Abstract
BACKGROUND: Activated macrophages in the experimental model of multiple sclerosis (MS) express folate receptor-β (FR-β), 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 68Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated folate ( 68Ga-FOL) for assessing inflammatory lesions. In addition, we investigated whether FR-β is expressed in the brain of patients with MS.
METHODS: Focal 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). 68Ga-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-β expression in postmortem brain samples from 5 patients with MS and 5 healthy controls.
RESULTS: Immunofluorescence and histological analyses revealed significant reductions in FR-β 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 68Ga-FOL in the brain was low and did not differ between the groups, but the in vitro binding of 68Ga-FOL was significantly lower in EC2319-treated rats (P < 0.01). FR-β positivity was observed in chronically active lesions and in normal-appearing white matter in MS brain samples.
CONCLUSIONS: EC2319 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-β-positive cells in chronically active plaques, which suggests that these results may have translational relevance.
Original language | English (US) |
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Article number | 30 |
Pages (from-to) | 30 |
Journal | Journal of Neuroinflammation |
Volume | 18 |
Issue number | 1 |
DOIs | |
State | Published - Jan 20 2021 |
Keywords
- Aminopterin
- Experimental autoimmune encephalomyelitis
- Folate receptor
- Inflammation
- Macrophages
- Multiple sclerosis
- Positron emission tomography
- Encephalomyelitis, Autoimmune, Experimental/pathology
- Humans
- Rats, Inbred Lew
- Rats
- Animals
- Multiple Sclerosis/metabolism
- Folic Acid/pharmacology
- Aminopterin/pharmacology
- Folate Receptor 2/metabolism
- Folic Acid Antagonists/pharmacology
ASJC Scopus subject areas
- Neurology
- Cellular and Molecular Neuroscience
- General Neuroscience
- Immunology