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Effects of advanced glycation end products‐inductor glyoxal and hydrogen peroxide as oxidative stress factors on rat retinal organ cultures and neuroprotection by UK‐14,304
Author(s) -
Knels Lilla,
Worm Maximilian,
Wendel Martina,
Roehlecke Cora,
Kniep Eva,
Funk Richard H. W.
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05540.x
Subject(s) - microbiology and biotechnology , reactive oxygen species , neuroprotection , ganglion cell layer , oxidative stress , chemistry , mitochondrion , biochemistry , biology , pharmacology , retinal
Abstract Retinal ganglion cell degeneration is supposed to be mediated by reactive oxygen species (ROS) and advanced glycation end products (AGEs). The alpha2‐adrenergic agonist, 5‐bromo‐ N ‐(4,5‐dihydro‐1H‐imidazol‐2‐yl)‐6‐quinoxalinamine (brimonidine; UK‐14,304), is said to exert a neuroprotective effect. To investigate these mechanisms in detail, we exposed rat whole mounts to glyoxal or H 2 O 2 and treated them with either UK‐14,304 alone or additionally with the phosphatidylinositide 3 kinase (PI3) kinase inhibitor, 2‐(4‐Morpholinyl)‐8‐phenyl‐4 H ‐1‐benzopyran‐4‐one (Ly 294002). The accumulation of Nε‐[carboxymethyl] lysine (CML) was assessed immunohistochemically and changes in intracellular pH (pHi), mitochondrial transmembrane potential (MTMP) and ROS production in cell bodies of multipolar ganglion cell layer were studied by intravital fluorescence microscopy and confocal laser scanning microscopy. Ultrastructural changes in mitochondria of multipolar ganglion cell layer cell bodies were determined by transmission electron microscopy. We found that glyoxal and H 2 O 2 increased accumulation of CML‐modified proteins and ROS production and decreased pHi and MTMP in cell bodies of multipolar ganglion cell layer. UK‐14,304 could prevent production of ROS, accumulation of CML‐modified proteins, ameliorate acidification, preserve MTMP and attenuate ultrastructural damages of ganglion cell mitochondria. Ly 294002 reversed the UK‐14,304‐mediated attenuation of CML and ROS production. We conclude that the protective effects of UK‐14,304 seem partly to be mediated by PI3 kinase‐dependent pathways.