TY - JOUR
T1 - Myxoma virus derived immune modulating proteins, M-T7 and Serp-1, reduce early inflammation after spinal cord injury in the rat model
AU - Kwiecien, Jacek M.
AU - Dabrowski, Wojciech
AU - Marzec-Kotarska, Barbara
AU - Kwiecien-Delaney, Christian J.
AU - Yaron, Jordan R.
AU - Zhang, Liqiang
AU - Schutz, Lauren
AU - Lucas, Alexandra R.
N1 - Funding Information:
The funding provided by the Medical University of Lublin, Poland to JMK and WD and by Start- up funds to ARL at the Biodesign Institute at Arizona State University, Tempe, AZ, USA. We would also like to thank the American Heart Association (17GRNT33460327) and National Institutes of Health (NIH, 1 R01 AI100987-01A1) for funding for protein expression and purification. Serp-1 was expressed and purified by Viron Therapeutics, Inc (previously London, ON, Canada; this company is not currently active). M-T7 was expressed and purified in the Lucas lab. The authors wish to acknowledge the excellent histologic and immunohistochemical work by Mary Jo Smith and Mary Bruni of MIRC Histology Laboratory, McMaster University.
Publisher Copyright:
© 2019 Termedia Publishing House Ltd. All Rights Reserved.
PY - 2019
Y1 - 2019
N2 - Spinal cord injury (SCI)-initiated inflammation was treated with anti-inflammatory reagents. We compared local spinal cord or intraperitoneal infusion of two Myxoma virus derived immune modulating proteins, Serp-1 and M-T7, with dexamethasone (DEX). Hemorrhage and necrosis after SCI initiate a complex pathogenesis dominated by early, severe and highly destructive inflammatory macrophage infiltration. We examined sustained, 7-day, subdural infusion of either M-T7, a chemokine modulator or Serp-1, a plasminogen activator and factor inhibitor. Mature male rats had epidural balloon crush SCI and sustained subdural infusion of Serp-1, M-T7, DEX or saline for 7 days via the osmotic pump. A separate group of rats with SCI had intra-peritoneal infusion. Clinical evaluation included endpoint monitoring with body weight, hemorrhagic cystitis and bilateral toe pinch response. Sections of the spinal cord were analyzed histologically and macrophage numbers counted by standardized protocol in the cavity of injury (COI). While the rats administered DEX demonstrated substantial body weight loss, dehydration and dermal atrophy consistent with steroid toxicity, rats infused with Serp-1 and M-T7 had no toxicity. Serp-1 improved withdrawal responses. Subdural infusion of Serp-1, M-T7 and DEX significantly reduced numbers of phagocytic, CD68-positive macrophages. With intraperitoneal infusion only M-T7 reduced macrophage counts, Serp-1 showed only a trend. Local infusion of highly active immune modulating proteins; Serp-1 and M-T7, targeting serine protease and chemokine pathways demonstrated excellent potential for neuroprotection after severe SCI in a rat model, without adverse side effects. Sustained subdural infusion offers an alternative route of administration for treatment of SCI.
AB - Spinal cord injury (SCI)-initiated inflammation was treated with anti-inflammatory reagents. We compared local spinal cord or intraperitoneal infusion of two Myxoma virus derived immune modulating proteins, Serp-1 and M-T7, with dexamethasone (DEX). Hemorrhage and necrosis after SCI initiate a complex pathogenesis dominated by early, severe and highly destructive inflammatory macrophage infiltration. We examined sustained, 7-day, subdural infusion of either M-T7, a chemokine modulator or Serp-1, a plasminogen activator and factor inhibitor. Mature male rats had epidural balloon crush SCI and sustained subdural infusion of Serp-1, M-T7, DEX or saline for 7 days via the osmotic pump. A separate group of rats with SCI had intra-peritoneal infusion. Clinical evaluation included endpoint monitoring with body weight, hemorrhagic cystitis and bilateral toe pinch response. Sections of the spinal cord were analyzed histologically and macrophage numbers counted by standardized protocol in the cavity of injury (COI). While the rats administered DEX demonstrated substantial body weight loss, dehydration and dermal atrophy consistent with steroid toxicity, rats infused with Serp-1 and M-T7 had no toxicity. Serp-1 improved withdrawal responses. Subdural infusion of Serp-1, M-T7 and DEX significantly reduced numbers of phagocytic, CD68-positive macrophages. With intraperitoneal infusion only M-T7 reduced macrophage counts, Serp-1 showed only a trend. Local infusion of highly active immune modulating proteins; Serp-1 and M-T7, targeting serine protease and chemokine pathways demonstrated excellent potential for neuroprotection after severe SCI in a rat model, without adverse side effects. Sustained subdural infusion offers an alternative route of administration for treatment of SCI.
KW - Neuroinflammation
KW - Neuroprotection
KW - Spinal cord injury
KW - Subdural infusion
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U2 - 10.5114/fn.2019.83830
DO - 10.5114/fn.2019.83830
M3 - Article
C2 - 31038187
AN - SCOPUS:85064182024
SN - 1641-4640
VL - 57
SP - 41
EP - 50
JO - Folia Neuropathologica
JF - Folia Neuropathologica
IS - 1
ER -