Protection from brain damage and bacterial infection in murine stroke by the novel caspase-inhibitor Q-VD-OPH.
Infarction size and infections are important determinants of stroke outcome in humans. Bacterial infections are promoted by stroke-induced immunodeficiency which in experimental stroke is mainly characterized by extensive lymphocyte apoptosis and dysfunction. Pharmacological inhibition of caspases may improve stroke outcome not only by reducing apoptotic brain damage but also by attenuating stroke-induced immunodeficiency. We investigated the effects of systemic administration of the novel, non-toxic caspase-inhibitor quinolyl-valyl-O-methylaspartyl-[-2,6-difluorophenoxy]-methyl ketone (Q-VD-OPH) on stroke-induced neuronal and lymphocyte apoptosis, susceptibility to infections, and mortality in a murine model of stroke induced by middle cerebral artery occlusion (MCAO). Q-VD-OPH reduced ischemic brain damage and stroke-induced programmed cell death in thymus and spleen, decreased susceptibility to post-stroke bacteremia, and improved survival. Therefore, Q-VD-OPH may be a promising therapeutic agent in stroke.
Braun
Johann Sebastian
JS
Department of Experimental Neurology, Charité Universitaetsmedizin Berlin, Germany. johannb@uuaeu.ac.ae
Prass
Konstantin
K
Dirnagl
Ulrich
U
Meisel
Andreas
A
Meisel
Christian
C
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D016470:Bacteremia / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D061945:Caspase Inhibitors; D020169:Caspases / Q000276:immunology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000276:immunology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000150:complications / Q000276:immunology / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D013950:Thymus Gland / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D016896:Treatment Outcome
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D011804:Quinolines; C468548:quinoline-val-asp(OMe)-CH2-OPH; D020169:Caspases