| 1. |
- Abbas, Abdul-Karim, 1959, et al.
(författare)
-
S-sulfo-cysteine is an endogenous amino acid in neonatal rat brain but an unlikely mediator of cysteine neurotoxicity.
- 2008
-
Ingår i: Neurochemical research. - : Springer Science and Business Media LLC. - 0364-3190 .- 1573-6903. ; 33:2, s. 301-7
-
Tidskriftsartikel (refereegranskat)abstract
- S-sulfo-cysteine (SSC) is an agonist of glutamate receptors which could be involved in cysteine-induced neurotoxicity. Here we analyzed SSC by HPLC and demonstrated that the concentration of SSC in cortex of cysteine-injected rats increased to 1.4 microM, about four times the value of control rats. The neurotoxic effect of SSC was evaluated in slice cultures of rat hippocampus and compared to NMDA and cysteine. The neurotoxicity threshold of SSC was well above the tissue concentration. Our results show that SSC increases in neonatal rat brain after cysteine injection but reaches a tissue concentration far below concentrations that induce neurotoxicity in vitro. Thus, even if all the tissue SSC after cysteine injection was extracellular it would be below the threshold for toxicity, indicating that SSC is not a main excitotoxin involved in cysteine toxicity.
|
|
| 2. |
|
|
| 3. |
- Arkblad, Eva L, et al.
(författare)
-
A Caenorhabditis elegans mutant lacking functional nicotinamide nucleotide transhydrogenase displays increased sensitivity to oxidative stress.
- 2005
-
Ingår i: Free radical biology & medicine. - : Elsevier BV. - 0891-5849. ; 38:11, s. 1518-25
-
Tidskriftsartikel (refereegranskat)abstract
- Proton-translocating mitochondrial nicotinamide nucleotide transhydrogenase (NNT) was investigated regarding its physiological role in Caenorhabditis elegans. NNT catalyzes the reduction of NADP(+) by NADH driven by the electrochemical proton gradient, Deltap, and is thus a potentially important source of mitochondrial NADPH. Mitochondrial detoxification of reactive oxygen species (ROS) by glutathione-dependent peroxidases depends on NADPH for regeneration of reduced glutathione. Transhydrogenase may therefore be directly involved in the defense against oxidative stress. nnt-1 deletion mutants of C. elegans, nnt-1(sv34), were isolated and shown to grow essentially as wild type under normal laboratory conditions, but with a strongly lowered GSH/GSSG ratio. Under conditions of oxidative stress, caused by the superoxide-generating agent methyl viologen, growth of worms lacking nnt-1 activity was severely impaired. A similar result was obtained by using RNAi. Reintroducing nnt-1 in the nnt-1(sv34) knockout mutant led to a partial rescue of growth under oxidative stress conditions. These results provide evidence for the first time that nnt-1 is important in the defense against mitochondrial oxidative stress.
|
|
| 4. |
- Jansson, Nina, 1976, et al.
(författare)
-
Down-regulation of placental transport of amino acids precedes the development of intrauterine growth restriction in rats fed a low protein diet.
- 2006
-
Ingår i: The Journal of physiology. - : Wiley. - 0022-3751. ; 576:Pt 3, s. 935-46
-
Tidskriftsartikel (refereegranskat)abstract
- Intrauterine growth restriction (IUGR) represents an important risk factor for perinatal complications and for adult disease. IUGR is associated with a down-regulation of placental amino acid transporters; however, whether these changes are primary events directly contributing to IUGR or a secondary consequence is unknown. We investigated the time course of changes in placental and fetal growth, placental nutrient transport in vivo and the expression of placental nutrient transporters in pregnant rats subjected to protein malnutrition, a model for IUGR. Pregnant rats were given either a low protein (LP) diet (n = 64) or an isocaloric control diet (n = 66) throughout pregnancy. Maternal insulin, leptin and IGF-I levels decreased, whereas maternal amino acid concentrations increased moderately in response to the LP diet. Fetal and placental weights in the LP group were unaltered compared to control diet at gestational day (GD) 15, 18 and 19 but significantly reduced at GD 21. Placental system A transport activity was reduced at GD 19 and 21 in response to a low protein diet. Placental protein expression of SNAT2 was decreased at GD 21. In conclusion, placental amino acid transport is down-regulated prior to the development of IUGR, suggesting that these placental transport changes are a cause, rather than a consequence, of IUGR. Reduced maternal levels of insulin, leptin and IGF-1 may link maternal protein malnutrition to reduced fetal growth by down-regulation of key placental amino acid transporters.
|
|
| 5. |
- Stridh, Malin, 1979, et al.
(författare)
-
Stimulated efflux of amino acids and glutathione from cultured hippocampal slices by omission of extracellular calcium: likely involvement of connexin hemichannels.
- 2008
-
Ingår i: The Journal of biological chemistry. - 0021-9258. ; 283:16, s. 10347-56
-
Tidskriftsartikel (refereegranskat)abstract
- Omission of extracellular Ca(2+) for 15 min from the incubation medium of cultured hippocampal slices stimulated the efflux of glutathione, phosphoethanolamine, hypotaurine, and taurine. The efflux was reduced by several blockers of gap junctions, i.e. carbenoxolone, flufenamic acid, and endothelin-1, and by the connexin43 hemichannel blocking peptide Gap26 but was unchanged by the P2X(7) receptor inhibitor oxidized ATP, a pannexin1 hemichannel blocking peptide and an inactive analogue of carbenoxolone. Pretreatment of the slices with the neurotoxin N-methyl-d -aspartate left the efflux by Ca(2+) omission unchanged, indicating that the stimulated efflux primarily originated from glia. Elevated glutamate efflux was detected when Ca(2+) omission was combined with the glutamate uptake blocker l-trans-pyrrolidine-2,4-dicarboxylate and when both Ca(2+) and Mg(2+) were omitted from the medium. Omission of Ca(2+) for 15 min alone did not induce delayed toxicity, but in combination with blocked glutamate uptake, significant cell death was observed 24 h later. Our results indicate that omission of extracellular Ca(2+) stimulates efflux of glutathione and specific amino acids including glutamate via opening of glial hemichannels. This type of efflux may have protective functions via glutathione efflux but can aggravate toxicity in situations when glutamate reuptake is impaired, such as following a stroke.
|
|
| 6. |
- Tranberg, Mattias, 1977, et al.
(författare)
-
In vitro studies on the putative function of N-acetylaspartate as an osmoregulator.
- 2007
-
Ingår i: Neurochemical research. - : Springer Science and Business Media LLC. - 0364-3190 .- 1573-6903. ; 32:7, s. 1248-55
-
Tidskriftsartikel (refereegranskat)abstract
- Efflux and tissue content of N-acetylaspartate (NAA) and amino acids were evaluated from cultured and acutely prepared hippocampal slices in response to changes in osmolarity. The osmoregulator taurine, but not NAA, was lost from both types of slices after moderate reductions in extracellular osmolarity (-60 mOsm) for 10-48 h. Hypoosmotic shock (-166 mOsm) for 5 min resulted in unselective efflux of several amino acids from acutely prepared slices. Notably, the efflux of taurine, but not NAA, was prominent also after the shock. Efflux of NAA was markedly enhanced by NMDA and high K(+), in particular after the stimulation period. The high K(+)-mediated efflux was decreased by high extracellular osmolarity and a NMDA-receptor antagonist. The results indicate that NAA efflux can be induced by a sudden non-physiological decrease in extracellular osmolarity but not by prolonged more moderate changes in osmolarity. The mechanisms behind the efflux of NAA by high K(+) are complex and may involve both swelling and activation of NMDA-receptors.
|
|
| 7. |
- Tranberg, Mattias, 1977
(författare)
-
N-acetylaspartate in brain - studies on efflux and function
- 2006
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- N-acetylaspartate (NAA) is an amino acid derivative present in high concentration in the brain. The function of NAA is still unsettled in spite of 50 years of research. The mainly neuronal synthesis and glial breakdown of NAA requires a well regulated neuronal efflux and glial uptake. In the present work hippocampal slices were used to study how NAA efflux from neurons is regulated and to further investigate possible functions of NAA. For the determination of NAA a reversed phase HPLC method with UV detection was developed. The method allowed for the simultaneous determination of NAA and creatine and was comparable or better in sensitivity than previous methods based on UV detection. A newly developed efflux protocol that allowed the determination of efflux and delayed cell death was used to study NAA efflux in cultured hippocampal slices. Activation of the NMDA receptor, a glutamate-receptor subtype that is involved in learning and memory but also in nerve cell death following stroke, evoked a prolonged Ca2+-dependent NAA efflux from cultured slices. The efflux of NAA was not due to unselective membrane rupture but at high NMDA concentrations the efflux of NAA correlated with the NMDA-mediated delayed (24 hours after efflux) excitotoxicity. However, no causal relationship between delayed excitotoxicity and extracellular NAA could be demonstrated as culturing with high concentrations of NAA was non-toxic. Extracellular osmolarity was decreased moderately for 10-48 hours to address the proposed function of NAA as an osmoregulator but no change in the tissue content of NAA was observed from either cultured or acutely prepared hippocampal slices. However, depolarisation resulted in efflux of NAA from acutely prepared slices that could be reduced both by a NMDA-receptor blocker and hyperosmotic solution. Culturing of hippocampal slices with the monomethyl ester of NAA increased intracellular NAA levels. This was followed by reduced levels of the anion phosphoethanolamine and a tendency towards decreased Cl- concentration in the slices. NMDA-mediated delayed excitotoxicity was unaffected by increased intracellular NAA concentration. Overall, the results suggest that the NMDA receptor is involved in the regulation of NAA efflux from neurons. Increased extracellular as well as intracellular NAA is non-toxic and NAA does not seem to function as an important Ca2+ chelator or as an osmoregulator under physiological decreases in osmolarity.
|
|
| 8. |
- Tranberg, Mattias, 1977, et al.
(författare)
-
N-acetylaspartate monomethyl ester increases N-acetylaspartate concentration in cultured rat hippocampal slices: effects on excitotoxicity and levels of amino acids and chloride.
- 2007
-
Ingår i: Journal of neuroscience methods. - : Elsevier BV. - 0165-0270. ; 163:1, s. 105-10
-
Tidskriftsartikel (refereegranskat)abstract
- N-acetylaspartate (NAA) was discovered in mammalian brain 50 years ago but its functions remain debated. One reason for the relatively slow progress of NAA research is the paucity of tools to specifically modify NAA concentrations. In this work we evaluated the use of the monomethyl ester of NAA (NAA MME) to increase the relatively low level of NAA in cultured hippocampal slices. When slices were treated with 30 mM NAA MME for 3 days the NAA concentration increased from 31.6 to 185.3 nmol/mg protein. Incubation with NAA alone increased the NAA concentration non-significantly to 65.6 nmol/mg protein. NAA MME treatment increased NAA in neurons and the increase was non-toxic as determined by the low uptake of propidium iodide, a dye that only enters damaged cells. NMDA-mediated excitotoxicity which is initiated by influx of Ca(2+) was unaltered by increased NAA levels indicating poor intracellular Ca(2+)-chelation by NAA.
|
|
| 9. |
- Tranberg, Mattias, 1977, et al.
(författare)
-
NMDA-receptor mediated efflux of N-acetylaspartate: physiological and/or pathological importance?
- 2004
-
Ingår i: Neurochemistry international. - : Elsevier BV. - 0197-0186. ; 45:8, s. 1195-204
-
Tidskriftsartikel (refereegranskat)abstract
- N-Acetylaspartate (NAA) is a largely neuron specific dianionic amino acid present in high concentration in vertebrate brain. Many fundamental questions concerning N-acetylaspartate in brain remain unanswered. One such issue is the predominantly neuronal synthesis and largely glial catabolism which implies the existence of a regulated efflux from neurons. Here we show that transient (5 min) NMDA-receptor activation (60 microM) induces a long lasting Ca2+ -dependent efflux of N-acetylaspartate from organotypic slices of rat hippocampus. The NMDA-receptor stimulated efflux was unaffected by hyper-osmotic conditions (120 mM sucrose) and no efflux of N-acetylaspartate was evoked by high K+ -depolarization (50 mM) or kainate (300 microM). These results indicate that the efflux induced by NMDA is not related directly to either cell swelling or depolarization but is coupled to Ca2+ -influx via the NMDA-receptor. The efflux of N-acetylaspartate persisted at least 20 min after the omission of NMDA, similar to the efflux of the organic anions glutathione and phosphoethanolamine. The efflux of taurine and hypotaurine was also stimulated by NMDA but returned more quickly to basal levels. The NMDA-receptor stimulated efflux of N-acetylaspartate, glutathione, phosphoethanolamine, taurine and hypotaurine correlated with delayed nerve cell death measured 24 h after the transient NMDA-receptor stimulation. However, exogenous administration of high concentrations of N-acetylaspartate to the culture medium was non-toxic. The results suggest that Ca2+ -influx via the NMDA-receptor regulates the efflux of N-acetylaspartate from neurons which may have both physiological and pathological importance.
|
|
| 10. |
|
|
