Neuroprotective effects of KCL-440, a new poly(ADP-ribose) polymerase inhibitor, in the rat middle cerebral artery occlusion model

• Published in: Brain research 2005-10, Vol.1060 (1), p.73-80
• Main Authors: Ikeda, Yasuhiko, Hokamura, Kazuya, Kawai, Tomoyuki, Ishiyama, Junichi, Ishikawa, Kumi, Anraku, Tsuyoshi, Uno, Takashi, Umemura, Kazuo
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Brain - drug effects; Brain - pathology; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - analysis; Enzyme Inhibitors - pharmacokinetics; Infarction, Middle Cerebral Artery - drug therapy; Male; Medical sciences; Neurology; Neurons - drug effects; Neuropharmacology; Neuroprotection; Neuroprotective agent; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - analysis; Neuroprotective Agents - pharmacokinetics; Pharmacology. Drug treatments; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases - drug effects; Rats; Rats, Sprague-Dawley; Stroke; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2005.08.046

It is reported that ischemic brain injury is mediated by the activation of poly(ADP-ribose) polymerase (PARP). In this study, we examined the pharmacological profile of KCL-440, a new PARP inhibitor, and its neuroprotective effects in the rat acute cerebral infarction model induced by photothrombotic middle cerebral artery (MCA) occlusion. In an in vitro study, KCL-440 exhibited potency with regard to inhibition of PARP activity, with an IC 50 value of 68 nM. An in vivo pharmacokinetic study showed that the brain concentration of KCL-440 was sufficient to inhibit PARP activity during the intravenous infusion of KCL-440 at the rate of 1 mg/kg/h. KCL-440 at various doses or saline was administered for 24 h immediately after the MCA occlusion. Administration of KCL-440 led to a dose-dependent reduction in the infarct size at 24 h after MCA occlusion. Infarct sizes were 44.8% ± 3.0% ( n = 8), 40.5% ± 1.1% ( n = 8), 38.2% ± 1.4% ( n = 8), 35.1% ± 2.1% ( n = 8), 34.2% ± 2.3% ( n = 7), 32.6% ± 1.9% ( n = 8), and 31.0% ± 2.1% ( n = 5) at doses of 0, 0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg/h. When compared to the control group, a statistically significant difference was observed in the doses that were higher than 0.03 mg/kg/h. When the infusion of KCL-440 (1 mg/kg/h, n = 8) was started at 1 h after the MCA occlusion, a significant reduction in infarct size was observed; this was not observed when KCL-440 infusion was started 2 or 3 h after the MCA occlusion. Furthermore, increased poly(ADP-ribose) immunostaining was confirmed at the ischemic border zone 2 h after the MCA occlusion, and it was reduced by KCL-440 treatment. These results suggest that KCL-440 is a possible neuroprotective agent with high blood–brain barrier permeability and high PARP inhibitory activity.