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

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.

• Authors: Petri Elo, Xiang-Guo Li, Heidi Liljenbäck, Maria Gardberg, Olli Moisio, Maxwell Miner, Jenni Virta, Antti Saraste, Madduri Srinivasarao, Michael Pugh, Philip S Low, Juhani Knuuti, Sirpa Jalkanen, Laura Airas, Yingjuan June Lu, Anne Roivainen
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 18 Issue 1 Pg. 30 (Jan 20 2021) ISSN: 1742-2094 [Electronic] England
• PMID: 33472663 (Publication Type: Journal Article)

Chemical References

• Folate Receptor 2
• Folic Acid Antagonists
• Folic Acid
• Aminopterin

Topics

• Aminopterin (pharmacology)
• Animals
• Encephalomyelitis, Autoimmune, Experimental (pathology)
• Folate Receptor 2 (metabolism)
• Folic Acid (pharmacology)
• Folic Acid Antagonists (pharmacology)
• Humans
• Multiple Sclerosis (metabolism)
• Rats
• Rats, Inbred Lew