Poly(ADP-ribose) polymerase during reperfusion after transient forebrain ischemia: its role in brain edema and cell death.
The activation of poly(ADP-ribose) polymerase (PARP) in the reperfused brain after ischemia has been assumed but never has been directly presented. Our studies indicate a different dynamic of PARP activity alteration in hippocampus during reperfusion after 3 and 10 min of transient forebrain ischemia in gerbils. The phasic stimulation of PARP activity was observed during reperfusion 15 min, 120 min, and 4 d after 3 min of ischemia with subsequent lowering of its activity close to control value on the seventh day of reperfusion. After 10 min of ischemic insult, PARP activity significantly increased from the third to the seventh day of reperfusion. The protein level of PARP was not significantly changed during reperfusion after 3 and 10 min of ischemia, with one exception: On the third day after 10 min of ischemia, PARP protein level was 28% lower compared to control; however, no enhancement of 85-kDa protein immunoreactivity was observed. These data indicate the lack of PARP cleavage in hippocampus of gerbils subjected to ischemia-reperfusion injury. The inhibitor of PARP, 3-aminobenzamide (3-AB) in a dose of 30 mg/kg b.w. (body weight) injected intravenously directly after 3 min of ischemia protects >60% of neuronal cells against death in the CA1 layer of hippocampus but has no effect after 10 min of ischemic episode. 3-AB decreased forebrain edema significantly after 3 and 10 min of ischemia. Our data indicate that PARP inhibitor(s) might offer a potent therapeutic strategy for short global ischemia. The combination of PARP inhibitor with potent antioxidant might enhance its ameliorating effect.
Strosznajder
Robert P
RP
Department of Neurophysiology, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland. roberts@cmdik.pan.pl
Gadamski
Roman
R
Czapski
Grzegorz A
GA
Jesko
Henryk
H
Strosznajder
Joanna B
JB
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004334:Drug Administration Schedule; D004487:Edema / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D008297:Male; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D016548:Prosencephalon / Q000098:blood supply / Q000201:enzymology* / Q000503:physiopathology; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D015427:Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D001549:Benzamides; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; C025160:3-aminobenzamide; D011065:Poly(ADP-ribose) Polymerases