Specific caspase inhibitor Q-VD-OPh prevents neonatal stroke in P7 rat: a role for gender

• Published in: Journal of neurochemistry 2007-02, Vol.100 (4), p.1062-1071
• Main Authors: Renolleau, Sylvain, Fau, Sébastien, Goyenvalle, Catherine, Joly, Luc-Marie, Chauvier, David, Jacotot, Etienne, Mariani, Jean, Charriaut-Marlangue, Christiane
• Format: Article
• Language: English
• Subjects: Amino Acid Chloromethyl Ketones; Amino Acid Chloromethyl Ketones - therapeutic use; Animals; Animals, Newborn; Apoptosis; Biochemistry; Biological and medical sciences; Brain damage; brain injury; Cardiology. Vascular system; caspase inhibitor; Caspase Inhibitors; Caspases; Cell Death; Cell Death - drug effects; Cerebrovascular Accident; Enzyme Inhibitors; Enzyme Inhibitors - therapeutic use; gender; Gender differences; Gender Identity; Gene Expression Regulation; Gene Expression Regulation - drug effects; Humans; In Situ Nick-End Labeling; Life Sciences; Male; Medical sciences; neonatal stroke; Neurobiology; Neurologic Examination; Neurologic Examination - methods; Neurology; Neurons and Cognition; Quinolines; Quinolines - therapeutic use; Rats; Rodents; Statistics, Nonparametric; Stroke - pathology; Stroke - prevention & control; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2006.04269.x

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.