KRN-633 / Kyowa Kirin - LARVOL DELTA

Lutein Emulsion Stabilized by a Food-Grade Biopolymer Enhanced Lutein Bioavailability and Improved Retinal Vessel Morphology in Neonatal Rats with Retinopathy of Prematurity. (PubMed, J Nutr) - "Lutein, in both unemulsified and emulsified forms, effectively inhibited ROP progression in neonatal rats. The biopolymer-based lutein emulsion showed promise as a delivery system to enhance lutein bioavailability and mitigate ROP in preterm infants."

Journal • Preclinical • Ophthalmology • Retinal Disorders • Retinopathy of Prematurity • CDKN1A

Repeated treatment with VEGF receptor inhibitors induces phenotypic changes in endothelial cells and pericytes in the rat retina. (PubMed, Microvasc Res) - "KRN633 (10 mg/kg), a VEGF receptor tyrosine kinase inhibitor, was subcutaneously administered on postnatal day (P)-7 and P8 (first round), P14 and P15 (second round), and P21 and P22 (third round)...Overall, these results revealed that repeated interruption of VEGF receptor signaling pathway altered the phenotypes of endothelial cells and pericytes and induced anti-VEGF drug resistance. Therefore, careful follow-up is necessary when using anti-VEGF drugs to treat abnormal angiogenesis-associated ocular diseases."

Journal • Preclinical • Ophthalmology • CDKN1A

Role of mammalian target of rapamycin in the formation and progression of retinopathy of prematurity-like vascular abnormalities in neonatal rats. (PubMed, Microvasc Res) - "To induce ROP-like vascular abnormalities, rats were subcutaneously treated with KRN633, an inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinase, on postnatal day 7 (P7) and P8...These results suggest that activation of the mTORC1 pathway in proliferating endothelial cells contributes to the appearance and progression of ROP-like retinal blood vessels. Therefore, inhibition of mTORC1 may be a promising approach for selectively targeting abnormal retinal blood vessels in ROP."

Journal • Preclinical • Ophthalmology • Retinal Disorders • Retinopathy of Prematurity • CDKN1A • mTOR

Platelet rich plasma affects gap junctional features in myofibroblasts in vitro via Vascular Endothelial Growth Factor (VEGF)-A/VEGF receptor. (PubMed, Exp Physiol) - "VEGF-A neutralization by blocking antibodies or pharmacological VEGFR inhibition by KRN633 in TGF-β1-treated fibroblasts prevented the PRP-promoted effects such as the reduction of voltage-dependent transjunctional currents in cell pairs and a decreased expression of connexin (Cx) 43, the typical Cx isoform forming voltage-dependent connexons...The results obtained when cells were differentiated using KRN633 alone suggest an antagonistic cross-talk between TGF-?1 and VEGFR. In conclusion, this study identifies for the first time GJ currents as crucial targets in the VEGF-A/VEGFR-mediated antifibrotic pathway and contributes to bring new insights into mechanisms behind PRP action on preventing fibroblast to myofibroblast differentiation."

Journal • Preclinical • Fibrosis • Immunology • TGFB1 • VCL • VEGFA

Impairment of endothelium-dependent vasodilator function of retinal blood vessels in adult rats with a history of retinopathy of prematurity. (PubMed, J Pharmacol Sci) - "ROP was induced in rats by subcutaneous injection of a vascular endothelial growth factor receptor tyrosine kinase inhibitor (KRN633) on postnatal day (P) 7 and P8...These results suggest that the production of and/or release of NO is impaired in retinal blood vessels in adult rats with a history of ROP. A history of ROP might increase the risk of impaired retinal circulation in adulthood."

Journal • Preclinical • Retinal Disorders • Retinopathy of Prematurity

Coupling between macrophage phenotype, angiogenesis and bone formation by calcium phosphates. (PubMed, Mater Sci Eng C Mater Biol Appl) - "Bone formation was observed histologically in TCP-S 6 weeks after implantation, and bone formation was inhibited when an angiogenesis inhibitor (KRN633) was loaded onto TCP-S...This manuscript presented demonstrates strong links between surface topography, macrophage polarization, angiogenesis and bone formation in CaP materials implanted in non-osseous sites. The finding may provide new clues for further exploring the possible mechanism underlying osteoinduction by CaP materials."

Journal • Immunology • Inflammation • IL10 • TGFB1

Changes in components of the neurovascular unit in the retina in a rat model of retinopathy of prematurity. (PubMed, Cell Tissue Res) - "Neonatal rats were treated subcutaneously with the vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor KRN633 (10 mg/kg) on postnatal day (P) 7 and P8 to induce ROP...The developmental cell death was slightly accelerated in ROP rats; however, no visible changes in the morphology of retinal layers were observed on P35. The abnormalities in astrocytes might contribute, at least in part, to the formation of abnormal retinal blood vessels and the pathogenesis of ROP."

Journal • Preclinical • Ophthalmology • Retinal Disorders • Retinopathy of Prematurity

Pharmacological depletion of retinal neurons prevents vertical angiogenic sprouting without affecting the superficial vascular plexus. (PubMed, Dev Dyn) - "Our results suggest that inner retinal neurons play a crucial role in forming the deep vascular plexus by directing the sprouts from the superficial blood vessels to the deep layer."

Journal • FN1

The process of revascularization in the neonatal mouse retina following short-term blockade of vascular endothelial growth factor receptors. (PubMed, Cell Tissue Res) - "After the completion of a 2-day treatment with the VEGF receptor tyrosine kinase inhibitor KRN633 on postnatal day (P) 4 and P5, revascularization started on P8 in the central avascular area where capillaries had been dropped out...Mechanistic analysis revealed that higher levels of VEGF attenuated the migratory response of endothelial cells without decreasing the proliferative activity. These results suggest that the presence of concentration range of VEGF, which enhances both migration and proliferation of the endothelial cells, and the structurally normal fibronectin network contribute to determine the proper direction of angiogenesis."

Journal • Preclinical

Abnormal Vascular Phenotypes Associated with the Timing of Interruption of Retinal Vascular Development in Rats. (PubMed, Biol Pharm Bull) - "Vascular defects of two different degrees were created in the retina by subcutaneously treating neonatal rats with the VEGF receptor (VEGFR) tyrosine kinase inhibitor KRN633 on postnatal day (P) 4 and P5 (P4/5) or P7 and P8 (P7/8)...These results suggest that an interruption of the retinal vascular development at different time points induces different vascular pathological features in the retina. Pharmacological agents targeting the VEGF signaling pathway are useful for creating an abnormal retinal vasculature with various pathological features in order to evaluate the efficacy of anti-angiogenic compounds."

Journal • Preclinical

The in vitro effect of VEGF receptor inhibition on primary alveolar osteoblast nodule formation. (PubMed, Aust Dent J) - "VEGF/VEGFR1 pathway appears to be important for intramembranous- derived osteoblast differentiation and maturation in vitro."

Journal • Preclinical • FLT1 • KDR

Cellular Mechanisms of Angiogenesis in Neonatal Rat Models of Retinal Neurodegeneration. (PubMed, Int J Mol Sci) - "The re-vascularization was suppressed by a two-day treatment with KRN633, an inhibitor of VEGF receptor tyrosine kinase, on P21 and P22...During re-vascularization, angiogenic sprouts from pre-existing blood vessels were present along the network of fibronectins formed by astrocytes. These results suggest that glial cells contribute to angiogenesis in neonatal rat models of retinal neurodegeneration."

Journal • Preclinical

Attenuation of Retinal Endothelial Vasodilator Function in a Rat Model of Retinopathy of Prematurity. (PubMed, Curr Eye Res) - "... ROP was induced in rats by the subcutaneous injection of the vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor KRN633 (10 mg/kg) on postnatal day (P) 7 and P8... Phenotypic changes in pericytes occur in the ROP model rats and endothelium-dependent vasodilatory mechanisms in retinal blood vessels are impaired. The impaired vasodilator function may contribute to the progression and pathogenesis of ROP."

Journal • Preclinical