Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0851184 (thinning)
 11,252 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reduced oxygen consumption and lactic acidosis were observed frequently in patients with peritonitis. This study was designed to evaluate whether reduced oxygen consumption is secondary to deficient oxygen delivery or is a function of primary injury to mitochondria. Peritonitis was produced in rats by cecal ligation and perforation. Animals were killed at 2, 4, and 6 hours and agonally. Oxygen utilization was studied polarographically in isolated hepatic mitochondria with glutamate, pyruvate, and succinate substrates. State 3, state 4, respiratory control index (RCI), and ADP:O ratios were determined. Whole tissue and isolated mitochondrial ultrastructure were examined by electron microscopy. Systemic blood pressure and oxygenation were monitored. Hepatic tissue oxygenation was examined using a surface oxygen electrode. Peritonitis resulted in acceleration of state 3 respiratory rates and increased respiratory control indices at all time intervals. Maximal respiratory control was observed at 4 hours with all substrates. Whole tissue mitochondria demonstrated mild swelling and thinning of membranes and matrix. Experimental and control isolates showed similar orthodox-to-condensed conformational changes. Hepatic tissue oxygenation declined to less than 10% of control by 6 hours, while arterial Po2 was unchanged. The conclusions of this study are that lethal peritonitis results in (1) no primary injury to the hepatic mitochondria, (2) increased efficiency of hepatic mitochondrial oxygen utilization, and (3) reduced hepatic tissue oxygenation. The exact mechanisms of defective oxygen delivery require further study.
 ...
PMID:Hepatic cellular hypoxia in murine peritonitis. 45 75

L-Glutamate, a putative photoreceptor cell neurotransmitter, causes thinning of the inner layers of the retina and has been used for preparing biologically fractionated photoreceptor cells. However, it is possible that absence of the inner retinal layers may affect the remaining retina, and/or glutamate may directly affect photoreceptor cells. We evaluated quantitatively the effects of L-glutamate on the developing photoreceptor cells by measuring the rod photoreceptor cell-specific protein, opsin. We purified rat rhodopsin and used it as the standard for measuring opsin content of rat retinas with competitive enzyme-linked immunosorbent assay. Various concentrations of glutamate were injected into 7-day-old rats, and the effects of the amino acid concentration on opsin expression were determined on postnatal day 14. Inner layers of the retina degenerated when 10 microliters or 15 microliters of 2.4 M glutamate/gram body weight was administered subcutaneously. Opsin content of these glutamate-treated retinas decreased significantly compared with control retinas. We administered glutamate to rats at various stages of development and determined the effects by light microscopy on postnatal day 14. The administration of glutamate resulted in no degeneration of the inner retina if injected on postnatal day 1 or 2, degeneration of the inner retina between day 3 to 7, and again, no degeneration after postnatal day 13. Opsin content decreased significantly when glutamate was administered between postnatal day 1 to 7, but not after day 13, the day the blood-retinal barrier seems to reach maturity. Our findings indicate that systemic administration of L-glutamate affects the expression of opsin in the developing rod photoreceptor cells.
 ...
PMID:Decrease of opsin content in the developing rat photoreceptor cells by systemic administration of L-glutamate. 183 98

Monosodium L-glutamate is known to cause intracellular swelling, necrosis, and disappearance of most inner retinal neurons, with concomitant thinning of inner retinal layers within hours after subcutaneous injection into neonatal rodents. A similar process can be observed in adult rat retina after intravitreal glutamate injection. To better describe and compare this process with that reported after systemic application, adult Sprague-Dawley rat eyes were intravitreally injected with 1 mumol monosodium L-glutamate and the retinas studied by LM and EM over a 2-month period. Results demonstrated that adult rat retina experienced severe degenerative changes which progressed in two stages: an initial stage of massive intracellular swelling and a second stage of necrosis and cell loss. Degeneration involved ganglion and inner nuclear layer cells. Inner retinal thickness decreased concurrently. By 2 months post-injection, degenerative changes in rod spherules and some loss of photoreceptor nuclei were observed. Both time course and severity of the lesion differed from that described in prior studies after systemic treatment.
 ...
PMID:Histologic changes in the inner retina of albino rats following intravitreal injection of monosodium L-glutamate. 406 91

An ultrastructural study of rat hippocampus was performed on young (group 1) and old (group 4) rats receiving daily subcutaneous injections of aluminum L-glutamate and on old untreated rats (group 5). Young controls were treated with sodium L-glutamate (group 2) and physiological saline (group 3). Group 1 showed vacuolated astrocytes with numerous lipofuscin deposits, mitochondrial swelling, a thinning of the myelin sheath, and many multivesicular bodies invading the cytoplasm. Cellular structure did not appear to be affected in groups 2 and 3. Group 4 showed swollen mitochondria, a demyelination process in axonal regions, sizable perivascular oedema with vessel retraction and gliofilament bundles. In this group, lipofuscin deposits in astrocytes were associated with multivesicular bodies that thinned the myelin sheath to the breaking point; however, no excitotoxic glutamate-induced effects were observed. In group 5, extreme cytoplasmic vacuolation was observed, with massive mitochondrial swelling, considerable thinning of the myelin sheath (at times to the breaking point), sizable vacuolar degeneration and gliofilament bundles. These results indicate that ultrastructural alterations in the hippocampus, such as cell vacuolization, massive mitochondrial swelling and the demyelination process, occur with aging and independently of aluminum intoxication. Similar alterations were observed in aluminum L-glutamate-intoxicated young rats, but not in controls. These results are consistent with aluminum-induced acceleration of the aging process.
 ...
PMID:Ultrastructural study of rat hippocampus after chronic administration of aluminum L-glutamate: an acceleration of the aging process. 1122 39

Shaken baby syndrome, a rotational acceleration injury, is most common between 3 and 6 months of age and causes death in about 10 to 40% of cases and permanent neurological abnormalities in survivors. We developed a mouse model of shaken baby syndrome to investigate the pathophysiological mechanisms underlying the brain damage. Eight-day-old mouse pups were shaken for 15 seconds on a rotating shaker. Animals were sacrificed at different ages after shaking and brains were processed for histology. In 31-day-old pups, mortality was 27%, and 75% of survivors had focal brain lesions consisting of hemorrhagic or cystic lesions of the periventricular white matter, corpus callosum, and brainstem and cerebellar white matter. Hemorrhagic lesions were evident from postnatal day 13, and cysts developed gradually between days 15 and 31. All shaken animals, with or without focal lesions, had thinning of the hemispheric white matter, which was significant on day 31 but not earlier. Fragmented DNA labeling revealed a significant increase in cell death in the periventricular white matter, on days 9 and 13. White matter damage was reduced by pre-treatment with the NMDA receptor antagonist MK-801. This study showed that shaking immature mice produced white matter injury mimicking several aspects of human shaken baby syndrome and provided evidence that excess release of glutamate plays a role in the pathophysiology of the lesions.
 ...
PMID:Delayed white matter injury in a murine model of shaken baby syndrome. 1214

The neuroprotective effect of MCI-9042 (Mitsubishi Pharma Corporation) was investigated on glutamate-induced retinal ganglion cell (RGC) death in vitro and on rat retinal ischemia in vivo. RGCs were purified from retinal cells isolated from 6-day-old Wistar rats and cultured in serum-free media. After application of 25 microM glutamate, the viability of RGCs treated with or without several serotonin 2 (5-HT(2)) receptor antagonists: MCI-9042, M-1 (a major metabolite of MCI-9042), ketanserin, and LY-53857; was evaluated by calcein-acetoxymethyl ester staining. Retinal ischemia was induced by intraocular pressure (IOP) elevation (130 mmHg, 50 min). Rats were intraperitoneally injected with MCI-9042 at a dose of 3, 30 mg/kg or base at 30 min before and just after ischemia-reperfusion. Retinal damages were evaluated by histology, morphometric analysis and electroretinograms (ERGs) recordings at 7 days after ischemia-reperfusion. 25 microM glutamate decreased the number of viable RGCs to about 60 to 65% of untreated RGCs. MCI-9042, M-1, ketanserin, and LY-53857 significantly reduced glutamate-induced RGC death at concentrations of more than 100 nM, 1 nM, 1 microM and 100 nM, respectively. Ischemia-reperfusion caused thinning of the thickness between the inner plexiform layer and the outer plexiform layer and attenuation of a-and b-waves in ERG recordings. The intraperitoneal injection of MCI-9042 significantly reduced morphological and functional damages in retinal ischemia. Our data demonstrate that 5-HT(2) receptor antagonists including MCI-9042 and M-1 have the neuroprotective effects in cultured RGCs and that MCI-9042 protects against ischemic retinal diseases.
 ...
PMID:Effect of MCI-9042, a 5-HT2 receptor antagonist, on retinal ganglion cell death and retinal ischemia. 1263 9

A case of adult-onset ataxia-telangiectasia (AT) is presented, with debut at the age of 18 years and survival into the fourth decade. The clinical picture included cerebellar ataxia, distal weakness and hypopalesthesia in the lower limbs, oculomotor apraxia, dysarthria, and conjunctival telangiectasiae. Carcinoembrionic antigen was raised in plasma. MR imaging showed atrophy of the cerebellar vermis and thinning of the spinal cord. Deficiencies of gamma-aminobutyric acid and glutamate have been found in the cerebellar cortex in a case of AT. These were attributed to the loss of Purkinje cells and granule cells. In spite of some ataxias having improved with the gabaergic drugs gabapentin and tiagabine, the administration of gabapentin, acetazolamide and a placebo, did not benefit this patient. Pregabalin, 225 mg/day, ameliorated the ataxia unexpectedly, with further improvement after the addition of tiagabine. The authors suggest that the beneficial effect observed might have been due, either to the higher affinity of pregabalin towards alpha2-delta, a subtype of the alpha2-delta subunit which forms part of the voltage-gated calcium channel; either to the profusion of this subtype in the Purkinje cell layer, or to its larger capacity to let calcium into the neuron; or to the combination of these. These differences with gabapentin could explain the higher power of pregabalin in the stimulation of the cerebellar structures, thus justifying the improvement of ataxia in this case of AT. A synergistic effect with pregabalin is proposed as the cause of the improvement obtained with the addition of tiagabine.
 ...
PMID:[Adult-onset ataxia-telangiectasia. A clinical and therapeutic observation]. 1701 92

The cystine/glutamate exchanger (xCT) provides intracellular cyst(e)ine for production of glutathione, a major cellular antioxidant. Using xCT overexpression and underexpression, we present evidence that xCT-dependent glutathione production modulates both neuroprotection from oxidative stress and cell proliferation. In embryonic and adult rat brain, xCT protein was enriched at the CSF-brain barrier (i.e., meninges) and also expressed in the cortex, hippocampus, striatum, and cerebellum. To examine the neuroprotective role of xCT, various non-neuronal cell types (astrocytes, meningeal cells, and peripheral fibroblasts) were cocultured with immature cortical neurons and exposed to oxidative glutamate toxicity, a model involving glutathione depletion. Cultured meningeal cells, which naturally maintain high xCT expression, were more neuroprotective than astrocytes. Selective xCT overexpression in astrocytes was sufficient to enhance glutathione synthesis/release and confer potent glutathione-dependent neuroprotection from oxidative stress. Moreover, normally nonprotective fibroblasts could be re-engineered to be neuroprotective with ectopic xCT overexpression indicating that xCT is a key step in the pathway to glutathione synthesis. Conversely, astrocytes and meningeal cells derived from sut/sut mice (xCT loss-of-function mutants) showed greatly reduced proliferation in culture attributable to increased oxidative stress and thiol deficiency, because growth could be rescued by the thiol-donor beta-mercaptoethanol. Strikingly, sut/sut mice developed brain atrophy by early adulthood, exhibiting ventricular enlargement, thinning of the cortex, and shrinkage of the striatum. Our results indicate that xCT can provide neuroprotection by enhancing glutathione export from non-neuronal cells such as astrocytes and meningeal cells. Furthermore, xCT is critical for cell proliferation during development in vitro and possibly in vivo.
 ...
PMID:Cystine/glutamate exchange modulates glutathione supply for neuroprotection from oxidative stress and cell proliferation. 1703 36

The alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) type ionotropic glutamate receptors participate in fast neuronal transmission. GluR2, a subunit of AMPA receptors, is the determinant of Ca2+-permeability and surface expression of the receptors. To elucidate the role of AMPA receptors in the cells expressing glial fibrillary acidic protein (GFAP), we constructed mice expressing rat GluR2 cDNA under the control of a human GFAP promoter. The mice expressed approximately two folds increase of GluR2 in primary culture of astrocytes. Colocalization of GluR2 and GFAP was observed in Bergmann glial cells, which normally expressed AMPA receptors lacking GluR2. The diameter of glial fibers was significantly reduced and the leading edge of the processes was thinning or retracted in primary cultured BG cells. Interestingly, the transgenic mice had smaller brains compared with wild type mice. We found a 32% decrease in the number of cerebellar granule cells and a 31% decreases in cerebral cortical neurons. These results indicate that the increased expression of GluR2 in GFAP-positive cells alters neuron-glial interaction and leads to reduction in the number of neurons in adult mice.
 ...
PMID:GluR2 expressed by glial fibrillary acidic protein promoter decreases the number of neurons. 1798 53

Disruption of the postsynaptic density (PSD), a network of scaffold proteins located in dendritic spines, is thought to be responsible for synaptic dysfunction and loss in early-stage Alzheimer's disease (AD). Extending our previous demonstration that derangement of the PSD by soluble amyloid-beta (Abeta) involves proteasomal degradation of PSD-95, a protein important for ionotropic glutamate receptor trafficking, we now show that Abeta also disrupts two other scaffold proteins, Homer1b and Shank1, that couple PSD-95 with ionotropic and metabotropic glutamate receptors. Treatment of fronto-cortical neurons with soluble Abeta results in rapid (within 1 h) and significant thinning of the PSD, decreased synaptic levels of Homer1b and Shank1, and reduced synaptic mGluR1 levels. We show that de novo protein synthesis is required for the declustering effects of Abeta on Homer1b (but not Shank1) and that, in contrast to PSD-95, Abeta-induced Homer1b and Shank1 cluster disassembly does not depend on proteasome activity. The regulation of Homer1b and Shank1 by Abeta diverges in two other respects: i) whereas the activity of both NMDAR and VDCC is required for Abeta-induced declustering of Homer1b, Abeta-induced declustering of Shank1 only requires NMDAR activity; and ii) whereas the effects of Abeta on Homer1b involve engagement of the PI-3K pathway and calcineurin phosphatase (PP2B) activity, those on Shank1 involve activation of the ERK pathway. In summary, soluble Abeta recruits discrete signalling pathways to rapidly reduce the synaptic localization of major components of the PSD and to regulate the availability of mGluR1 in the synapse.
 ...
PMID:Disassembly of shank and homer synaptic clusters is driven by soluble beta-amyloid(1-40) through divergent NMDAR-dependent signalling pathways. 1954 99


1 2 3 4 Next >>