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- 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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| 2. |
- 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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