Systematic Review of Traumatic Brain Injury and the Impact of Antioxidant Therapy on Clinical Outcomes

Abstract

Background: Traumatic brain injury (TBI) is an acquired brain injury that occurs when there is sudden trauma that leads to brain damage. This acute complex event can happen when the head is violently or suddenly struck or an object pierces the skull or brain. The current principal treatment of TBI includes various pharmaceutical agents, hyperbaric oxygen, and hypothermia. There is evidence that secondary injury from a TBI is specifically related to oxidative stress. However, the clinical management of TBI often does not include antioxidants to reduce oxidative stress and prevent secondary injury.

Oxidation of KCNB1 Potassium Channels Causes Neurotoxicity and Cognitive Impairment in a Mouse Model of Traumatic Brain Injury

“…Thus, it appears that a moderate KCNB1 gain of function is well tolerated in the brain even though we cannot completely exclude that the transgenic mice may have developed some sort of cognitive decompensation that went undetected in our investigations. These findings also argue against the idea that augmented KCNB1 current is proapoptotic, as suggested by some in vitro studies (for review, see Sesti et al, 2014). Moreover, since the N terminus and the C terminus of the channel physically interact during the channel's activation (Ju et al, 2003;Kobrinsky et al, 2006) and oligomerization probably links the two termini together through disulfide bridges, it is possible that the antiapoptotic effect of some KCNB1 inhibitors Zhou et al, 2016) stems from their ability to prevent oligomerization rather than conduction, or, alternatively, as in the case of heme oxygenase-1 in in vitro models of Alzheimer's disease, through interfering with KCNB1 regulatory pathways (Hettiarachchi et al, 2014).…”

“…1). KCNB1 oligomers have been detected in the brains of aged mice and, in larger quantities, in the brain of the 3x-Tg-AD mouse model of Alzheimer's disease, which expresses abnormal amounts of ROS (Oddo et al, 2003;Smith et al, 2005;Sensi et al, 2008;Yao et al, 2009;Chou et al, 2011;McManus et al, 2011;Cotella et al, 2012). This body of evidence argues that oxidized KCNB1 channels may affect cortical and/or hippocampal excitability and, when oxidation is elevated, cause neuronal death.…”

“…LFP produces both focal and diffuse brain injury and is associated with extensive axonal damage and cell death that result in longterm neuromotor and cognitive deficits (Smith et al, 1991;Miyazaki et al, 1992;Hamm et al, 1993;Hicks et al, 1993;Dixon et al, 1999). These deficits reflect the outcomes observed in human victims of TBI and the model has therefore been used extensively to identify potential therapeutic treatments (Thompson et al, 2005;Masel and DeWitt, 2010).…”

“…To determine the role that oxidation of KCNB1 plays for the pathophysiology of the brain, we constructed a transgenic mouse that expresses a redox-resistant variant of human KCNB1 (C73A), which we showed previously does not oligomerize and thus conducts normally (Cotella et al, 2012). To expose the channels to controlled and reproducible conditions of oxidative stress, we subjected the animals to mild to moderate traumatic brain injury-which is associated with extensive oxidation during the secondary injury (Corps et al, 2015;Hiebert et al, 2015;Shen et al, 2016)-using the lateral fluid percussion (LFP) method (McIntosh et al, 1989;Alder et al, 2011;Roth et al, 2014). LFP produces both focal and diffuse brain injury and is associated with extensive axonal damage and cell death that result in longterm neuromotor and cognitive deficits (Smith et al, 1991;Miyazaki et al, 1992;Hamm et al, 1993;Hicks et al, 1993;Dixon et al, 1999).…”

Acute administration of catalase targeted to ICAM-1 attenuates neuropathology in experimental traumatic brain injury

“…While several antioxidant strategies have been attempted in TBI, the marginal success of such trials has limited the translation of these therapies to clinical practice. Additionally, heterogeneity of antioxidant therapies, treatment regimens, patient populations, and patient TBI severity has prevented clear conclusions and guidelines regarding the use of these therapies in TBI 72 . Emerging platforms in nanomedicine offer widespread implication to the treatment of various disorders; however, further study is warranted regarding their use in TBI 73 .…”