Infliximab reduces Zaprinast-induced retinal degeneration in cultures of porcine retina.

Abstract

BACKGROUND:

cGMP-degrading phosphodiesterase 6 (PDE6) mutations cause around 4 to 5% of retinitis pigmentosa (RP), a rare form of retinal dystrophy. Growing evidence suggests that inflammation is involved in the progression of RP. The aims of this study were to corroborate the presence of high TNFα concentration in the eyes of RP patients and to evaluate whether the blockade of TNFα with Infliximab, a monoclonal anti-TNFα antibody, prevented retinal degeneration induced by PDE6 inhibition in cultures of porcine retina.

METHODS:

Aqueous humor from 30 patients with RP and 13 healthy controls were used to quantify the inflammatory mediators IL-6, TNFα, IL-1β, IL-10 by a multiplex enzyme-linked immunosorbent assay (ELISA) system. Retinal explants from pig were exposed to Zaprinast, a PDE6 inhibitor, for 24 hours in the absence or the presence of Infliximab. Cell death was evaluated by TUNEL assay. The number and distribution of caspase-3 positive cells, indirect poly(ADP)ribose polymerase (PARP) activation and glial fibrillary acidic protein (GFAP) content were visualized by immunolabeling. Antioxidant total capacity, nitrites and thiobarbituric acid reactive substances (TBARS) formation were determined to evaluate antioxidant-oxidant status.

RESULTS:

IL-6 and TNFα concentrations were higher in the aqueous humor of RP patients than in controls. Infliximab prevented retinal degeneration, as judging by the reduced presence of TUNEL-positive cells, the reduction of caspase-3 activation and also reduction of glial activation, in an ex vivo model of porcine retina. Additionally, Infliximab partially reduced oxidative stress in retinal explants exposed to Zaprinast.

CONCLUSIONS:

Inflammatory mediators IL-6 and TNFα were elevated in the aqueous humor of RP patients corroborating previous studies suggesting sustained chronic inflammation. Our study suggests that TNFα is playing an important role in cell death in an ex vivo model of retinal degeneration by activating different cell pathways at different cell layers of the retina that should be further studied.

• Authors: Cristina Martínez-Fernández de la Cámara, Lorena Olivares-González, David Hervás, David Salom, José M Millán, Regina Rodrigo
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 11 Pg. 172 (Oct 10 2014) ISSN: 1742-2094 [Electronic] England
• PMID: 25301432 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antibodies, Monoclonal
• Interleukin-6
• Phosphodiesterase Inhibitors
• Purinones
• Tumor Necrosis Factor-alpha
• Infliximab
• zaprinast

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Antibodies, Monoclonal (pharmacology)
• Aqueous Humor (immunology)
• Cells, Cultured
• Enzyme-Linked Immunosorbent Assay
• Female
• Humans
• In Situ Nick-End Labeling
• Infliximab
• Interleukin-6 (immunology)
• Male
• Middle Aged
• Phosphodiesterase Inhibitors (toxicity)
• Purinones (toxicity)
• Retina (drug effects)
• Retinitis Pigmentosa (immunology)
• Swine
• Tumor Necrosis Factor-alpha (immunology)