| 1. |
- Andersson, Åsa, et al.
(författare)
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Pivotal Advance : HMGB1 expression in active lesions of human and experimental multiple sclerosis
- 2008
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Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 0741-5400 .- 1938-3673. ; 84:5, s. 1248-1255
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Forskningsöversikt (refereegranskat)abstract
- Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the CNS, most frequently starting with a series of bouts, each followed by complete remission and then a secondary, progressive phase during which the neurological deficit increases steadily. The underlying molecular mechanisms responsible for disease progression are still unclear. Herein, we demonstrate that high mobility group box chromosomal protein 1 (HMGB1), a DNA-binding protein with proinflammatory properties, is evident in active lesions of MS and experimental autoimmune encephalomyelitis (EAE) and that HMGB1 levels correlate with active inflammation. Furthermore, the expression of the innate HMGB1 receptors--receptor for advanced glycation end products, TLR2, and TLR4--was also highly increased in MS and rodent EAE. Additionally, in vitro activation of rodent CNS-derived microglia and bone marrow-derived macrophages demonstrated that microglia were equally as capable as macrophages of translocating HMGB1 following LPS/IFN-gamma stimulation. Significant expression of HMGB1 and its receptors on accumulating activated macrophages and resident microglia may thus provide a positive feedback loop that amplifies the inflammatory response during MS and EAE pathogenesis.
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| 2. |
- Covacu, Ruxandra, et al.
(författare)
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Nitric oxide exposure diverts neural stem cell fate from neurogenesis towards astrogliogenesis
- 2006
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Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1066-5099 .- 1549-4918. ; 178, s. 268-268
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Regeneration of cells in the central nervous system is a process that might be affected during neurological disease and trauma. Because nitric oxide (NO) and its derivatives are powerful mediators in the inflammatory cascade, we have investigated the effects of pathophysiological concentrations of NO on neurogenesis, gliogenesis, and the expression of proneural genes in primary adult neural stem cell cultures. After exposure to NO, neurogenesis was downregulated, and this corresponded to decreased expression of the proneural gene neurogenin-2 and beta-III-tubulin. The decreased ability to generate neurons was also found to be transmitted to the progeny of the cells. NO exposure was instead beneficial for astroglial differentiation, which was confirmed by increased activation of the Janus tyrosine kinase/signal transducer and activator of transcription transduction pathway. Our findings reveal a new role for NO during neuroinflammatory conditions, whereby its proastroglial fate-determining effect on neural stem cells might directly influence the neuroregenerative process.
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| 3. |
- Danilov, Alexandre, et al.
(författare)
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Ectopic Ependymal Cells in Striatum Accompany Neurogenesis in a Rat Model of Stroke.
- 2012
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Ingår i: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 214, s. 159-170
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Tidskriftsartikel (refereegranskat)abstract
- Stroke-induced neurogenesis originates from a neural stem cell (NSC) niche in subventricular zone (SVZ). In mice, NSCs are concentrated in a so-called "neurogenic spot" in the lateral angle area of SVZ. We aimed to identify the "neurogenic spot" in the rat SVZ and to characterize the cellular changes in the ependymal cell compartment in this area at different time points after middle cerebral artery occlusion. The majority of ependymal cells outlining the ventricular wall did not proliferate, and their numbers in the "neurogenic spot" declined at six and sixteen weeks after stroke. Cells with the ultrastructural properties of ependymal cells were detected in the adjacent striatum. The number of these ectopic ependymal cells correlated positively with the magnitude of lateral ventriclar enlargement and negatively with the ependymal cell number in the "neurogenic spot". Ectopic ependymal cells were found along blood vessels, accumulated in the pericyst regions, and participated in scar formation but did not incorporate BrdU. We provide the first evidence for the occurrence of ectopic ependymal cells in the ischemic striatum following stroke.
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| 4. |
- Danilov, Alexandre I
(författare)
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Neurogenesis, neural stem cells and nitric oxide in neuroinflammation
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- We investigated whether nitric oxide (NO) is produced in MS patients, determining the concentrations of its oxidation products (NOx) in CSF. The total levels of NOx in CSF were significantly increased in all MS groups as compared to healthy controls and tension headache patients. Since CSF nitrite levels correlated with clinical disease activity the determination of nitrite levels may be used as a surrogate marker for disease activity. Systemically and intrathecally produced nitric oxide might play different roles in EAE pathogenesis. We therefore administered the NOS inhibitor L-NAME intrathecally or systemically via osmotic minipumps to DA rats with MOG-induced experimental autoimmune encephalomyelitis (EAE). NOS inhibition decreased EAE severity, the extent of CNS inflammation and demyelination. Intrathecal administration was more effective than systemic administration. The observed effect was accompanied by enhanced anti-MOG IgG1 production. Next we examined if NOS and reactive oxygen species (ROS) inhibition would be beneficial in a traumatic brain injury model (TBI). We administered NOS inhibitor (LNAME) alone and in combination with nitrone radical scavenger (S-PBN) after TBI. NOS inhibition and ROS scavenging significantly reduced neuronal degeneration, possibly via limiting peroxynitrite formation and thus promoting neuronal survival. The combination of LNAME and S-PBN was neuroprotective, but no additive effect was achieved. We also studied the possible activation and differentiation of central nervous system (CNS) stem cells in EAE lesioned spinal cord. Labelled stem cells from the ependymal layer in the spinal cord respond to the MS-like condition by proliferation and migration into demyelinated areas. Some of the theses cells expressed oligodendrocyte and astrocyte markers. Macrophage attacks on the stem cell population were observed. We have also addressed the question whether neurogenesis can occur in neuroinflammatory lesions. We found that the progeny of labelled ependymal cells proliferate and migrate to the neuroinflammatory lesions, differentiating into cells expressing neuronal markers. These cells were immunoreactive for markers of cells undergoing cell-proliferation. Freshly isolated DiI labelled cells from spinal cord lesions were able to fire overshooting action potentials comparable to those of immature neurons. We provide the first evidence for neurogenesis in neuroinflammatory lesions in the adult spinal cord. Accordingly, we investigated the effects of NO exposure on the fate acquisition of neuronal stem cells. Neurogenesis was suppressed and gliogenesis promoted. The suggested mechanisms were related to downregulation of neurogenin-2 and activation of the JAK/STAT- 1 signal transduction pathway.
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| 5. |
- Danilov, Alexandre, et al.
(författare)
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Neurogenesis in the adult spinal cord in an experimental model of multiple sclerosis
- 2006
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Ingår i: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 23:2, s. 394-400
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is an inflammatory disease of the central nervous system characterized by inflammation, demyelination, axonal degeneration and accumulation of neurological disability. Previously, we demonstrated that stem cells constitute a possible endogenous source for remyelination. We now addressed the question of whether neurogenesis can occur in neuroinflammatory lesions. We demonstrated that, in experimental autoimmune encephalomyelitis, induced in rats 1,1'-dioctadecyl-6,6'-di(4sulphopentyl)-3,3,3',3'tetramethylindocarbocyani n(DiI)-labelled ependymal cells not only proliferated but descendants migrated to the area of neuroinflammation and differentiated into cells expressing the neuronal markers beta-III-tubulin and NeuN. Furthermore, these cells were immunoreactive for bromodeoxyuridine and PCNA, markers for cells undergoing cell proliferation. Using the whole-cell patch-clamp technique on freshly isolated 1, DiI-labelled cells from spinal cord lesions we demonstrated the ability of these cells to fire overshooting action potentials similar to those of immature neurones. We thus provide the first evidence for the initiation of neurogenesis in neuroinflammatory lesions in the adult spinal cord.
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| 6. |
- Danilov, Alexandre, et al.
(författare)
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Ultrastructural and antigenic properties of neural stem cells and their progeny in adult rat subventricular zone.
- 2009
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Ingår i: GLIA. - : Wiley. - 1098-1136 .- 0894-1491. ; Aug 15, s. 136-152
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Tidskriftsartikel (refereegranskat)abstract
- Neural stem cells (NSCs) in the subventricular zone (SVZ) continuously generate olfactory bulb interneurons in the adult rodent brain. Based on their ultrastructural and antigenic properties, NSCs, transient amplifying precursor cells, and neuroblasts (B, C, and A cells, respectively) have been distinguished in mouse SVZ. Here, we aimed to identify these cell types in rat SVZ ultrastructurally and at the light microscopy level, and to determine the antigenic properties of each cell type using gold and fluorescence immunolabeling. We found astrocytes with single cilia (NSCs, correspond to B cells) and neuroblasts (A cells). We also observed mitotic cells, ependymal cells, displaced ependymal cells, and mature astrocytes. In contrast, transient amplifying precursor cells (C cells) were not detected. The NSCs and neuroblasts had epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor alpha (PDGFRalpha) expressed on the ciliary apparatus and were the only cell types incorporating the proliferation marker BrdU. Throughout mitosis, EGFR and PDGFRalpha were associated with the microtubule of the mitotic spindle. Ependymal and displaced ependymal cells also expressed EGFR and PDGFRalpha on their cilia but did not incorporate BrdU. Our findings indicate that the NSCs in adult rat SVZ give rise directly to neuroblasts. During mitosis, the NSCs disassemble the primary cilium and symmetrically distribute EGFR and PDGFRalpha among their progeny. (c) 2008 Wiley-Liss, Inc.
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| 7. |
- Fagerlund, Michael, et al.
(författare)
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Proliferation, migration and differentiation of ependymal region neural progenitor cells in the brainstem after hypoglossal nerve avulsion
- 2011
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Ingår i: Restorative Neurology and Neuroscience. - 1878-3627. ; 29:1, s. 47-59
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Cells in the ependymal region in the adult central nervous system (CNS) have been found to possess neural progenitor cell (NPC) like features including capacity for generating new neurons and glia in response to injury and inflammatory disease. Whether these cells are activated after a peripheral nerve injury has not previously been extensively evaluated. Methods: We investigate the possible activation and effect of NPCs in the ependymal region in the immediate vicinity to the hypoglossal nucleus in the brainstem using two models of injuries, hypoglossal nerve transection and nerve avulsion after which the proliferation, migration and differentiation of ependymal regional NPCs were evaluated. Results: We showed that: (i) immunoreactivity for Sox2 was detected in cells in the ependymal region of the brainstem and that BrdU/Sox2-positive cells were observed after avulsion, but not after transection injury; (ii) avulsion induces re-expression of nestin in the ependymal layer as well as induced NPC migration from the ependymal layer; (iii) the chemokine SDF-1 alpha (a marker for migrating cells) was upregulated ipsilateral to the nerve injury; (iiii) the NPCs migrating differentiated only into GFAP-positive astrocytes in the hypoglossal nucleus. Conclusion: These results suggest that nerve avulsion injury induces in parallel with the retrograde "axon reaction" activation of endogenous NPCs in the ependymal region and further suggest that these cells could be involved in repair and neuroregeneration after injury within the brainstem.
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| 8. |
- Gahm, Caroline, et al.
(författare)
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Reduced neuronal injury after treatment with NG-nitro-L-arginine methyl ester (L-NAME) or 2-sulfo-phenyl-N-tert-butyl nitrone (S-PBN) following experimental brain contusion
- 2005
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Ingår i: Neurosurgery. - : Ovid Technologies (Wolters Kluwer Health). - 0148-396X .- 1524-4040. ; 57:6, s. 1272-1281
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Nitric oxide (NO) and oxygen free radicals are implicated in the pathophysiology of traumatic brain injury (TBI). Peroxynitrite formation from NO and superoxide contributes to secondary neuronal injury but the neuroprotective effects of nitric oxide synthase (NOS)-inhibitors have been contradictory. This study was undertaken to examine whether PTtic administration of the (NOS)-inhibitor N-nitro-l-arginine methyl ester (L-NAME), and a combination of L-NAME and the nitrone radical scavenger 2-sulfo-phenyl-N-tert-butyl nitrone (S-PBN) favorable affects neuronal injury in a model of TBI. METHODS: A weight-drop model of TBI was used. The animals received L-NAME, S-PBN or a combination of the drugs 15 minutes prothrombin time (PT) and sacrificed after 24 hours or six days. NOS activity was measured by the conversion of L-[U-C]arginine to L-[U-C]citrulline. Peroxynitrite formation, cellular apoptosis, neuronal degeneration and survival were assessed by nitrotyrosine-, TUNEL-, Fluoro-Jade- and NeuN-stainings. RESULTS: eNOS and nNOS activity was significantly reduced in animals that received L-NAME alone or the combination with S-PBN. iNOS activity or iNOS immunoreactivity was not affected. All treatments significantly reduced neuronal degeneration and nitrotyrosine immunoreactivity at 24 hours and increased neuronal survival at six days PT. No differences were detected between L-NAME and L-NAME + S-PBN groups. CONCLUSION: NO from NOS contributes to secondary neuronal injury in this TBI-model. PTtic treatment does not inhibit early beneficial NO-related effects. L-NAME and S-PBN limit peroxynitrite formation, promoting neuronal survival. The combination of L-NAME and S-PBN was neuroprotective; surprisingly no additive effects were found on nitrotyrosine formation, apoptosis or neuronal survival.
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