a problem in networks characterized by excessive density.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral Cortex↗
PubMed1992

5-HT1A receptor-effector system responsivity in panic disorder.

To explore 5-HT1A receptor responsivity in panic disorder (PD), hypothermic, neuroendocrine and behavioral responses to the selective partial 5-HT1A receptor agonist ipsapirone (IPS) were investigated in patients with primary PD and healthy controls. Fourteen patients and matched controls received a single oral dose of 0.3 mg/kg IPS or placebo under double-blind, random-assignment conditions. IPS induced hypothermia and corticotropin (ACTH)/cortisol release but had only minimal effects on behavior. Compared with controls, the patients with PD exhibited significantly attenuated thermoregulatory and neuroendocrine responses to IPS. Although the healthy subjects reported increased drowsiness and the PD patients rated themselves more nervous and less calm following administration of IPS, no consistent changes in ratings of anxiety or panic symptoms were recorded. The impaired hypothermic and ACTH/cortisol responses following 5-HT1A receptor activation reflects subsensitivity of both the pre- and post-synaptic 5-HT1A receptor-effector system, thus supporting the hypothesis that a 5-HT1A receptor-related serotonergic dysfunction may be linked to the pathophysiology of PD. Future studies of 5-HT1A receptor-effector complex function in conjunction with assessment of the responsivity of other subtypes (e.g. 5-HT2, 5-HT3) should promote the evaluation of 5-HT system integrity in anxiety disorders and its involvement in anxiolytic drug effects.

Adrenocorticotropic Hormone↗
PubMed1988

Amyloid beta protein precursor is possibly a heparan sulfate proteoglycan core protein.

The amyloid beta protein peptide is a major constituent of amyloid plaque cores in Alzheimer's disease and is apparently derived from a higher molecular weight precursor. It is now shown that the core protein of a heparan sulfate proteoglycan secreted from a nerve cell line (PC12) has an amino acid sequence and a size very similar to those of the amyloid beta protein precursor and that these molecules are antigenically related. This amyloid beta protein precursor-related protein is not found in the conditioned medium of a variant cell line (F3 PC12) that does not secrete heparan sulfate proteoglycan. The synaptic localization and metabolism of this class of proteoglycans are consistent with its potential involvement in central nervous system dysfunction.

Alzheimer Disease↗
PubMed1987

Serotonin pharmacodynamics in hypothalamic tissues from young and old female rats.

The purpose of this study was to determine the effects of aging on serotonin (5-HT) pharmacodynamics in rostral hypothalamic tissue of female rats. Monoamine oxidase (MAO) activity was greater in old (19 months old) than in young (3 months old) animals. This difference resulted from a higher Vmax for hypothalamic MAO from old rats, whereas Km's were comparable in both age groups. These enzymatic changes were accompanied by altered uptake and release of [3H]5-HT. Although [3H]5-HT uptake was not different at equilibrium between groups, the equilibrium state was achieved more slowly by hypothalamic tissue from old rats. Basal and potassium-stimulated efflux of [3H]5-HT was significantly greater in old rats compared with young ones and these differences remained during multiple depolarizations. The findings of this study suggest that synaptic levels of hypothalamic 5-HT increase with age. Since pharmacological simulation of this condition in young rats produces physiologic dysfunction, the spontaneous changes that occur in hypothalamic 5-HT pharmacodynamics during aging have the potential to promote senescence.

Aging↗
PubMed1989

Neural degeneration and non-neuronal cellular reactions in the hypoglossal nucleus following an intraneural injection of toxic ricin.

The present study describes neuronal degeneration and its accompanying non-neuronal cellular reaction in the hypoglossal nucleus following an intraneural injection of Ricinus communis agglutinin-60 (RCA-60) into the hypoglossal nerve. The first noticeable structural changes were observed in neurons in hamsters killed 3 days after the RCA injection. Drastic alterations occurred in the period extending from the 5th to the 15th postoperative day. Two forms of neuronal degeneration were observed: light and dark types. In the light type, masses of free ribosomes were observed; other changes included the dilation of Golgi saccules and the presence of abnormal mitochondria. In the dark type of degeneration, the cells became condensed with vacuoles in their cytoplasm. Axon terminals presynaptic to the degenerating cells during this period appeared to be normal. A massive influx of mononuclear leucocytes by diapedesis occurred at the large venules. Some of the infiltrated cells were clearly lymphocytes, while others were monocytes which became indistinguishable from indigenous microglia once they were in the neuropil. Neural macrophages, most probably derived both from microglia and the infiltrated monocytes, were engaged in the phagocytosis of neuronal debris. A remarkable finding in the present study was the wide-spread occurrence of dark axon terminals in the neuropil in longer surviving animals (90 and 120 days). The structural alterations, e.g., clumping and swelling of some of the synaptic vesicles in the enhanced cytoplasmic density, suggest that these were undergoing atrophic changes resulting from the long period of dysfunction following the death of postsynaptic neurons induced by RCA.

Animals↗