MAY 1997 VOLUME 10, NUMBER 5 © Copyright 1997 by the American Chemical Society
Editorial Free Radical Mechanisms of Neurotoxicity The past 20 years have witnessed an explosion of research on the role of oxygen radicals in a range of diseases. One of the most exciting areas of contemporary research is the involvement of free radicals in neurodegenerative diseases. The results of biochemical, genetic, and molecular biological research suggest that oxidation plays an important role in Alzheimer’s disease, stroke, and amyotrophic lateral sclerosis, to name a few. Conversely, agents that scavenge radical oxidants or antagonize the sequelae triggered by oxidants protect against the damage. The ability to prevent or treat neurological damage has stimulated considerable interest in the pharmaceutical industry. In fact, a number of companies have been created to exploit radical-based approaches to the prevention of neurological disease. Despite an impressive body of information from descriptive experiments implicating radical damage in neurological disorders, our understanding of the molecular details of the pathology is incomplete and controversial. Thus, we have dedicated the 1997 Forum to Free Radical Mechanisms of Neurotoxicity. It begins with an overview by Stadtman and Berlett of the chemistry of protein oxidation by reactive oxygen species. Protein oxidation is particularly relevant to neurological dysfunction because nerve cells do not divide and proteins play critical roles in their function. Thus, protein oxidation and loss of activity could contribute to the degeneration of nervous tissue. Whether or not protein oxidation is responsible for neurological death, it is correlated to the process so it constitutes an excellent biomarker of oxidative stress in cells. In fact, feeding radical traps to rodents lowers the level of protein oxidation and improves neurological function. One of the hallmarks of Alzheimer’s disease is the presence of senile plaques containing aggregates of β-amyloid protein. β-Amyloid aggregation is believed to be an important contributor to the genesis of the disease, and strategies are being developed to prevent it. There is strong evidence that aggregation of β-amyloid leads S0893-228x(97)00493-1 CCC: $14.00
to oxygen radical generation, and this plays a causative role in neurological toxicity. Butterfield reviews the evidence supporting his hypothesis that β-amyloid itself is an important source of free radicals. Peptide fragments of β-amyloid generate radicals that are detectable by spin traps in vitro, and these fragments induce lipid peroxidation when incubated with membrane fractions. Insertion of β-amyloid into cell membranes followed by radical generation could lead to loss of membrane integrity, alteration of receptor-mediated signaling, and altered calcium fluxes. This could eventually result in cell dysfunction and death. Mattson et al. expand on this theme and focus on the mechanism that the brain has evolved to protect against such damage. After all, the brain exists in a highly oxygenated environment and generates most of its energy by oxidative phosphorylation. Thus, it must have ways to deal with oxidative stress. In fact, growth factors and cytokines, acting through their cell surface receptors, appear to be strongly protective against oxidative stress. This provides an opportunity for pharmacological protection by manipulation of signal transduction pathways. The complexity of β-amyloid toxicity is highlighted in a contribution by Sayre et al. Multiple mechanisms have been proposed for the aggregation of β-amyloid into senile plaques, and intermediates in the process rather than the final aggregates may be responsible for the toxicity. There is no disputing that β-amyloid aggregation leads to radical production and that this plays an important role in toxicity. But the mechanism of radical production is a matter of contention. Alternates to the direct radical generation hypothesis are reviewed including the possibility that radicals may be generated by activation of neighboring brain macrophages (microglia) through receptor-dependent or receptor-independent mechanisms. Hensley et al. conclude the Forum with a reminder that a range of radicals may mediate neurological pathology. These authors focus on the role of nitric oxide and its derivative, peroxynitrite, in stroke and AIDS-related © 1997 American Chemical Society
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dementia. Treatment of astrocytoma or glial cells with the HIV coat protein gp120 leads to the induction of nitric oxide synthase and nitric oxide generation. Furthermore, spin traps demonstrate the production of nitric oxide in the brain of rodents treated with gp120. Spin traps also are known to protect against neurological injury by ischemia/reperfusion suggesting a role for nitric oxide or its derivatives in stroke. This year’s Forum underscores the challenges, frustrations, and excitement of studies of the role of free radicals in neuronal injury. Oxidative stress is certainly involved in the pathological processes, but details regarding the key mediators and the pathways of their generation are hard to come by. These details are critical not only
Editorial
because they satisfy our intellectual curiosity but also because they provide opportunities for therapeutic interdiction and prevention. We are grateful to the authors for their participation in this Forum. The editors found them professional, passionate, and easy to work with. We are especially grateful to Allan Butterfield for suggesting this topic and helping to identify contributing authors. We think you’ll like the finished product. Lawrence J. Marnett Editor TX970493U
