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-κB. 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 Aβ, 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.

Complement Component C5a Primes Retinal Pigment Epithelial Cells for Inflammasome Activation by Lipofuscin-mediated Photooxidative Damage

“…The activation signal subsequently triggers assembly of NLRP3 and other protein components into the active inflammasome protein complex that results in caspase-1-mediated cleavage of pro-IL-1␤ and pro-IL-18 into mature IL-1␤ and IL-18. Several substances have been suggested to provide the inflammasome activation signal in AMD including drusen components such as C1q (13) and amyloid-␤ (14), Alu RNA accumulation secondary to DICER1 deficiency (8), the lipofuscin component Nretinylidene-N-retinyl-ethanolamine (A2E) (15), and the lipid peroxidation product 4-hydroxynonenal (HNE) (16). We have recently suggested an additional mechanism by demonstrating that photooxidative damage to the RPE, enhanced by accumulated lipofuscin, can activate the NLRP3 inflammasome by inducing lysosomal membrane permeabilization and cytosolic leakage of lysosomal enzymes (17,18).…”

Overexpression of Angiotensin-Converting Enzyme 2 Ameliorates Amyloid β-Induced Inflammatory Response in Human Primary Retinal Pigment Epithelium

“…40 It has been reported that a single intraocular injection of oligomeric Ab leads to overproduction of inflammatory cytokines and activation of nuclear factor (NF)-jB signaling in the RPE in rats. 38,41 This model may become useful for exploring the potential mechanisms involved in the early phases of AMD. Here, in agreement with Cao et al, 7 we further demonstrated Ab is an inducer of inflammatory responses in human RPE cells in vitro.…”

“…7,38 Briefly, 1 mg lyophilized Ab1-42 or Ab42-1 (reverse peptide) was dissolved in 400 lL 1,1,1,3,3,3-Hexafluoro-2-propanol (HFIP) and incubated overnight at 48C. Of the resulting seedless solution, 100 lL was subjected to a gentle stream of nitrogen for 5 to 10 minutes to evaporate the HFIP and incubated the peptide in 100% dimethyl sulfoxide at 2 mM for 15 minutes at room temperature with periodic vortexing at moderate speed.…”

Кавинтон (Винпоцетин): Новые Возможности Клинического Применения

“…Ïðåïàðàò ñíèaeàë óðîâåíü öèòîêèíîâ è â ñòåêëîâèäíîì òåëå. Ïî-âèäè-ìîìó, áëîêàäà ñèñòåìû NF-kÂ, íàáëþäàåìàÿ ïðè ïðè-ìåíåíèè âèíïîöåòèíà, ìîaeåò áûòü ýôôåêòèâíûì ñïî-ñîáîì ïðîôèëàêòèêè è ëå÷åíèÿ ÂÌÄ [41].…”