The role of complement inhibition in experimental murine stroke: trangsgenic intracerebral overexpression and pharmacological application of the murine complement inhibitor Cry

• Applicant: Professor Dr. George Trendelenburg
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2004 to 2009
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5443644

Activation of the complement cascade seems to play an important role in neuroinflammation and adverse outcome after stroke. Transgenic mice with central nervous system (CNS)-targeted expression of the soluble murine complement inhibitor sCrry (GFAP-sCrry mice) have recently been developed and were shown to be neuroprotected in experimental models of autoimmune and traumatic brain injury. GFAP-sCrry mice, due to an almost complete brain-specific shutdown of complement activation, are a highly attractive model to elucidate the role of the complement system in stroke. We plan to subject transgenic GFAP-sCrry mice and their wild-type (WT) littermates to experimental stroke, using a clinically relevant and well-established model of transient focal cerebral ischemia. The effects of CNS-specific complement inhibition will be analyzed with regard to the extent of neuronal apoptosis, infarct volume, blood-brain-barrier dysfunction, neurological scores and regulation of expression of pro-inflammatory and neuroprotective genes in the brains of transgenic mice and WT littermates. To establish a therapeutic approach with potential clinical significance, we will furthermore inject WT mice with the recombinant complement inhibitor Crry-Ig after induction of cerebral ischemia. The above-mentioned neuropathological sequelae will be determined as outcome parameters in CrryIg-injected and compared to vehicle-treated mice. We believe that our experimental approach has unique features due to the intrinsic and continuous inhibition of complement activation in the CNS of the transgenic mice, and translation to a pharmacological approach using the recombinant molecule as a potential therapeutic agent.

• DFG Programme: Research Grants
• Participating Persons: Professor Dr. Ulrich Dirnagl; Professor Dr. Philip F. Stahel