A1 Refereed original research article in a scientific journal
Efficacy and tolerability of folate-aminopterin therapy in a rat focal model of multiple sclerosis
Authors: Elo Petri, Li Xiang-Guo, Liljenbäck Heidi, Gardberg Maria, Moisio Olli, Miner Maxwell, Virta Jenni, Saraste Antti, Srinivasarao Madduri, Pugh Michael, Low Philip S., Knuuti Juhani, Jalkanen Sirpa, Airas Laura, Lu Yingjuan June, Roivainen Anne
Publisher: BMC
Publication year: 2021
Journal: Journal of Neuroinflammation
Journal name in source: JOURNAL OF NEUROINFLAMMATION
Journal acronym: J NEUROINFLAMM
Article number: ARTN 30
Volume: 18
Issue: 1
Number of pages: 15
DOI: https://doi.org/10.1186/s12974-021-02073-7(external)
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/52674071(external)
BackgroundActivated macrophages in the experimental model of multiple sclerosis (MS) express folate receptor-beta (FR-beta), representing a promising target for the treatment of MS. Here, we both evaluated the efficacy of a novel folate-aminopterin construct (EC2319) in a rat focal model of multiple sclerosis (MS) and investigated the utility of Ga-68-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated folate (Ga-68-FOL) for assessing inflammatory lesions. In addition, we investigated whether FR-beta is expressed in the brain of patients with MS.MethodsFocal delayed-type hypersensitivity experimental autoimmune encephalomyelitis (fDTH-EAE) was induced in 40 Lewis rats; 20 healthy Lewis rats were used as controls. Rats were divided into six groups according to the duration of disease (control, acute, or chronic) and intervention (vehicle versus EC2319). Ga-68-FOL analyses, histology, and immunofluorescence of the brain were performed to evaluate the efficacy of subcutaneously administered EC2319 on lesion development. Immunofluorescence was used to assess FR-beta expression in postmortem brain samples from 5 patients with MS and 5 healthy controls.ResultsImmunofluorescence and histological analyses revealed significant reductions in FR-beta expression (P < 0.05) and lesion size (P < 0.01), as well as improved inducible nitric oxide synthase/mannose receptor C type 1 ratios (P < 0.01) in macrophages and microglia during the chronic but not acute phase of fDTH-EAE in EC2319-treated rats. The uptake of IV-injected Ga-68-FOL in the brain was low and did not differ between the groups, but the in vitro binding of Ga-68-FOL was significantly lower in EC2319-treated rats (P < 0.01). FR-beta positivity was observed in chronically active lesions and in normal-appearing white matter in MS brain samples.ConclusionsEC2319 was well tolerated and attenuated inflammation and lesion development in a rat model of a chronic progressive form of MS. Human MS patients have FR-beta -positive cells in chronically active plaques, which suggests that these results may have translational relevance.
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