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• W4380300800 abstract "<p><b>Multiple sclerosis is a debilitating, neurodegenerative disorder which is characterized by the demyelinated lesion caused by immune cells infiltrating into the central nervous system and breaking down the myelin sheaths. Current treatments include immunosuppressives and immunomodulators to prevent or limit further neuronal damage but little is done to support the repair of the injured areas. Recently, kappa opioid receptors (KOR) were identified as a promising target to induce remyelination.</b></p> <p>Nalfurafine (Nalf) is a KOR agonist and thus far the only agonist approved for clinical use. It enhances the repair of myelin and reduces neuroinflammation in a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). While the in volvement of KOR in nociception is well understood, the mechanism of how it influences remyelination is not. To gain a better understanding of the mechanism of action of Nalf in the context of remyelination, certain aspects, such as pharmakokinetics, neurotransmitter and lipid abundance, and gene expression changes were investigated.</p> <p>The pharmacokinetic study was preceded by the development and optimization of a liquid chromatography coupled mass spectrometry method. Due to the high potency of Nalf, only a low dose is required to achieve the desired effects. Therefore, a highly sensitive and high throughput detection method was developed, which allowed the detection of Nalf in plasma and brain tissue. For the pharmacokinetics, different parameters were evaluated such as drug delivery route, sex, and dose.</p> <p>KOR are known to influence the release of other neurotransmitters such as dopamine, γ-aminobutyric acid, and serotonin. Some of these have also been shown to regulate remyelination. This prompted the investigation of neurotransmitters by mass spectrometry imaging, a technique capable of detecting hundreds of molecules simultaneously without labeling. The distribution and abundance of neurotransmitter in the brain of EAE animals was investigated in response to Nalf treatment.</p> <p>Mass spectrometry imaging was also applied to explore alterations of lipid abundance in the spinal cord by Nalf. A certain lipid class, sulfatides, were the focus due to the recently proposed link between sulfatide fatty acid length and the developmental stage of oligodendrocyte precursor cells.</p> <p>Finally, the effects of Nalf on gene expression during EAE were investigated by RNA sequencing. This, taken together with the results from the pharmacokinetics the observed neurotransmitter and lipid changes, highlighted potential pathways of how Nalf could affect remyelination.</p>" @default.
• W4380300800 created "2023-06-13" @default.
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• W4380300800 date "2023-06-13" @default.
• W4380300800 modified "2023-09-26" @default.
• W4380300800 title "The kappa opioid receptor agonist, nalfurafine, and its mechanism of action in promoting remyelination" @default.
• W4380300800 doi "https://doi.org/10.26686/wgtn.23504808" @default.
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