Biomedical subjects

R Dawson

Publications and source records attributed to R Dawson.

At least 19 recordsLinked to original sources

PubMed1995

Excitotoxins, aging, and environmental neurotoxins: implications for understanding human neurodegenerative diseases.

We are an aging society and current demographic trends point to a likely increase in age-related neurodegenerative diseases. The aged population may have a number of unique risk factors that result in a predisposition to neuronal damage from environmental neurotoxins. This symposium addressed the involvement of excitatory amino acids as final common mediators of neuronal death associated with various types of neurotoxic insult. The roles of oxidative stress, mitochondrial energy metabolism, and disruption of calcium homeostasis were discussed in relation to excitoxicity and several experimental models of human neurodegenerative diseases. The neurotoxic actions of kainic acid, 3-nitropropionic acid, cyanide, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and methamphetamine were examined for their relevance as models of human neurodegenerative disorders. The mechanisms of action of excitotoxins in experimental models of Huntingtons's disease and Parkinson's disease were explored in light of the enhanced susceptibility and potential vulnerability of the aged nervous system to neurotoxins that perturb cellular metabolism and homeostatic processes. Bioenergetic defects and oxidative stress were found to be critical links in a neurotoxic cascade of events that trigger the sustained release of excitotoxic amino acids. The interrelationships among the aging process, the pathophysiology of neurodegenerative diseases, and the mechanism of action of various neurotoxins were addressed from the unifying perspective of the excitotoxic hypothesis of neuronal death.

Aging↗

PubMed1995

Endogenous excitatory amino acid release from brain slices and astrocyte cultures evoked by trimethyltin and other neurotoxic agents.

Trimethyltin (TMT) is a toxic alkyltin compound that is known to produce neuronal necrosis in the CNS. The present study examined the effects of TMT on the release of excitatory amino acids (EAA) from cortical slices prepared from adult and aged (24 months old) rats. The calcium dependence of TMT-induced EAA efflux was evaluated and compared to other neurotoxic agents. The actions of TMT were also evaluated in an astrocyte culture model to assess glial contributions to TMT-induced EAA efflux. TMT (10-1000 microM) evoked a dose-related increase in GLU and ASP efflux during a 30 min incubation period and this efflux was sustained or slightly higher during a 15 min recovery period. TMT-stimulated GLU efflux was not altered in aged rats. TMT-induced GLU efflux was significantly reduced by removing extracellular calcium and including 10 microM EGTA in the incubation media. Calcium channel blockers (nifedipine, verapamil, flunarizine, amiloride, neomycin) and MK-801 did not significantly attenuate TMT-induced GLU efflux. Diltiazem (25 microM) produced modest but inconsistent reductions in TMT-induced GLU efflux from brain slices, and significantly inhibited the leakage of lactate dehydrogenase (LDH) from TMT-treated astrocyte cultures. TMT did not increase GLU efflux from glial cultures during a 30 min incubation period, but did significantly elevate GLU efflux during the 15 min recovery period. TMT evoked the release of EAA by both calcium dependent and independent mechanisms in brain slices. TMT at high concentrations also produced a delayed increase in glial GLU efflux. These studies suggest that excitotoxic mechanisms may contribute to TMT-induced neurotoxicity.

Aging↗

PubMed1992

[3H]D-aspartic acid release in brain slices of adult and aged Fischer 344 rates.

Alterations in glutamate content and uptake have been reported to occur in aged animals. The present studies used [3H]D-Aspartic acid [( 3H]-D-ASP) release as a marker for glutamate neurotransmission. Frequency dependent [3H]-D-ASP release was measured in adult (8 month) and aged (28-30 month) Fischer 344 rats. Relatively high stimulation frequencies (greater than 10 Hz) were required to induce [3H]-D-ASP release in both adult and aged F344 rats in temporal cortex and hippocampus. In both brain areas aged animals showed significantly more [3H]-D-ASP release than adult animals. Kainic acid 1 mM failed to induce the release of [3H]-D-ASP in either temporal cortex or hippocampus. Omega conotoxin GVIA (5 x 10(-9) M) a N and L type voltage sensitive calcium channel antagonist failed to inhibit [3H]-D-ASP stimulated release. These results demonstrate an increase in [3H]-D-ASP release in aged compared to adult F344 rats. The data also suggest a novel calcium channel may be involved in [3H]-D-ASP release.

Aging↗

PubMed1992

Ammonia regulation of phosphate-activated glutaminase displays regional variation and impairment in the brain of aged rats.

The regulation of PAG by ammonia in whole brain (Sprague-Dawley) and regional (Fischer-344) synaptosomal preparations from adult and aged animals was assessed. Whole brain synaptosomal preparations from both age groups displayed a significant decrease in PAG activity with increasing ammonium chloride concentrations, however, the aged rats exhibited a significant attenuation in ammonia-induced PAG inhibition. PAG activity measured in synaptosomes prepared from the striatum (STR), temporal cortex (TCX) and hippocampus (HIPP) was also inhibited by ammonium chloride. The STR showed the greatest degree of ammonia-induced PAG inhibition (55%) followed by the HIPP (30-35%) and the TCX (25-30%). This reduction in PAG activity was significantly attenuated in STR from aged rats at ammonium chloride concentrations greater than 50 microM and in the TCX, PAG activity was significantly attenuated in the aged rats at ammonia concentrations of 0.5 and 1.0 mM. Ammonia regulation of PAG activity in the HIPP appeared to be unaffected by age. Ammonium chloride concentrations up to 5 mM had no effect on GLU release from cortical slices, although GLN efflux was significantly enhanced. These findings suggest that isozymes of PAG may exist in different brain regions based on their differential sensitivity to ammonia. The attenuation of ammonia-induced PAG inhibition seen in aged rats may have deleterious effects in the aged brain.

Aging↗

PubMed1992

Glutamine synthetase and nitrogen cycling in colonies of the marine diazotrophic cyanobacteria Trichodesmium spp.

We examined freshly collected samples of the colonial planktonic cyanobacterium Trichodesmium thiebautii to determine the pathways of recently fixed N within and among trichomes. High concentrations of glutamate and glutamine were found in colonies. Glutamate and glutamine uptake rates and concentrations in cells were low in the early morning and increased in the late morning to reach maxima near midday; then uptake and concentration again fell to low values. This pattern followed that previously observed for T. thiebautii nitrogenase activity. Our results suggest that recently fixed nitrogen is incorporated into glutamine in the N2-fixing trichomes and may be passed as glutamate to non-N2-fixing trichomes. The high transport rates and concentrations of glutamate may explain the previously observed absence of appreciable uptake of NH4+, NO3-, or urea by Trichodesmium spp. Immunolocalization, Western blots (immunoblots), and enzymatic assays indicated that glutamine synthetase (GS) was present in all cells during both day and night. GS appeared to be primarily contained in cells of T. thiebautii rather than in associated bacteria or cyanobacteria. Double immunolabeling showed that cells with nitrogenase (Fe protein) contained levels of the GS protein that were twofold higher than those in cells with little or no nitrogenase. GS activity and the uptake of glutamine and glutamate dramatically decreased in the presence of the GS inhibitor methionine sulfoximine. Since no glutamate dehydrogenase activity was detected in this species, GS appears to be the primary enzyme responsible for NH3 incorporation.

Animals↗

PubMed1992

Norepinephrine content in cardiovascular tissues from the aged Fischer 344 rat.

The major aim of the present study was to examine cardiovascular tissues and to determine if norepinephrine (NE) stores declined in aged (22-30 months old) male Fischer 344 (F344) rats. NE content was measured by HPLC in the whole heart, ventricle, atria, caudal artery, renal arteries, portal vein and kidney. The release of [3H]NE from the caudal artery of adult and aged rats was assessed as a functional index of sympathetic innervation. Renal alpha 2-adrenergic binding sites were also determined using 2.0 nM [3H]rauwolscine. In general, total NE content per organ was not altered in aged rats. The exception was the ventricle of aged rats which exhibited a 25% decrease in NE content. In contrast, NE content per gram of tissue weight was significantly decreased in the whole heart, atria, ventricle, kidney and caudal artery of aged rats when compared to that of adults (6-8 months old). Neither basal nor potassium-stimulated NE release was altered in the caudal artery of aged rats. Presynaptic regulation of NE release by taurine and alpha 2-adrenoceptors was also not affected by age. Renal alpha 2-adrenergic binding sites were decreased 23% in aged rats. Tissue growth that occurs as a function of aging does not appear to receive a concomitant increase in sympathetic growth as indexed by NE content. The findings of the present study would lead to the conclusion that with the exception of the ventricle, sympathetic nerve terminals of the aged male F344 rat are relatively intact.

Aging↗

PubMed1991

Flow support catheter for prolonged maintenance of coronary blood flow.

A newly designed flow support catheter with a supporting wire mesh cage which can be expanded into a tubular configuration and then readily reduced was evaluated in mongrel dogs. Regional myocardial blood flow (RMBF) was measured using the radioactive microsphere technique in the area of both balloon-denuded instrumented and control non-instrumented coronary arteries following placement of either a fixed-wire or a higher profile rapid exchange flow support catheter. At 5, 20, and 180 min following delivery and expansion of either device, RMBF was not significantly different in left ventricular subepicardium and subendocardium perfused by the instrumented vs. the control coronary arteries. Angiography demonstrated widely patent instrumented arteries in 15/18 dogs; in no dog was side branch occlusion observed. Significant cage thrombus deposition was seen angiographically in 3 animals causing temporary total coronary occlusion in 1. Following reduction and removal of the flow support catheter, vessel patency was present in all dogs. The flow support catheter is an effective endovascular stenting device capable of providing structural arterial support, while simultaneously maintaining distal coronary blood flow. It is envisioned that the primary application of this catheter will be to enable primary salvage of vessels acutely injured during coronary angioplasty, by "tacking up" intimal flaps for an extended period. It may also provide a bridge to emergency surgical revascularization.

Angioplasty, Balloon, Coronary↗

PubMed1991

Regulation of 35S-TBPS binding by bicuculline is region specific in rat brain.

The allosteric regulation of specific 35S-TBPS binding to the convulsant site on the GABAA receptor/chloride (Cl-) ionophore complex was studied in various brain regions in an attempt to characterize regional heterogeneity of the protein subunits forming the complex. Bicuculline methiodide (BIC), a GABAA antagonist, enhanced binding in cortex (CTX), substantia nigra (SN) and cerebellum (CBL), inhibited binding in inferior colliculus (IC) and did not affect binding in superior colliculus (SC). Similar results were found in CBL and IC using SR-95531, another GABAA antagonist. The levels of endogenous GABA in the different tissue samples could not account for the regional differences in binding. When the functional regulation of these receptors was measured using 36Cl- uptake in microsomes, muscimol-stimulated uptake was completely blocked by BIC in CBL and IC but was not affected by BIC in SC. Additionally, picrotoxin completely blocked muscimol-stimulated uptake in CBL but had no effect in IC or SC. These findings provide a functional basis for regional heterogeneity of GABAA receptor.

Animals↗

PubMed1990

Dopamine synthesis and release in LLC-PK1 cells.

A porcine-derived renal epithelial cell line, LLC-PK1, was used to examine dopamine (DA) synthesis from L-dopa and DA release into the media. DA synthesis and release were elevated by increasing either L-dopa concentration or incubation time. DA synthesis was shown to be entirely due to conversion of L-dopa to DA by aromatic amino acid decarboxylase. DA release from LLC-PK1 cells was stimulated by NaCl and other Na+ or Cl- salts. DA release by LLC-PK1 cells was not dependent on extracellular Ca2+ or significantly stimulated by the depolarizing actions of KCl. LLC-PK1 cells which are devoid of any neural contributions to renal DA production can synthesize DA from L-dopa and release DA in response to stimulation by either Na+ or Cl-.

Animals↗

PubMed1990

Excitatory amino acid involvement in retinal degeneration.

Amino acid analysis using high-performance liquid chromatography demonstrated high levels of the excitatory amino acids, aspartate and glutamate, in the retinas of congenitally blind chicks at the time of photoreceptor degeneration. Concentrations of aspartate were about 2 times higher in blind chicks than in retinas of age-matched sighted chicks that were carriers for the genetic defect. Glutamate levels were similar in blind chicks and carriers at 1 day of age, but doubled and tripled sighted chick values at 1 week and 2 weeks of age in blind chick retinas. Light microscopic immunocytochemistry using antibodies that recognize aspartate and glutamate revealed increased levels of these two amino acids specifically in the photoreceptor layer of blind chicks. This report is the first to demonstrate high endogenous levels of excitatory amino acids associated with a hereditary degeneration of photoreceptor cells.

Animals↗

PubMed1990

Effect of age and monosodium-L-glutamate (MSG) treatment on neurotransmitter content in brain regions from male Fischer-344 rats.

Peripheral administration of monosodium-L-glutamate (MSG) has been found to be neurotoxic in neonatal rats. When administered in an acute, subconvulsive dose (500 mg/kg i.p.), MSG altered neurotransmitter content in discrete brain regions of adult (6 month old) and aged (24 month old) male Fischer-344 rats. Norepinephrine (NE) content was reduced in both the hypothalamus (16%) and cerebellum (11%) of adult rats, but was increased in both the hypothalamus (7%) and cerebellum (14%) of aged rats after MSG treatment. MSG also altered the dopamine content in adult rats in both the posterior cortex and the striatum, causing a reduction (23%) and an increase (12%), respectively. Glycine content in the midbrain of aged rats increased (21%) after MSG injection. Of particular interest is the widespread monoamine and amino acid deficits found in the aged rats in many of the brain regions examined. NE content was decreased (11%) in the cerebellum of aged rats. Dopamine content was reduced in both the posterior cortex (35%) and striatum (10%) of aged rats compared to adult animals. Cortical serotonergic deficits were present in aged rats with reductions in both the frontal (13%) and posterior cortex (21%). Aged rats also displayed deficits in amino acids, particularly the excitatory amino acids. There were glutamate deficits (9-18% reductions) in the cortical regions (posterior and frontal) as well as midbrain and brain stem. Aspartate, the other excitatory amino acid transmitter, was reduced 10% in the brainstem of aged rats. These data indicate that an acute, subconvulsive, dose of MSG may elicit neurochemical changes in both adult and aged male Fisher-344 rats, and that there are inherent age-related deficits in particular neurotransmitters in aged male Fisher-344 rats as indicated by the reductions in both monoamines and amino acids.

Aging↗

PubMed1990

Monoamine and amino acid content in brain regions of Brattleboro rats.

Monoamine and amino acid content were measured in brain regions from 12 week old male, homozygous Brattleboro (DI, n = 12) and Long-Evans control (LE, n = 12) rats. Norepinephrine (NE) content was significantly elevated (16-25%) in the spinal cord, pons-medulla and anterior hypothalamus of DI rats when compared to LE controls. NE content of the neurointermediate lobe of pituitary in DI rats was almost twice that of LE controls. Serotonin content was also significantly elevated in the spinal cord, pons-medulla, anterior hypothalamus and forebrain of DI rats relative to the LE controls. Taurine content in DI rats was increased (31-42%) above that of LE rats in the anterior hypothalamus, striatum and forebrain. Glutamine content was also greater in DI rats than LE in the spinal cord, pons-medulla, anterior hypothalamus, striatum, hippocampus and forebrain. The changes in monoamine and amino acid content were discussed in relation to the cardiovascular and osmoregulatory deficits that are present in DI rats due to arginine vasopressin (AVP) deficiency. The possible role of AVP in modulating NE turnover was also discussed. The increase in brain TAU content in DI rats may be a physiological response to hypernatremia.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Neural-renal interactions in the hypertension induced by papillary necrosis: role of dietary salt intake.

The effects of high salt intake (1.0% NaCl in the drinking water) on rats made hypertensive by 2-bromoethylamine hydrobromide (BEA) treatment (200 mg/kg, i.p.) were examined. BEA-induced medullary necrosis resulted in a mild hypertension (146 +/- 5 mm Hg) that was exacerbated by 4 weeks of high salt intake (163 +/- 6 mmHg). BEA-treated rats had significant salt-induced increases in urinary norepinephrine excretion and hypothalamic and brainstem norepinephrine content, that were not present in BEA-treated rats drinking tap water or control rats drinking saline. BEA treatment in combination with increased salt intake produced a decrease (p less than 0.05) in renal dopamine content and adrenal norepinephrine stores relative to BEA treatment alone. BEA treatment also significantly decreased renal norepinephrine stores and dopamine binding sites irrespective of salt intake. Renal alpha 2-adrenergic receptors and central nervous system stores of dopamine and serotonin were unaffected by BEA treatment. Renal function was well preserved as indicated by normal creatinine, glucose and protein excretion; however, significant (p less than 0.05) disruption of the urinary concentrating mechanism was present. These studies suggest that BEA-induced hypertension has a neural component that is exacerbated by high salt intake. The primary defect in BEA hypertension appears to be the lack of circulating antihypertensive lipids that attenuate the ability of salt loads to simulate sympathetic nervous system activity.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Decreased plasma taurine in aged rats.

Taurine (TAU) is thought to be a neuromodulator or an inhibitory neurotransmitter in the mammalian brain. In the periphery, TAU is involved in a wide spectrum of physiological functions. One of the most important putative physiological function of TAU is the modulation of cardiovascular activity including blood pressure control. TAU also appears to be important for the development of an organism, especially early central nervous system development. Regional TAU content was measured in brains of adult (6-month) and aged (23- to 26-month) Fischer-344 (F-344) male rats. To assess the putative neurotransmitter role of TAU, release due to potassium depolarization was studied using slices from frontal cortex of F-344 rats. Circulating levels of TAU were also determined in male F-344 rats (6 and 24 months of age) and female Long-Evans rats (LE, 6 and 30 months old). We found no age-related change in TAU stores from the brain regions examined, nor did we find any indication of TAU release due to potassium depolarization in the release paradigm utilized. There was, however, a significant reduction (28 and 42%) in plasma TAU concentration in F-344 and LE rats, respectively. This age-related reduction in plasma TAU may have important consequences both peripherally and centrally with respect to regulation of blood pressure, cardiovascular function, and cardioprotection, as well as possible CNS complications.

Aging↗

PubMed1990

Upregulation of renal alpha 2-adrenergic receptors is not indicative of salt-related increases in blood pressure in spontaneously hypertensive rats.

The aim of the present study was to determine if elevations in salt intake were coupled to increases in renal alpha 2-adrenergic receptors in SHR that differ in their blood pressure response to high salt diets. Salt-resistant spontaneously hypertensive rats (SHR-R), which do not increase their blood pressure in response to high salt intake, and salt-sensitive spontaneously hypertensive rats (SHR-S), which do exhibit significant elevations in blood pressure on high salt diets (3.15% NaCl), were used. Radioligand binding studies using [3H]rauwolscine were performed on 6- and 11-week-old SHR-S and Wistar-Kyoto (WKY) rats to determine the effects of age, strain, and salt intake on alpha 2-adrenergic receptor number and affinity. One week of high salt intake significantly increased blood pressure 22% in 6-week-old SHR-S and increased the blood pressure of 11-week-old SHR-S 12% without altering WKY rat controls. This treatment did not significantly increase renal alpha 2-adrenergic receptors in either SHR-S or WKY rats. SHR-S had significantly higher numbers of renal alpha 2-adrenergic receptors than WKY rats on the high salt diets. One week of high (3.15%) or low (0.05%) salt intake did not significantly alter renal alpha 2-adrenergic receptor number in 11-week-old SHR-S or WKY rats; however, blood pressure was significantly elevated in the SHR-S (175.0 +/- 3.5 versus 196.0 +/- 3.0 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Determination of the molecular nature and cellular localization of Thy-1 in human renal tissue.

The molecular nature and cellular localization of Thy-1 antigen in human renal tissue were studied. Strong immunohistochemical staining was observed in frozen sections of human kidney using monoclonal anti-human Thy-1 antibody; this reaction was almost completely abolished by pretreating the kidney section with phosphatidyl inositol (PI)-specific phospholipase C (PI-PLC). Immunohistochemical analysis revealed that the Thy-1 antigen is localized on the proximal tubular epithelial cells and the Bowman's capsule of the glomerulus. Northern blot analysis of renal mRNA using a cloned human Thy-1 gene revealed the presence of human Thy-1 mRNA of a similar size to the one in human brain. When a human kidney cDNA library was screened with the same probe, a cDNA of human Thy-1 was isolated. Moreover, human Thy-1 protein with a molecular weight (MW) of 21,000 was detected in renal tissue by gel electrophoresis and Western blot analysis using monoclonal anti-human Thy-1 antibody. These data demonstrate for the first time the production of human Thy-1 as a PI-anchored protein with a unique cellular location in human renal tissue.

Adult↗

PubMed1989

Different long-term effects of bilateral and unilateral nucleus basalis lesions on rat cerebral cortical neurotransmitter content.

Young adult rats received either unilateral or bilateral ibotenic acid infusions in their nucleus basalis, destroying most of the cholinesterase-staining neurons in that region. Cerebral cortex levels of choline acetyltransferase, somatostatin, neuropeptide Y, and monoamines were then assayed 2.5 and 10 months after bilateral lesions, or, 2.5, 10, and 14 months after unilateral lesions. Entorhinal and cerebral cortex levels of several amino acid transmitters were also measured. As expected, choline acetyltransferase activity was decreased in the frontal cortex ipsilateral to the ibotenic acid infusion in unilaterally or bilaterally lesioned animals. Parietal cortex concentrations of somatostatin and neuropeptide Y were altered by lesioning in a complicated, time-dependent manner. Thus, while unilateral lesions transiently decreased or had no effect on these neuropeptide levels, bilateral lesions elevated the level of each neuropeptide by over 100% at 10 months. Other cortical transmitter systems investigated appeared to be less affected by nucleus basalis-lesions. Unilateral lesions had no effect on prefrontal cortex norepinephrine, serotonin, or dopamine content at 14 months post-lesioning. These different neurochemical effects of unilateral and bilateral nucleus basalis lesions may be important for developing a model for the trans-synaptic effects of cortical cholinergic deafferentation.

Acetylcholine↗

PubMed1989

A pharmacological analysis of food intake regulation in rats treated neonatally with monosodium L-glutamate (MSG).

Studies were conducted to examine deficits in food intake regulation in MSG-treated rats that result from known or suspected damage to neurotransmitter systems involved in feeding. Male rats were injected with either MSG (4 mg/g) or sodium chloride on postnatal days 2 and 4 (MSG-Lo) or postnatal days 2, 4, 6 and 8 (MSG-Hi). As adults, MSG-treated and control rats (n = 12/group) were examined for deficits in pharmacologically elicited feeding and other measures of food intake regulation. A second group of MSG-treated (n = 9/group) and control rats (n = 12) were used to measure basal blood pressure and nociceptive reactivity in adulthood. Organ weights, body weight and neuropeptide Y (NPY) content in brain regions were determined at the end of the study. MSG-Hi rats consumed significantly less food than controls during the dark part of the light cycle. Both MSG-Hi and MSG-Lo groups ate significantly less food than controls after a 48-hour fast. MSG-Hi and MSG-Lo rats consumed significantly less food than controls in response to 1.0 mg/kg morphine. MSG-Hi rats consumed significantly less food than controls during the dark phase and significantly more food than controls during the light phase in response to naloxone (1.0 mg/kg). MSG-Lo ate significantly more than controls in response to 0.1 mg/kg guanfacine. MSG-Hi and MSG-Lo showed a significant attenuation in diazepam-stimulated feeding when compared to controls. Blood pressure was significantly lower in both MSG-Hi and MSG-Lo rats compared to controls. Tail flick latencies were not altered by MSG-treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗