Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, particularly amongst young adults. Ten million individuals are affected by TBI annually, costing a staggering $9–10 billion/year (Gardner et al., 2017). The aged population have a greater risk of sustaining a TBI, with frequent falls being the major cause of injury, and they also have worse outcomes post-injury compared to other age groups (Stocchetti et al., 2012). Aging is also accompanied by a number of co-morbidities which may contribute to poorer outcomes in these individuals following TBI (Stocchetti et al., 2012). Common secondary events that follow the primary impact are neuronal cell death, oxidative stress, brain oedema, blood-brain barrier (BBB) breakdown, and inflammation (Toklu and Tumer, 2015). TBI often results in debilitating long-term cognitive and motor impairments, and there are currently no approved treatments available for TBI patients (Bramlett and Dietrich, 2015). This highlights the need for therapeutic agents that can alleviate brain damage and the deficits caused by the primary injury and more specifically the reversible secondary pathologies that develop after TBI.
Iron homeostasis appears to be an important process in the pathobiology of TBI. Iron is essential for normal brain functioning where it acts as an essential cofactor for several enzymatic/cellular processes (Ke and Qian, 2007). However, impaired regulation of iron can result in the production of reactive oxygen species (ROS) and the consequent promotion of oxidative stress, which can wreak havoc on an already compromised brain in the context of TBI (Nunez et al., 2012). Interestingly, the accumulation of iron in various tissues and cells in the body and brain is an inevitable consequence of aging (Hagemeier et al., 2012; Del et al., 2015). A concomitant increase in the iron storage protein (i.e., ferritin), which can scavenge any excess iron and prevent undesired production of ROS, is also evident with aging (Andersen et al., 2014). However, failed or weakened antioxidant defenses and mitochondrial dysfunction that progresses with aging can disrupt the balance and allow for excessive iron to be released (Venkateshappa et al., 2012a,b; Andersen et al., 2014). This can cause pathological iron overload resulting in cellular damage that is considered to be a contributing factor in several degenerative diseases that are more prevalent with age, such as cancer, liver fibrosis, cardiovascular disease, diabetes (type II), and particularly neurological conditions such as Alzheimer’s disease (AD) (Smith et al., 1997; Kalinowski and Richardson, 2005; Ward et al., 2014; Hare et al., 2016). Abnormal brain iron deposition has also been discovered in other neurodegenerative diseases, such as Parkinson’s disease (PD) (Griffiths et al., 1999; Zhang et al., 2010; Barbosa et al., 2015), multiple sclerosis (MS) (Bergsland et al., 2017), amyotrophic lateral sclerosis (ALS) (Oshiro et al., 2011), Huntington’s disease (Agrawal et al., 2018), and Friedreich’s ataxia (Martelli and Puccio, 2014), and there is now increasing evidence of altered iron levels in TBI patients (Raz et al., 2011; Lu et al., 2015). This raises the interesting proposition of an intersection between aging, iron, TBI and neurodegenerative disease. Whilst the role of iron in TBI is not well known, the literature suggests that the levels of iron (and other metals such as zinc) are abnormally regulated following injury, and that the pharmacological targeting (e.g., using chelators or chaperones) of these metals may be beneficial in improving outcomes. Iron chelation therapy has been approved for decades for the treatment of iron overload conditions, and there is a recent heightened interest for their use in neurodegenerative diseases (Kalinowski and Richardson, 2005; Dusek et al., 2016). Here, we review the role of iron dyshomeostasis in TBI and gain a deeper understanding of its involvement in neurodegeneration as well as neuroinflammation (Figure 1). We further examine the potential benefit of utilizing iron chelation therapy with the hope of limiting iron-induced neurotoxicity in TBI.