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- Carlström, Karl
(författare)
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Demyelinating conditions regulated by ROS pathways outside and inside the brain
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Multiple sclerosis (MS) is a chronic inflammatory condition of the central nervous system with immune-mediated damage on myelinated nerve tracts. Accumulating evidence support a role for autoreactive T-lymphocytes orchestrating immuneattacks on myelinating oligodendrocytes (OLs). While oligodendrocyte precursor cells (OPCs) may initially compensate for loss of myelin by differentiating into OLs, later stages of MS are characterized by arrest of OPC differentiation and clinical disease progression. Reactive oxygen species (ROS) are important in many contexts, but their role in regulation of adaptive immune processes and remyelination in MS is still uncertain. We here first characterized the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)- activating MS-therapy dimethyl fumarate (DMF/ Tecfidera™) in cell cultures and an experimental model for neuroinflammation. In MS patients we assessed the effect of DMF on transcription and epigenetic modification in immune cells, as well as ROS production by monocytes. Our findings indicate that monocytederived ROS is linked to the clinical efficacy of DMF by modulating the adaptive immune response, in turn highlighting modulation of redox processes as a therapeutic target in autoimmune disease. In order to study the effect of DMF and other redox active agents, we developed a cell based reporter system (pTRAF) that enabled the visualization of transcription factor activity in real-time. Using pTRAF and other in vitro and in vivo models we further characterized the downstream effects of DMF and a set of more selective Nrf2-activating compounds. Finally, we performed extensive in vitro and in vivo characterization of Glutathione S-transferase 4α (Gsta4), which is regulated by Nrf2 and serves an important role for scavenging of the lipid peroxidation product 4-hydroxynonenal (4-HNE). Interestingly, higher levels of Gsta4 was associated with faster and more complete remyelination by facilitating the differentiation of OPC into mature myelinating OLs. This was suggested to be mediated through modulation of the Fas/Casp8/Bid-axis, leading to increased survival of differentiating OPCs. Collectively, our findings support a role for redox processes in regulating adaptive immune responses in MS. Furthermore, a specific redox-related process involving 4-HNE and Gsta4 was found to regulate OPC survival during remyelination. Both these mechanisms may represent interesting novel therapeutic targets in MS, as well as in other autoimmune and demyelinating conditions.
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| 2. |
- Carlström, Karl E., et al.
(författare)
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Characterization of More Selective Central Nervous System Nrf2-Activating Novel Vinyl Sulfoximine Compounds Compared to Dimethyl Fumarate
- 2020
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Ingår i: NEUROTHERAPEUTICS. - : SPRINGER. - 1933-7213 .- 1878-7479. ; 17, s. 1142-1152
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Tidskriftsartikel (refereegranskat)abstract
- The Nrf2 transcription factor is a key regulator of redox reactions and considered the main target for the multiple sclerosis (MS) drug dimethyl fumarate (DMF). However, exploration of additional Nrf2-activating compounds is motivated, since DMF displays significant off-target effects and has a relatively poor penetrance to the central nervous system (CNS). We de novo synthesized eight vinyl sulfone and sulfoximine compounds (CH-1-CH-8) and evaluated their capacity to activate the transcription factors Nrf2, NF kappa B, and HIF1 in comparison with DMF using the pTRAF platform. The novel sulfoximine CH-3 was the most promising candidate and selected for further comparison in vivo and later an experimental model for traumatic brain injury (TBI). CH-3 and DMF displayed comparable capacity to activate Nrf2 and downstream transcripts in vitro, but with less off-target effects on HIF1 from CH-3. This was verified in cultured microglia and oligodendrocytes (OLs) and subsequently in vivo in rats. Following TBI, DMF lowered the number of leukocytes in blood and also decreased axonal degeneration. CH-3 preserved or increased the number of pre-myelinating OL. While both CH-3 and DMF activated Nrf2, CH-3 showed less off-target effects and displayed more selective OL associated effects. Further studies with Nrf2-acting compounds are promising candidates to explore potential myelin protective or regenerative effects in demyelinating disorders.
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