Inhibition of poly (ADP-ribose) polymerase and caspase-3, but not caspase-1, prevents apoptosis and improves spatial memory of rats with twice-repeated cerebral ischemia.
The effect of inhibition of PARP [(poly (ADP-ribose) polymerase], caspase-3 and caspase-1 on twice-repeated ischemia-induced apoptosis and memory impairment were examined. The twice repeated ischemia was induced by four-vessel occlusion method in which a 10 min ischemic episode was repeated once after 60 min. The spatial memory was assessed using 8-arm radial maze. The results of this study showed that the repeated ischemia impaired memory and induced apoptosis in hippocampus CA1 field after 7 days. Moreover, 3-aminobezamide (10 mg/kg i.v.), a PARP inhibitor, and Ac-DEVD-CHO (8.4 microg/5 microL i.c.v., bilaterally), a caspase-3 inhibitor, decreased apoptosis by 45% and 58% respectively. Both drugs reduced the error choices, but 3-aminobezamide additionally increased the correct choices and improved the memory when either drug was injected immediately after the ischemic insult. The results also showed that inhibition of interleukin-1beta-converting enzyme, ICE (caspase-1) by Z-ASP-DCB-CH2 (100 microg/kg i.c.v., bilaterally) neither decreased apoptosis (13% reduction) nor improved memory of the ischemic rats. These results suggest that direct inhibition of PARP and caspase-3, but not of caspase-1, prevents apoptosis and improves spatial memory impaired by repeated ischemia.
Hatip-Al-Khatib
Izzettin
I
Department of Pharmacology, Division of Internal Medicine, Faculty of Medicine, Pamukkale, University, Denizli, Turkey. izhatip@yahoo.com
Iwasaki
Katsunori
K
Chung
Eun-hee
EH
Egashira
Nobuaki
N
Mishima
Kenichi
K
Fujiwara
Michihiro
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D002545:Brain Ischemia / Q000503:physiopathology; D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D004305:Dose-Response Relationship, Drug; D020287:In Situ Nick-End Labeling; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy*; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017208:Rats, Wistar
D001549:Benzamides; D061945:Caspase Inhibitors; D009842:Oligopeptides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; C025160:3-aminobenzamide; C505410:Casp3 protein, rat; D053148:Caspase 3; D020170:Caspase 1