Desferrioxamine enhances hypoxic ventilatory response and induces tyrosine hydroxylase gene expression in the rat brainstem in vivo.
The iron chelator desferrioxamine (DFO) induces accumulation of the hypoxia-inducible factor (HIF-1), a transcription factor that up-regulates genes involved in adaptative responses to hypoxia. This property makes DFO a potential neuroprotector against hypoxic stress. We investigated in rats the effects of DFO on the ventilatory response to mild hypoxic tests and the expression of tyrosine hydroxylase (TH), a target gene of HIF-1. Two protocols were used, the first with repeated injections of 50 mg/kg DFO every 2 days during a 2-week period. This was aimed at define the time course of the ventilatory responses to a hypoxic test. In the second protocol, rats were given a single injection of 300 mg/kg DFO. Every day over 4 days, the hypoxic ventilatory response was recorded before the animal was sacrificed, and Western blot analysis of TH in the dorsal brainstem cardiorespiratory area was performed. DFO produced a delayed increase in the hypoxic ventilatory response, which appeared in the same time window as TH up-regulation (2-3 days after the bolus injection of DFO). This delay suggests a genic effect of the drug that improves the ventilatory response to hypoxia.
Nguyen
M V C
MV
CNRS UPR 2216, Neurobiologie Génétique et Intégrative, Institut Alfred Fessard, Gif/Yvette, France. mvchuong@yahoo.fr
Pouvreau
S
S
El Hajjaji
F Z
FZ
Denavit-Saubie
M
M
Pequignot
J M
JM
D000818:Animals; D002395:Catecholamines / Q000096:biosynthesis; D003676:Deferoxamine / Q000494:pharmacology* / Q000627:therapeutic use; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D000860:Hypoxia / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012119:Respiration / Q000187:drug effects* / Q000235:genetics; D012125:Respiratory Center / Q000187:drug effects* / Q000201:enzymology; D017262:Siderophores / Q000494:pharmacology / Q000627:therapeutic use; D017552:Solitary Nucleus / Q000187:drug effects / Q000201:enzymology; D016896:Treatment Outcome; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D002395:Catecholamines; D051793:Hypoxia-Inducible Factor 1; D012333:RNA, Messenger; D017262:Siderophores; D014446:Tyrosine 3-Monooxygenase; D003676:Deferoxamine