IκB Kinase-β Inhibitor IMD-0354 Beneficially Suppresses Retinal Vascular Permeability in Streptozotocin-Induced Diabetic Mice

Lennikov, Anton; Hiraoka, Miki; Abe, Akira; Ohno, Shigeaki; Fujikawa, Tomoyuki; Itai, Akiko; Ohguro, Hiroshi

doi:10.1167/iovs.14-14671

Cited by 18 publications

(13 citation statements)

References 30 publications

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“…No cell death was noted in vitro at up to 10 ng/ml concentration of IMD0354, teratogenic effects in zebrafish embryos occurred only at 10–20 times the nominal dose, while in the rat liver no histological abnormalities or increased cell death (cleaved caspase 3 signal) was detectable. This observation is in accordance with a previous study that reported no noticeable adverse effects in mice treated with IMD0354 (30 mg/kg) over 12 weeks [ 22 ]. Considering the effects of IMD0354 on the actin microfilament meshwork and its capacity to arrest and disrupt the cell cycle [ 62 ], a potential carcinogenic effect might be expected during chronic use at higher doses.…”

Section: Discussionsupporting

confidence: 93%

“…Here, NF-κB blockade by selective IKK2 inhibition down-regulated the expression of crucial downstream chemokines, resulting in a weaker vasodilation response, reduced cellular chemotaxis and reduced infiltration of inflammatory cells into the corneal stroma. These findings in the cornea are novel, but consistent with the effects of IKK2 disruption in other tissues [ 20 , 22 , 46 ]. Our results in assays lacking active inflammatory components, such as HUVEC migration and tube formation, rat aortic ring sprouting and zebrafish embryonic vascular development, indicate IKK2 blockade has an inhibitory effect on endothelial cell function and VEGF-A production under physiological conditions.…”

Section: Discussionsupporting

confidence: 78%

“…In 2001, the anti-inflammatory effects of IMD0354 were demonstrated by its ability to ameliorate endotoxin-induced uveitis in rats [ 21 ]. Furthermore, IMD0354 treatment revealed an inhibitory effect on Vegf expression in a murine model of diabetic retinopathy, while preserving vessel wall integrity [ 22 ]. These results were later independently confirmed in ovarian cancer cells [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

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Selective IKK2 inhibitor IMD0354 disrupts NF-κB signaling to suppress corneal inflammation and angiogenesis

et al. 2018

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Corneal neovascularization is a sight-threatening condition caused by angiogenesis in the normally avascular cornea. Neovascularization of the cornea is often associated with an inflammatory response, thus targeting VEGF-A alone yields only a limited efficacy. The NF-κB signaling pathway plays important roles in inflammation and angiogenesis. Here, we study consequences of the inhibition of NF-κB activation through selective blockade of the IKK complex IκB kinase β (IKK2) using the compound IMD0354, focusing on the effects of inflammation and pathological angiogenesis in the cornea. In vitro, IMD0354 treatment diminished HUVEC migration and tube formation without an increase in cell death and arrested rat aortic ring sprouting. In HUVEC, the IMD0354 treatment caused a dose-dependent reduction in VEGF-A expression, suppressed TNFα-stimulated expression of chemokines CCL2 and CXCL5, and diminished actin filament fibers and cell filopodia formation. In developing zebrafish embryos, IMD0354 treatment reduced expression of Vegf-a and disrupted retinal angiogenesis. In inflammation-induced angiogenesis in the rat cornea, systemic selective IKK2 inhibition decreased inflammatory cell invasion, suppressed CCL2, CXCL5, Cxcr2, and TNF-α expression and exhibited anti-angiogenic effects such as reduced limbal vessel dilation, reduced VEGF-A expression and reduced angiogenic sprouting, without noticeable toxic effect. In summary, targeting NF-κB by selective IKK2 inhibition dampened the inflammatory and angiogenic responses in vivo by modulating the endothelial cell expression profile and motility, thus indicating an important role of NF-κB signaling in the development of pathologic corneal neovascularization.Electronic supplementary materialThe online version of this article (10.1007/s10456-018-9594-9) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

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Selective IKK2 inhibitor IMD0354 disrupts NF-κB signaling to suppress corneal inflammation and angiogenesis

et al. 2018

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“…The small molecule TPCA-1, a specific IKKβ inhibitor, efficiently inhibits NF-κB activation and attenuates laser-induced retinal vascular leakage and macrophage accumulation [33] . Administration of IMD-0354, a non–ATP-binding competitive selective IKKβ inhibitor, also significantly suppresses retinal inflammation and vascular damage in streptozotocin-induced diabetic mice [34] . However, little information about the effect of IMD-0354 on Ang II-induced hypertensive retinopathy has been reported.…”

Section: Discussionmentioning

confidence: 96%

The immunoproteasome subunit LMP10 mediates angiotensin II-induced retinopathy in mice

Wang

Bai

et al. 2018

Redox Biology

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Inflammation has been implicated in a variety of retinal diseases. The immunoproteasome plays a critical role in controlling inflammatory responses, but whether activation of immunoproteasome contributes to angiotensin II (Ang II)-induced retinopathy remains unclear. Hypertensive retinopathy (HR) was induced by infusion of Ang II (3000 ng/kg/min) in wild-type (WT) and immunoproteasome subunit LMP10 knockout (KO) mice for 3 weeks. Changes in retinal morphology, vascular permeability, superoxide production and inflammation were examined by pathological staining. Our results showed that immunoproteasome subunit LMP10 expression and its trypsin-like activity were significantly upregulated in the retinas and serum of Ang II-infused mice and in the serum from patients with hypertensive retinopathy. Moreover, Ang II-infused WT mice showed an increase in the central retinal thickness, vascular permeability, reactive oxygen species (ROS) production and inflammation compared with saline controls, and these effects were significantly attenuated in LMP10 KO mice, but were aggravated in mice intravitreally injected with rAAV2-LMP10. Interestingly, administration of IKKβ specific inhibitor IMD-0354 remarkably blocked an Ang II-induced increase in vascular permeability, oxidative stress and inflammation during retinopathy. Mechanistically, Ang II-induced upregulation of LMP10 promoted PTEN degradation and activation of AKT/IKK signaling, which induced IkBα phosphorylation and subsequent degradation ultimately leading to activation of NF-kB target genes in retinopathy. Therefore, this study provided novel evidence demonstrating that LMP10 is a positive regulator of NF-kB signaling, which contributes to Ang II-induced retinopathy. Strategies for inhibiting LMP10 or IKKβ activity in the eye could serve as a novel therapeutic target for treating hypertensive retinopathy.

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“…Therefore, we screened multiple related compounds and found that N-(3,5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxybenzamide (IMD 0354) is a non-ATP binding competitive and selective molecular inhibitor of IKK-β. IMD 0354 has been reported in several studies as an effective agent for the treatment of acute and subacute inflammatory diseases including myocarditis, pulmonary arterial hypertension, and diabetic retinopathy via the suppression of NF-κB activation in various cells, such as pulmonary arterial smooth muscle cells or myocardial cells [18][19][20][21] . There are considerable issues in regard to the drugs for osteoporosis treatment currently.…”

Section: Introductionmentioning

confidence: 99%

The emerging role of IMD 0354 on bone homeostasis by suppressing osteoclastogenesis and bone resorption, but without affecting bone formation

et al. 2019

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Osteoporosis is caused by an imbalance between bone formation and bone resorption. Receptor activator of nuclear factor-κB ligand (RANKL) promotes the activity and differentiation of osteoclasts via activating the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. IMD 0354 is a selective molecular inhibitor of inhibitor of NF-κB kinase subunit beta (IKKβ) and effective for treatment of acute and subacute inflammatory diseases through the suppression of NF-κB activation. However, the effect of IMD 0354 on bone homeostasis is unknown. In this study, we demonstrated that IMD 0354 significantly attenuated ovariectomy-induced bone loss and inhibited osteoclastogenesis in mice, whereas bone formation was not affected. Additionally, IMD 0354 dramatically inhibited osteoclast differentiation and function induced by RANKL and macrophage colony-stimulating factor in bone marrow monocytes as verified by tartrate-resistant acid phosphatase (TRAP) staining as well as bone resorption assay in vitro. Subsequently, we found that activation of NF-κB signaling and the ERK/c-Fos axis were blunted during osteoclast formation induced by RANKL. Transcription factors nuclear factor of activated T cells c1 (NFATc1) and c-Fos were suppressed with the decreased expression of osteoclast-related genes by IMD 0354. Our findings suggest that IMD 0354 could be a potential preventive and therapeutic drug for osteoporosis.

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IκB Kinase-β Inhibitor IMD-0354 Beneficially Suppresses Retinal Vascular Permeability in Streptozotocin-Induced Diabetic Mice

Abstract: The present data indicate that NF-κB activation is the key step in the development of DR. Its suppression by IMD-0354 may present a promising therapeutic strategy for DR, especially in the early stages of the disease.

Cited by 18 publications

References 30 publications

Selective IKK2 inhibitor IMD0354 disrupts NF-κB signaling to suppress corneal inflammation and angiogenesis

Selective IKK2 inhibitor IMD0354 disrupts NF-κB signaling to suppress corneal inflammation and angiogenesis

The immunoproteasome subunit LMP10 mediates angiotensin II-induced retinopathy in mice

The emerging role of IMD 0354 on bone homeostasis by suppressing osteoclastogenesis and bone resorption, but without affecting bone formation

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