title: Specific caspase inhibitor Q-VD-OPh prevents neonatal stroke in P7 rat: a role for gender.
abstract: 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.
authors.affiliation: UMR-CNRS, Paris, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Renolleau
authors.forename: Sébastien
authors.initials: S
authors.lastname: Fau
authors.forename: Catherine
authors.initials: C
authors.lastname: Goyenvalle
authors.forename: Luc-Marie
authors.initials: LM
authors.lastname: Joly
authors.forename: David
authors.initials: D
authors.lastname: Chauvier
authors.forename: Etienne
authors.initials: E
authors.lastname: Jacotot
authors.forename: Jean
authors.initials: J
authors.lastname: Mariani
authors.forename: Christiane
authors.initials: C
authors.lastname: Charriaut-Marlangue
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005783:Gender Identity; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D009460:Neurologic Examination / Q000379:methods; D011804:Quinolines / Q000627:therapeutic use*; D051381:Rats; D018709:Statistics, Nonparametric; D020521:Stroke / Q000473:pathology / Q000517:prevention & control*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D011804:Quinolines; C468548:quinoline-val-asp(OMe)-CH2-OPH