TY - JOUR
T1 - Efficacy and tolerability of folate-aminopterin therapy in a rat focal model of multiple sclerosis
AU - Elo, Petri
AU - Li, Xiang Guo
AU - Liljenbäck, Heidi
AU - Gardberg, Maria
AU - Moisio, Olli
AU - Miner, Maxwell
AU - Virta, Jenni
AU - Saraste, Antti
AU - Srinivasarao, Madduri
AU - Pugh, Michael
AU - Low, Philip S.
AU - Knuuti, Juhani
AU - Jalkanen, Sirpa
AU - Airas, Laura
AU - Lu, Yingjuan June
AU - Roivainen, Anne
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/1/20
Y1 - 2021/1/20
N2 - 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.
AB - 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.
KW - Aminopterin
KW - Experimental autoimmune encephalomyelitis
KW - Folate receptor
KW - Inflammation
KW - Macrophages
KW - Multiple sclerosis
KW - Positron emission tomography
KW - Encephalomyelitis, Autoimmune, Experimental/pathology
KW - Humans
KW - Rats, Inbred Lew
KW - Rats
KW - Animals
KW - Multiple Sclerosis/metabolism
KW - Folic Acid/pharmacology
KW - Aminopterin/pharmacology
KW - Folate Receptor 2/metabolism
KW - Folic Acid Antagonists/pharmacology
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UR - http://www.scopus.com/inward/citedby.url?scp=85099699588&partnerID=8YFLogxK
U2 - 10.1186/s12974-021-02073-7
DO - 10.1186/s12974-021-02073-7
M3 - Article
C2 - 33472663
AN - SCOPUS:85099699588
SN - 1742-2094
VL - 18
SP - 30
JO - Journal of Neuroinflammation
JF - Journal of Neuroinflammation
IS - 1
M1 - 30
ER -