HIF prolyl hydroxylase inhibition augments dopamine release in the rat brain in vivo.
The transcription factor hypoxia-inducible factor (HIF) is essential for the activation of several genes that promote the survival of cells exposed to oxidative stress. Expression of tyrosine hydroxylase (TH), which is the rate-limiting enzyme in the dopamine (DA) synthesis, is one of the genes that are positively regulated by HIF. Accordingly, HIF induction results in elevated DA release in various cell lines in vitro. HIF prolyl hydroxylase (HPH) is critically involved in the negative regulation of HIF levels. We investigated the in vivo effects of the HPH inhibitor FG0041 on brain DA function in rats by microdialysis in freely moving rats, locomotor activity, and Western blot analysis. Administration of FG0041 (10 mg/kg i.p.), as an acute (single injection), or as subchronic (once daily for 6 days) treatment and cobalt chloride (CoCl2) (60 mg/kg s.c.) potentiated potassium (K+) induced increases in extracellular levels of DA levels in the rat striatum. The increase in extracellular DA of freely moving rats was sought in relationship to locomotor activity in rats. A significant increase in locomotor activity was observed in FG0041-treated rats compared with vehicle on a cocaine challenge. In support of these findings, protein levels of TH in the rat brain stem were increased after treatment with FG0041. These data indicate that FG0041 augments DA function in the rat brain. Inhibition of HPH enhances DA function by increasing DA release, which has implications for the use of HIF induction in the treatment of neurodegenerative diseases.
Witten
Louise
L
Discovery Pharmacology Research, H. Lundbeck A/S, Valby, Denmark. low@lundbeck.com
Sager
Thomas
T
Thirstrup
Kenneth
K
Johansen
Jens Leander
JL
Larsen
Dorrit Bjerg
DB
Montezinho
Liliana P
LP
Mørk
Arne
A
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D003035:Cobalt / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005110:Extracellular Space / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010618:Phenanthrolines / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; C533349:FG 0041; D010618:Phenanthrolines; D003035:Cobalt; D011393:Procollagen-Proline Dioxygenase; D014446:Tyrosine 3-Monooxygenase; C018021:cobaltous chloride; D003042:Cocaine; D011188:Potassium; D004298:Dopamine