The neuroprotective effect of cerebral poly(ADP-ribose)polymerase inhibition in a rat model of global ischemia.
In the present study, the effect of poly(ADP-ribose) polymerase (PARP) inhibition on rat cortical energy state was investigated at 24 h after global cerebral ischemia induced by permanent bilateral common carotid artery ligation plus transient hypotension. The specific PARP inhibitor 3-aminobenzamide was injected 10 min before induction of ischemia at a dosage of 5, 10, and 20 mg/kg intracerebroventricularly. Twenty-four hours after ischemia cortical PARP enzyme activity increased from 0.425+/-0.144 to 0.794+/-0.193 units/mg protein. Cerebral ischemia was associated by a decrease in adenosine triphosphate (ATP) and phosphocreatine concentrations to 72.5 and 76.8% of controls, respectively. In addition, an 1.9- and 2. 2-fold increase in adenosine monophosphate and adenosine was observed. Specific PARP inhibition with 10 mg/kg 3-aminobenzamide protected the rat energy state by preserving cortical phosphocreatine and NAD(+). Cortical ATP was not changed significantly after PARP inhibition. In conclusion, activation of the nuclear enzyme PARP plays an important role in cerebral energy metabolism during rat global ischemia. Therefore, specific PARP inhibition may offer new strategies in the therapy of vascular diseases such as stroke.
Plaschke
K
K
Clinic of Anesthesiology, University of Heidelberg, Im Neuenheimer Feld 110, D-69120, Heidelberg, Germany.
Kopitz
J
J
Weigand
M A
MA
Martin
E
E
Bardenheuer
H J
HJ
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy / Q000503:physiopathology; D001549:Benzamides / Q000494:pharmacology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology*; D017536:Carotid Artery, Common / Q000601:surgery; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D007022:Hypotension / Q000503:physiopathology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D001549:Benzamides; D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C025160:3-aminobenzamide; D011065:Poly(ADP-ribose) Polymerases