Biomedical subjects

G E Gibson

Publications and source records attributed to G E Gibson.

At least 91 records · Page 5Linked to original sources

PubMed1991

Interactions between inositol phosphates and cytosolic free calcium following bradykinin stimulation in cultured human skin fibroblasts.

The inositol triphosphate (IP3) that results from hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) is generally accepted to be responsible for the mobilization of intracellular calcium. However, some studies suggest that low concentrations of agonists elevate cytosolic free calcium concentration ([Ca2+]i) without IP3 formation. Thus, in the present studies, a comparison of the temporal response of inositol phosphates (IP3, IP2 and IP) and [Ca2+]i to a wide range of bradykinin concentrations was used to examine the relation of these two signal transduction events in cultured human skin fibroblasts (GM3652). In addition, the effects of alterations in internal or external calcium on the response of these second messengers to bradykinin were determined. Bradykinin stimulated accumulation of inositol phosphates and a rise of [Ca2+]i in a time- and dose-dependent manner. Decreasing the bradykinin concentration from 1 microM to 0.1 microM increased the time until the IP3 peak, and when the bradykinin concentration was reduced to 0.01 microM IP3 was not detected. [Ca2+]i was examined under parallel conditions. As the bradykinin concentration was reduced from 1 microM to 0.01 microM, the time to reach the peak of [Ca2+]i increased progressively, but the magnitude of the peak was unaltered. These two second messengers were variably dependent on external calcium. Although the bradykinin-stimulated initial spike of [Ca2+]i did not depend on extracellular calcium, the subsequent sustained levels of [Ca2+]i were abolished in calcium free medium. The bradykinin-stimulated inositol phosphate formation was not dependent on the extracellular calcium nor on the elevation of [Ca2+]i that was produced with Br-A23187. These results demonstrate that bradykinin-induced IP3 formation can be independent of [Ca2+]i and of external calcium, whereas changes in [Ca2+]i are partially dependent on external calcium.

Bradykinin↗

PubMed1991

Acetylcholine formation from glucose following acute choline supplementation.

The effects of choline administration on acetylcholine metabolism in the central nervous system are controversial. Although choline supplementation may elevate acetylcholine (ACh) content in brain, turnover studies with labelled choline precursors suggest that systemic choline administration either has no effect or actually diminishes brain ACh synthesis. Since choline supplementation elevates brain choline levels, the apparent decreases in previous turnover studies may reflect dilution of the labelled choline precursor pool rather than altered ACh formation. Therefore, brain ACh formation from [U-14C]glucose was determined after choline supplementation. A two to three fold elevation of brain choline did not alter ACh levels or [U-14C]glucose incorporation into ACh in the cortex, hippocampus or striatum. Although atropine stimulated ACh formation from [U-14C]glucose in hippocampus, two to three fold increases in brain choline did not augment ACh synthesis or content in atropine pretreated animals. Atropine depressed brain regional glucose utilization and this effect was not reversed by choline treatment. These results suggest that short-term elevation of brain choline does not enhance ACh formation from [U-14C]glucose, and argue against enhanced presynaptic cholinergic function after acute, systemic choline administration.

Acetylcholine↗

PubMed1991

The cellular basis of delirium and its relevance to age-related disorders including Alzheimer's disease.

A wide variety of conditions lead to delirium (i.e., metabolic encephalopathies) in human beings and animals. Despite the varied etiology the clinical consequences are relatively stereotyped which suggests that the diverse insults that cause delirium may act by common metabolic and cellular "final pathways." Related molecular and cellular mechanisms may be involved in aging and Alzheimer's disease, conditions that predispose to the development of delirium. Animal models of delirium better reflect age-related disorders such as Alzheimer's disease than those that impair a single neurotransmitter system such as the cholinergic system; the metabolic encephalopathies produce global cognitive disturbance, which is more typical of these disorders. Thus, research related to delirium has far-reaching implications for normal and abnormal brain function.

Acetylcholine↗

PubMed1991

The role of oxidative abnormalities in the pathophysiology of Alzheimer's disease.

Several lines of evidence suggest that abnormalities in oxidative metabolism and specifically in mitochondria may play an important role in Alzheimer's disease. Abnormalities of oxidative metabolism exist in this disorder. They have been demonstrated in brain studied in vivo, ex vivo (biopsies), at autopsy, and in non-neural tissues including cultured cells. The abnormalities include a profound deficit in the activity of the ketoglutarate dehydrogenase complex (KGDHC), which is likely to lead to impaired metabolism of glutamate and might contribute to selective neuronal cell death by excitotoxic mechanisms as well as by direct effects on energy metabolism through its role in the tricarboxylic acid cycle. Abnormalities in oxidative metabolism may be related to the pathophysiology of Alzheimer's disease by plausible mechanisms for which there is evidence at least in model systems. Hypoxia is known to induce neuropsychological impairments analogous to those which occur in dementing syndromes. Brain, and specifically neurons, are likely to be particularly vulnerable to impairments of oxidative metabolism because of their demonstrated tight dependence on continuous oxidation of glucose to maintain their structure and function. Neuroanatomic studies as well as recent data from CT, PET, and SPECT scanning agree with formulations that suggest the brain areas of greatest vulnerability in Alzheimer's disease include those particularly sensitive to oxidative impairments. Although the mechanisms of accumulation of the classical neuropathological hallmarks of Alzheimer's disease (paired helical filaments, amyloid plaques) are not known, experimental data suggest that metabolic stresses may contribute to the accumulation of these materials. These data include the accumulation of immunoreactivity of anti-paired helical filament antibodies in cells exposed to a mitochondrial poison, the uncoupler CCCP. Impairments of oxidative metabolism are known to impair the metabolism of neurotransmitters involved in Alzheimer's disease; the synthesis of acetylcholine, which is characteristically involved, is exquisitely sensitive to oxidative abnormalities. Experimental evidence suggests that abnormalities of cellular calcium homeostasis, which have been demonstrated in Alzheimer cells, may mediate key deleterious effects of the abnormalities in oxidative metabolism in this disorder. Experimental studies in animals indicate that age potentiates the effects of inherent oxidative abnormalities on the brain, as does cerebrovascular disease. These observations might help to explain the increasing clinical expression of the gene for Alzheimer's disease with age. They are also in accord with difficulties in separating the role of vascular from that of inherent degenerative factors in dementia of later onset. Treatment with L-carnitine, a manipulation designed to mitigate consequences of a mitochondrial abnormality, normalized several non-mitochondrial abnormalities in cultured Alzheimer cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Alzheimer Disease↗

PubMed1989

Cytosolic-free calcium and neurotransmitter release with decreased availability of glucose or oxygen.

Exposing brain slices to reduced oxygen tensions or impairing their ability to utilize oxygen with KCN decreases acetylcholine (ACh) but increases dopamine (DA) and glutamate in the medium at the end of a release incubation. To determine if these changes are due to alterations in the presynaptic terminals, release from isolated nerve endings (i.e. synaptosomes) was determined during histotoxic hypoxia (KCN). KCN reduced potassium-stimulated synaptosomal ACh release and increased dopamine and glutamate release. Since several lines of evidence suggest that altered calcium homeostasis underlies these changes in release, the effects of reducing medium calcium concentrations from 2.3 to 0.1-mM were determined. In low calcium medium, KCN still increased dopamine and glutamate release, but had no effect on ACh release. Hypoxia increased cytosolic-free calcium in both the normal and low calcium medium, although the elevation was less in the low calcium medium. Thus, the effects of histotoxic hypoxia on cytosolic free calcium concentration paralleled those on glutamate and dopamine release. Reducing the glucose concentration of the medium also increased cytosolic-free calcium. The data are consistent with the hypothesis that hypoxia and hypoglycemia increase cytosolic-free calcium, which stimulates the release of dopamine and glutamate, whose excessive release may lead to subsequent cellular damage postsynaptically.

Animals↗

PubMed1989

Dopamine and serotonin in rat striatum during in vivo hypoxic-hypoxia.

Dopamine and serotonin were determined in extracellular fluid of rat striatum by semiderivative in vivo voltammetry during normoxia and a single or repeated exposure to 15% O2 (i.e., mild hypoxia) or 12.5% O2 (i.e., moderate hypoxia). A single exposure to 15% oxygen increased extracellular dopamine 76%. With reintroduction of air to the animals, dopamine values returned to baseline. During a second episode of 15% oxygen, dopamine increased 63% and remained elevated even during a final exposure to air. On the other hand, serotonin was unaffected by 15% oxygen. Moderate hypoxia (12.5% oxygen) increased dopamine (79%) and serotonin (26%) and both remained elevated even after the initial reintroduction of air. These studies demonstrate that in vivo hypoxia increases rat striatal extracellular dopamine and, to a lesser extent, extracellular serotonin. Furthermore, after repeated, mild hypoxic episodes or moderate hypoxia, the increases in rat striatal extracellular dopamine and serotonin continue even during normoxia. These studies further support a role for dopamine and serotonin in hypoxic-induced changes in brain function. The hypoxic-induced elevation of these two neurotransmitters during normoxia may be important in the production of hypoxic/ischemic-induced cell damage.

Animals↗

PubMed1989

Effects of in vitro hypoxia on depolarization-stimulated accumulation of inositol phosphates in synaptosomes.

The effects of potassium and in vitro histotoxic hypoxia (i.e. KCN) on phosphatidylinositol turnover in rat cortical synaptosomes were determined. [2-3H] Inositol prelabelled rat synaptosomes were prepared from cerebral cortex slices that had been incubated with [2-3H] inositol. Depolarization with 60 mM KCl increased [2-3H] inositol phosphates in a time dependent manner. Depolarization with 60 mM KCl increased [2-3H] inositol trisphosphate transiently at 5 s. K+ induced rapid formation of [2-3H]-inositol bisphosphate and maintained an elevated level for at least 5 min. K+ stimulated gradual formation of [2-3H] inositol monophosphate with time. One minute of hypoxia enhanced potassium-stimulated [2-3H] inositol bisphosphate formation. However, 30 min of hypoxia impaired potassium-stimulated accumulation of [2-3H] inositol phosphates. The effects of histotoxic hypoxia were all dependent upon calcium in the medium and on K+-depolarization. Thus, hypoxia altered the K+-induced accumulation of inositol phosphates in prelabelled synaptosomes in a time dependent, biphasic manner that was calcium dependent.

Analysis of Variance↗

PubMed1989

Phosphatidylinositol metabolism during in vitro hypoxia.

The effects of in vitro histotoxic hypoxia (0.5 mM KCN) on potassium-stimulated phosphatidylinositol turnover were determined. In rat cortical slices that were prelabeled with [2-3H]inositol, depolarization with 60 mM KCl increased [2-3H]inositol monophosphate and [2-3H]inositol bisphosphate accumulation in a Ca2+-dependent manner. At early times (10 s and 1 min), histotoxic hypoxia enhanced potassium-stimulated [2-3H]inositol monophosphate and inositol bisphosphate accumulation. Under basal conditions, hypoxia did not alter the accumulation of [2-3H]inositol phosphates. These results are consistent with the following hypothesis. The hypoxic-induced increase in cytosolic free calcium that we reported previously may lead to the early stimulation of inositol phosphates formation during hypoxia through activation of phospholipase C. The impairment of inositol phosphates formation during more prolonged hypoxia may be due to negative feedback regulation of the phosphatidylinositol cascade by protein kinase C or to a reduction in ATP levels.

Animals↗

PubMed1988

Changes in cytosolic free calcium with 1,2,3,4-tetrahydro-5-aminoacridine, 4-aminopyridine and 3,4-diaminopyridine.

The effects of 1,2,3,4-tetrahydro-5-aminoacridine (THA), 4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP) on cytosolic free calcium (Ca2+i) were determined. Both 4-AP and THA have been used to treat Alzheimer's disease. THA is a structural analog of the aminopyridines, which alter calcium homeostasis in nerve terminals. The structural similarities between these compounds suggest a common mechanism of action. The aminopyridines raised Ca2+i concentrations in non-depolarized synaptosomes, whereas THA had no effect. Neither the aminopyridines nor THA had any effect on Ca2+i concentrations in potassium-depolarized synaptosomes. These results suggest that the beneficial effects of THA may be mediated by other mechanisms (i.e. neurotransmitter degradative enzyme inhibition), whereas those of 4-AP and 3,4-DAP may be due, at least in part, to their elevation of Ca2+i, which may enhance neurotransmitter release or other calcium-dependent processes.

4-Aminopyridine↗

PubMed1988

Preliminary experience with a combined-modality approach to the management of oesophageal cancer.

A synchronous chemoradiotherapy schedule of modest dosage has been used in 36 patients with oesophageal cancer since July 1984 at the Royal Adelaide Hospital. The schedule, which comprises two five-day continuous infusions of 5-fluorouracil, each of which is followed by a short cisplatin infusion, together with 30-35 Gy of megavoltage irradiation over three weeks, has been used alone, or before surgical resection or further chemo-irradiation. It has been extremely well tolerated and has caused complete endoscopic resolution of disease before surgery or further chemo-irradiation in 69% of patients. At the end of the full course of treatment, complete relief of dysphagia has been achieved in 27 (84%) of the 32 patients in whom this symptom was present at the start of treatment. The median duration of relief has not yet been reached with a median follow-up of over one year. This degree of palliation is significantly better than that which was achieved in a series of patients who were treated radically either by surgery or radiation alone between the years 1978 and 1983 at the Royal Adelaide Hospital. The 12- and 18-month actuarial survival figures of 72% and 55%, respectively, for the 30 patients in this series whose disease remained apparently localized to the thorax at presentation, compare very favourably with the corresponding figures for the much more highly-selected group of patients who were treated surgically between 1978 and 1983.

Actuarial Analysis↗

PubMed1988

Reduced activities of thiamine-dependent enzymes in the brains and peripheral tissues of patients with Alzheimer's disease.

A report of cell loss in the nucleus basalis of Meynert in patients with Wernicke-Korsakoff disease prompted the examination of thiamine pyrophosphate (TPP)-dependent enzymes in the brain and peripheral tissues of patients with Alzheimer's disease. In these brains, the activities of the 2-ketoglutarate dehydrogenase complex were reduced more than 75% and those of transketolase more than 45%. Decreases occurred in histologically damaged and in relatively undamaged areas. Small but statistically significant abnormalities of transketolase, but not of 2-ketoglutarate dehydrogenase complex, were identified in red blood cells and cultured fibroblasts. Previous studies have shown deficiencies in the brain and variable effects in peripheral tissues on another TPP-dependent enzyme--the pyruvate dehydrogenase complex. Activities of TPP-dependent enzymes appear to be deficient in the brain and perhaps in some peripheral tissues in patients with Alzheimer's disease.

Aged↗

PubMed1988

An in vitro model of anoxic-induced damage in mouse brain.

An in vitro model of anoxic-induced brain damage was developed to help elucidate the biochemical basis of cell damage due to reduced oxygen availability. Mouse forebrain slices were preincubated under various conditions (treatment incubation). The effects of this treatment incubation on [14C]acetylcholine (ACh) and 14CO2 production from [U-14C]glucose were subsequently assessed in an incubation under optimal conditions (test incubation). A variety of treatment incubation conditions decreased 14CO2 and 14C-ACh production in the test incubation in parallel (r = 0.932). For example, treatment incubations with no oxygen and high K+ reduced test incubation ACh (-63.2%) and CO2 (-67.3%) production. An anoxic-induced increase in calcium-45 uptake and the amelioration of anoxic induced changes by the calcium antagonist verapamil or by the omission of calcium from the treatment incubation suggest that altered calcium homeostasis was important in the production of the anoxic-induced deficits. These results provide in vitro evidence that anoxic induced increases in calcium may be pathophysiologically important and that reducing calcium entry postsynaptically may alleviate anoxic-induced changes. This model may prove useful in elucidating the molecular basis of these changes.

Acetylcholine↗

PubMed1988

Selective damage in striatum and hippocampus with in vitro anoxia.

An in vitro model of anoxia-induced brain damage was utilized to help elucidate the biochemical basis of cell damage due to reduced oxygen availability. Previous studies suggest that anoxia-induced damage may vary presynaptically, post-synaptically or in the cell body. Thus, the consequences of an anoxic treatment incubation were examined with hippocampal slices, which contain cholinergic nerve terminals but not cell bodies, and with slices from whole striatum or its subregions, which contain both cholinergic cell bodies and nerve terminals. Slices were preincubated with either oxygen or nitrogen (treatment incubation) and the persistent effects of this treatment on [14C]acetylcholine and 14CO2 production from [U-14C]glucose were assessed in a subsequent incubation under optimal conditions (test incubation). An anoxic treatment incubation reduced the subsequent test incubation production of CO2 about 40% in the hippocampus and striatum. The anoxic treatment incubation diminished ACh production by 46% in the striatum, but only minimally affected that in the hippocampus. Anoxic treatment incubations of synaptosomes did not alter test-incubation ACh synthesis or CO2 production. Omission of calcium from the anoxic treatment incubation increased striatal ACh synthesis by 88% and CO2 production in both regions. These results suggest that anoxia produces persistent changes in postsynaptic processes or cell bodies (in this model cholinergic ones) that differ from those in nerve terminals and that calcium is important in the production of these deficits.

Acetylcholine↗

PubMed1988

Dopamine, acetylcholine, and glutamate interactions in aging. Behavioral and neurochemical correlates.

Aging, hypoxia, and thiamin deficiency diminish motor performance. Similar alterations of ACh, DA, and glutamate metabolism accompany hypoxia, thiamin deficiency, and aging. Both aging and hypoxia reduce ACh release and stimulate DA and glutamate release. Presynaptic enhancement of DA and glutamate release may be important in the production of cell damage that may contribute, in part, to age-related deficits in motor as well as cognitive function. The decline in ACh release may be important in the production of the cognitive deficits. An understanding of the interactions of neurotransmitters in hypoxia and thiamin deficiency aids our understanding of normal aging and increases the possibility of developing better treatments for the multiple neurotransmitter deficiencies that accompany many metabolic, age-related, and chronic degenerative disorders.

Acetylcholine↗

PubMed1988

Olsalazine in the treatment of active ulcerative colitis: a placebo controlled clinical trial and assessment of drug disposition.

The efficacy, safety and disposition of olsalazine was assessed in patients with left-sided ulcerative colitis or proctitis in a double-blind placebo controlled trial. Thirty patients with a mild-to-moderate attack of ulcerative colitis were randomly allocated to olsalazine capsules, 1 g b.d., or placebo for 6 weeks. Good clinical response was found in six patients receiving olsalazine and in two receiving placebo. Improvement in sigmoidoscopic findings and histological appearance of rectal biopsies was also seen more often in olsalazine-treated patients. Plasma concentrations of olsalazine were significantly higher in patients who improved. Olsalazine showed an advantage over placebo which needs to be confirmed by further studies; it was safe in sulphasalazine-sensitive patients but appeared to cause watery diarrhoea in two patients.

Aminosalicylic Acids↗

PubMed1987

Differential alteration of dopamine, acetylcholine, and glutamate release during anoxia and/or 3,4-diaminopyridine treatment.

The potassium-stimulated release of acetylcholine (ACh), glutamate (GLU) and dopamine (DA) from mouse striatal slices was studied during anoxia and/or 3,4-diaminopyridine (DAP) treatment. Anoxia, in the presence of calcium, increased DA and GLU release, but depressed ACh release. Omission of calcium from an anoxic incubation further stimulated GLU and DA release and impaired ACh release. Under normoxic conditions, DAP (100 microM) increased the release of all three neurotransmitters; the sensitivity of the slices to DAP changed with the presence or absence of an acetylcholinesterase inhibitor in the preincubation media. During an anoxic incubation, DAP did not ameliorate the anoxic-induced, K+-stimulated impairment of ACh release, but significantly reduced the K+-stimulated release of GLU and DA. These results are consistent with the hypothesis that hypoxia induces a presynaptic deficit that may underlie postsynaptic ischemic-induced changes. Amelioration of these presynaptic alterations in neurotransmitter release may be an effective approach to preventing hypoxic-induced damage.

4-Aminopyridine↗

PubMed1987

Diminished mitogen-induced calcium uptake by lymphocytes from Alzheimer patients.

Recent studies demonstrate diminished calcium uptake by cultured skin fibroblasts from Alzheimer patients. To determine if altered calcium homeostasis is also present in tissue taken from Alzheimer patients, calcium homeostasis was assessed in mitogen-stimulated lymphocytes. Calcium uptake by lymphocytes from Alzheimer patients was 10%-15% lower (p less than 0.002) than that of lymphocytes from age-matched controls. However, neither superficially bound nor total calcium was altered by Alzheimer's disease. These small differences in uptake may reflect larger differences in cytosolic calcium, in later calcium-mediated events, or in the response of particular subsets of lymphocytes. Their biological significance remains to be determined.

Aged↗

PubMed1987

Locomotor activity as a predictor of times and dosages for studies of nicotine's neurochemical actions.

Nicotine's action on the central nervous system is complex and likely involves an interaction of neurotransmitters. To determine the time after administration of nicotine and dosage for neurochemical studies, locomotor activity of CD-1 mice was determined at 5 min intervals between 0-60 min. A low nicotine dosage (0.05 mg/kg) did not alter activity 5-15 min after drug injection, but increased activity 28% at 15-25 min post-injection. A high dosage (0.8 mg/kg) reduced total distance 62% and rearing 87% at 5-15 min; at 15-25 minutes total distance declined 56% and rearing 69%; all measures returned to control values after 30 minutes; rearing then increased at 40 min after nicotine. Pretreatment (15 min before nicotine) with mecamylamine (1.0 mg/kg), but not hexamethonium (1.0 mg/kg), prevented the depressant effect of nicotine. Dopamine (DA) and its metabolites as well as acetylcholine (ACh) synthesis were measured at the point of nicotine's maximal depressant action. Striatal levels of dihydroxyphenylacetic acid (DOPAC) were increased and ACh utilization was reduced in striatum (-25%) and cortex (-24%) 10 min after nicotine (0.8 mg/kg). Mecamylamine, while preventing the depressant effect of nicotine on locomotor activity, did not alter its effects on DA metabolism. These results demonstrate that the behavioral outcome of acute nicotine treatment is time and dose-dependent. Nicotine's depressant action appears not to be due to altered DA but may be related to changes in carbohydrate and acetylcholine metabolism.

Acetylcholine↗