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

ABSTRACT

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 IC50 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.