Evidence for the Therapeutic Efficacy of Either Mild Hypothermia or Oxygen Radical Scavengers after Repetitive Mild Traumatic Brain Injury

Abstract

Repetitive brain injury, particularly that occurring with sporting-related injuries, has recently garnered increased attention in both the clinical and public settings. In the laboratory, we have demonstrated the adverse axonal and vascular consequences of repetitive brain injury and have demonstrated that moderate hypothermia and/or FK506 exerted protective effects after repetitive mild traumatic brain injury (mTBI) when administered within a specific time frame, suggesting a range of therapeutic modalities to prevent a dramatic exacerbation. In this communication, we revisit the utility of targeted therapeutic intervention to seek the minimal level of hypothermia needed to achieve protection while probing the role of oxygen radicals and their therapeutic targeting. Male Sprague-Dawley rats were subjected to repetitive mTBI by impact acceleration injury. Mild hypothermia (35°C, group 2), superoxide dismutase (group 3), and Tempol (group 4) were employed as therapeutic interventions administered 1 h after the repetitive mTBI. To assess vascular function, cerebral vascular reactivity to acetylcholine was evaluated 3 and 4 h after the repetitive mTBI, whereas to detect the burden of axonal damage, amyloid precursor protein (APP) density in the medullospinal junction was measured. Whereas complete impairment of vascular reactivity was observed in group 1 (without intervention), significant preservation of vascular reactivity was found in the other groups. Similarly, whereas remarkable increase in the APP-positive axon was observed in group 1, there were no significant increases in the other groups. Collectively, these findings indicate that even mild hypothermia or the blunting free radical damage, even when performed in a delayed period, is protective in repetitive mTBI.

iTRAQ-Based Quantitative Proteomics Reveals the New Evidence Base for Traumatic Brain Injury Treated with Targeted Temperature Management

“…Similar to our previous studies and other reports, TBI produces behavioral abnormalities and neurodegenerative changes resulting from regional patterns of cell death and circuit dysfunction [21,44]. As supported by previous studies of TTM on TBI, we also demonstrated that using CCI rats as an in vivo model that TTM attenuated several phenotypes of animal post-TBI, markedly reduced cell death [7,8,11], BBB leakage [45][46][47], cortical lesion volume [48], cerebrovascular histopathology [49,50], and improved behavioral and pathological outcomes [51]. These results may help determine both the safety and efficacy for postinjury TTM, and such laboratory models (in vitro or in vivo) may present an ideal opportunity for the application of proteomic technological approach to biomarker discovery after TBI.…”

Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy

“…53 It has long been postulated that TBI leads to chronic neurodegeneration. 30,32,47 Recent findings have confirmed that changes in tau, amyloid, and cognition can result from neurotrauma. 9,34,51 The mechanisms underlying how these changes develop is currently unknown.…”

Emerging Therapies in Traumatic Brain Injury

“…151 This includes benefit injury in repetitive mTBI. 134 In summary, an emerging area TBI is mitigating microvascular dysregulation. These approaches and others deserve further investigation in TBI, including testing in mTBI.…”