Vol. 54, Issue 2, 271-284, June 2002

Antioxidant Therapy in Acute Central Nervous System Injury: Current State

Yossi Gilgun-Sherki, Ziv Rosenbaum, Eldad Melamed and Daniel Offen

Departments of Neurology and the Felsenstein Medical Research Center (Y.G.-S., E.M., D.O.); and the Department of Neurosurgery (Z.R.), Rabin Medical Center, The Sackler School of Medicine, Tel Aviv University, Petah Tikva, Israel

I. Introduction
    A. Acute Central Nervous System Injury Mechanisms
    B. Reactive Free Radicals and Oxidative Stress in Acute Central Nervous System Injury
        1. Oxidative Stress-Mediated Brain Damage.
        2. Excitotoxicity Insults.
        3. Oxidative Stress and Excitotoxicity.
        4. Oxidative Stress-Induced Gene Expression.
    C. Blood-Brain Barrier Integrity
II. Antioxidants in the Treatment of Acute Central Nervous System Injury
    A. Antioxidants
    B. Experimental and Clinical Treatments of Acute Central Nervous System Injury
        1. Vitamins.
            a. In Prevention.
            i. Clinical Studies.
            b. In Treatment.
        2. Coenzyme Q₁₀.
        3. Melatonin.
        4. -Lipoic Acid.
        5. Ebselen.
            i. Animal Models.
            ii. Clinical Studies.
        6. Human Superoxide Dismutase/Superoxide Dismutase-Like Molecules.
            i. Animal Studies.
            ii. Clinical Studies.
        7. Spin-Trap Scavenging Agents.
        8. N-Acetylcysteine.
        9. Glutathione.
        10. Metal Ion Chelators.
        11. Uric Acid.
        12. Creatine.
        13. Lazaroids.
            i. Animal Model Studies.
            ii. Clinical Studies.
        14. Nicaraven.
        15. Other Antioxidants.
            i. 2,4-Diamino-Pyrrolo[2,3-D] Pyrimidines.
            ii. Polyamines.
            iii. MCI-186.
III. Conclusion and Future Strategies
Acknowledgments
References

Free radicals are highly reactive molecules generated predominantly during cellular respiration and normal metabolism. Imbalance between cellular production of free radicals and the ability of cells to defend against them is referred to as oxidative stress (OS). OS has been implicated as a potential contributor to the pathogenesis of acute central nervous system (CNS) injury. After brain injury by ischemic or hemorrhagic stroke or trauma, the production of reactive oxygen species (ROS) may increase, sometimes drastically, leading to tissue damage via several different cellular molecular pathways. Radicals can cause damage to cardinal cellular components such as lipids, proteins, and nucleic acids (e.g., DNA), leading to subsequent cell death by modes of necrosis or apoptosis. The damage can become more widespread due to weakened cellular antioxidant defense systems. Moreover, acute brain injury increases the levels of excitotoxic amino acids (such as glutamate), which also produce ROS, thereby promoting parenchymatous destruction. Therefore, treatment with antioxidants may theoretically act to prevent propagation of tissue damage and improve both the survival and neurological outcome. Several such agents of widely varying chemical structures have been investigated as therapeutic agents for acute CNS injury. Although a few of the antioxidants showed some efficacy in animal models or in small clinical studies, these findings have not been supported in comprehensive, controlled trials in patients. Reasons for these equivocal results may include, in part, inappropriate timing of administration or suboptimal drug levels at the target site in CNS. Better understanding of the pathological mechanisms of acute CNS injury would characterize the exact primary targets for drug intervention. Improved antioxidant design should take into consideration the relevant and specific harmful free radical, blood brain barrier (BBB) permeability, dose, and time administration. Novel combinations of drugs providing protection against various types injuries will probably exploit the potential synergistic effects of antioxidants in stroke.