Complement mediates neuroinflammation and cognitive decline at extended chronic time points after traumatic brain injury

• Type of Material: Article
• Authors: Khalil Mallah, Medical University of South Carolina; Christine Couch, Medical University of South Carolina; Mohammed Alshareef, Medical University of South Carolina; Davis Borucki, Medical University of South Carolina; Xiaofeng Yang, Emory University; Ali Alawieh, Medical University of South Carolina; Stephen Tomlinson, Medical University of South Carolina
• Language: English
• Date: 2021-12-01
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s40478-021-01179-6
• Title of Journal or Parent Work: Acta Neuropathologica Communications
• Volume: 9
• Issue: 1
• Start Page: 72
• End Page: 72
• Grant/Funding Information: NIH National Center for Advancing Translational Sciences (NCATS) (TL1 TR001451 and UL1 TR001450) to CC, and Neurosurgery Research and Education Foundation (NREF) Research Fellowship Grant to MA.; This work was supported by grants from the Department of Veterans Affairs (1BX004256, 1RX001141 and IK6BX005235) to S.T, the National Institute of Health (NIH) (T32AI132164) to KM
• Keywords: Inflammation Mediators; Brain Injuries, Traumatic; Cognitive decline; Mice, Inbred C57BL; Animals; Complement System Proteins; Maze Learning; Male; Traumatic brain injury; Mice; Complement Activation; Complement inhibition; Cognitive Dysfunction
• Research Categories: Biology, Neuroscience; Health Sciences, Immunology; Biology, Microbiology; Health Sciences, Medicine and Surgery

Abstract

Traumatic brain injury (TBI) can result in progressive cognitive decline occurring for years after the initial insult, and for which there is currently no pharmacological treatment. An ongoing chronic inflammatory response after TBI is thought to be an important factor in driving this cognitive decline. Here, we investigate the role of complement in neuroinflammation and cognitive decline for up to 6 months after murine TBI. Male C57BL/6 mice were subjected to open head injury using a controlled cortical impact device. At 2 months post TBI, mice were moved to large cages with an enriched environment to simulate rehabilitation therapy, and assigned to one of three treatment groups: 1. vehicle (PBS), 2. CR2Crry (3 doses over 1 week), 3. CR2Crry (continuous weekly dose until the end of the study). The study was terminated at 6 months post-TBI for all groups. Motor and cognitive function was analyzed, with histopathological analysis of brain tissue. Measured at 6 months after TBI, neither of the complement inhibition paradigms improved motor performance. However, mice receiving continuous CR2Crry treatment showed improved spatial learning and memory compared to both mice receiving only 3 doses and to mice receiving vehicle control. Analysis of brain sections at 6 months after injury revealed ongoing complement activation in the control group, with reduced complement activation and C3 deposition in the continuous CR2Crry treatment group. The ipsilateral hemisphere of continuously treated animals also showed a decrease in microglia/macrophage and astrocyte activation compared to vehicle. There was also increased astrocytosis in the contralateral hippocampus of vehicle treated vs. naïve mice, which was reduced in mice continuously treated with CR2Crry. This study demonstrates continued complement mediated neuroinflammation at extended chronic time points after TBI, and extends the potential treatment window for complement inhibition, which has previously been shown to improve outcomes after murine TBI.