Neuroprotective effect of 4-amino-1,8-napthalimide, a poly(ADP ribose) polymerase inhibitor in middle cerebral artery occlusion-induced focal cerebral ischemia in rat.
In the present study, neuroprotective effect of 4-amino-1,8-napthalimide (4-ANI), a poly(ADP-ribose) polymerase (PARP) inhibitor was investigated in middle cerebral artery occlusion (MCAo)-induced focal ischemia. Sprague-Dawley rats were subjected to 2 h of middle cerebral artery occlusion followed by 22 h of reperfusion. After 22 h of reperfusion rats were evaluated for cerebral infarction, neurological deficits, brain NAD levels, and in situ terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL). Focal ischemia produced significant infarct volume (201 +/- 14 mm3), neurological scores (2 +/- 0.5) and 28 +/- 4.5% brain NAD depletion. Ischemia was associated with increased in TUNEL positive cells in brain sections indicating DNA fragmentation. 4-ANI treatment (1 and 3 mg/kg, i.p.) significantly decreased infarct volume to 35 +/- 7% and 70 +/- 6%, respectively. Neurological functions were also significantly improved at these doses. 4-ANI (3 mg/kg) completely reversed brain NAD depletion and significantly reduced the increase in the number of TUNEL positive cells. Nevertheless, 4-ANI treatment did not alter cerebral blood flow and blood pressure. Our study suggests 4-ANI is a potent neuroprotective agent in focal cerebral ischemia and its neuroprotective effects may be attributed to reduction of NAD depletion and DNA fragmentation.
Kabra
Dhiraj G
DG
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector 67, SAS Nagar Mohali, Punjab 160 062, India.
Thiyagarajan
Meenakshisundaram
M
Kaul
Chaman L
CL
Sharma
Shyam S
SS
D015057:1-Naphthylamine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008297:Male; D009243:NAD / Q000032:analysis; D053644:Naphthalimides; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects; D015363:Quinolones / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy
D004791:Enzyme Inhibitors; D053644:Naphthalimides; D018696:Neuroprotective Agents; D015363:Quinolones; D009243:NAD; C086538:4-amino-1,8-naphthalimide; D015057:1-Naphthylamine; D011065:Poly(ADP-ribose) Polymerases