Kinetics of myelin breakdown products: A labeling study in patients with progressive multiple sclerosis.

Autor: Kanhai KMS; Centre for Human Drug Research, Leiden, The Netherlands.; Prothya Biosolutions, Amsterdam, The Netherlands., Goulooze SC; Centre for Human Drug Research, Leiden, The Netherlands.; Department of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands., van der Grond J; Radiology Department, Leiden University Medical Center, Leiden, The Netherlands., Harms AC; Prothya Biosolutions, Amsterdam, The Netherlands.; Radiology Department, Leiden University Medical Center, Leiden, The Netherlands., Hankemeier T; Department of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.; Netherlands Metabolomics Centre, Leiden, The Netherlands., Verma A; Yumanity Pharmaceuticals, Boston, Massachusetts, USA., Dent G; Biogen, Cambridge, Massachusetts, USA., Chavez J; Biogen, Cambridge, Massachusetts, USA., Meijering H; Ardena Bioanalytical Laboratory, Assen, The Netherlands., Groeneveld GJ; Centre for Human Drug Research, Leiden, The Netherlands.
Jazyk: angličtina
Zdroj: Clinical and translational science [Clin Transl Sci] 2022 Mar; Vol. 15 (3), pp. 638-648. Date of Electronic Publication: 2021 Nov 19.
DOI: 10.1111/cts.13181
Abstrakt: The majority of disease modifying therapies for multiple sclerosis (MS) reduce inflammation, but do no't target remyelination. Development of remyelinating therapies will benefit from a method to quantify myelin kinetics in patients with MS. We labeled myelin in vivo with deuterium, and modeled kinetics of myelin breakdown products β-galactosylceramide (β-GalC) and N-Octadecanoyl-sulfatide (NO-Sulf). Five patients with MS received 120 ml 70% D 2 O daily for 70 days and were compared with six healthy subjects who previously received the same procedure. Mass spectrometry and compartmental modeling were used to quantify the turnover rate of β-GalC and NO-Sulf in cerebrospinal fluid (CSF). Turnover rate constants of the fractions of β-GalC and NO-Sulf with non-negligible turnover were 0.00186 and 0.00714, respectively, in both healthy subjects and patients with MS. The turnover half-life of β-GalC and NO-Sulf was calculated as 373 days and 96.5 days, respectively. The effect of MS on the NO-Sulf (49.4% lower fraction with non-negligible turnover) was more pronounced compared to the effect on β-GalC turnover (18.3% lower fraction with non-negligible turnover). Kinetics of myelin breakdown products in the CSF are different in patients with MS compared with healthy subjects. This may be caused by slower myelin production in these patients, by a higher level of degradation of a more stable component of myelin, or, most likely, by a combination of these two processes. Labeling myelin breakdown products is a useful method that can be used to quantify myelin turnover in patients with progressive MS and can therefore be used in proof-of-concept studies with remyelination therapies.
(© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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