Neuroprotective effect of peroxynitrite decomposition catalyst and poly(adenosine diphosphate-ribose) polymerase inhibitor alone and in combination in rats with focal cerebral ischemia.
OBJECTIVE
The authors evaluated the neuroprotective effect of 5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphyrinato-iron(III) (FeTMPyP), a peroxynitrite decomposition catalyst, and 1,5-isoquinolinediol (ISO), a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, alone and in combination in rats with focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO).


METHODS
Male Sprague-Dawley rats were subjected to 2 hours of MCAO followed by 22 hours of reperfusion. Cerebral infarction and neurological deficits were estimated after ischemia. Intraperitoneal injections of FeTMPyP (1 and 2 mg/kg) and ISO (0.05 and 0.1 mg/kg) were administered alone or in combination in ischemic animals. The PARP activity in vehicle- and drug-treated groups was estimated using anti-poly(ADP-ribose) antibody in immunofluorescence and immunoblotting studies. Two hours of MCAO and 22 hours of reperfusion produced significant cerebral infarction and neurological deficits. Treatment with FeTMPyP (1 and 2 mg/kg) and ISO (0.05 and 0.1 mg/kg) produced a significant reduction in cerebral infarction and neurological deficits. Combination therapy (2 mg/kg FeTMPyP and 0.1 mg/kg ISO) enhanced the inhibition of ischemic volume (77.81+/-0.86%) compared with monotherapies (FeTMPyP 54.07+/-5.6% and ISO 53.06+/-3.88%). Immunoblotting and immunofluorescence studies showed PARP activation after ischemia, which was reduced by drug treatment.


CONCLUSIONS
Neuroprotection observed with FeTMPyP and ISO alone and in combination may be attributed to inhibition of the peroxynitrite-PARP cascade of cerebral ischemia/reperfusion injury.
Sharma
Shyam S
SS
Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Punjab, India. sssharma@niper.ac.in
Munusamy
Shankar
S
Thiyagarajan
Meenakshisundaram
M
Kaul
Chaman L
CL
D000818:Animals; D002545:Brain Ischemia / Q000517:prevention & control* / Q000662:veterinary; D002539:Cerebral Arterial Diseases / Q000150:complications / Q000662:veterinary; D004359:Drug Therapy, Combination; D007546:Isoquinolines; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
C492721:5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphyrinato-iron(III); D007546:Isoquinolines; D008665:Metalloporphyrins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011804:Quinolines; C095653:1,5-dihydroxyisoquinoline