We investigated the pharmacological profiles of
DR2313 [2-methyl-3,5,7,8-tetrahydrothiopyrano[4,3-d]
pyrimidine-4-one], a newly synthesized
poly(ADP-ribose) polymerase (
PARP) inhibitor, and its
neuroprotective effects on ischemic
injuries in vitro and in vivo.
DR2313 competitively inhibited poly(ADP-ribosyl)ation in nuclear extracts of rat brain in vitro (K(i) = 0.23 microM). Among several
NAD(+)-utilizing
enzymes,
DR2313 was specific for PARP but not selective between PARP-1 and PARP-2.
DR2313 also showed excellent profiles in water solubility and rat brain penetrability. In in vitro models of
cerebral ischemia, exposure to
hydrogen peroxide or
glutamate induced cell death with overactivation of PARP, and treatment with
DR2313 reduced excessive formation of
poly(ADP-ribose) and cell death. In both permanent and transient focal
ischemia models in rats, pretreatment with
DR2313 (10 mg/kg i.v. bolus and 10 mg/kg/h i.v. infusion for 6 h) significantly reduced the cortical
infarct volume. To determine the therapeutic time window of neuroprotection by
DR2313, the effect of post-treatment was examined in transient focal
ischemia model and compared with that of a
free radical scavenger,
MCI-186 (3-methyl-1-phenyl-2-pyrazolone-5-one). Pretreatment with
MCI-186 (3 mg/kg i.v. bolus and 3 mg/kg/h i.v. infusion for 6 h) significantly reduced the
infarct volume, whereas the post-treatment failed to show any effects. In contrast, post-treatment with
DR2313 (same regimen) delaying for 2 h after
ischemia still prevented the progression of
infarction. These results indicate that
DR2313 exerts
neuroprotective effects via its potent PARP inhibition, even when the treatment is initiated after
ischemia. Thus, a
PARP inhibitor like
DR2313 may be more useful in treating
acute stroke than a
free radical scavenger.