Neuroprotective Effect of Subdural Infusion of Serp-1 in Spinal Cord Trauma
Jacek M. Kwiecien,
Wojciech Dabrowski,
Bryce J. Kwiecien-Delaney,
Christian J. Kwiecien-Delaney,
Dorota Siwicka-Gieroba,
Jordan R. Yaron,
Liqiang Zhang,
Kathleen H. Delaney,
Alexandra R. Lucas
Affiliations
Jacek M. Kwiecien
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada
Wojciech Dabrowski
Department of Anaesthesiology and Intensive Therapy, Medical University of Lublin, 20-090 Lublin, Poland
Bryce J. Kwiecien-Delaney
Faculty of Science, McMaster University, Hamilton, ON L8S 4K1, Canada
Christian J. Kwiecien-Delaney
Faculty of Science, McMaster University, Hamilton, ON L8S 4K1, Canada
Dorota Siwicka-Gieroba
Department of Anaesthesiology and Intensive Therapy, Medical University of Lublin, 20-090 Lublin, Poland
Jordan R. Yaron
Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
Liqiang Zhang
Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
Kathleen H. Delaney
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada
Alexandra R. Lucas
Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
Spinal cord injury (SCI) initiates a severe, destructive inflammation with pro-inflammatory, CD68+/CD163−, phagocytic macrophages infiltrating the area of necrosis and hemorrhage by day 3 and persisting for the next 16 weeks. Inhibition of macrophage infiltration of the site of necrosis that is converted into a cavity of injury (COI) during the first week post-SCI, should limit inflammatory damage, shorten its duration and result in neuroprotection. By sustained subdural infusion we administered Serp-1, a Myxoma virus-derived immunomodulatory protein previously shown to improve neurologic deficits and inhibit macrophage infiltration in the COI in rats with the balloon crush SCI. Firstly, in a 7 day long study, we determined that the optimal dose for macrophage inhibition was 0.2 mg/week. Then, we demonstrated that a continuous subdural infusion of Serp-1 for 8 weeks resulted in consistently accelerated lowering of pro-inflammatory macrophages in the COI and in their almost complete elimination similar to that previously observed at 16 weeks in untreated SCI rats. The macrophage count in the COI is a quantitative test directly related to the severity of destructive inflammation initiated by the SCI. This test has consistently demonstrated anti-inflammatory effect of Serp-1 interpreted as neuroprotection, the first and necessary step in a therapeutic strategy in neurotrauma.
