Combinatorial-approached neuroprotection using pan-caspase inhibitor and poly (ADP-ribose) polymerase (PARP) inhibitor following experimental stroke in rats; is there additional benefit?
Energy requiring apoptosis and presumably unregulated necrosis are considered conceptually and morphologically distinct forms of cell death which have been initially identified as two exclusive pathways. However, several apoptotic characteristics have been observed in the necrotic core lesion in ischemia which led to the controversial theory that cell death advances via a number of hybrid pathways among a continuum between the two processes. ATP availability has been shown to influence the decision between apoptosis and necrosis. The aims of our study are 1) to determine if combined inhibitors administration of pan-caspase inhibitor Carbobenzoxy-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk) and non-selective poly (ADP-ribose) polymerase (PARP) inhibitor 3-aminobenzamide (3-AB) can further reduce infarct volume compared to single modality of either inhibitor following ischemic insult, 2) to ascertain the pharmacological intervention up to 24 hour post-middle cerebral artery occlusion (MCAo), and 3) to correlate intracellular ATP level with infarct volume. Single modality treatment was optimised at 3 mg/kg z-VAD-fmk and 30 mg/kg 3-AB with infarct volume measured at 24.13%+/-3.89% and 26.98%+/-2.22% respectively, while untreated control group was determined at 45.97%+/-1.86%. Combined inhibitors treatment rendered further reduction in infarct volume, measuring 7.228%+/-1.988%, 21.02%+/-1.06%, 24.40%+/-2.12% at 30 min, 6 h, 24 h post-ischemia respectively. In conclusion, the combined inhibitors administration of both z-VAD-fmk and 3-AB show further increased in infarct volume reduction with our ischemic model up to the 24 hour post-MCAo. However, in our in vivo study, no correlation between intracellular ATP level and infarct size was established.
Yap
Elgin
E
Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, MD10, 4 Medical Drive, Singapore 117597.
Tan
Wan-Loo
WL
Ng
Ivan
I
Ng
Yee-Kong
YK
D000255:Adenosine Triphosphate / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000008:administration & dosage*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001549:Benzamides / Q000008:administration & dosage*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism*; D002544:Cerebral Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004359:Drug Therapy, Combination; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D008297:Male; D009336:Necrosis / Q000201:enzymology / Q000517:prevention & control; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
D000590:Amino Acid Chloromethyl Ketones; D001549:Benzamides; D004791:Enzyme Inhibitors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C025160:3-aminobenzamide; D000255:Adenosine Triphosphate; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases