Functional role of brain-derived neurotrophic factor in neuroprotective autoimmunity: therapeutic implications in a model of multiple sclerosis

Linker, Ralf A.; Lee, Dong Hoon; Demir, Seray; Wiese, Stefan; Kruse, Niels; Siglienti, Ines; Gerhardt, Ellen; Neumann, Harald; Sendtner, Michael; Lühder, Fred; Gold, Ralf

doi:10.1093/brain/awq179

Cited by 187 publications

(183 citation statements)

References 66 publications

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“…In this article, we found that cortistatin protected oligodendrocytes from cell death in an oxidative milieu as occurs in EAE. Moreover, cortistatin increased the local levels of BDNF and ADNP, which induce axonal outgrowth, remyelination, and rescue of degenerating neurons (24,25). For ADNP, this effect is exerted on both peripheral lymphoid cells and resident CNS cells.…”

Section: Discussionmentioning

confidence: 96%

Paradoxical Effect of Cortistatin Treatment and Its Deficiency on Experimental Autoimmune Encephalomyelitis

Souza-Moreira

Morell

Delgado-Maroto

et al. 2013

The Journal of Immunology

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Cortistatin is a cyclic-neuropeptide produced by brain cortex and immune cells that shows potent anti-inflammatory activity. In this article, we investigated the effect of cortistatin in two models of experimental autoimmune encephalomyelitis (EAE) that mirror chronic and relapsing-remitting multiple sclerosis. A short-term systemic treatment with cortistatin reduced clinical severity and incidence of EAE, the appearance of inflammatory infiltrates in spinal cord, and the subsequent demyelination and axonal damage. This effect was associated with a reduction of the two deleterious components of the disease, namely, the autoimmune and inflammatory response. Cortistatin decreased the presence/activation of encephalitogenic Th1 and Th17 cells in periphery and nervous system, and downregulated various inflammatory mediators, whereas it increased the number of regulatory T cells with suppressive effects on the encephalitogenic response. Moreover, cortistatin regulated glial activity and favored an active program of neuroprotection/regeneration. We further used cortistatin-deficient mice to investigate the role of endogenous cortistatin in the control of immune responses. Surprisingly, cortistatin-deficient mice were partially resistant to EAE and other inflammatory disorders, despite showing competent inflammatory/autoreactive responses. This unexpected phenotype was associated with elevated circulating glucocorticoids and an anxiety-like behavior. Our findings provide a powerful rationale for the assessment of the efficacy of cortistatin as a novel multimodal therapeutic approach to treat multiple sclerosis and identify cortistatin as a key endogenous component of neuroimmune system.

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Section: Discussionmentioning

confidence: 96%

Paradoxical Effect of Cortistatin Treatment and Its Deficiency on Experimental Autoimmune Encephalomyelitis

Souza-Moreira

Morell

Delgado-Maroto

et al. 2013

The Journal of Immunology

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“…Transgenic mice with BDNF depletion in either astrocytes or immune cells show enhanced disease severity associated with axonal loss (Linker et al, 2010), suggesting a BDNF-mediated neuroprotective mechanism. However, neurotrophins have a Janus-like nature as they may also induce neuronal death in vitro (Friedman, 2000), and heterozygous BDNF /+ mice, which display half-normal BDNF levels, show ameliorated EAE (Javeri et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration

Colombo¹,

Cordiglieri²,

Melli³

et al. 2012

J Cell Biol

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“…Our observations also raise the possibility that several different mechanisms contribute to the oligodendrotrophic effect of myelin-specific T cells. In addition to IFN-␥, subpopulations of T cells in inflammatory lesions produce BDNF, 84 -86 which in addition to its multiple beneficial effects on neurons 87 is a potent stimulus of remyelination 88 and neuronal plasticity. 49 That we did not detect BDNF mRNA expression in vitro suggests that BDNF in vivo is produced by CNS neurons and glial cells, which is in line with in situ hybridization studies that demonstrated high BDNF mRNA expression, in particular in hippocampal neurons.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

Nielsen

Toft-Hansen

Lambertsen

et al. 2011

The American Journal of Pathology

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In multiple sclerosis (MS), myelin-specific T cells are normally associated with destruction of myelin and axonal damage. However, in acute MS plaque, remyelination occurs concurrent with T-cell infiltration, which raises the question of whether T cells might stimulate myelin repair. We investigated the effect of myelin-specific T cells on oligodendrocyte formation at sites of axonal damage in the mouse hippocampal dentate gyrus. Infiltrating T cells specific for myelin proteolipid protein stimulated proliferation of chondroitin sulfate NG2-expressing oligodendrocyte precursor cells early after induction via axonal transection, resulting in a 25% increase in the numbers of oligodendrocytes. In contrast, T cells specific for ovalbumin did not stimulate the formation of new oligodendrocytes. In addition, infiltration of myelinspecific T cells enhanced the sprouting response of calretinergic associational/commissural fibers within the dentate gyrus. These results have implications for the perception of MS pathogenesis because they show that infiltrating myelin-specific T cells can stimulate oligodendrogenesis in the adult central nervous system. T cell infiltration, demyelination, and axonal damage are central pathologic features of multiple sclerosis (MS). Whereas the primary immune attack on oligodendrocytes and myelin is effected by T cells, 1,2 remyelination occurs in acute plaques, also in the presence of T cells. 3,4 Remyelination depends on chondroitin sulfate NG2-expressing adult oligodendrocyte precursor cells (OPCs). 5,6 OPCs retain the capacity to proliferate and differentiate into myelinating oligodendrocytes in response to toxic or inflammatory demyelination 7-9 and other forms of central nervous system (CNS) injury such as ischemia, 10 spinal cord injury, 11,12 axonal lesions, 13,14 and inflammation. 15 During differentiation, OPCs downregulate NG2 as cells acquire markers of mature oligodendrocytes such as 2=,3=-cyclic nucleotide 3=-phosphodiesterase (CNP). 16 The axonal damage that occurs within and distal to the acute MS lesion can be modeled in the hippocampal dentate gyrus by transection of the perforant pathway (PP), resulting in degeneration of the PP axons and their myelin sheaths in the outer part of the molecular layer. [17][18][19] PP lesions also induce proliferation of OPCs, which results in formation of new oligodendrocytes. 14 These newly formed oligodendrocytes are presumed to myelinate the axonal sprouts that extend from other afferent fiber systems in the dentate gyrus 20,21 such as the associational/commissural afferents from the calretinergic hilar mossy cells. 20,22,23 Indeed, in stratum radiatum of the hippocampal CA3 region, lesion-induced axonal sprouting is associated with formation of more oligodendrocytes and more myelin. 24 Because remyelination ultimately fails in MS, 25 it is assumed that autoimmune demyelination reduces the capacity for myelin repair. 26,27 We investigated the effect of myelin-specific T cells on the formation of oligodendrocytes in the dentate gyrus of ...

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Functional role of brain-derived neurotrophic factor in neuroprotective autoimmunity: therapeutic implications in a model of multiple sclerosis

Cited by 187 publications

References 66 publications

Paradoxical Effect of Cortistatin Treatment and Its Deficiency on Experimental Autoimmune Encephalomyelitis

Paradoxical Effect of Cortistatin Treatment and Its Deficiency on Experimental Autoimmune Encephalomyelitis

Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

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