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R. Funk, E.-M. Kniep, C. Roehlecke, L. Knels; Protection of Neuronal Cells by the 2 Adrenergic Receptor Agonist UK 14,304. Invest. Ophthalmol. Vis. Sci. 2007;48(13):620.
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To investigate the neuroprotective capacity of UK 14,304 (brimonidine) with cells of a neuronal cell line and with rat retina organ cultures.
Rat retinae were freshly prepared and used immediately. For testing at the cellular level we used the mouse neuroblastoma - rat glioma hybrid cell line NG108-15, which expresses the α2B receptor. Cells and retinae were treated with either glyoxal or hydrogen peroxide to induce stress. In parts of the assays, UK 14,304 was added to retinae, or cell cultures, respectively, together with the stress inducing agents. The effects of glyoxal and hydrogen peroxide on the cells in the presence and in the absence of UK,14,304 were assessed by cell counts, binding of annexin V, determination of necrotic and apoptotic cells, measurement of cytosolic pH, analysis of ROS production, and investigation of changes in the mitochondrial membrane potential.
Treatment of NG108-15 cells with H2O2 led to loss of mitochondrial membrane potential, a decrease in proliferation and cytosolic pH, and to an increase in binding of annexin V, ROS production and necrosis in a concentration dependent manner (0.1 - 1.0 mM).All these manifestations of cell stress were reduced when UK 14,304 was present together with H2O2. Glyoxal (0.4 - 0.8 mM) led to similar indications of cell stress but the protective effect of UK 14,304 was less pronounced. With retina organ cultures, acidification of cytosol by treatment with either H2O2 or glyoxal was reduced by UK 14,304, accordingly, mitochondrial membrane potential was protected and ROS production inhibited. Clonidine, another α2 receptor agonist, had no protective capacities in our assays. Accordingly, yohimbine, which binds to α adrenergic receptors and inhibits their activation, could not reverse the protective effects of UK 14,304.
Agonists of the α2 adrenergic receptor are widely used to lower the intraocular pressure (IOP) of the glaucomatous eye. Recent evidence suggests that the rescue of retinal ganglion cells (RGC) observed after treatment with α2 adrenergic receptor agonists like UK 14,304 not only results from lowering the IOP but that there is a direct protection of the RGCs. With the present investigation we proved a direct influence of UK 14,304 on cells. Possibly the mechanism is not due to stimulation of the α2 adrenergic receptor.
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