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Departments of Obstetrics and Gynecology (S.D., T.L.H.), Neurobiology (R.T.M., C.J.B., T.L.H.), Neurosurgery (P.P.), and Ophthalmology-Visual Science (C.J.B.), Yale University School of Medicine, New Haven, Connecticut 06520; and Department of Neurology and Neuroscience, Weill Medical College of Cornell University (L.Y., M.F.B.), New York, New York 10021
Address all correspondence and requests for reprints to: Dr. Tamas L. Horvath, Department of Obstetrics and Gynecology, Yale Medical School, 333 Cedar Street, FMB 339, New Haven Connecticut 06520. 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 UCPs precondition neurons by dissociating cellular energy production from that of free radicals to withstand the harmful effects of cellular stress occurring in a variety of neurodegenerative disorders, including epilepsy.
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