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Discovery of novel L-type voltage-gated calcium channel blockers and application for the prevention of inflammation and angiogenesis
Department of Ophthalmology, School of Medicine, University of Missouri-Columbia, Columbia, USA.
Department of Ophthalmology, School of Medicine, University of Missouri-Columbia, Columbia, USA.
Linköping University, Department of Biomedical and Clinical Sciences, Division of Sensory Organs and Communication. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.ORCID iD: 0000-0002-9645-8942
Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO, USA.
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2020 (English)In: Journal of Neuroinflammation, E-ISSN 1742-2094, Vol. 17, no 1, article id 132Article in journal (Refereed) Published
Abstract [en]

Background The ways in which microglia activate and promote neovascularization (NV) are not fully understood. Recent in vivo evidence supports the theory that calcium is required for the transition of microglia from a surveillance state to an active one. The objectives of this study were to discover novel L-type voltage-gated channel (L-VGCC) blockers and investigate their application for the prevention of inflammation and angiogenesis. Methods Pharmacophore-based computational modeling methods were used to screen for novel calcium channel blockers (CCBs) from the ZINC compound library. The effects of CCBs on calcium blockade, microglial pro-inflammatory activation, and cell toxicity were validated in BV-2 microglial cell and freshly isolated smooth muscle cell (SMC) cultures. Laser-induced choroidal neovascularization (NV) and the suture-induced inflammatory corneal NV models of angiogenesis were used for in vivo validation of the novel CCBs. CX3CR1(gfp/+) mice were used to examine the infiltration of GFP-labeled microglial cells. Results We identified three compounds from the ZINC database (Zinc20267861, Zinc18204217, and Zinc33254827) as new blockers of L-type voltage-gated calcium channels (L-VGCC) using a structure-based pharmacophore approach. The effects of the three CCBs on Ca2+ influx into cells were verified in BV-2 microglial cells using Fura-2 fluorescent dye and in freshly isolated SMCs using the voltage-patch clamp. All three CCBs reduced microglial cell migration, activation stimulated by lipopolysaccharide (LPS), and reduced the expression of the inflammatory markers NF-kappa B (phospho-I kappa B alpha) and cyclooxygenase-2 (COX-2) as well as reactive oxygen species. Of the three compounds, we further examined the in vivo activity of Zinc20267861. Topical treatment with Zinc20267861 in a rat model of suture-induced inflammatory cornea neovascularization demonstrated efficacy of the compound in reducing monocyte infiltration and overall corneal NV response. Subconjunctival administration of the compound in the choroidal NV mouse model effectively prevented CNV and microglial infiltration. Conclusions Our findings suggest that the novel CCBs identified here are effective anti-inflammatory agents that can be further evaluated for treating NV disorders and can be potentially applied in the treatment of ocular inflammatory and pathological angiogenetic disorders.

Place, publisher, year, edition, pages
BMC , 2020. Vol. 17, no 1, article id 132
Keywords [en]
Angiogenesis; Calcium; Inflammation; L-VGCC; Microglia; Neovascularization; Pharmacophore; Retina; Smooth muscle cells
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:liu:diva-165951DOI: 10.1186/s12974-020-01801-9ISI: 000529995100001PubMedID: 32334630OAI: oai:DiVA.org:liu-165951DiVA, id: diva2:1434924
Note

Funding Agencies|NIH R01 grantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [EY027824]; University of Missouri start-up fund (Hu Huang research group); Ogonfonden award (Neil Lagali research group, Linkoping University, Linkoping, Sweden)

Available from: 2020-06-04 Created: 2020-06-04 Last updated: 2024-03-06Bibliographically approved

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Mukwaya, AnthonyLagali, Neil S

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Division of Sensory Organs and CommunicationFaculty of Medicine and Health SciencesDepartment of Ophthalmology in Linköping
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