Reduced astrocytic NFκB activation by laquinimod

Authors: Wolfgang Brück Ramona Pförtner Trinh Pham Jingya Zhang Liat Hayardeny Victor Piryatinsky UweKarsten Hanisch Tommy Regen Denise van Rossum Lars Brakelmann Karin Hagemeier Tanja Kuhlmann Christine Stadelmann Gareth R John Nadine Kramann Christiane Wegner

Publish Date: 2012/07/06

Volume: 124, Issue: 3, Pages: 411-424

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Abstract

Laquinimod LAQ is a new oral immunomodulatory compound that reduces relapse rate brain atrophy and disability progression in multiple sclerosis MS LAQ has welldocumented effects on inflammation in the periphery but little is known about its direct activity within the central nervous system CNS To elucidate the impact of LAQ on CNSintrinsic inflammation we investigated the effects of LAQ on cuprizoneinduced demyelination in mice in vivo and on primary CNS cells in vitro Demyelination inflammation axonal damage and glial pathology were evaluated in LAQtreated wild type and Rag1deficient mice after cuprizone challenge Using primary cells we tested for effects of LAQ on oligodendroglial survival as well as on cytokine secretion and NFκB activation in astrocytes and microglia LAQ prevented cuprizoneinduced demyelination microglial activation axonal transections reactive gliosis and oligodendroglial apoptoses in wild type and Rag1deficient mice LAQ significantly decreased proinflammatory factors in stimulated astrocytes but not in microglia Oligodendroglial survival was not affected by LAQ in vitro Astrocytic but not microglial NFκB activation was markedly reduced by LAQ as evidenced by NFκB reporter assay LAQ also significantly decreased astrocytic NFκB activation in cuprizonetreated mice Our data indicate that LAQ prevents cuprizoneinduced demyelination by attenuating astrocytic NFκB activation These effects are CNSintrinsic and not mediated by peripheral immune cells Therefore LAQ downregulation of the astrocytic proinflammatory response may be an important mechanism underlying its protective effects on myelin oligodendrocytes and axons Modulation of astrocyte activation may be an attractive therapeutic target to prevent tissue damage in MSMultiple sclerosis MS is the most common chronic neurological disease leading to disability in early to middle adulthood The pathology of MS is characterized by inflammationinduced demyelination and axonal damage in the central nervous system CNS Recent pathological investigations highlight that axonal injury starts early in the disease course 17 20 41 and these pathological changes are confirmed by in vivo magnetic resonance imaging MRI studies showing early brain volume loss 6 11 14 Acute axonal damage leads to irreversible axonal loss that is thought to be the major correlate of chronic disability in MS 2 So far the currently approved treatments for MS mainly target the peripheral immune system Drugs with myelin or axonprotecting effects might limit the tissue damage especially neurodegeneration and thus prevent accumulation of disability throughout the course of MS There is a largely unmet need for therapeutics that enter the CNS and directly inhibit myelin and axonal damageLaquinimod LAQ is a novel immunomodulatory substance that has been shown to be effective safe and welltolerated Phase II studies indicate that LAQ reduces the formation of MRIactive lesions in relapsingremitting MS 12 29 Recent findings from the Phase III study “ALLEGRO” indicate that LAQ has even more pronounced effects on sustained disability progression as well as on brain atrophy compared to its effect on relapses 7 13 In this study LAQ significantly reduced the risk of sustained disability progression and the rate of MRImeasured brain volume loss by about onethird Moreover previous studies using wholebody autoradiography demonstrated that 7–8  of the blood concentration of LAQ penetrates the intact blood–brain barrier and reaches the brain 8 More evidence of neuroprotective effects of LAQ comes from a recent study indicating that MS patients exhibited higher serum levels of brainderived neurotrophic factor under LAQ treatment 40 Combined with the robust clinical effects these data suggest that LAQ might have direct CNSprotective effects in addition to its known peripheral antiinflammatory propertiesExperimental autoimmune encephalomyelitis EAE represents the principle autoimmune animal model of MS and has proven useful in the development of new treatments for this disease 38 LAQ has been found to inhibit clinical signs of EAE in mice 9 and Lewis rats 47 In addition the analysis of cytokine profiles demonstrated that LAQ redirected the cytokine production in favor of the TH2/TH3 cytokines interleukin 4 IL4 interleukin 10 IL10 and transforming growth factorbeta TGFβ 47 Recently LAQ has also been shown to induce type II myeloid cells and regulatory T cells 33 Compatible with the findings from the ALLEGRO trial experimental data suggest that LAQ might also exert protective central effects in EAE 46Feeding of the copper chelator cuprizone leads to toxic demyelination in the brain of young adult mice Cuprizone induces oligodendrocyte apoptosis and subsequent demyelination in the near absence of T cells with an intact blood–brain barrier 25 The exact mechanisms of cuprizoneinduced oligodendrocyte death are not well understood With this model it is possible to study the effect of LAQ on CNS cells without the influence of the peripheral immune system component Recent findings provide evidence that astrocytic NFκB activation plays a crucial role for oligodendrocyte damage under cuprizone 31 Mice deficient in astrocytic NFκB activation have been reported to show myelin preservation under cuprizone 31

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