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Identification of Rat Hippocampal mRNAs Altered by the Mitochondrial Toxicant, 3-NPA


Address for correspondence: Dr. Beata Przybyla-Zawislak, Division of Neurotoxicology, HFT-132, FDA/NCTR, Jefferson, AR 72079-9502. Voice: 870-543-7053; fax: 870-543-7745.


Abstract: 3-Nitropropionic acid (3-NPA) is a model mitochondrial inhibitor that causes selective neurodegeneration in brain. 3-NPA-induced neurodegeneration occurs via a secondary neurotoxicity, caused initially by ATP depletion and redox changes in the cell. It is known that the hippocampal degeneration caused by mitochondrial dysfunction affects learning and memory, cognitive functions commonly disturbed in neurodegenerative diseases. The 3-NPA- treated animal model can be used to study molecular mechanisms underlying selective degeneration in the brain. In this study, a microarray approach was utilized to define changes in the expression of 530 genes in the rat hippocampus after acute exposure to 3-NPA at 30 mg/kg, sc. The microarray data were collected at 30 min, 2 h, and 4 h post-3-NPA. Statistical modeling using an ANOVA mixed model applied to Van der Waerden scores of rank-transformed intensity data was used to assign statistical significance to 44 transcripts. These transcripts represent genes associated with energy metabolism, calcium homeostasis, the cytoskeleton, neurotransmitter metabolism, and other cellular functions. Changes in the transcripts of genes encoding 2 transporters [blood-brain specific anion transporter (Slco1c1) and sodium-dependent inorganic phosphate cotransporter (Slc17a7)] were confirmed by real-time RT-PCR. In conclusion, this study identified 2 new potential targets for enhancement of neuroprotection or inhibition of neurodegeneration associated with ATP depletion in the hippocampus.