Deletion of macrophage migration inhibitory factor attenuates neuronal death and promotes functional recovery after compression-induced spinal cord injury in mice

Nishio, Yutaka; Koda, Masao; Hashimoto, Masayuki; Kamada, Takahito; Koshizuka, Shuhei; Yoshinaga, Katsunori; Onodera, Shin; Nishihira, Jun; Okawa, Akihiko; Yamazaki, Masashi

doi:10.1007/s00401-008-0476-x

Cited by 57 publications

(62 citation statements)

References 17 publications

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“…MIF is a proinflammatory cytokine that is upregulated early during episodes of acute inflammation, including SCI. 40 MIF knockout mice show more rapid recovery of hindlimb function after SCI and have decreased neuronal cell death 6 weeks after injury, demonstrating that this cytokine plays a role in retarding recovery after SCI. 40 Blocking MIF expression results in anti-inflammatory effects in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…40 MIF knockout mice show more rapid recovery of hindlimb function after SCI and have decreased neuronal cell death 6 weeks after injury, demonstrating that this cytokine plays a role in retarding recovery after SCI. 40 Blocking MIF expression results in anti-inflammatory effects in vitro and in vivo. 20,21 MIF also displays keto-enol tautomerase activity.…”

Section: Discussionmentioning

confidence: 99%

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Neuroprotective Effects of Sulforaphane after Contusive Spinal Cord Injury

Benedict

Mountney

Hurtado

et al. 2012

Journal of Neurotrauma

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Traumatic spinal cord injury (SCI) leads to oxidative stress, calcium mobilization, glutamate toxicity, the release of proinflammatory factors, and depletion of reduced glutathione (GSH) at the site of injury. Induction of the Keap1/Nrf2/ ARE pathway can alleviate neurotoxicity by protecting against GSH depletion, oxidation, intracellular calcium overload, mitochondrial dysfunction, and excitotoxicity. Sulforaphane (SF), an isothiocyanate derived from broccoli, is a potent naturally-occurring inducer of the Keap1/Nrf2/ARE pathway, leading to upregulation of genes encoding cytoprotective proteins such as NAD(P)H: quinone oxidoreductase 1, and GSH-regulatory enzymes. Additionally, SF can attenuate inflammation by inhibiting the nuclear factor-jB (NF-jB) pathway, and the enzymatic activity of the proinflammatory cytokine macrophage inhibitory factor (MIF). Our study examined systemic administration of SF in a rat model of contusion SCI, in an effort to utilize its indirect antioxidant and anti-inflammatory properties to decrease secondary injury. Two doses of SF (10 or 50 mg/kg) were administered at 10 min and 72 h after contusion SCI. SF (50 mg/kg) treatment resulted in both acute and long-term beneficial effects, including upregulation of the phase 2 antioxidant response at the injury site, decreased mRNA levels of inflammatory cytokines (i.e., MMP-9) in the injured spinal cord, inactivation of urinary MIF tautomerase activity, enhanced hindlimb locomotor function, and an increased number of serotonergic axons caudal to the lesion site. These findings demonstrate that SF provides neuroprotective effects in the spinal cord after injury, and could be a candidate for therapy of SCI.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of Sulforaphane after Contusive Spinal Cord Injury

Benedict

Mountney

Hurtado

et al. 2012

Journal of Neurotrauma

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“…5 More recently, it has been found that MIF is constitutively expressed in neurons, and that its expression levels are inversely correlated with neuronal survival after injury, oxygen-glucose deprivation, or neurotoxic insult. 6,7 It is upregulated in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, 8 stroke, 9 spinal chord injury, 6 and Alzheimer's disease. 10 In amyotrophic lateral sclerosis (ALS), there are two ways in which MIF might contribute to disease progression.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Inhibitors of the Tautomerase Activity of Macrophage Migration Inhibitory Factor (MIF)

Zapatero¹,

Pérez²,

Vázquez³

et al. 2016

SLAS Discovery

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Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine associated with multiple diseases, including neurodegenerative disorders. With the ultimate goal of providing novel chemotypes as starting points for development of disease-modifying therapeutics for neurodegeneration, we endeavored to screen the GSK compound collection for MIF inhibitors using a miniaturized, activity-based kinetic assay. The assay monitors the increase in absorbance at 320 nm resulting from keto-to-enol tautomerization of 4-hydroxyphenylpyruvate, a reaction catalyzed by MIF. We ran a fulldiversity screen evaluating the inhibitory activity of 1.6 million compounds. Primary hits were confirmed and retested in an orthogonal assay measuring tautomerization of l-dopachrome methyl ester by the decrease in absorbance at 475 nm in kinetic mode. Selected compounds were progressed to medium-throughput mode-of-inhibition studies, which included time dependence, enzyme concentration dependence, and reversibility of their inhibitory effect. With these results and after inspection of the physicochemical properties of compounds, 17 chemotypes were prioritized and progressed to further stages of validation and characterization to better assess their therapeutic potential.

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“…Furthermore, MIF exhibits tautomerase activity toward oxidized cathecholamines, and has thereby been implicated in neurodegenerative disorders (Matsunaga et al, 1999). Cultured cerebellar granular neurons from Mif À/À mice are resistant to excitotoxicity (Nishio et al, 2009), suggesting that MIF can affect neuronal susceptibility to ischemia. Although MIF has been shown upregulated after global (Yoshimoto et al, 1997) and focal ischemia (Wang et al, 2009), the functional relevance of MIF in stroke has not been assessed.…”

Section: Introductionmentioning

confidence: 99%

Macrophage Migration Inhibitory Factor Promotes Cell Death and Aggravates Neurologic Deficits after Experimental Stroke

Inácio

Ruscher

Leng

et al. 2010

J Cereb Blood Flow Metab

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Multiple mechanisms contribute to tissue demise and functional recovery after stroke. We studied the involvement of macrophage migration inhibitory factor (MIF) in cell death and development of neurologic deficits after experimental stroke. Macrophage migration inhibitory factor is upregulated in the brain after cerebral ischemia, and disruption of the Mif gene in mice leads to a smaller infarct volume and better sensory-motor function after transient middle cerebral artery occlusion (tMCAo). In mice subjected to tMCAo, we found that MIF accumulates in neurons of the peri-infarct region, particularly in cortical parvalbumin-positive interneurons. Likewise, in cultured cortical neurons exposed to oxygen and glucose deprivation, MIF levels increase, and inhibition of MIF by (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) protects against cell death. Deletion of MIF in Mif À/À mice does not affect interleukin-1b protein levels in the brain and serum after tMCAo. Furthermore, disruption of the Mif gene in mice does not affect CD68, but it is associated with higher galectin-3 immunoreactivity in the brain after tMCAo, suggesting that MIF affects the molecular/cellular composition of the macrophages/microglia response after experimental stroke. We conclude that MIF promotes neuronal death and aggravates neurologic deficits after experimental stroke, which implicates MIF in the pathogenesis of neuronal injury after stroke.

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Deletion of macrophage migration inhibitory factor attenuates neuronal death and promotes functional recovery after compression-induced spinal cord injury in mice

Cited by 57 publications

References 17 publications

Neuroprotective Effects of Sulforaphane after Contusive Spinal Cord Injury

Neuroprotective Effects of Sulforaphane after Contusive Spinal Cord Injury

Discovery of Novel Inhibitors of the Tautomerase Activity of Macrophage Migration Inhibitory Factor (MIF)

Macrophage Migration Inhibitory Factor Promotes Cell Death and Aggravates Neurologic Deficits after Experimental Stroke

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