title: Vinpocetine inhibits amyloid-beta induced activation of NF-κB, NLRP3 inflammasome and cytokine production in retinal pigment epithelial cells.
abstract: Chronic inflammation is a key pathogenic process in age-related macular degeneration (AMD). Amyloid-beta (Aβ) is a constituent of AMD drusen and promotes the activation of NLRP3 inflammasome which facilitates the production of cytokines. We investigated the role of transcription factor NF-κB in the activation of inflammasome in the RPE and the effect of vinpocetine, a dietary supplement with inhibitory effect on NF-κΒ. ARPE19/NF-κB-luciferase reporter cells treated with Aβ demonstrated enhanced NF-κB activation that was significantly suppressed by vinpocetine. Intraperitoneal injection of vinpocetine (15 mg/kg) inhibited NF-κB nuclear translocation and reduced the expression and activation of NLRP3, caspase-1, IL-1β, IL-18, and TNF-α in the RPE of adult rats that received intraocular Αβ, as measured by retinal immunohistochemistry and Western blot. Cytokine level in the vitreous was assayed using multiplex suspension arrays and revealed significantly lower concentration of MIP-3α, IL-6, IL-1α, IL-1β, IL-18, and TNF-α in vinpocetine treated animals. These results suggest that the NF-κB pathway is activated by Aβ in the RPE and signals the priming of NLRP3 inflammasome and the expression of pro-inflammatory cytokines including the inflammasome substrates IL-1β and IL-18. NF-κB inhibition may be an effective approach to stem the chronic inflammatory milieu that underlies the development of AMD. Vinpocetine is a potentially useful anti-inflammatory agent that is well-tolerated in long term use.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Ruozhou Tom
authors.initials: RT
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology and Visual Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Aikun
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology and Visual Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Eleanor
authors.initials: E
authors.lastname: To
authors.affiliation: Department of Ophthalmology and Visual Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jiangyuan
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Ophthalmology and Visual Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Sijia
authors.initials: S
authors.lastname: Cao
authors.affiliation: Department of Ophthalmology and Visual Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jing Z
authors.initials: JZ
authors.lastname: Cui
authors.affiliation: Department of Ophthalmology and Visual Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada. Electronic address: jms@mail.ubc.ca.
authors.forename: Joanne A
authors.initials: JA
authors.lastname: Matsubara
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D016328:NF-kappa B / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D051381:Rats; D020318:Rats, Long-Evans; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*; D014748:Vinca Alkaloids / Q000494:pharmacology*; D014822:Vitreous Body / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D016207:Cytokines; D058847:Inflammasomes; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; D014748:Vinca Alkaloids; C013983:vinpocetine
keywords: AMD; NF-κB; RPE; amyloid-β; cytokine; inflammasome; vinpocetine