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PubMed2003

Losses of NG2 and NeuN immunoreactivity but not astrocytic markers during early reperfusion following severe focal cerebral ischemia.

The ability of glia to recover essential functions following a period of focal cerebral ischemia is likely to be one important factor influencing the severity of tissue damage that subsequently develops. In this study, we have compared changes in immunoreactivity of markers specific for astrocytes, NG2-positive glia and neurons in tissue subregions during early reperfusion following 3 h of middle cerebral artery occlusion to provide insights into possible differential susceptibility of these cell populations. Under the conditions used, infarction ultimately encompasses most of the perfusion territory of the occluded artery. Nonetheless, alterations in immunoreactivity during the first 3 h of recirculation were restricted to brain regions that had been subjected to severe ischemia. In the striatum, cellular immunoreactivity for NG2 and neuronal markers, NeuN and microtubule-associated protein 2, was greatly reduced by 1 h of reperfusion and declined further at 3 h. NG2 labeling of blood vessels in the striatum appeared post-ischemically, mimicking expression of this protein during development. Less severe changes were seen in the neuronal markers in overlying cerebral cortex. In contrast to the losses of other cellular proteins, immunoreactivity for the astrocytic marker, glial fibrillary acidic protein, was preserved in all tissue that had been subjected to severe ischemia and labeling of another astrocytic protein, glutamine synthetase, was increased by 3 h of reperfusion. These findings provide the first evidence of marked sensitivity of NG2-immunoreactivity to severe ischemia and suggest a greater initial resistance of astrocytes compared with neurons and NG2-positive glia to ischemia-reperfusion damage.

Animals↗
PubMed1998

Chloride concentration in cultured hippocampal neurons increases during long-term exposure to ammonia through enhanced expression of an anion exchanger.

The effects of long-term exposure to ammonia on [Cl-]i in cultured hippocampal neurons were examined. Ammonia increased the [Cl-]i time- (>/=24 h) and concentration- (>/=2 mM) dependently, resulting in a depolarizing shift of the equilibrium potential of the GABAA receptor-Cl- channel opening (EGABA). Such an effect of ammonia was diminished by the inhibitors of Cl-/HCO3- exchangers, 0.1 mM 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS) and 0.1 mM 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), and a carbonic anhydrase inhibitor, 2 mM acetazolamide, but not by a Na+/K+/2Cl-cotransport inhibitor, 50 microM bumetanide, suggesting an enhanced Cl-/HCO3- exchange activity by ammonia. The ammonia-induced increase in [Cl-]i was also abolished by the inhibitors of protein kinase C (PKC), 0.1 microM calphostin C and 10 microM 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine dihydrochloride (H-7), and of transcription and de novo protein synthesis, 1 microM actinomycin D and 0.5 microg/ml cycloheximide, while a PKC activator, 0.1 h microM phorbor 12-myristate 13-acetate (PMA), increased the [Cl-]i. The mRNA level of the AE3 Cl-/HCO3- exchanger was increased by ammonia in a calphostin C- and H-7-sensitive manner. The AE3-like immunoreactivity was also increased by ammonia. These findings suggest that long-term exposure to ammonia increases the expression of AE3 through the activation of PKC, resulting in an increase in [Cl-]i in neurons and a reduction of inhibitory postsynaptic potentials.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1999

Lithium decreases Cl--ATPase activity and increases intracellular Cl- concentration in cultured rat hippocampal neurons.

Under the conditions of stimulated phosphatidylinositol turnover (0. 1 mM carbachol plus 20 mM KCl), LiCl (0.1-10 mM) reduced the activity of Cl--ATPase in cultured rat hippocampal neurons without affecting Na+/K+- or anion-insensitive Mg2+-ATPase. This inhibition of Cl--ATPase was attenuated by the addition of 0.5 mM inositol to culture media. The intracellular Cl- concentrations of the LiCl-treated neurons increased in an inositol-sensitive manner.

Adenosine Triphosphatases↗
PubMed1999

Fluorescence imaging of GABAA receptor-mediated intracellular [Cl-] in P19-N cells reveals unique pharmacological properties.

This study describes the pharmacological properties of GABAA receptors expressed in P19-N cells using fluorescence imaging of intracellular chloride with 6-methoxy-N-ethylquinolinium iodide (MEQ). We show that application of the GABA agonist, muscimol (10-200 microM), produces time- and concentration-dependent increases in intracellular [Cl-] that are blocked by bicuculline. Diazepam (10 microM) and pentobarbital (1 mM) potentiate muscimol-stimulation. These receptors exhibit novel pharmacological properties. The neurosteroid, 3alpha-hydroxy-5alpha-pregnane-20-one (1-10 microM) exhibited weak potency in enhancement of muscimol-stimulation. Ethanol (50 and 100 mM) exhibited high efficacy on muscimol responses, a 4- to 5-fold potentiation, respectively, of muscimol (10 microM) alone. GABA and muscimol allosterically modulated specific binding of [3H]flunitrazepam to differentiated P19 cells. Modulation of GABAA receptor mediated increases in intracellular [Cl-] demonstrated stability in response magnitude from 7 to 15 days following removal of retinoic acid. In concert, GABAA receptor subunit mRNA and protein expression patterns in these neuron-like cells were stable over the same period. Using RT-PCR we determined that differentiated P19 cells lack gamma1, gamma2L, alpha6 and delta subunit mRNAs while expressing alpha1, alpha2, alpha3, alpha4, alpha5, beta1, beta2, beta3, gamma2S and gamma3. Furthermore, subunit specific antibody immunocytochemical labeling of cells with a neuronal morphology indicated the presence of alpha1, alpha2, alpha4, and gamma2 subunits (the only subunits tested). Therefore, P19-N cells should prove useful to researchers in need of a model cell culture system in which to study function and regulation of neuronal GABAA receptors.

Animals↗
PubMed1999

Inhibition of Drosophila acetylcholinesterase by 7-(methylethoxyphosphinyloxy)1-methyl-quinolinium iodide.

The kinetic behaviour of Drosophila melanogaster acetylcholinesterase toward its substrate shows, in comparison with classic Michaelis-Menten kinetics, an apparent homotropic cooperative double activation-inhibition pattern. In order to construct an appropriate kinetic model and obtain further information on the mechanism of the catalytic action of this enzyme, the hydrolysis of acetylthiocholine in the absence and presence of different concentrations of synthetic quaternary methylphosphonate, 7-(methylethoxyphosphinyloxy)1-methyl-quinolinium iodide (MEPQ), was followed on a stopped-flow apparatus. The reaction at low substrate concentrations was followed until the change of the absorbance became negligible and at high concentrations only initial parts were recorded. A simultaneous analysis of the progress curves using numerical integration showed that the powerful organophosphonate inhibitor binds and compete with the substrate for the same binding sites. The results are also in accordance with the hypothesis that virtually every substrate or quasi-substrate molecule that enters into the gorge of active site is hydrolysed.

Acetylcholinesterase↗
PubMed1997

Competitive and non-competitive inhibition of L-3, 4-dihydroxyphenylalanine uptake in Opossum kidney cells.

The present study aimed to determine the kinetics of L-3,4-dihydroxyphenylalanine (L-DOPA) uptake in Opossum kidney (OK) cells and to define the type of inhibition produced by L-5-hydroxytryptophan (L-5-HTP), cyanine 863 and 3,3'-diethyloxacarbocyanine (3,3'-DOC). Non-linear analysis of the saturation curves revealed for L-DOPA a Km (in microM) of 129 (114, 145) and a Vmax (in nmol/mg protein per 6 min) of 30.0 +/- 0.4 IC50 values for L-5-HTP (1454 microM) obtained in the presence of a nearly saturating (250 microM) concentration of L-DOPA were almost 4-fold those obtained when non-saturating (25 microM) concentrations of L-DOPA were used (330). IC50 values for cyanine 863 and 3,3'-DOC (638 and 353 microM) obtained in the presence of a nearly saturating (250 microM) concentration of L-DOPA were similar to those obtained when non-saturating (25 microM) concentrations of L-DOPA were used (654 and 339 microM). Vmax values (in nmol/mg protein per 6 min) for L-DOPA uptake were identical in the absence (36.4 +/- 0.7) and the presence of L-5-HTP (39.2 +/- 1.3), but Km values (microM) were significantly greater (P < 0.05) when L-DOPA uptake was studied in the presence of L-5-HTP (121 (100, 142) versus 318 (237, 399)). In contrast, the effect of cyanine 863 and 3,3'-DOC was to cause a significant reduction in Vmax values without significant changes in Km values. It is concluded that L-5-HTP exerts a competitive type of inhibition of L-DOPA uptake in cultured OK cells, whereas both cyanine 863, an organic cation transport inhibitor and 3,3'-DOC behave as non-competitive inhibitors.

Animals↗
PubMed1997

Regulation of intracellular chloride concentration in rat lactotrophs: possible role of mitochondria.

Increasing evidence is accumulating for the involvement of chloride ions in the stimulus-secretion coupling of pituitary cells. We show that the mean intracellular chloride concentration [Cl-]i of rat lactotroph cells maintained in culture is high, close to 60 mM (59.4 mM), using the Cl- sensitive fluorescent probe 6-methoxy-N-(3-sulfopropyl) quinolinium (SPQ), coupled with whole-cell patch-clamp recordings. We demonstrate that this high level is correlated with the presence of mitochondrial stores of Cl- as shown by the release of Cl- in response to various metabolic inhibitors. We determine that CCP (50 microM) induces a mean [Cl-]i increase of 15.8+/-5.8 mM, using combined electrophysiology and microspectrofluorimetry methods. These data strongly suggest that cell metabolism, including the mitochondrial function, modulate [Cl-]i.

Animals↗
PubMed1997

Inactive fatty acids are unable to flip-flop across the lipid bilayer.

Free fatty acids (FA) were found which did not acidify liposome interior. This is interpreted as their inability to rapidly flip-flop across the lipid bilayer. However, they were able to partition in lipids as detected directly using HPLC or from the shift of their equilibrium binding to acrylodated intestinal binding protein (ADIFAB) in the presence of vesicles. Various bipolar FA, such as 12-hydroxylauric acid, dicarboxylic acids, or FA with benzene ring at the tail were found to be inactive in this way. A phenomenon of shielding, where an additional alkyl chain or non-polar group can restore the flip-flop activity, is described.

Carrier Proteins↗
PubMed1997

A structure-activity study of fatty acid interaction with mitochondrial uncoupling protein.

Fatty acid (FA) uniport via mitochondrial uncoupling protein (UcP) was detected fluorometrically with PBFI, potassium-binding benzofuran phthalate and SPQ, 6-methoxy-N-(3-sulfopropyl)-quinolinium, indicating K+ and H+, respectively. The FA structural patterns required for FA flip-flop, UcP-mediated FA uniport, activation of UcP-mediated H+ transport in proteoliposomes, and inhibition of UcP-mediated Cl- uniport by FA, were identical. Positive responses were found exclusively with FA which were able to flip-flop in a protonated form across the membrane and no responses were found with 'inactive' FA lacking the flip-flop ability. The findings support the existence of FA cycling mechanism.

Benzoates↗
PubMed1997

P2X7 purinoceptor expression in Xenopus oocytes is not sufficient to produce a pore-forming P2Z-like phenotype.

The purinergic rP2X7 receptor expressed in a number of heterologous systems not only functions as a cation channel but also gives rise to a P2Z-like response, i.e. a reversible membrane permeabilization that allows the passage of molecules with molecular masses of > or = 300 Da. We investigated the properties of rP2X7 receptors expressed in Xenopus oocytes. In two-electrode voltage-clamp experiments, ATP or BzATP caused inward currents that were abolished or greatly diminished when NMDG+ or choline replaced Na+ as the principal external cation. In fluorescent dye experiments, BzATP application did not result in entry of the fluorophore YO-PRO-1(2+). Thus, rP2X7 expression in Xenopus oocytes does not by itself give rise to the pore-forming P2Z phenotype, suggesting that ancillary factors are involved.

Adenosine Triphosphate↗
PubMed1998

Cloning and functional characterisation of the mouse P2X7 receptor.

We have isolated a 1785-bp complementary DNA (cDNA) encoding the murine P2X7 receptor subunit from NTW8 mouse microglial cells. The encoded protein has 80%, and 85% homology to the human and rat P2X7 subunits, respectively. Functional properties of the heterologously expressed murine P2X7 homomeric receptor broadly resembled those of the P2X7 receptor in the native cell line. However, marked phenotypic differences were observed between the mouse receptor, and the other P2X7 receptor orthologues isolated with respect to agonist and antagonist potencies, and the kinetics of formation of the large aqueous pore.

Amino Acid Sequence↗
PubMed1988

Improved hepatic function in the 24-hour preserved rat liver with UW-lactobionate solution and SRI 63-441.

The present study compares rat liver preservation for 9, 12, and 24 h in the standard Eurocollins solution with preservation for the same time periods in the new UW-lactobionate solution. Pharmacologic manipulation with a potent platelet-activating factor antagonist, SRI 63-441, was also evaluated. After cold storage in each of the test solutions, the livers underwent 90 min of warm, oxygenated, sanguinous perfusion. A significant increase in liver weight was noted in Eurocollins-stored versus UW-lactobionate-stored livers. After 90 min of perfusion, livers preserved in UW-lactobionate produced significantly more bile and liberated significantly less glucose and transaminases when compared with Eurocollins-stored livers. Significant augmentation of bile production was observed when donor animals were pretreated with SRI 63-441 and the livers were then stored in UW-lactobionate for 24 h. Eurocollins-stored livers demonstrated increased hepatocyte vacuolization and endothelial disruption when compared with UW-lactobionate-stored livers after 12 and 24 h of preservation. This study demonstrates the superiority of UW-lactobionate solution in liver preservation and suggests that SRI 63-441 may be beneficial in the further reduction of cold ischemic injury.

Adenosine↗
PubMed1990

Studies on the uptake of N-methylisoquinolinium ion into rat striatal slices using high-performance liquid chromatography with fluorimetric detection.

A simple and sensitive procedure for the measurement of N-methylisoquinolinium ion (NMIQ+), a putative neurotoxin, was devised using high-performance liquid chromatography (HPLC) with fluorescence detection. Separation of NMIQ+ was carried out by gel filtration and reversed-phase HPLC on a column of hydrophilic polymer gels (Asahipak GS-302H). The method was sensitive enough to measure 50 fmol of NMIQ+. Uptake of NMIQ+ into rat striatal slices was confirmed by this method.

Animals↗
PubMed1999

Visual quantification of DNA double-strand breaks in bacteria.

In this paper, we describe a method for the visualization of double-strand breaks in a single electrostretched Escherichia coli DNA molecule. We also provide evidence that electrostretched or migrated DNA under neutral microgel electrophoresis conditions is made up of individual chromosomes. Using the neutral microgel electrophoresis technique, DNA migration (stretching) was measured and the number of DNA double-strand breaks were counted following exposure of E. coli cells to 0, 12.5, 25, 50, or 100 rad of X-rays. The use of an intense fluorescent dye, YOYO and custom-made slides have helped us in visualizing individual bacterial DNA molecules. Bacterial DNA appears similar in structure compared to electrostretched DNA from human lymphocytes. We were able to detect changes in DNA migration (stretching) induced by an X-ray dose as low as 12.5 rad and an increase in the number of DNA breaks induced by a dose as low as 25 rad. The extent of DNA migration and number of breaks were directly correlated to X-ray dosage.

Benzoxazoles↗
PubMed2001

In situ detection of apoptosis in normal pressure glaucoma. a preliminary examination.

Retinal ganglion cell (RGC) neurons are believed to die via apoptosis in human primary and secondary open-angle glaucoma. Previous studies have relied solely on the TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate [UTP]-biotin nick end-labeling) method of detecting DNA fragmentation to identify apoptotic nuclei. However, it is now clear that the TUNEL method cannot distinguish between the single- and double-strand DNA breaks that can be a feature of both apoptosis and necrosis. We have developed a double fluorescent labeling method that simultaneously combines in situ end-labeling (ISEL) to detect DNA fragmentation followed by staining with a cyanine dye, YOYO-1, to visualize apoptotic chromatin condensation. This allows for the unequivocal identification of an apoptotic nucleus. Our preliminary data obtained from one case of normal pressure glaucoma suggests that RGC neurons may die via apoptosis when intraocular pressure is not elevated.

Aged↗
PubMed2000

Measuring pore formation by Bcl-2 family proteins.

Two methods for assaying Bcl-2 protein family-induced solute efflux from liposomes have been outlined. They utilize either ion-selective electrodes to follow ion efflux or fluorescence to monitor changes in fluorescence of the liposome-encapsulated dye SPQ or carboxyfluorescein. Both methods provide a simple means of determining protein activity. These methods do not have the capability to detect either single-channel conductivity or ion selectivity, but they indicate whether the bulk of the protein population is inducing solute efflux. Although in in vivo significance of Bcl-2 protein family pore formation remains to be determined, in vitro measurements of channel activity should provide a means to determine whether a given protein preparation has activity and whether mutations have an adverse effect on channel formation.

Animals↗