Antioxidant Therapies in Traumatic Brain Injury

Abstract

Due to a multiplicity of causes provoking traumatic brain injury (TBI), TBI is a highly heterogeneous pathology, characterized by high mortality and disability rates. TBI is an acute neurodegenerative event, potentially and unpredictably evolving into sub-chronic and chronic neurodegenerative events, with transient or permanent neurologic, cognitive, and motor deficits, for which no valid standardized therapies are available. A vast body of literature demonstrates that TBI-induced oxidative/nitrosative stress is involved in the development of both acute and chronic neurodegenerative disorders. Cellular defenses against this phenomenon are largely dependent on low molecular weight antioxidants, most of which are consumed with diet or as nutraceutical supplements. A large number of studies have evaluated the efficacy of antioxidant administration to decrease TBI-associated damage in various animal TBI models and in a limited number of clinical trials. Points of weakness of preclinical studies are represented by the large variability in the TBI model adopted, in the antioxidant tested, in the timing, dosages, and routes of administration used, and in the variety of molecular and/or neurocognitive parameters evaluated. The analysis of the very few clinical studies does not allow strong conclusions to be drawn on the real effectiveness of antioxidant administration to TBI patients. Standardizing TBI models and different experimental conditions, as well as testing the efficacy of administration of a cocktail of antioxidants rather than only one, should be mandatory. According to some promising clinical results, it appears that sports-related concussion is probably the best type of TBI to test the benefits of antioxidant administration.

Keywords: concussion; low molecular weight antioxidants; oxidative/nitrosative stress; traumatic brain injury.

Figure 1

Rates of traumatic brain injury (TBI) according to the severity classification based on the Glasgow Coma Scale (GCS) score. Of the total TBI, 80% are mild TBI. Of these, 20% are concussions; 80% of all concussions are sports-related concussions.

Figure 2

Classification of TBI patients in terms of rates and types of the most frequent events causing a traumatic head injury. Data refer to USA epidemiological data, which are currently the most accurate worldwide.

Figure 3

Schematic representation of some of the main pathological processes characterizing the TBI-associated secondary insult. The force discharged and partly absorbed by the cerebral tissue at the time of impact (primary insult) induces immediate glutamate release by neurons, change in the blood–brain barrier (BBB) permeability, frequent hemorrhage, and decrease in the cerebral blood flow (CBF). Excitotoxic phenomena due to sustained glutamate (Glu) release deeply alter ionic homeostasis, particularly causing an increase in mitochondrial Ca²⁺. Malfunctioning of the mitochondrial electron transport chain (ETC) and oxidative phosphorylation (OXPHOS) is consequent to increased Ca²⁺ entry and decreased oxygen and glucose delivery (due to a decrease in CBF), and ultimately generating decreased ATP formation with an energy crisis. Ca²⁺ also activates endothelial (eNOS) and neuronal (nNOS) isoforms of nitric oxide (NO) synthase, promotes the conversion of xanthine dehydrogenase (XDH) into xanthine oxidase (XO), and triggers the arachidonic acid cascade activating phospholipases. The change in BBB permeability modifies water vascular permeability, causing vasogenic brain edema, and allows infiltration and activation of macrophages/microglia, that are responsible either for NO overproduction by the inducible NO synthase (iNOS) or for the release of pro-inflammatory cytokines. Hematomas generate the release of hemoglobin (Hb) from ruptured erythrocytes and the consequent oxidation of Fe²⁺ of Hb to Fe³⁺. This last process, together with XO activity, the arachidonic acid cascade, activated macrophages/microglia, and dysfunctional mitochondria, generates a flow of superoxide anion (O₂•⁻) and gives rise to the reaction with NO and the formation of peroxynitrite (ONOO•⁻). The damaging action of ROS and RNS on polyunsaturated fatty acids of phospholipids of biological membranes triggers a lipid peroxidation reaction chain, culminating in neuronal cell death.

Figure 4

Schematic representation of the central role played by mitochondria in most of the events characterizing the TBI-mediated secondary insult. ETC and OXPHOS are impaired by the increase in Ca2+ and the change in the mitochondrial quality control (MCQ) network. A decrease in fusion (OPA1, MFN1, MFN2) and an increase in fission (DRP1, FIS1) and mitophagy (PINK1, PARK2) greatly contribute to the reduced mitochondrial phosphorylating capacity, unbalanced ATP production and consumption, leading to an energy crisis. Concomitantly, an insurgence of oxidative/nitrosative stress takes place due to the overproduction of ROS and RNS exceeding the cell antioxidant defenses. The intrinsic pathway of apoptosis via cytochrome c release and caspase activation leads to increasing cerebral cell death.

Figure 5

Schematic representation of the main sources of ROS and RNS during oxidative/nitrosative stress occurring after TBI. The severity of injury is quite well correlated with high or low oxidative/nitrosative stress and with protraction of intra- and extracellular ROS and RNS generation from the various potential sources. For instance, mild TBI rarely causes hematomas with hemoglobin extravasation and mobilization of ferritin iron, thus strongly decreasing the amount of iron used in the Haber–Weiss-sustained Fenton reaction. Conversely, severe TBI induces long-lasting conditions of metabolic derangement due to mitochondrial dysfunction. A vicious cycle is formed between the increased energy requirement, either to satisfy repairing processes or to counteract dangerous phenomena (glutamate excitotoxicity, ionic homeostatic disequilibrium), and the damaging molecules originating from mitochondrial ETC unable to manage the tetravalent reduction of molecular oxygen to water minimizing superoxide formation.

Figure 6

Summary of the main water- and fat-soluble antioxidants potentially useful as an adjuvant therapy to TBI patients. Their respective chemical properties localize the components of the two categories into hydrophilic (cytoplasm, mitochondrial matrix) or hydrophobic compartments (biological membranes), therefore characterizing the potential antioxidant activities of the different compounds.