Inhibition of myeloperoxidase by N-acetyl lysyltyrosylcysteine amide reduces experimental autoimmune encephalomyelitis-induced injury and promotes oligodendrocyte regeneration and neurogenesis in a murine model of progressive multiple sclerosis

Abstract

It is known that oxidative stress produced by proinflammatory myeloid cells plays an important role in demyelination and neuronal injury in progressive multiple sclerosis (MS). Myeloperoxidase (MPO) is a pro-oxidative enzyme released from myeloid cells during inflammation. It has been shown that MPO-dependent oxidative stress plays important roles in inducing tissue injury in many inflammatory diseases. In this report, we treated NOD experimental autoimmune encephalomyelitis (EAE) mice, a murine model of progressive MS, with N-acetyl lysyltyrosylcysteine amide (KYC), a novel specific MPO inhibitor. Our data showed that KYC treatment not only attenuated MPO-mediated oxidative stress but also reduced demyelination and axonal injury in NOD EAE mice. More importantly, we found that KYC treatment increased oligodendrocyte regeneration and neurogenesis in NOD EAE mice. Taken together, our data suggests that targeting MPO should be a good therapeutic approach for reducing oxidative injury and preserving neuronal function in progressive MS patients.

Autoimmune encephalomyelitis in NOD mice is not initially a progressive multiple sclerosis model

“…41 However, when mice were followed for up to several months longer it was reported that disease might become chronically progressive as animals accumulate disability. 47 However, with the urgent unmet clinical need to develop treatment options for advanced MS, MOG induced EAE has become used as a "progressive EAE" model that purportedly resembles secondary progressive MS. 24,25,48 This clinical progression appears to begin from about day 20 after immunization when it is used to test therapeutics for use in progressive MS. [24][25][26][27][28][29][30][31] However, through literature review and as shown here, the same clinical course has been reported to be a form of chronic relapsing EAE. 23,[48][49][50] At the cellular level, CD4 T cells from MOG T-cell receptor (TCR MOG )-specific transgenic NOD mice, that select CD4 and CD8 T cells, induce a phenotypic progressive disease in NOD.Scid mice, similar to that reported using MOG immunized wild-type NOD mice.…”

“…22 This is consistent with other mouse strains that demonstrate a dynamic degree of adaptive immune cells infiltration as clinical disease develops and wanes. 22,36 Glial cell inflammation is thought to be part of the substrate for slow progressive nerve loss in MS. 11 However, the loss of axons and myelin, accumulation of microglial activation and gliosis reported in progressive EAE models, [24][25][26][27][28][29][30][31] is not qualitatively different from that found following the accumulation of disability from relapsing EAE in mice. 20,36 This perhaps is not surprising as monophasic or relapsing inflammatory disease activity probably creates and conditions the neurodegenerative environment that leads to the slow loss nerve loss, which does not respond rapidly to agents that target relapsing disease.…”

“…16,19,20,46 This may explain the disease course reported in NOD mice. [24][25][26][27][28][29][30][31] Therefore, to avoid unnecessary use of animals, the literature was investigated further. Indeed, the first descriptions of MOG reported that the disease in NOD mice was relapsing and remitting.…”

“…[21][22][23] This mouse strain has also been reported to develop progressive neurological disease that mimics progressive MS. 24,25 Progressive worsening appears to develop within 20-30 days postinduction following immunization with myelin oligodendrocyte glycoprotein (MOG) peptide residues 35-55 (MOG ). [24][25][26][27][28][29][30][31] Thus, this EAE model could have significant utility for screening potential neuroprotective and repair agents. 24,[27][28][29][30][31] Here, we have investigated the response of NOD mice to various autoantigens to assess the validity of this system to model progressive MS.…”

“…[24][25][26][27][28][29][30][31] Thus, this EAE model could have significant utility for screening potential neuroprotective and repair agents. 24,[27][28][29][30][31] Here, we have investigated the response of NOD mice to various autoantigens to assess the validity of this system to model progressive MS. In contrast to some of the published literature indicating the progressive nature of early MOG induced EAE in NOD mice, we found no evidence that this model exhibits a progressive worsening independent of relapsing disease indicating that existing data are an artifact of data handling and interpretation.…”