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.
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-4H-1-benzopyran-4-one (Ly 294002). The accumulation of Nepsilon-[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.
Knels
Lilla
L
Institute of Anatomy, Medical Faculty Carl Gustav Carus, Technische Universitat, Dresden, Germany. lilla.knels@mailbox.tu-dresden.de
Worm
Maximilian
M
Wendel
Martina
M
Roehlecke
Cora
C
Kniep
Eva
E
Funk
Richard H W
RH
D000818:Animals; D000068438:Brimonidine Tartrate; D005260:Female; D017127:Glycation End Products, Advanced / Q000819:agonists / Q000096:biosynthesis*; D006037:Glyoxal / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D017127:Glycation End Products, Advanced; D018696:Neuroprotective Agents; D011810:Quinoxalines; D017382:Reactive Oxygen Species; D000068438:Brimonidine Tartrate; D006037:Glyoxal; D006861:Hydrogen Peroxide