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Submitted on May 29, 2003
Accepted on August 8, 2003
1 Departments of Obstetrics and Gynecology, Neurobiology, Neurosurgery, and Ophthalmology-Visual Science, Yale University School of Medicine, New Haven CT, 06520, Dept of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021
* To whom correspondence should be addressed. E-mail: tamas.horvath{at}yale.edu.
The mitochondrial uncoupling protein UCP2 is expressed in selected regions of the brain. Here we demonstrate that up-regulation of UCP2 is part of a neuroprotective set of responses to various cellular stresses in vitro and in vivo. PC12 cells, when transfected with UCP2, were protected against free-radical-induced cell death. Seizure activity was associated with elevated UCP2 levels and mitochondrial uncoupling activity. In transgenic mice that expressed UCP2 constitutively in the hippocampus before seizure induction, a robust reduction in cell death was seen. Because UCP2 increased mitochondrial number and ATP levels with a parallel decrease in free radical-induced damage, it is reasonable to suggest that mitochondrial uncoupling proteins precondition neurons by dissociating cellular energy production from that of free radicals to withstand harmful effects of cellular stress occurring in a variety of neurodegenerative disorders, including epilepsy.
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