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Updated: Aug 29, 2026
2-Vessel Occlusion/Hypotension: A Rat Model of Global Brain Ischemia
Published on: June 22, 2013
Caspase inhibition after neonatal ischemia in the rat brain
Luc-Marie Joly1, Valérie Mucignat, Jean Mariani
1UMR-CNRS 7102, Laboratoire Developpement et Vieillissement du Système Nerveux, Paris, France.
Abstract:
Caspase-3 has been identified as a key protease in the execution of apoptosis and appears to be an important downstream event after hypoxia-ischemia in the immature brain. The efficacy of a pan-caspase inhibitor, boc-aspartyl-(Ome)-fluoromethyl-ketone (BAF), was tested in a model of unilateral focal ischemia with reperfusion in 7-day-old rats. The BAF inhibitor was given intraperitoneally 5 minutes before reperfusion via the carotid artery. This procedure reduced the activity of caspase-3 by 79% but did not induce a significant reduction in infarct volume (23.8 +/- 7.5% versus 30.1 +/- 6.4%). Animals were distributed in two populations. One population exhibited an infarct, whereas the other appeared to be fully protected. BAF-treated animals exhibiting an infarct mostly displayed necrotic cell death, whereas apoptotic nuclei were observed in untreated or vehicle-treated animals. Repeated dose of BAF (5 minutes before and 9 hours after reperfusion) did not also provide benefit after neonatal ischemia, although a general trend to reduce lesion was observed (20.5 +/- 3.7% versus 34.4 +/- 5.9%). These findings raise critical questions about the use of peptide ketone apoptotic inhibitors in improving histopathologic outcomes after neonatal stroke.
Insights
A pan-caspase inhibitor (BAF) reduced caspase-3 activity in neonatal stroke models but did not significantly decrease infarct volume. This suggests limited efficacy of such inhibitors for improving outcomes in neonatal brain injury.
Area of Science:
- Neuroscience
- Biochemistry
- Developmental Biology
Background:
- Caspase-3 is a key protease in apoptosis execution.
- Apoptosis is a significant downstream event following hypoxia-ischemia in the immature brain.
Purpose of the Study:
- To evaluate the efficacy of a pan-caspase inhibitor, BAF, in a rat model of neonatal focal ischemia with reperfusion.
- To assess the impact of BAF on caspase-3 activity and infarct volume.
Main Methods:
- A unilateral focal ischemia and reperfusion model was used in 7-day-old rats.
- The pan-caspase inhibitor BAF was administered intraperitoneally before reperfusion.
- Caspase-3 activity and infarct volume were measured.
- Repeated BAF dosing was also tested.
Main Results:
- BAF administration reduced caspase-3 activity by 79% but did not significantly reduce infarct volume.
- BAF-treated animals with infarcts showed necrotic cell death, unlike untreated animals with apoptotic nuclei.
- Repeated BAF dosing showed a trend toward reduced lesion but no significant benefit.
Conclusions:
- Peptide ketone caspase inhibitors may have limited efficacy in improving histopathologic outcomes after neonatal stroke.
- The role of caspase-3 in neonatal ischemia requires further investigation regarding therapeutic interventions.
