Abstract
Traumatic brain injury (TBI) is the principal cause of death and disability in children and young adults. Clinical and preclinical research efforts have been carried out to understand the acute, life-threatening pathophysiological events happening after TBI. In the past few years, however, it was recognized that TBI causes significant morbidity weeks, months, or years after the initial injury, thereby contributing substantially to the overall burden of TBI and the decrease of life expectancy in these patients. Long-lasting sequels of TBI include cognitive decline/dementia, sensory-motor dysfunction, and psychiatric disorders, and most important for patients is the need for socio-economic rehabilitation affecting their quality of life. Cerebrovascular alterations have been described during the first week after TBI for direct consequence development of neuroinflammatory process in relation to brain edema. Within the brain–immune interactions, the complement system, which is a family of blood and cell surface proteins, participates in the pathophysiology process. In fact, the complement system is part of the primary defense and clearance component of innate and adaptive immune response. In this review, the complement activation after TBI will be described in relation to the activation of the microglia and astrocytes as well as the blood–brain barrier dysfunction during the first week after the injury. Considering the neuroinflammatory activity as a causal element of neurological handicaps, some major parallel lines of complement activity in multiple sclerosis and Alzheimer pathologies with regard to cognitive impairment will be discussed for chronic TBI. A better understanding of the role of complement activation could facilitate the development of new therapeutic approaches for TBI.
Highlights
Reviewed by: Rodolfo Gabriel Gatto, University of Illinois at Chicago, United States Lisa Anne Brenner, University of Colorado Anschutz Medical Campus, United States
It includes a wide collection of blood and cell surface proteins (C3, complement 5 (C5), complement factor B (CFB), complement factor D (CFD), complement factor H (CFH), C1q, etc.), whose activation results in a self-amplifying cascade of proteolytic reactions (Walport, 2001)
C3b product binds to complement factor B (CFB) and its co-factor complement factor D (CFD) to form a molecular complex “C3bBb,” called C3 convertase complex, which acts on additional C3 to form more C3b and C3a products (Figure 1)
Summary
Traumatic brain injury (TBI) is a consequence of a direct or indirect external mechanical impact on the brain inducing the disruption of the normal structure and function of the brain. The post-TBI outcome is more severe for younger patients; it is important to consider the age of the animal in the preclinical models (McMillan and Teasdale, 2007; Himanen et al, 2011; Pop and Badaut, 2011). The changes in BBB permeability play a role in edema formation with disruption of brain homeostasis It exacerbates the cascade of secondary injury events including excitotoxicity (glutamate release and resulting higher metabolic demand) and inflammation (with the complement pathway, see below). TBI is a chronic brain disorder with molecular changes at the BBB several months after the initial injury (Jullienne et al, 2016) As it has been suggested in AD, the long-term alterations at the blood–brain interface could be associated with premature aging of the brain after TBI (Pop and Badaut, 2011; Keightley et al, 2014; Jullienne et al, 2016)
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