Hypoxia-ischaemia in the developing brain results in
brain injury with prominent features of apoptosis. In the present study, a third generation dipeptidyl broad-spectrum
caspase inhibitor, quinoline-Val-Asp(Ome)-CH2-O-phenoxy (
Q-VD-OPh), was tested in a model of unilateral focal ischaemia with reperfusion in 7-day-old rats.
Q-VD-OPh (1 mg/kg, i.p.) reduced cell death, resulting in significant neuroprotection at 48 h of recovery (
infarct volume of 12.6 +/- 2.8 vs. 24.3 +/- 2.2%, p = 0.006). The
neuroprotective effects observed at 48 h post-ischaemia hold up at 21 days of survival time and attenuate neurological dysfunction. Analysis by gender revealed that females were strongly protected (6.7 +/- 3.3%, p = 0.006), in contrast to males in which there was no significant effect, when
Q-VD-OPh was given after
clip removal on the left common carotid artery. Immunoblot analysis demonstrated that
Q-VD-OPh inhibits
caspase 3 cleavage into its p17 active form and
caspase 1 up-regulation and cleavage in vivo. Following ischaemia in P7 rats, males and females displayed different time course and pattern of
cytochrome c release and active p17
caspase 3 during the first 24 h of recovery. In contrast, no significant difference was observed for
caspase 1 expression between genders. These results indicate that ischaemia activates
caspases shortly after reperfusion and that the sex of the animal may strongly influences apoptotic pathways in the pathogenesis of neonatal
brain injury. The specificity, effectiveness, and reduced toxicity of
Q-VD-OPh may determine the potential use of
peptide-derived irreversible
caspase inhibitors as promising
therapeutics.