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Cheng-mao Lin, Steven F. Abcouwer, Sumathi Shanmugam, Alistair J. Barber, Thomas W. Gardner, David A. Antonetti; Alpha2-Adrenergic Receptor Agonists Alleviate Retinal Vascular Permeability and Neurodegeneration in Ischemia-Reperfusion Injury. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1379.
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The alpha2-adrenergic receptor (α2AR) agonist brimonidine is used to treat glaucoma and exhibits neuroprotective potential beyond its ability to reduce intraocular pressure. In the retinal ischemia-reperfusion (IR) injury model brimonidine prevents loss of electroretinography (ERG) response and retinal layer thinning. Guanfacine is another α2AR agonist that is highly selective for the α2A receptor subtype and exhibits a long in vivo half-life. Using the retinal IR injury model, we compared the protective effects of brimonidine and guanfacine on retinal cell death and vascular permeability.
Male Brown-Norway rats were treated by intraperitoneal injections with either brimonidine (1 mg per kg) or guanfacine (2 mg per kg). Ischemia was induced in one eye for 45 min while the contralateral eye served as the sham control. At different times of reperfusion, two functional assays, DNA fragmentation and Evan’s blue dye accumulation, were performed to assess apoptosis and vascular permeability, respectively.
Retinal DNA fragmentation and Evan’s blue dye accumulation were both significantly reduced by three consecutive brimonidine treatments at -24h, -1h and +24h, relative to ischemia induction. However, whereas a single injection of brimonidine at 1h before ischemia effectively inhibited DNA fragmentation it had a minimal effect on vascular permeability. In contrast, a single injection of guanfacine at 1h before ischemia, demonstrated significant ability to prevent both apoptosis and vascular permeability.
Brimonidine and guanfacine both inhibited neuronal and vascular responses to IR. However, repeated injections of brimonidine were necessary to afford vascular protection, but not neuroprotection. This suggests that a continual presence of the α2AR agonist is necessary to inhibit the vascular response and that cell death and vascular permeability are separable responses to IR. The α2A adrenergic receptor is a potential target for development of treatments for eye diseases involving neurodegeneration and macular edema.
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