Antioxidant therapies in traumatic brain and spinal cord injury

Abstract

Free radical formation and oxidative damage have been extensively investigated and validated as important contributors to the pathophysiology of acute central nervous system injury. The generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is an early event following injury occurring within minutes of mechanical impact. A key component in this event is peroxynitrite-induced lipid peroxidation. As discussed in this review, peroxynitrite formation and lipid peroxidation irreversibly damages neuronal membrane lipids and protein function, which results in subsequent disruptions in ion homeostasis, glutamate-mediated excitotoxicity, mitochondrial respiratory failure and microvascular damage. Antioxidant approaches include the inhibition and/or scavenging of superoxide, peroxynitrite, or carbonyl compounds, the inhibition of lipid peroxidation and the targeting of the endogenous antioxidant defense system. This review covers the preclinical and clinical literature supporting the role of ROS and RNS and their derived oxygen free radicals in the secondary injury response following acute traumatic brain injury (TBI) and spinal cord injury (SCI) and reviews the past and current trends in the development of antioxidant therapeutic strategies. Combinatorial treatment with the suggested mechanistically complementary antioxidants will also be discussed as a promising neuroprotective approach in TBI and SCI therapeutic research. This article is part of a Special Issue entitled: Antioxidants and antioxidant treatment in disease.

Fig. 1

Time course of measured secondary injury events in the mouse CCI model of TBI. Mitochondrial oxidative damage and dysfunction precedes the onset (by 3 h) of neurodegeneration as measured by the respiratory control ratio and mitochondrial calcium-buffering capacity following CCI-TBI-induced injury [134]. Oxidative damage-induced increases in cytoplasmic Ca²⁺ and subsequent cell membrane damage as measured by calpain-mediated spectrin degradation begins by 6 h and continues through 48 h (peak at 24 h) post-TBI [135]. PN-induced oxidative damage as measured by immunohistochemical elevations in the oxidative markers, 3-NT and 4-HNE, occurs by 1 h and remains elevated for several days [23]. Post-traumatic time course of neurodegeneration as demonstrated by de olmos silver staining begins at 12 h and reaches its peak by 72 h following injury [135].

Fig. 2

Strategy for combination antioxidant therapy for TBI and SCI. Injury triggers an increase in cytoplasmic Ca²⁺ via voltage dependent and glutamate receptor-operated channels, which initiates the depicted cascade of events. Mitochondria Ca²⁺ uptake causes O₂•⁻ leakage from the electron transport chain and activation of mitochondrial nitric oxide synthase (NOS). O₂•⁻ and •NO combine to form the highly reactive nitrogen species PN (ONOO−) giving rise to nitrogen dioxide •NO₂, hydroxyl •OH and •CO₃. These PN-derived radicals induce cell membrane and mitochondrial oxidative damage resulting in the inhibition of Ca²⁺ ATPase and a decrease in the mitochondrial ATP production and membrane potential (ΔΨ), respectively. Mitochondrial dysfunction causes the dumping of mitochondrial Ca²⁺ into the cytoplasm where it exacerbates cytoplasmic calcium overload and calpain activation. Calpain initiates the proteolysis of cytoskeletal proteins and other substrates ultimately contributing to neurodegeneration. The combination of the antioxidant penicillamine or tempol, which catalytically reacts with PN-derived radicals with a chain-breaking LP inhibitor such as U-83836E or a carbonyl (CHO) scavenging compound (Phenelzine) should produce a better neuroprotective effect than any of these compounds alone.