Abstract/Description
Structural and Functional Effects of Combination Complement and Hypothermia Therapies in a Rat Model of HIE
Angela Saadata,b,c, Haree Pallerab,d, Frank Lattanzioe, Richard A. Brittenf,g, Asna Sulaimand, Stephanie Newmand, Tushar Shaha,b,c,d
aPediatrics, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA, USA. bNeonatal Brain Institute, cChildren’s Specialty Group, Norfolk, VA, USA. dChildren’s Hospital of the King’s Daughters, Norfolk, VA, eDepartment of Biomedical and Translational Sciences, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA, USA. fDepartment of Radiation Oncology and Biophysics, Old Dominion University, Norfolk, VA, USA. gCenter for Integrative Neuroscience and Inflammatory Disease, Old Dominion University, Norfolk, VA, USA. hSchool of Health Professions, Old Dominion University, Norfolk, VA, USA.
Complement is an innate immune defense with important roles in normal development. In neonatal HIE and other diseases of reperfusion injury, complement pathways are key contributors to excessive inflammation and injury. Complement proteins C3a and C5a are central to all complement pathways. C3a plays a paradoxical role in neuroinflammation and can be anti-inflammatory in acute phases of injury. C5a facilitates inflammation by binding C5aR1, and PMX205 is a small molecule inhibitor of this interaction. We aimed to determine if complement modulation following HI-injury in conjunction with TH improves functional and structural neurological outcomes. Injury was induced in P10-P12 rat pups by Vannucci’s method. Following, subsets of rats received no treatment (NT), complement therapy (CT; PMX205 and C3a peptides), hypothermic therapy (TH), or combination CT and TH (CT+TH). Structural injury, inflammatory and injury markers, and functional abilities were assessed. Complement therapy and TH each yielded smaller brain lesions compared to untreated, injured rats, and combining the treatments further reduced lesion sizes. Complement therapy reduced levels of inflammatory and apoptosis markers. Functional improvement was most often observed with combination complement and TH therapy. While CT demonstrated more improvement in male outcomes, TH treated demonstrated more improvement in females, and combining the two treatments (CT+TH) showed additive improvement in both sexes. These results may help us better understand the sex-specific differences in HIE pathology and response to treatment, and could translate to a TH adjuvant in the future.
Included in
Structural and Functional Effects of Combination Complement and Hypothermia Therapies in a Rat Model of HIE
Structural and Functional Effects of Combination Complement and Hypothermia Therapies in a Rat Model of HIE
Angela Saadata,b,c, Haree Pallerab,d, Frank Lattanzioe, Richard A. Brittenf,g, Asna Sulaimand, Stephanie Newmand, Tushar Shaha,b,c,d
aPediatrics, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA, USA. bNeonatal Brain Institute, cChildren’s Specialty Group, Norfolk, VA, USA. dChildren’s Hospital of the King’s Daughters, Norfolk, VA, eDepartment of Biomedical and Translational Sciences, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA, USA. fDepartment of Radiation Oncology and Biophysics, Old Dominion University, Norfolk, VA, USA. gCenter for Integrative Neuroscience and Inflammatory Disease, Old Dominion University, Norfolk, VA, USA. hSchool of Health Professions, Old Dominion University, Norfolk, VA, USA.
Complement is an innate immune defense with important roles in normal development. In neonatal HIE and other diseases of reperfusion injury, complement pathways are key contributors to excessive inflammation and injury. Complement proteins C3a and C5a are central to all complement pathways. C3a plays a paradoxical role in neuroinflammation and can be anti-inflammatory in acute phases of injury. C5a facilitates inflammation by binding C5aR1, and PMX205 is a small molecule inhibitor of this interaction. We aimed to determine if complement modulation following HI-injury in conjunction with TH improves functional and structural neurological outcomes. Injury was induced in P10-P12 rat pups by Vannucci’s method. Following, subsets of rats received no treatment (NT), complement therapy (CT; PMX205 and C3a peptides), hypothermic therapy (TH), or combination CT and TH (CT+TH). Structural injury, inflammatory and injury markers, and functional abilities were assessed. Complement therapy and TH each yielded smaller brain lesions compared to untreated, injured rats, and combining the treatments further reduced lesion sizes. Complement therapy reduced levels of inflammatory and apoptosis markers. Functional improvement was most often observed with combination complement and TH therapy. While CT demonstrated more improvement in male outcomes, TH treated demonstrated more improvement in females, and combining the two treatments (CT+TH) showed additive improvement in both sexes. These results may help us better understand the sex-specific differences in HIE pathology and response to treatment, and could translate to a TH adjuvant in the future.