Address for correspondence: Philip K. Liu, Ph.D., Department of Neurosurgery, Baylor College of Medicine, 6560 Fannin, Suite 944 Houston, TX 77030, U.S.A. Voice: 713-798-5177; fax: 713-798-4124.
philipl{at}bcm.tmc.edu
Ann. N.Y. Acad. Sci. 962: 226-241 (2002).
Injury to the central nervous system is the leading cause of
disability in the United States. Neuronal death is one of the
causes of disability. Among patients who survive this type of
injury, various degrees of recovery in brain function are observed.
The molecular basis of functional recovery is poorly understood.
Clinical observations and research using experimental injury
models have implicated several metabolites in the cascade of
events that lead to neuronal degeneration. The levels of intracellular
ATP (energy source) and pH are decreased, whereas levels of
extracellular glutamate, intracellular calcium ions, and oxidative
damage to RNA/DNA, protein, and lipid are increased. These initiating
events can be associated with energy failure and mitochondrial
dysfunction, resulting in functional or structural brain damage.
The injured brain is known to express immediate early genes.
Recent studies show that reactive oxygen species (ROS) cause
lesions in genes from which mRNA is transcribed as part of the
endogenous neuroprotective response. Although degenerating proteins
and lipids may contribute to necrosis significantly after severe
injury, abnormalities in genetic material, if not repaired,
disturb cellular function at every level by affecting replication,
transcription, and translation. These lesions include abnormal
nucleic acids, known as oxidative lesions of DNA (ODLs) or of
RNA (ORLs). In this review, we focus on our current understanding
of the various effects of neuronal nitric oxide synthase on
the formation of modified bases in DNA and RNA that are induced
in the brain after injury, and how ODLs and ORLs affect cell
function.
