| 1. |
- Broberg, Marita, 1973, et al.
(författare)
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Spreading depression: Evidence of five electroencephalogram phases.
- 2014
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Ingår i: Journal of Neuroscience Research. - : Wiley. - 0360-4012 .- 1097-4547. ; 92:10, s. 1384-1394
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Tidskriftsartikel (refereegranskat)abstract
- Spreading depression (SD), a self-propagating wave of astroglial and neuronal depolarization, is an accompaniment of several neurological disorders including epilepsy. Its well-described features are initial depolarization, followed by EEG flattening. In this in vivo study in awake animals, the relationship of SDs to epileptiform activity was re-examined. We assessed SDs generated by mechanical stimulation and by metabolic inhibition with fluorocitrate. In addition to identifying prolonged EEG depression, we identified two periods, one prior to and another during depression, characterized by increases in power of specific frequencies that were sometimes associated with epileptiform discharges. The first period was characterized by ripple activity close to the induction site (88% of SDs with intracortical electrodes). The second period was characterized by localized low-frequency spikes (100% with dural screw electrodes, 65% with intracortical electrodes). By using fluorocitrate to induce SDs, the initial period was also characterized by runs of spikes (52%). Finally, with SDs induced by both methods, there was a period at the end of depression when additional, unprovoked SDs occurred (20%). Five stages of SD were defined by these phenomena, in the order: excitation, depression, excitation, depression, SD, with metabolic inhibition enhancing the expression of epileptiform spiking.
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| 2. |
- Corell, Mikael, et al.
(författare)
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Spatiotemporal Distribution and Function of N-Cadherin in Postnatal Schwann Cells : A Matter of Adhesion?
- 2010
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Ingår i: Journal of Neuroscience Research. - : Wiley. - 0360-4012 .- 1097-4547. ; 88:11, s. 2338-2349
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Tidskriftsartikel (refereegranskat)abstract
- During embryonic development of the peripheral nervous system (PNS), the adhesion molecule neuronal cadherin (N-cadherin) is expressed by Schwann cell precursors and associated with axonal growth cones. N-cadherin expression levels decrease as precursors differentiate into Schwann cells. In this study, we investigated the distribution of N-cadherin in the developing postnatal and adult rat peripheral nervous system. N-cadherin was found primarily in ensheathing glia throughout development, concentrated at neuron glial or glial glial contacts of the sciatic nerve, dorsal root ganglia (DRG), and myenteric plexi. In the sciatic nerve, N-cadherin decreases with age and progress of myelination. In adult animals, N-cadherin was found exclusively in nonmyelinating Schwann cells. The distribution of N-cadherin in developing E17 DRG primary cultures is similar to what was observed in vivo. Functional studies of N-cadherin in these cultures, using the antagonist peptide INPISGQ, show a disruption of the attachment between Schwann cells, but no interference in the initial or long-term contact between Schwann cells and axons. We suggest that N-cadherin acts primarily in the adhesion between glial cells during postnatal development. It may form adherents/junctions between nonmyelinating glia, which contribute to the stable tubular structure encapsulating thin caliber axons and thus stabilize the nerve structure as a whole.
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| 3. |
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| 4. |
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| 5. |
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| 6. |
- Guloglu, Oktar, et al.
(författare)
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Adipocytes derived from PA6 cells reliably promote the differentiation of dopaminergic neurons from human embryonic stem cells.
- 2014
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Ingår i: Journal of Neuroscience Research. - : Wiley. - 1097-4547 .- 0360-4012. ; 92:5, s. 564-573
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Tidskriftsartikel (refereegranskat)abstract
- The PA6 stromal cell line comprises a heterogeneous population of cells that can induce both mouse and human embryonic stem cells to differentiate into dopaminergic neurons. This ability of PA6 cells has been termed stromal cell-derived inducing activity (SDIA). The level of SDIA has been found to vary considerably between and within batches of PA6 cells. Not only are the molecular mechanisms that underlie SDIA unknown but also the cell type(s) within the heterogeneous PA6 cultures that underlie SDIA remain poorly defined. In this study, we reveal that adipocytes, which are present within the heterogeneous PA6 cell population, robustly release the factors mediating SDIA. Furthermore, we report that the coculture of human embryonic stem cells with PA6-derived adipocytes reliably induces their differentiation into midbrain dopaminergic neurons. © 2014 Wiley Periodicals, Inc.
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| 7. |
- Kucharz, Krzysztof, et al.
(författare)
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Potassium-induced structural changes of the endoplasmic reticulum in pyramidal neurons in murine organotypic hippocampal slices.
- 2011
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Ingår i: Journal of Neuroscience Research. - : Wiley. - 1097-4547 .- 0360-4012. ; 89:8, s. 1150-1159
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Tidskriftsartikel (refereegranskat)abstract
- The endoplasmic reticulum (ER) structure is of central importance for the regulation of cellular anabolism, stress response, and signal transduction. Generally continuous, the ER can temporarily undergo dramatic structural rearrangements resulting in a fragmented appearance. In this study we assess the dynamic nature of ER fission in pyramidal neurons in organotypic hippocampal slice cultures stimulated by depolarizing concentration of potassium (50 mM). The slices were obtained from transgenic mice expressing fluorescent ER-targeted DsRed2 protein. We employed live tissue confocal microscopy imaging with fluorescence recovery after photobleaching (FRAP) to monitor the extent of structural rearrangements of the ER. In control slices, the ER structure was continuous. Potassium stimulation resulted in extensive fragmentation (fission), whereas return to basal potassium levels (2.5 mM) led to ER fusion and normalization of ER structure. This ER fission/fusion could be repeated several times in the same neuron, demonstrating the reversibility of the process. Blockade of the N-methyl-D-aspartate receptor (NMDAR) with the antagonist D-AP5 or removal of extracellular Ca(2+) prevented depolarization-induced ER fission. ER fission is sensitive to temperature, and decreasing temperature from 35°C to 30°C augments fission, implying that the altering of ER continuity may be a protective response against damage. We conclude that events that generate membrane depolarisation in brain tissue lead to the release of endogenous glutamate that may regulate neuronal ER continuity. The rapid and reversible NMDAR-mediated changes in ER structure reflect an adaptive, innate property of the ER for synaptic activation as well as response to tissue stress, injury, and disease. © 2011 Wiley-Liss, Inc.
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| 8. |
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| 9. |
- Morizane, Asuka, et al.
(författare)
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A simple method for large-scale generation of dopamine neurons from human embryonic stem cells.
- 2010
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Ingår i: Journal of Neuroscience Research. - : Wiley. - 1097-4547 .- 0360-4012. ; 88:16, s. 3467-3478
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Tidskriftsartikel (refereegranskat)abstract
- Dopamine (DA) neurons derived from human embryonic stem cells (hESCs) are potentially valuable in drug screening and as a possible source of donor tissue for transplantation in Parkinson's disease. However, existing culture protocols that promote the differentiation of DA neurons from hESCs are complex, involving multiple steps and having unreliable results between cultures. Here we report a simple and highly reproducible culture protocol that induces expandable DA neuron progenitors from hESCs in attached cultures. We found that the hESC-derived neuronal progenitors retain their full capacity to generate DA neurons after repeated passaging in the presence of basic fibroblast growth factor (bFGF) and medium conditioned with PA6 stromal cells. Using immunocytochemistry and RT-PCR, we found that the differentiated DA neurons exhibit a midbrain phenotype and express, e.g., Aldh1a, Ptx3, Nurr1, and Lmx1a. Using HPLC, we monitored their production of DA. We then demonstrated that the expanded progenitors are possible to cryopreserve without loosing the dopaminergic phenotype. With our protocol, we obtained large and homogeneous populations of dopaminergic progenitors and neurons. We conclude that our protocol can be used to generate human DA neurons suitable for the study of disease mechanisms, toxicology, drug screening, and intracerebral transplantation. © 2010 Wiley-Liss, Inc.
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| 10. |
- Ng, Ai Na, et al.
(författare)
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Dendritic EGFP-STIM1 activation after type I metabotropic glutamate and muscarinic acetylcholine receptor stimulation in hippocampal neuron.
- 2011
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Ingår i: Journal of Neuroscience Research. - : Wiley. - 1097-4547 .- 0360-4012. ; 89:8, s. 1235-1244
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Tidskriftsartikel (refereegranskat)abstract
- Several signaling pathways in neurons engage the endoplasmic reticulum (ER) calcium store by triggering calcium release. After release, ER calcium levels must be restored. In many non-neuronal cell types, this is mediated by store-operated calcium entry (SOCE), a cellular homeostatic mechanism that activates specialized store-operated calcium channels (SOC). Although much evidence supports the existence of SOCE in neurons, its importance has been difficult to determine because of the abundance of calcium channels expressed and the lack of SOC-specific pharmacological agents. We have explored the function of the SOCE-inducing protein STIM1 in neurons. In EGFP-STIM1-expressing hippocampal neurons, the sarco- and endoplasmic reticulum calcium ATPase (SERCA) inhibitor thapsigargin caused rapid aggregation (i.e., activation) of STIM1 in soma and dendrites. Upon STIM1 activation by thapsigargin, a dramatic reduction in STIM1 mobility was detected by fluorescence recovery after photobleaching (FRAP). By triggering release of ER calcium with 3,5-dihydroxyphenylglycine (DHPG) or carbachol (Cch), agonists of type I metabotropic glutamate receptors (mGluR) and muscarinic acetylcholine receptors (mAChR), respectively, STIM1 was activated, and calcium entry (likely to represent SOCE) occurred in dendrites. It is therefore possible that neuronal SOCE is activated by physiological stimuli, some of which may alter the postsynaptic calcium signaling properties. © 2011 Wiley-Liss, Inc.
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| 11. |
- Olesen, M. V., et al.
(författare)
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Neuropeptide Y Y1 Receptor Hippocampal Overexpression Via Viral Vectors Is Associated With Modest Anxiolytic-Like and Proconvulsant Effects in Mice
- 2012
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Ingår i: Journal of Neuroscience Research. - : Wiley. - 1097-4547 .- 0360-4012. ; 90:2, s. 498-507
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Tidskriftsartikel (refereegranskat)abstract
- Neuropeptide Y (NPY) exerts anxiolytic-and antidepressant-like effects in rodents that appear to be mediated via Y1 receptors. Gene therapy using recombinant viral vectors to induce overexpression of NPY in the hippocampus or amygdala has previously been shown to confer anxiolytic-like effect in rodents. The present study explored an alternative and more specific approach: overexpression of Y1 receptors. Using a recombinant adeno-associated viral vector (rAAV) encoding the Y1 gene (rAAV-Y1), we, for the first time, induced overexpression of functional transgene Y1 receptors in the hippocampus of adult mice and tested the animals in anxiety- and depression-like behavior. Hippocampal Y1 receptors have been suggested to mediate seizure-promoting effect, so the effects of rAAV-induced Y1 receptor overexpression were also tested in kainate-induced seizures. Y1 receptor transgene overexpression was found to be associated with modest anxiolytic-like effect in the open field and elevated plus maze tests, but no effect was seen on depression-like behavior using the tail suspension and forced swim tests. However, the rAAV-Y1 vector modestly aggravated kainate-induced seizures. These data indicate that rAAV-induced overexpression of Y1 receptors in the hippocampus could confer anxiolytic-like effect accompanied by a moderate proconvulsant adverse effect. Further studies are clearly needed to determine whether Y1 gene therapy might have a future role in the treatment of anxiety disorders. (C) 2011 Wiley Periodicals, Inc.
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| 12. |
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| 13. |
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| 14. |
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| 15. |
- Schizas, Nikos, et al.
(författare)
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Interleukin-1 Receptor Antagonist Promotes Survival of Ventral Horn Neurons and Suppresses Microglial Activation in Mouse Spinal Cord Slice Cultures
- 2014
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Ingår i: Journal of Neuroscience Research. - : Wiley. - 0360-4012 .- 1097-4547. ; 92:11, s. 1457-1465
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Tidskriftsartikel (refereegranskat)abstract
- Secondary damage after spinal cord injury (SCI) induces neuronal demise through neurotoxicity and inflammation, and interleukin (IL)-1 beta is a key inflammatory mediator. We hypothesized that IL-1 beta is released in spinal cord slice cultures (SCSC) and aimed at preventing the potentially neurotoxic effects of IL-1 beta by using interleukin-1 receptor antagonist (IL1RA). We hypothesized that IL1RA treatment enhances neuronal survival and suppresses microglial activation. SCSC were cultured up to 8 days in vitro (DIV) in the presence of IL1RA or without, either combined with trophic support using neurotrophin (NT)-3 or not. Four groups were studied: negative control, IL1RA, NT-3, and IL1RA1NT-3. IL-1 beta concentrations in supernatants were measured by ELISA. SCSC were immunohistochemically stained for NeuN and a-neurofilament, and microglial cells were visualized with isolectin B-4. After 8 DIV, ventral horn neurons were significantly more numerous in the IL1RA, NT-3, and IL1RA1NT-3 groups compared with negative controls. Activated microglial cells were significantly less numerous in the IL1RA, NT-3, and IL1RA1NT-3 groups compared with negative controls. Axons expanded into the collagen matrix after treatment with IL1RA, NT-3, or IL1RA1NT-3, but not in negative controls. IL-1 beta release from cultures peaked after 6 hr and was lowest in the IL1RA1NT-3 group. We conclude that IL-1 beta is released in traumatized spinal cord tissue and that IL1RA could exert its neuroprotective actions by blocking IL-1-receptors. IL1RA thereby sustains neuronal survival irrespective of the presence of additional trophic support. Microglial activation is suppressed in the presence of IL1RA, suggesting decreased inflammatory activity. IL1RA treatment approaches may have substantial impact following SCI.
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| 16. |
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| 17. |
- Sedzik, Jan, et al.
(författare)
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High-Resolution Structural Model of Porcine P2 Myelin Membrane Protein With Associated Fatty Acid Ligand : Fact or Artifact?
- 2011
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Ingår i: Journal of Neuroscience Research. - : Wiley. - 0360-4012 .- 1097-4547. ; 89:6, s. 909-920
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Tidskriftsartikel (refereegranskat)abstract
- Myelin membrane is a biological complex of glial cells origin; it is composed of 25% (w/w) proteins and 75% lipids, and more than 300 proteins are associated with central nervous system myelin (for peripheral nervous system myelin, such data are lacking). Myelin plays an important role in maintaining propagation of nerve signals. To uncover the nature of propagation phenomena, it is essential to study biochemistry of myelin proteins and lipids, myelin composition, and myelin structure. Nearly all myelin proteins are like antigens, causing clinically well-defined devastating diseases; multiple sclerosis and Guillain-Barre syndrome are two of them. In this article, a high-resolution study (1.8 angstrom) of porcine myelin P2 protein is presented. Myelin was purified from porcine intradural spinal roots, which were stored at -80 degrees C for 10 years before myelin and P2 protein were purified (spinal roots were a gift of Prof. Kunio Kitamura, Saitama Medical School). The three-dimensional structural analysis uncovered embedded 18-carbons-long fatty acid. Some speculative interpretation is presented, to uncover how this ligand of fatty acid may form cholesterol ester and stabilize the myelin structure or form simple raft microdomain. Protein crystallography indicates that the ligand may be 18-carbons-long fatty acid. This is unlike previous work with mass spectrometry, in which three ligands were determined. In other protein crystallography-based studies of P2 (bovine), an oleic fatty acid was suggested, but, for recombinant (human) protein, palmitic acid was found. There is no fatty acid ligand in equine P2 protein.
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| 18. |
- Sedzik, Jan, et al.
(författare)
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Sequence motifs of myelin membrane proteins : Towards the molecular basis of diseases
- 2013
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Ingår i: Journal of Neuroscience Research. - : Wiley. - 0360-4012 .- 1097-4547. ; 91:4, s. 479-493
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Tidskriftsartikel (refereegranskat)abstract
- The shortest sequence of amino acids in protein containing functional and structural information is a motif. To understand myelin protein functions, we intensively searched for motifs that can be found in myelin proteins. Some myelin proteins had several different motifs or repetition of the same motif. The most abundant motif found among myelin proteins was a myristoylation motif. Bovine MAG held 11 myristoylation motifs and human myelin basic protein held as many as eight such motifs. PMP22 had the fewest myristoylation motifs, which was only one; rat PMP22 contained no such motifs. Cholesterol recognition/interaction amino-acid consensus (CRAC) motif was not found in myelin basic protein. P2 protein of different species contained only one CRAC motif, except for P2 of horse, which had no such motifs. MAG, MOG, and P0 were very rich in CRAC, three to eight motifs per protein. The analysis of motifs in myelin proteins is expected to provide structural insight and refinement of predicted 3D models for which structures are as yet unknown. Analysis of motifs in mutant proteins associated with neurological diseases uncovered that some motifs disappeared in P0 with mutation found in neurological diseases. There are 2,500 motifs deposited in a databank, but 21 were found in myelin proteins, which is only 1% of the total known motifs. There was great variability in the number of motifs among proteins from different species. The appearance or disappearance of protein motifs after gaining point mutation in the protein related to neurological diseases was very interesting.
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| 19. |
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| 20. |
- Sikka, Pilleriin, et al.
(författare)
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D-Serine metabolism in C6 glioma cells : Involvement of alanine-serine-cysteine transporter (ASCT2) and serine racemase (SRR) but not D-amino acid oxidase (DAO)
- 2010
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Ingår i: Journal of Neuroscience Research. - : John Wiley & Sons. - 0360-4012 .- 1097-4547. ; 88:8, s. 1829-1840
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Tidskriftsartikel (refereegranskat)abstract
- D-serine is an endogenous N-methyl-D-aspartate (NMDA) receptor coagonist. It is synthesized from L-serine by serine racemase (SRR), but many aspects of its metabolism remain unclear, especially in the forebrain, which lacks active D-amino acid oxidase (DAO), the major D-serine degradative enzyme. Candidate mechanisms include SRR operating in alpha,beta-eliminase mode (converting D-serine to pyruvate) and regulation by serine transport, in which the alanine-serine-cysteine transporter ASCT2 is implicated. Here we report studies in C6 glioma cells, which "simulate" the forebrain, in that the cells express SRR and ASCT2 but lack DAO activity. We measured D-serine, ASCT2, SRR, and DAO expression and DAO activity in two situations: after incubation of cells for 48 hr with serine isomers and after increased or decreased SRR expression by transfection and RNA interference, respectively. Incubation with serine enantiomers decreased [(3)H]D-serine uptake and ASCT2 mRNA and increased SRR immunoreactivity but did not alter DAO immunoreactivity, and DAO activity remained undetectable. SRR overexpression increased D-serine and pyruvate and decreased [(3)H]D-serine uptake and ASCT2 mRNA but did not affect DAO. SRR knockdown did not alter any of the parameters. Our data suggest that D-serine transport mediated by ASCT2 contributes prominently to D-serine homeostasis when DAO activity is absent. The factors regulating D-serine are important for understanding normal NMDA receptor function and because D-serine, along with DAO and SRR, is implicated in the pathogenesis and treatment of schizophrenia.
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| 21. |
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| 22. |
- Tomasevic, Gregor, et al.
(författare)
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Deletion of the p53 tumor suppressor gene improves neuromotor function but does not attenuate regional neuronal cell loss following experimental brain trauma in mice.
- 2010
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Ingår i: Journal of Neuroscience Research. - : Wiley. - 1097-4547 .- 0360-4012. ; 88:15, s. 3414-3423
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Tidskriftsartikel (refereegranskat)abstract
- Deletion of the tumor suppressor gene p53 has been shown to improve the outcome in experimental models of focal cerebral ischemia and kainate-induced seizures. To evaluate the potential role of p53 in traumatic brain injury, genetically modified mice lacking a functional p53 gene (p53(-/-), n = 9) and their wild-type littermates (p53(+/+), n = 9) were anesthetized and subjected to controlled cortical impact (CCI) experimental brain trauma. After brain injury, neuromotor function was assessed by using composite neuroscore and rotarod tests. By 7 days posttrauma, p53(-/-) mice exhibited significantly improved neuromotor function, in the composite neuroscore (P = 0.002) as well as in two of three individual tests, when compared with brain-injured p53(+/+) animals. CCI resulted in the formation of a cortical cavity (mean volume = 6.1 mm(3)) 7 days postinjury in p53(+/+) as well as p53(-/-) mice. No difference in lesion volume was detected between the two genotypes (P = 0.95). Although significant cell loss was detected in the ipsilateral hippocampus and thalamus of brain-injured animals, no differences between p53(+/+) and p53(-/-) mice were detected. Although our results suggest that lack of the p53 gene results in augmented recovery of neuromotor function following experimental brain trauma, they do not support a role for p53 acting as a mediator of neuronal death in this context, underscoring the complexity of its role in the injured brain.
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| 26. |
- Hultman, Karin, 1980, et al.
(författare)
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Expression of Plasminogen Activator Inhibitor-1 and Protease Nexin-1 in Human Astrocytes: Response to Injury-Related Factors.
- 2010
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Ingår i: Journal of Neuroscience Research. - 1097-4547. ; 88:11, s. 2441-2449
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Tidskriftsartikel (refereegranskat)abstract
- Astrocytes play a diverse role in central nervous system (CNS) injury. Production of the serine protease inhibitors (serpins) plasminogen activator inhibitor-1 (PAI-1) and protease nexin-1 (PN-1) by astrocytes may counterbalance excessive serine protease activity associated with CNS pathologies such as ischemic stroke. Knowledge regarding the regulation of these genes in the brain is limited, so the objective of the present study was to characterize the effects of injury-related factors on serpin expression in human astrocytes. Native human astrocytes were exposed to hypoxia or cytokines, including interleukin-6 (IL-6), IL-1beta, tumor necrosis factor-alpha (TNF-alpha), IL-10, transforming growth factor-alpha (TGF-alpha), and TGF-beta for 0-20 hr. Serpin mRNA expression and protein secretion were determined by real-time RT-PCR and ELISA, respectively. Localization of PAI-1 and PN-1 in human brain tissue was examined by immunohistochemistry. Hypoxia and all assayed cytokines induced a significant increase in PAI-1 expression, whereas prolonged treatment with IL-1beta or TNF-alpha resulted in a significant down-regulation. The most pronounced induction of both PAI-1 and PN-1 was observed following early treatment with TGF-alpha. In contrast to PAI-1, the PN-1 gene did not respond to hypoxia. Positive immunoreactivity for PAI-1 in human brain tissue was demonstrated in reactive astrocytes within gliotic areas of temporal cortex. We show here that human astrocytes express PAI-1 and PN-1 and demonstrate that this astrocytic expression is regulated in a dynamic manner by injury-related factors.
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