Poxvirus-derived cytokine response modifier A (CrmA) does not protect against focal cerebral ischemia in mice.
In ischemic stroke, cytosolic death pathways are activated in injured neurons destined to die. Neuronal injury is modulated by cell surface receptors, among which the tumor necrosis factor receptor family obtained particular interest. Cytokine response modifier A (CrmA) is a cowpox virus-derived caspase inhibitor, which interferes with the so-called death-inducing signaling complex, thereby blocking receptor-mediated apoptosis. To elucidate CrmA's therapeutic potential in ischemic stroke, we characterized a transgenic mouse line expressing CrmA under a Thy1 promoter, which we subjected to intraluminal middle cerebral artery (MCA) occlusion. Using in situ hybridization histochemistry and Western blots, we show that the crmA gene integrated into chromosome 8 of the mouse genome, CrmA being expressed in the cerebral cortex and striatum. Although robustly expressed, transgenic CrmA did not influence ischemic injury, both when relatively long-lasting (90 min) and mild (30 min) MCA occlusions were imposed. As such, neither infarct volume, brain swelling or neurological deficits following 90-min ischemia, nor disseminated neuronal injury or caspase-3 activation following 30-min ischemia were influenced by CrmA. Our data argue against a therapeutic effect of CrmA in ischemic stroke.
Kilic
Ertugrul
E
Department of Neurology, University Hospital Zürich, Frauenklinikstr. 26, CH-8091 Zürich, Switzerland. ertugrul.kilic@usz.ch
Wippel
Andreas
A
Kilic
Ulkan
U
Vogel
Peter
P
Kim
Mia
M
van der Putten
Herman
H
Wiessner
Christoph
C
Rovelli
Giorgio
G
Böttiger
Bernd W
BW
Hermann
Dirk M
DM
D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000209:etiology / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002470:Cell Survival; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D018800:Thy-1 Antigens / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D015843:Serpins; D018800:Thy-1 Antigens; D014764:Viral Proteins; C074641:interleukin-1beta-converting enzyme inhibitor; D053148:Caspase 3; D053181:Caspase 8