Identification of rat hippocampal mRNAs altered by the mitochondrial toxicant, 3-NPA.
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.
Przybyla-Zawislak
Beata D
BD
Division of Neurotoxicology, HFT-132, National Center for Toxicology Research, Food and Drug Administration, Jefferson, Arkansas 72079-9502, USA. bzawislak@nctr.fda.gov
Thorn
Brett T
BT
Ali
Syed F
SF
Dennis
Richard A
RA
Amato
Antonino
A
Virmani
Ashraf
A
Binienda
Zbigniew K
ZK
D000465:Algorithms; D000818:Animals; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D017403:In Situ Hybridization; D008297:Male; D009498:Neurotoxins / Q000633:toxicity*; D009574:Nitro Compounds / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis; D027701:Organic Cation Transport Proteins / Q000235:genetics; D011422:Propionates / Q000633:toxicity*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis* / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050598:Vesicular Glutamate Transport Protein 1 / Q000235:genetics
D018076:DNA, Complementary; D009498:Neurotoxins; D009574:Nitro Compounds; D027701:Organic Cation Transport Proteins; D011422:Propionates; D012333:RNA, Messenger; C493466:Slc17a7 protein, rat; C451262:Slco1c1 protein, rat; D050598:Vesicular Glutamate Transport Protein 1; C015392:3-nitropropionic acid