Efficacy and tolerability of folate-aminopterin therapy in a rat focal model of multiple sclerosis.

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  • Additional Information
    • Source:
      Publisher: BioMed Central Country of Publication: England NLM ID: 101222974 Publication Model: Electronic Cited Medium: Internet ISSN: 1742-2094 (Electronic) Linking ISSN: 17422094 NLM ISO Abbreviation: J Neuroinflammation Subsets: MEDLINE
    • Publication Information:
      Original Publication: [London] : BioMed Central, c2004-
    • Subject Terms:
      Aminopterin/*pharmacology ; Encephalomyelitis, Autoimmune, Experimental/*pathology ; Folate Receptor 2/*metabolism ; Folic Acid/*pharmacology ; Folic Acid Antagonists/*pharmacology; Animals ; Humans ; Multiple Sclerosis/metabolism ; Rats ; Rats, Inbred Lew
    • 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 68 Ga-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated folate ( 68 Ga-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). 68 Ga-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 68 Ga-FOL in the brain was low and did not differ between the groups, but the in vitro binding of 68 Ga-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.
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    • Grant Information:
      ERVA#13303 State Research Funding of Turku University Hospital
    • Contributed Indexing:
      Keywords: Aminopterin; Experimental autoimmune encephalomyelitis; Folate receptor; Inflammation; Macrophages; Multiple sclerosis; Positron emission tomography
    • Accession Number:
      0 (Folate Receptor 2)
      0 (Folic Acid Antagonists)
      935E97BOY8 (Folic Acid)
      JYB41CTM2Q (Aminopterin)
    • Publication Date:
      Date Created: 20210121 Date Completed: 20211013 Latest Revision: 20211013
    • Publication Date:
      20240829
    • Accession Number:
      PMC7819223
    • Accession Number:
      10.1186/s12974-021-02073-7
    • Accession Number:
      33472663