Madison Demmer

Introduction: Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. 1.7 million people in the United States are afflicted by TBI annually.¹ Immune response to a TBI consists of a Primary and Secondary response. Secondary insult can also include breakdown of the blood brain barrier and white matter of which the complement pathway is shown to be largely involved in. ^2,3 The complement system forms the Membrane attack complex or MAC which forms pores in the targeted cells ultimately resulting in cell death and cytolysis. This causes microglia accumulation, neuronal cell apoptosis, axonal loss and further neurological impairment.² Inhibition of the Mannose-Binding-Lectin pathway and MASP-2, a serine protease involved in the initiation cascade of the pathway, in animal models has shown to have neuroprotective affects.^4,5 Methods: Controlled cortical impact was given to MBL^(-/-), MASP-1^(-/-), MASP-2^(-/-), and Wild type mice. Sensorimotor deficits were assessed 4 weeks post TBI sensorimotor using neuroscore and beam walk tests. The brain specimens of the mice were removed 6 weeks post injury and the contusion size, neuronal count, microglial/astrocyte histological slides, MBL-C deposition, Western Blot of neurofilament composition and Lectin-assay were observed and compared.^4,5 Results:  Results showed that the TBI-induced neutrophil invasion was reduced in the MBL^(-/-) mice compared to the wild type mice.⁵ MBL^(-/-) showed to have higher levels of cortical neurofilament when compared to wild type and therefore before axonal preservation. Results concluded that the MASP-2^(-/-) mice had reduced sensorimotor deficits and higher neuronal density when compared to wild-type mice. They also had decreased MBL pathway activity with normal MBL-C deposition.^4,5 Conclusions: While MBL^(-/-) had higher levels of neuroprotection and preservation when compared to Wild type mice, MASP-2^(-/-) had the best overall outcome including sensorimotor and neuronal preservation. This shows that inhibition of the Mannose Binding Lectin Pathway has neuroprotective affects after TBI and is a possible pharmacological target for treatment.

References

1. Jassam YN, Izzy S, Whalen M, McGavern DB, El Khoury J. Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift. Neuron. 2017;95(6):1246-1265. doi:10.1016/j.neuron.2017.07.010
2. ‌Corps, Kara N., et al. “Inflammation and Neuroprotection in Traumatic Brain Injury.” JAMA Neurology, vol. 72, no. 3, 1 Mar. 2015, p. 355, www.ncbi.nlm.nih.gov/pmc/articles/PMC5001842/, 10.1001/jamaneurol.2014.3558. Accessed 28 Feb. 2019.
3. Russo, M. V., and D. B. McGavern. “Inflammatory Neuroprotection Following Traumatic Brain Injury.” Science, vol. 353, no. 6301, 18 Aug. 2016, pp. 783–785, 10.1126/science.aaf6260. Accessed 21 Dec. 2020.
4. Mercurio D, Oggioni M, Fumagalli S, et al. Targeted deletions of complement lectin pathway genes improve outcome in traumatic brain injury, with MASP-2 playing a major role. Acta Neuropathologica Communications. 2020;8(1). doi:10.1186/s40478-020-01041-1
5. Pedragosa J, Mercurio D, Oggioni M, Marquez-Kisinousky L, de Simoni M-G, Planas AM. Mannose-binding lectin promotes blood-brain barrier breakdown and exacerbates axonal damage after traumatic brain injury in mice. Experimental Neurology. 2021;346:113865. doi:10.1016/j.expneurol.2021.113865