INCREASED EXPRESSION AND FUNCTION OF MITOCHONDRIAL UNCOUPLING PROTEIN (UCP2) IN THE NEONATAL BRAIN CONTRIBUTE CRITICALLY TO DIMINISHED SEIZURE-INDUCED NEURONAL DEATH
Abstract number :
A.06
Submission category :
Year :
2002
Submission ID :
1542
Source :
www.aesnet.org
Presentation date :
12/7/2002 12:00:00 AM
Published date :
Dec 1, 2002, 06:00 AM
Authors :
Céline M. Dubé, Kristina A. Dorenbos, Patrick G. Sullivan, Oswald Steward, Tallie Z. Baram. Anatomy and Neurobiology, University of California, Irvine, Irvine, CA; Reeve-Irvine Research Center, University of California, Irvine, Irvine, CA; Center for the
RATIONALE: Prolonged seizures kill neurons in hippocampus and other regions contributing to the limbic circuit. In contrast, the neonatal brain is generally resistant to status epilepticus-induced excitotoxicity. The mechanisms for this phenomenon have not been elucidated.Here we tested the hypothesis that early in life, altered mitochondrial function protects limbic neurons from excitotoxicity.
METHODS: Mitochondrial uncoupling and the expression of the uncoupling protein 2 (UCP2) were determined in limbic structures of neonatal and adult rats. Induction of reactive oxygen species formation, mitochondrial function and neuronal injury were compared after prolonged seizures (induced by kainic acid) using standard methods.
RESULTS: Basal expression of UCP2 was higher and mitochondria were more uncoupled in immature limbic neurons. Unlike in the adult, prolonged seizures did not increase reactive oxygen species formation or result in mitochondrial dysfunction in neonatal brain. The enhanced UCP2 expression and function in neonatal brain were due to the high fat content of maternal milk, so that substituting a low-fat diet reduced UCP2, restored mitochondrial coupling to adult levels and permitted seizure-induced neuronal injury.
CONCLUSIONS: Modulation of UCP2 expression and function by dietary fat protects neonatal neurons from seizure-induced death by preventing mitochondrial dysfunction. This mechanism may be applicable to neuroprotective strategies in the prevention and therapy of epilepsy.
[Supported by: NIH NS28912, NS35439, NS074444, NS32280, Neotherapeutics fellowship]