title: Co-regulation of dopamine D1 receptor and uncoupling protein-2 expression in 3-nitropropionic acid-induced neurotoxicity: neuroprotective role of L-carnitine.
abstract: This study tested the hypothesis that the expression of uncoupling proteins (UCPs) and dopamine (DA) system genes is responsive to 3-nitropropionic acid (3-NPA) neurotoxic effects and to the neuroprotective effects of the mitochondrial enhancer, L-carnitine (LC), in the rat striatum. Inactivation of mitochondrial succinate dehydrogenase (SDH) by 3-NPA results in hypoxic brain damage. Hypoxic conditions induce uncoupling protein-2 (UCP-2). An increase in UCP-2 expression may lead to a decrease in production of reactive oxygen species (ROS) associated with energy depletion. However, this adaptive response can also lead to a reduction of ATP that may further contribute to energy deficit and mitochondrial dysfunction. Here, male adult Sprague-Dawley rats (n=5/group) were injected either with saline or 3-NPA at 30 mg/kg, s.c. alone or 30 min after pre-treatment with LC (100mg/kg, i.p.). Rectal temperature was monitored before treatment and 4h following 3-NPA administration. Animals were sacrificed 4h post-treatment. Total RNA was isolated from the striatum and transcripts of UCP-2, UCP-4 and UCP-5 genes, as well as genes related to dopamine metabolism, such as DA D(1) and D(2) receptors, tyrosine hydroxylase (TH), monoamine oxidase-B (MAO-B), and vesicular monoamine transporter-2 (VMAT-2), were measured using real-time reverse transcription polymerase chain reaction (RT-PCR). While core temperature decreased significantly in 3-NPA-treated rats, LC significantly inhibited the hypothermic effect of 3-NPA (p<0.05). 3-NPA caused a significant increase in UCP-2 and DA D(1) receptor gene expression in the striatum and both effects were attenuated by pre-treatment with LC. Since LC maintains the ATP/ADP ratio and was previously shown to be neuroprotective against 3-NPA toxicity, the modulation of UCP-2 expression by LC suggests that LC counteracts energy dissipation and thus prevents the negative effects of ATP decline on DA neurotransmission.
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079, USA. zbigniew.binienda@fda.hhs.gov <zbigniew.binienda@fda.hhs.gov>
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Binienda
authors.forename: Syed F
authors.initials: SF
authors.lastname: Ali
authors.forename: Ashraf
authors.initials: A
authors.lastname: Virmani
authors.forename: Antonino
authors.initials: A
authors.lastname: Amato
authors.forename: Nadia
authors.initials: N
authors.lastname: Salem
authors.forename: Beata D
authors.initials: BD
authors.lastname: Przybyla
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002331:Carnitine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D009498:Neurotoxins / Q000633:toxicity; D009574:Nitro Compounds; D011422:Propionates; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D000071246:Uncoupling Protein 2
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; C015392:3-nitropropionic acid; D002331:Carnitine