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S.J. McKinnon, L. Kasmala; Chronic Intravitreal Administration of Rat TNF– Inhibitor (Infliximab) Does Not Protect Optic Nerve Axons in a Hypertensive Rat Model of Glaucoma . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3922.
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Infliximab (Remicade®; Centocor, Inc., Horsham, PA) is a chimeric IgG1 monoclonal antibody that targets and binds to tumor necrosis factor alpha (TNF–α), and is used clinically to treat rheumatoid arthritis and inflammatory bowel disease. We sought to determine the neuroprotective effect of intravitreal infliximab administration on rat optic nerves subjected to chronic ocular hypertension (COH).
60 brown Norway rats were treated in the right eye to induce COH by the Morrison method of limbal injection of hypertonic (2.0 M) saline. The animals were then split into two treatment groups, receiving bi–weekly trans–scleral intravitreal injections using a pulled, beveled glass microcannula. The control and treatment groups received 2 µl of 10 mg/ml of rat IgG1 and infliximab, respectively. IOP was recorded weekly for 14 weeks with a calibrated Tonopen XL. After sedation, treated and control eyes were enucleated, and optic nerve cross–sections stained with toluidine blue. Axon counts were obtained in a masked fashion using the KS400 imaging system (Zeiss). Axon counts for treated and control eyes were obtained, and % axon survival (treated/control axon counts) for each rat were calculated. % axon survivals for the two groups were tested for significance with Student’s t–test.
18 rats from the both the control and treatment groups converted to COH (IOP integral > 200 mm–days), for an overall conversion rate of 60% (36/60). Mean IOP integrals for the control and treatment groups were 490 and 487 mm–days, respectively. One–way ANOVA showed no significant difference between the two groups in IOP integral distribution (P=0.99), indicating equivalent levels of IOP exposure between the two groups. The two groups showed average axon counts of: IgG control: 86,961 ± 27072 (right eye; mean ± SD), 116,736 ± 16891 (left eye); infliximab: 81,008 ± 24,115 (right eye), 121,596 ± 17,857 (left eye). The two groups showed average % axon survivals (treated/control axon counts) of: IgG control: 75.0% ± 23.0% (mean ± SD); infliximab: 68.3% ± 23.1%. One–way ANOVA showed no significant treatment difference between the two groups in % axon survival (P=0.56).
There was no significant neuroprotective effect of chronic intravitreal administration of a rat version of the TNF–α inhibitor infliximab. Systemic (sub–cutaneous) administration may provide higher optic nerve head levels of TNF–α inhibition with infliximab, and this study is now ongoing.
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