Abstract
No new therapies for traumatic brain injury (TBI) have been officially translated into current practice. At the tissue and cellular level, both inflammatory and oxidative processes may be exacerbated post-injury and contribute to further brain damage. N-acetylcysteine (NAC) has the potential to downregulate both processes. This review focuses on the potential neuroprotective utility of NAC and N-acetylcysteine amide (NACA) post-TBI. Medline, Embase, Cochrane Library, and ClinicalTrials.gov were searched up to July 2017. Studies that examined clinical and laboratory effects of NAC and NACA post-TBI in human and animal studies were included. Risk of bias was assessed in human and animal studies according to the design of each study (randomized or not). The primary outcome assessed was the effect of NAC/NACA treatment on functional outcome, while secondary outcomes included the impact on biomarkers of inflammation and oxidation. Due to the clinical and methodological heterogeneity observed across studies, no meta-analyses were conducted. Our analyses revealed only three human trials, including two randomized controlled trials (RCTs) and 20 animal studies conducted using standardized animal models of brain injury. The two RCTs reported improvement in the functional outcome post-NAC/NACA administration. Overall, the evidence from animal studies is more robust and demonstrated substantial improvement of cognition and psychomotor performance following NAC/NACA use. Animal studies also reported significantly more cortical sparing, reduced apoptosis, and lower levels of biomarkers of inflammation and oxidative stress. No safety concerns were reported in any of the studies included in this analysis. Evidence from the animal literature demonstrates a robust association for the prophylactic application of NAC and NACA post-TBI with improved neurofunctional outcomes and downregulation of inflammatory and oxidative stress markers at the tissue level. While a growing body of scientific literature suggests putative beneficial effects of NAC/NACA treatment for TBI, the lack of well-designed and controlled clinical investigations, evaluating therapeutic outcomes, prognostic biomarkers, and safety profiles, limits definitive interpretation and recommendations for its application in humans at this time.
Highlights
Traumatic brain injury (TBI) is a leading cause of death and disability in the United States and globally [1, 2]
This study found that pre-injury and repeated doses of N-acetylcysteine amide (NACA) were dose-dependently effective in reducing intracranial pressure (ICP) after TBI
NAC improved the neurofunctional status in humans and animals, reduced levels of mediators of oxidative stress and the inflammatory response at tissue and cellular levels, cell death, and had no safety concerns
Summary
Traumatic brain injury (TBI) is a leading cause of death and disability in the United States and globally [1, 2]. The initial tissue damage may be worsened by a complex secondary injury process following the primary insult [9] These processes consist of a cascade of metabolic, cellular, and molecular events related to extensive tissue destruction and repair [10]. It has been shown that these processes, or lack thereof, result in further damage to the already critically injured brain tissue [9, 14] Local consequences of this intricate process include vasoconstriction and formation of microthrombi in the microvasculature, with further ischemia and edema [15]; initiation and exacerbation of peripheral and central inflammatory process with release of pro- and anti-inflammatory mediators [16]; a subsequent rise of intracranial pressure (ICP) with unfavorable neurological outcome or death [17]. Due to the clinical and methodological heterogeneity observed across studies, no meta-analyses were conducted
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