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- Tranberg, Mattias, 1977, et al.
(författare)
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NMDA-receptor mediated efflux of N-acetylaspartate: physiological and/or pathological importance?
- 2004
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Ingår i: Neurochemistry international. - : Elsevier BV. - 0197-0186. ; 45:8, s. 1195-204
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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.
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- Wallin, Camilla, 1968, et al.
(författare)
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Searching for Mechanisms of N-Methyl-D-Aspartate-Induced Glutathione Efflux in Organotypic Hippocampal Cultures
- 2003
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Ingår i: Neurochemical Research. - 0364-3190. ; 28:2, s. 281-291
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Tidskriftsartikel (refereegranskat)abstract
- N-Methyl-D-aspartate (NMDA)-receptor stimulation evoked a selective and partly delayed elevated efflux of glutathione, phosphoethanolamine, and taurine from organotypic rat hippocampus slice cultures. The protein kinase inhibitors H9 and staurosporine had no effect on the efflux. The phospholipase A2 inhibitors quinacrine and 4-bromophenacyl bromide, as well as arachidonic acid, a product of phospholipase A2 activity, did not affect the stimulated efflux. Polymyxin B, an antimicrobal agent that inhibits protein kinase C, and quinacrine in high concentration (500 microM), blocked efflux completely. The stimulated efflux after but not during NMDA incubation was attenuated by a calmodulin antagonist (W7) and an anion transport inhibitor (DNDS). Omission of calcium increased the spontaneous efflux with no or small additional effects by NMDA. In conclusion, NMDA receptor stimulation cause an increased selective efflux of glutathione, phosphoethanolamine and taurine in organotypic cultures of rat hippocampus. The efflux may partly be regulated by calmodulin and DNDS sensitive channels.
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- Wang, Xiaoyang, 1965, et al.
(författare)
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The nonerythropoietic asialoerythropoietin protects against neonatal hypoxia-ischemia as potently as erythropoietin.
- 2004
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Ingår i: Journal of neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 91:4, s. 900-10
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Tidskriftsartikel (refereegranskat)abstract
- Recently, erythropoietin (EPO) and the nonerythropoietic derivative asialoEPO have been linked to tissue protection in the nervous system. In this study, we tested their effects in a model of neonatal hypoxia-ischemia (HI) in 7-day-old rats (unilateral carotid ligation and exposure to 7.7% O(2) for 50 min). EPO (10 U/g body weight = 80 ng/g; n = 24), asialoEPO (80 ng/g; n = 23) or vehicle (phosphate-buffered saline with 0.1% human serum albumin; n = 24) was injected intraperitoneally 4 h before HI. Both drugs were protective, as judged by measuring the infarct volumes, neuropathological score and gross morphological score. The infarct volumes were significantly reduced by both EPO (52%) and asialoEPO (55%) treatment, even though the plasma levels of asialoEPO had dropped below the detection limit (1 pm) at the onset of HI, while those of EPO were in the nanomolar range. Thus, a brief trigger by asialoEPO before the insult appears to be sufficient for protection. Proteomics analysis after asialoEPO treatment alone (no HI) revealed at least one differentially up-regulated protein, synaptosome-associated protein of 25 kDa (SNAP-25). Activation (phosphorylation) of ERK was significantly reduced in asialoEPO-treated animals after HI. EPO and the nonerythropoietic asialoEPO both provided significant and equal neuroprotection when administered 4 h prior to HI in 7-day-old rats. The protection might be related to reduced ERK activation and up-regulation of SNAP-25.
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- Wang, Xiaoyang, 1965, et al.
(författare)
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X-linked inhibitor of apoptosis (XIAP) protein protects against caspase activation and tissue loss after neonatal hypoxia-ischemia
- 2004
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Ingår i: Neurobiol Dis. - Univ Gothenburg, Dept Physiol, Perinatal Ctr, SE-40530 Gothenburg, Sweden. Zhengzhou Univ, Affiliated Hosp 3, Dept Pediat, Zhengzhou 450052, Peoples R China. Univ Gothenburg, Sahlgrens Univ Hosp, Dept Obstet & Gynecol, SE-41685 Gothenburg, Sweden. Uppsala Univ, Dept Neurosci, SE-75123 Uppsala, Sweden. Univ Gothenburg, Dept Med Biophys, SE-40530 Gothenburg, Sweden. Univ Gothenburg, Queen Silvia Childrens Hosp, Dept Pediat, SE-41685 Gothenburg, Sweden. : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0969-9961 .- 1095-953X. ; 16:1, s. 179-89
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Tidskriftsartikel (refereegranskat)abstract
- Nine-day-old transgenic XIAP overexpressing (TG-XIAP) and wild-type mice were subjected to left carotid artery ligation and 10% O(2) for 60 min, leading to widespread infarctions in the ipsilateral hemisphere during reperfusion. The activation of caspase-3 and -9 seen in wild-type animals was virtually abolished in TG-XIAP mice. Tissue loss was significantly reduced from 54.4 +/- 4.1 mm(3) (mean +/- SEM) in wild-type mice to 33.1 +/- 2.1 mm(3) in the TG-XIAP mice. Injured neurons displayed stronger XIAP staining during reperfusion, particularly in the nuclei. XIAP was colocalized with XAF-1, Smac, and HtrA2 in injured neurons after hypoxia-ischemia (HI). XIAP was cleaved after HI, and Smac immunoprecipitation co-precipitated a 25-kDa C-terminal fragment of XIAP, indicating that Smac preferentially bound to cleaved XIAP. These findings provide the first evidence that increased XIAP levels protect the neonatal brain against HI.
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