Novel Therapeutic Strategies for Traumatic Brain Injury: Acute Antioxidant Reinforcement

Abstract

Traumatic brain injury (TBI) is the most important cause of disability in individuals under the age of 45 years and thus represents a significant social and economic burden. Evidence strongly suggests that oxidative stress is a cornerstone event leading to and propagating secondary injury mechanisms such as excitotoxicity, mitochondrial dysfunction, apoptosis, autophagy, brain edema, and inflammation. TBI has defied conventional approaches to diagnosis and therapy development because of its heterogeneity and complexity. Therefore, it is necessary to explore alternative approaches to therapy development for TBI. The aim of this review is to present a therapeutic approach for TBI, taking into account the evidence supporting the role for oxidative stress in the pathophysiological processes of secondary brain injury. The role of agents such as mitochondria-targeted antioxidants (melatonin and new mitochondria-targeted antioxidants), nicotinamide adenine dinucleotide phosphate (NADPH) inhibitors (antioxidant vitamins and apocynin), and other compounds having mainly antioxidant properties (hydrogen-rich saline, sulforaphane, U-83836E, omega-3, and polyphenols) is covered. The rationale for innovative antioxidant therapies based on current knowledge and particularly the most recent studies regarding this field is discussed. Particular considerations and translational potential of new TBI treatments are examined and a novel therapeutic proposal for TBI is presented.

Antioxidant therapies in traumatic brain injury: a review

“…Antioxidant therapies are effective over a long period of time, allowing for suitable use in clinical settings. Due to the encouraging preclinical results and the antioxidant drug profiles, acute antioxidant reinforcement is emerging as a highly cost-effective alternative for neuroprotection in TBI patients (42).…”

“…U-83836E also has been shown to inhibit protein nitration (3-NT) in injured cortical tissue and mitochondria even though it does not interact directly with the reactive nitrogen species peroxynitrite. Further studies to determine the pharmacokinetics of U-83836E in humans are strongly recommended, as the compound appears to inhibit a crucial step of the secondary brain injury cascade of events (42).…”

“…In vitro studies, sulforaphane is demonstrated to disrupt the Nrf2/Keap1 interaction, leading to Nrf2 stabilization and nuclear localization and the expression of ARE-containing phase II genes, which play a major role in the detoxification of ROS produced by xenobiotics (42,73).…”

“…Patients received a total dose of 32 g of intravenous vitamin C during the first 7 days after TBI, with a maximum single dose of 10 g on the first day, resulting in a significant earlier stabilization of the perilesional edema compared with the placebo group. Although the absence of many parameters of Clinical importance and monitoring techniques may make the interpretation of these results challenging, although encouraging results regarding the use of vitamin C in humans (42).…”

“…For 7 days, patients received vitamin E at 400 IU/day intramuscularly, which resulted in improved clinical outcome and reduced mortality at discharge. Despite promising results, clinical trials using vitamins C and E, isolated or in combination, are needed to change current therapeutic measures in patients suffering TBI (42).…”