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Demyelinating diseases: myeloperoxidase as an imaging biomarker and therapeutic target.

Radiology (2012-03-23)
Reza Forghani, Gregory R Wojtkiewicz, Yinian Zhang, Daniel Seeburg, Benjamin R M Bautz, Benjamin Pulli, Andrew R Milewski, Wendy L Atkinson, Yoshiko Iwamoto, Elizabeth R Zhang, Martin Etzrodt, Elisenda Rodriguez, Clinton S Robbins, Filip K Swirski, Ralph Weissleder, John W Chen
ABSTRACT

To evaluate myeloperoxidase (MPO) as a newer therapeutic target and bis-5-hydroxytryptamide-diethylenetriaminepentaacetate-gadolinium (Gd) (MPO-Gd) as an imaging biomarker for demyelinating diseases such as multiple sclerosis (MS) by using experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Animal experiments were approved by the institutional animal care committee. EAE was induced in SJL mice by using proteolipid protein (PLP), and mice were treated with either 4-aminobenzoic acid hydrazide (ABAH), 40 mg/kg injected intraperitoneally, an irreversible inhibitor of MPO, or saline as control, and followed up to day 40 after induction. In another group of SJL mice, induction was performed without PLP as shams. The mice were imaged by using MPO-Gd to track changes in MPO activity noninvasively. Imaging results were corroborated by enzymatic assays, flow cytometry, and histopathologic analyses. Significance was computed by using the t test or Mann-Whitney U test. There was a 2.5-fold increase in myeloid cell infiltration in the brain (P = .026), with a concomitant increase in brain MPO level (P = .0087). Inhibiting MPO activity with ABAH resulted in decrease in MPO-Gd-positive lesion volume (P = .012), number (P = .009), and enhancement intensity (P = .03) at MR imaging, reflecting lower local MPO activity (P = .03), compared with controls. MPO inhibition was accompanied by decreased demyelination (P = .01) and lower inflammatory cell recruitment in the brain (P < .0001), suggesting a central MPO role in inflammatory demyelination. Clinically, MPO inhibition significantly reduced the severity of clinical symptoms (P = .0001) and improved survival (P = .0051) in mice with EAE. MPO may be a key mediator of myeloid inflammation and tissue damage in EAE. Therefore, MPO could represent a promising therapeutic target, as well as an imaging biomarker, for demyelinating diseases and potentially for other diseases in which MPO is implicated.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
4-Aminobenzoic acid, ReagentPlus®, ≥99%
Sigma-Aldrich
4-Aminobenzoic acid, ReagentPlus®, 99%
Supelco
4-Aminobenzoic acid, analytical standard
Sigma-Aldrich
4-Aminobenzoic acid, purified by sublimation, ≥99%