PubMed Health⌕ Search

Biomedical subjects

V L Dawson

Publications and source records attributed to V L Dawson.

At least 91 records · Page 5Linked to original sources
PubMed1995

Neuroprotective effects of gangliosides may involve inhibition of nitric oxide synthase.

Gangliosides are polar, sugar-containing lipids that are major constituents of neuronal membranes. Gangliosides are neuroprotective in animal models of neurotoxicity and may also be useful in patients with clinical conditions such as spinal cord injury. We show that a series of gangliosides inhibit nitric oxide synthase activity by binding calmodulin. The prevention of glutamate neurotoxicity in cortical cultures by gangliosides closely parallels their potencies in binding calmodulin and inhibiting nitric oxide synthase. Neuroprotective effects of gangliosides may arise from blockade of nitric oxide formation.

Amino Acid Oxidoreductases↗
PubMed1995

Physiological and toxicological actions of nitric oxide in the central nervous system.

NO has clearly revolutionized our thinking about aspects of neurotransmission and neuronal signaling. It has also radically altered our thoughts about how synaptic transmission takes place. NO is emerging as an important regulator of a variety of physiological processes; however, under certain conditions of excessive formation, NO is emerging as an important mediator of pathological nervous tissue damage. Understanding the role of NO in these processes will hopefully lead to the development of selective therapeutic agents and to a better understanding of basic processes underlying normal and pathological neuronal functions.

Animals↗
PubMed1995

Nitric oxide: role in neurotoxicity.

1. Nitric oxide (NO) is a novel neuronal messenger molecule which interacts with surrounding neurones, not by synaptic transmission but by diffusion between cells. 2. NO is produced following stimulation of the enzyme, NO synthase (NOS). After synthesis, NO exerts its biological actions by diffusion to the site of action. Therefore, the way to regulate the physiological actions of NO is to regulate NOS. 3. NOS is activated by the influx of calcium from glutamate-activated N-methyl-D-aspartate receptors. Overactivation of these receptors leads to overproduction of NO and neuronal cell death. 4. NOS can be regulated at the catalytic site, at the flavo-proteins, at the calmodulin site and by phosphorylation. 5. In excess, NO is toxic to neurones. This toxicity is mediated largely by an interaction with the superoxide anion, presumably through the generation of the oxidant, peroxynitrite. 6. NO or peroxynitrite-mediated neuronal injury involves the activation of the nuclear protein, poly(ADP-ribose)synthetase.

Amino Acid Oxidoreductases↗
PubMed1995

An evaluation of the nitric oxide/cGMP/cGMP-dependent protein kinase cascade in the induction of cerebellar long-term depression in culture.

Cerebellar long-term depression (LTD) is a model system of information storage in which a persistent attenuation of the parallel fiber-Purkinje neuron (PN) synapse is induced by conjunctive stimulation of parallel fiber and climbing fiber inputs at low frequency. As some studies have suggested that release of the gaseous second messenger, nitric oxide (NO), in the molecular layer and the consequent activation of soluble guanylate cyclase and cGMP-dependent protein kinase (PKG) in the PN, is necessary for LTD induction, we have further examined this hypothesis using a cell culture protocol. In cerebellar cultures made from transgenic mice in which the gene for neuronal nitric oxide synthase (nNOS) has been rendered null, LTD induced by glutamate/depolarization conjunctive stimulation was indistinguishable from that in cultures from wild-type mice in terms of amplitude, rate of onset, and duration. Bath application of cGMP analogs produced a large (80%), transient attenuation of glutamate-gated inward currents. However, application of an activator of soluble guanylate cyclase or an inhibitor of type V cGMP-phosphodiesterase did not mimic the effect of cGMP analogs, and inclusion of cGMP analogs in the patch pipette did not give rise to a slowly developing attenuation, suggesting that these compounds exert their effects at the cell surface. Free Ca was measured in the distal dendritic arbor of single PNs by fura-2 microfluorimetry.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate Ribose↗
PubMed1995

ADP-ribosylation as a mechanism for the action of nitric oxide in the nervous system.

Nitric oxide (NO.) is a unique biological messenger molecule in the central and peripheral nervous systems. The molecular targets of NO. are expanding, as are its physiologic and pathophysiologic roles in the nervous system. NO. may play a role in synaptic plasticity and nervous system morphogenesis and regulate neurotransmitter release and gene expression. It functions as a nonadrenergic, noncholinergic neurotransmitter in the gastrointestinal tract, where it mediates peristalsis through smooth muscle relaxation, and in the penis, where it regulates erectile function. NO. is emerging as an important endogenously derived neurotoxin that may contribute to neuronal cell death in a variety of disorders of the nervous system. NO. may mediate its neurotoxic properties through DNA damage and the subsequent activation of poly (ADP-ribose) synthetase which depletes neurons of their energy stores.

Adenosine Diphosphate Ribose↗
PubMed1994

Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity.

Poly(adenosine 5'-diphosphoribose) synthetase (PARS) is a nuclear enzyme which, when activated by DNA strand breaks, adds up to 100 adenosine 5'-diphosphoribose (ADP-ribose) units to nuclear proteins such as histones and PARS itself. This activation can lead to cell death through depletion of beta-nicotinamide adenine dinucleotide (the source of ADP-ribose) and adenosine triphosphate. Nitric oxide (NO) stimulated ADP-ribosylation of PARS in rat brain. Benzamide and other derivatives, which inhibit PARS, blocked N-methyl-D-aspartate- and NO-mediated neurotoxicity with relative potencies paralleling their ability to inhibit PARS. Thus, NO appeared to elicit neurotoxicity by activating PARS.

Animals↗
PubMed1994

Receptor alterations in subcortical structures after bilateral middle cerebral artery infarction of the cerebral cortex.

Ischemic damage to the prefrontal, motor, and somatosensory cortex induces alterations in the receptor systems of the caudate putamen and some subcortical brain regions. These alterations may represent an attempt of various neuronal systems to compensate for the reduction in innervation caused by the cortical infarction. Assessment of the receptor changes induced by cortical infarction define neuropharmacologic correlates of cortical damage, indicate possible neurotransmitters associated with neuroanatomically defined subcortical pathways, and suggest possible pharmacologic interventions to counteract the consequences of stroke. Bilateral cortical infarction, induced by ligation of both middle cerebral arteries and temporary occlusion of both common carotid arteries, was investigated in the rat. The infarction resulted in dramatic alterations in subcortical receptor populations as determined by autoradiography. Sodium-dependent, high-affinity, choline-uptake (SDHACU) sites and D1-dopamine receptors in the caudate putamen were unaffected by the infarction, whereas muscarinic and glutamate receptors were increased and D2 receptors were decreased in this structure. A reduction in SDHACU sites caused by the lesion was found in regions including the medial septum, vertical nucleus of the diagonal band, thalamus, nucleus basalis magnocellularis, and basolateral amygdala. M1 receptors were increased in the basolateral and central amygdaloid nuclei whereas non-M1 receptors were increased in the basolateral and central amygdaloid nuclei, but were diminished in the medial septum, vertical nucleus of the diagonal band, thalamus, and nucleus basalis magnocellularis. No significant alterations in muscarinic binding were observed in the various laminae of the hippocampus and dentate gyrus.

Animals↗
PubMed1994

Expression of inducible nitric oxide synthase causes delayed neurotoxicity in primary mixed neuronal-glial cortical cultures.

Nitric oxide (NO) is a potent biological messenger molecule in the central nervous system (CNS). There are several potential sources of NO production in the CNS, including neurons and endothelial cells which express NO synthase (NOS) constitutively. Astrocytes and microglia can be induced by cytokines to express a NOS isoform similar to macrophage NOS (mNOS). Primary mixed glial cultures exposed to lipopolysaccharide (LPS) or a combination of LPS and gamma-interferon (INF-gamma) produce nitrite, a breakdown product of NO formation, in a dose-dependent manner. Nitrite production is detectable at 12 hr, peaks at 48 hr and is sustained for at least 96 hr. The NOS inhibitor, nitro-L-arginine (NArg), inhibits nitrite formation, but the immunosuppressant agent, FK506, does not. In mixed glial-neuronal cultures exposed to 50 ng LPS or 5 ng LPS and 1 microgram INF-gamma, neurons begin to die at 48 hr, approx. 24-36 hr after detectable nitrite production. Neurotoxicity is attenuated by 100 microM NArg. These data indicate that expression of inducible mNOS causes delayed neurotoxicity.

Amino Acid Oxidoreductases↗
PubMed1994

gp120 neurotoxicity in primary cortical cultures.

The human immunodeficiency virus type 1 coat protein, gp120, kills neurons in a nitric oxide dependent manner in primary cortical cultures at low picomolar concentrations. gp120 neurotoxicity also requires calcium and glutamate and is blocked by glutamate receptor antagonists. In addition, superoxide anions play a role in gp120 neurotoxicity since superoxide dismutase also attenuates neurotoxicity.

AIDS Dementia Complex↗
PubMed1993

Immunosuppressant FK506 enhances phosphorylation of nitric oxide synthase and protects against glutamate neurotoxicity.

Immunosuppressants FK506 and cyclosporin A inhibit neurotoxicity of N-methyl-D-aspartate in primary cortical cultures, while having no effect on quisqualate- and kainate-mediated neurotoxicity. Rapamycin completely reverses the neuroprotective effect of FK506. Both FK506 and cyclosporin A inhibit NMDA-elicited/nitric oxide-mediated increases in cGMP levels in cortical cultures. FK506 has no effect on sodium nitroprusside-induced increases in cGMP. In a stably transfected human kidney 293 cell line overexpressing the gene encoding nitric oxide synthase [L-arginine, NADPH:oxygen oxidoreductase (nitric oxide-forming), EC 1.14.13.39], FK506 inhibits the calcium ionophore A23187, stimulated increases in nitrite (a breakdown product of nitric oxide), and potentiates phorbol ester-mediated inhibition of nitrite formation. FK506-mediated inhibition of nitric oxide formation is completely reversed by rapamycin. Calcineurin dephosphorylates protein kinase C-mediated phosphorylation of nitric oxide synthase. FK506 prevents the calcineurin-mediated dephosphorylation of nitric oxide synthase and thereby diminishes the enzyme's catalytic activity. These data establish nitric oxide synthase as a calcineurin substrate. Nitric oxide synthase catalytic activity is regulated by the phosphorylation state of the enzyme. Enhanced phosphorylation of nitric oxide synthase diminishes catalytic activity, and dephosphorylation (through activation of calcineurin) enhances catalytic activity. The neuroprotective effect of FK506 and cyclosporin A presumably involves the inhibition of calcineurin, preventing the dephosphorylation of nitric oxide synthase and its subsequent activation.

Amino Acid Oxidoreductases↗
PubMed1993

Human immunodeficiency virus type 1 coat protein neurotoxicity mediated by nitric oxide in primary cortical cultures.

The human immunodeficiency virus type 1 coat protein, gp120, kills neurons in primary cortical cultures at low picomolar concentrations. The toxicity requires external glutamate and calcium and is blocked by glutamate receptor antagonists. Nitric oxide (NO) contributes to gp120 toxicity, since nitroarginine, an inhibitor of NO synthase, prevents toxicity as does deletion of arginine from the incubation medium and hemoglobin, which binds NO. Superoxide dismutase also attenuates toxicity, implying a role for superoxide anions.

Animals↗
PubMed1993

Pharmacology of GABA rho 1 and GABA alpha/beta receptors expressed in Xenopus oocytes and COS cells.

1. The rho 1 protein, which we previously cloned from retina, assembles as a homooligomer that transduces the binding of gamma-aminobutyric acid (GABA) into robust chloride currents. However, its insensitivity to bicuculline, pentobarbitone and benzodiazepines, all potent agents at typical GABAA receptors, suggested that it may react atypically to other GABA agonists and antagonists. 2. cDNAs for the rho 1 and the alpha 5 beta 1 receptors for GABA were expressed as homo- and heterooligomers, respectively, in Xenopus oocytes. The selectivities of the respective receptors for various agonists were investigated using concentration-response experiments in voltage clamped cells. 3. The most potent agonists at the rho 1 receptor were trans-4-aminocrotonic acid (TACA) > GABA > muscimol; at the alpha 5 beta 1 receptor the rank order was muscimol > GABA > 4,5,6,7-tetrahydroisoxazole[4,5-c]pyridine-3-ol (THIP). The most specific agonists were cis-(2-(aminomethyl)-cyclopropyl-carboxylic acid (CAMP) and THIP for the rho 1 and the alpha 5 beta 1 receptors, respectively. 4. Comparing GABA, TACA and cis-aminocrotonic acid (CACA) at rho 1 receptors expressed in COS cells gave results almost indistinguishable from those found at oocytes; the pharmacology of rho 1 seems independent of the expression system. 5. Agonists THIP, piperidine-4-sulphonic acid (P4S), and isoguvacine, whose C-C-C-N chains are constrained by rings into a folded conformation and were potent at the alpha 5 beta 1 receptor, were among the weakest at the rho 1 receptor. However CACA and CAMP, which align better with the extended than the folded conformation, were weakest at the alpha 5 beta 1 receptor but moderately potent at the pl receptor. These findings suggest that the rho l receptor recognizes agonists in the extended conformation, in contrast to GABAA receptors, which are believed to recognize agonists in the partially folded conformation.6. In contrast to the alpha 5 beta 1 receptor, gradations in maximum responses were apparent in the rho l receptor,suggesting various degrees of partial agonism. In particular, imidazole-4-acetic acid (I4AA), whose maximum response was only 3% of GABA's maximum, had an apparent Kd for activating the rho l receptor of 16 microM; but it had an apparent Kd for competitively blocking the receptor of 0.64 microM. This difference suggests that steric constraints in the activated (open channel) receptor are tighter than in the resting receptor.7. Hill coefficients approached 2 at the rho l receptor, but were closer to unity at the alpha 5 beta 1 receptor. Thus,the rho l receptor displayed higher cooperativity.8. Unlike typical GABAA receptors, the rho l receptor was insensitive to the competitive antagonists bicuculline, SR95531, securinine, and (+)-tubocurarine.

Animals↗
PubMed1993

Mechanisms of nitric oxide-mediated neurotoxicity in primary brain cultures.

In addition to mediating several physiological functions, nitric oxide (NO) has been implicated in the cytotoxicities observed following activation of macrophages or excess stimulation of neurons by glutamate. We extend our previous observations of glutamate-stimulated, NO-mediated neurotoxicity in primary cultures of rat fetal cortical, striatal, and hippocampal neurons. Neurotoxicity elicited by either NMDA or sodium nitroprusside (SNP) exhibits a similar concentration-effect relationship and time course. The concentration-effect curve of NMDA-induced neurotoxicity is shifted to the right in the presence of nitro-L-arginine and farther to the right in arginine-free media. The rank order of potency of several NO synthase (NOS) inhibitors in preventing neurotoxicity is the same as the rank order of these compounds in inhibiting NOS, and this inhibition is stereospecific. NMDA neurotoxicity is also prevented by flavoprotein inhibitors and calmodulin inhibitors, fitting with the roles of flavoproteins and calmodulin as NOS regulators. 8-Bromo-cGMP and guanylyl cyclase inhibitors do not affect neurotoxicity, while superoxide dismutase attenuates neurotoxicity. NOS neurons appear to be the source of neurotoxic NO in culture, as lesions of these neurons with 20 microM quisqualate diminish subsequent NMDA neurotoxicity. Moreover, NMDA neurotoxicity develops over time in culture coincident with the expression of NOS. Immunohistochemical localization of NOS in cultures and intact brain demonstrates widespread distribution of the cell processes suggesting that NOS neurons contact the majority of cortical neurons and so could mediate widespread neurotoxicity.

Amino Acid Oxidoreductases↗
PubMed1992

A novel neuronal messenger molecule in brain: the free radical, nitric oxide.

Understanding of the organization and function of a newly identified neuronal messenger molecule, nitric oxide, has progressed rapidly. Nitric oxide synthase has been purified and molecularly cloned from brain. Its localization is exclusively neuronal and endothelial. The catalytic activity of nitric oxide synthase accounts for the NADPH diaphorase staining of neurons that are uniquely resistant to toxic insults and neurodegenerative disorders. Nitric oxide has diverse functions. In platelets it inhibits their aggregation, in macrophages it mediates cytotoxicity, and in blood vessels it acts as a vasodilator. In the nervous system nitric oxide may be the retrograde transmitter in long-term potentiation. It is the "neurotransmitter" of cerebral vasodilator nerves and the inhibitory "neurotransmitter" of the motor neurons of the intestines. Nitric oxide in situations of excessive production may function as a neurotoxin, suggesting a role for nitric oxide in neurodegenerative disorders.

Amino Acid Oxidoreductases↗
PubMed1991

Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures.

Nitric oxide (NO) mediates several biological actions, including relaxation of blood vessels, cytotoxicity of activated macrophages, and formation of cGMP by activation of glutamate receptors in cerebellar slices. Nitric oxide synthase (EC 1.14.23.-) immunoreactivity is colocalized with nicotinamide adenine di-nucleotide phosphate diaphorase in neurons that are uniquely resistant to toxic insults. We show that the nitric oxide synthase inhibitors, N omega-nitro-L-arginine (EC50 = 20 microM) and N omega-monomethyl-L-arginine (EC50 = 170 microM), prevent neurotoxicity elicited by N-methyl-D-aspartate and related excitatory amino acids. This effect is competitively reversed by L-arginine. Depletion of the culture medium of arginine by arginase or arginine-free growth medium completely attenuates N-methyl-D-aspartate toxicity. Sodium nitroprusside, which spontaneously releases NO, produces dose-dependent cell death that parallels cGMP formation. Hemoglobin, which complexes NO, prevents neurotoxic effects of both N-methyl-D-aspartate and sodium nitroprusside. These data establish that NO mediates the neurotoxicity of glutamate.

Animals↗