ABSTRACT
Increased oxidative damage in the central nervous system has become closely associated with several age-related neurodegenerative diseases. Results from our research effort in this area have lead to demonstrations that enhanced neuroin flammatory events and elevated signal transduction processes are closely tied to age-associated neurodegenerative etiology. Enhanced production of reactive oxygen species (ROS) leading to elevated oxidative damage is mostly understood as a result of enhanced activation of glial cells, which then lead to enhanced production of reactive nitrogen species (RNS). Increased amounts of RNS are due to enhanced signal transduction-mediated elevation of inducible nitric oxide synthase (iNOS) gene expression. Although this broad overview purposely over simplifies the many different dynamic control processes involved, on the whole the experimental data emerging do underscore its validity. We present a brief historical view of how our experimental data forced us to reach the conclusions drawn. Attempts to understand the mechanism of the neuroprotective action of a-phenyl-terr-butylnitrone (PBN), a nitrone-based free radical trap, provided an initial thrust. A summary of recently obtained data from brains of Alzheimer subjects, in comparison to age-matched controls, will be presented. These results
can be understood in the context of basic studies on cultured astrocytes demon strating cytokine-mediated upregulation of signal transduction processes, particu larly those involving the activation of the p38 protein kinase signal transduction pathway.
