Increased expression and activation of poly(ADP-ribose) polymerase (PARP) contribute to retinal ganglion cell death following rat optic nerve transection.
Excessive activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) by free-radical damaged DNA mediates necrotic cell death in injury models of cerebral ischemia-reperfusion and excitotoxicity. We recently reported that secondary retinal ganglion cell (RGC) death following rat optic nerve (ON) transection is mainly apoptotic and can significantly but not entirely be blocked by caspase inhibition. In the present study, we demonstrate transient, RGC-specific PARP activation and increased retinal PARP expression early after ON axotomy. In addition, intravitreal injections of 3-aminobenzamide blocked PARP activation in RGCs and resulted in an increased number of surviving RGCs when compared to control animals 14 days after ON transection. These data indicate that secondary degeneration of a subset of axotomized RGCs results from a necrotic-type cell death mediated by PARP activation and increased PARP expression. Furthermore, PARP inhibition may constitute a relevant strategy for clinical treatment of traumatic brain injury.
Weise
J
J
Department of Neurology, University of Tübingen Medical School, D-72076 Tübingen, Germany. jweise@gwdg.de
Isenmann
S
S
Bähr
M
M
D000818:Animals; D019771:Axotomy; D001549:Benzamides / Q000494:pharmacology; D001930:Brain Injuries / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D009336:Necrosis; D018696:Neuroprotective Agents / Q000494:pharmacology; D009900:Optic Nerve / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D012183:Retrograde Degeneration / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D014822:Vitreous Body / Q000187:drug effects / Q000502:physiology
D001549:Benzamides; D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C025160:3-aminobenzamide; D011065:Poly(ADP-ribose) Polymerases