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Updated: Jul 10, 2026
Two-vessel Occlusion Mouse Model of Cerebral Ischemia-reperfusion
Published on: March 1, 2019
Poxvirus-derived cytokine response modifier A (CrmA) does not protect against focal cerebral ischemia in mice
Ertugrul Kilic1, Andreas Wippel, Ulkan Kilic
1Department of Neurology, University Hospital Zürich, Frauenklinikstr. 26, CH-8091 Zürich, Switzerland. ertugrul.kilic@usz.ch
Abstract:
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.
Insights
Cytokine response modifier A (CrmA) did not protect against ischemic stroke in mice. Transgenic CrmA expression did not reduce brain injury or neuronal death following middle cerebral artery occlusion.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Ischemic stroke triggers neuronal death pathways.
- Tumor necrosis factor receptor family modulates neuronal injury.
- Cytokine response modifier A (CrmA) inhibits apoptosis by blocking caspase activation.
Purpose of the Study:
- To investigate the therapeutic potential of CrmA in ischemic stroke.
- To characterize a transgenic mouse model expressing CrmA under the Thy1 promoter.
Main Methods:
- Transgenic mice expressing CrmA were subjected to middle cerebral artery (MCA) occlusion (90-min and 30-min models).
- In situ hybridization histochemistry and Western blots were used to confirm CrmA expression.
- Infarct volume, brain swelling, neurological deficits, neuronal injury, and caspase-3 activation were assessed.
Main Results:
- The crmA gene integrated into mouse chromosome 8, with CrmA expressed in the cerebral cortex and striatum.
- Transgenic CrmA expression did not significantly alter infarct volume, brain swelling, or neurological deficits after 90-min MCA occlusion.
- CrmA did not influence disseminated neuronal injury or caspase-3 activation following 30-min MCA occlusion.
Conclusions:
- CrmA, despite robust expression, did not demonstrate a therapeutic effect in experimental ischemic stroke models.
- These findings suggest CrmA is not effective in mitigating ischemic brain injury.
- Further research into alternative neuroprotective strategies for ischemic stroke is warranted.
