Hydroxyurea induces vasopressin release and cytokine gene expression in the rat hypothalamus.
We previously showed that the cytostatic drug hydroxyurea (HU) activates the hypothalamo-pituitary-adrenal (HPA) axis in intact rats, whereas it is lethal in rats with impaired HPA function. In these animals, HU toxicity is mediated by increased circulating levels of proinflammatory cytokines, whose secretion cannot be counteracted by glucocorticoids, suggesting that HPA activation blunts HU toxicity. Here we investigated the mechanisms through which HU activates the HPA axis, looking at the direct effects of the drug on the isolated hypothalamus. We found that HU significantly increases the release of arginine vasopressin but not that of corticotrophin-releasing hormone in short-term incubation experiments. The levels of arginine vasopressin are also increased in the hypothalamus and systemic circulation 2 h after the in vivo administration of the drug. Furthermore, HU increased significantly the expression of interleukin-6 and, to a lesser extent, interleukin-1beta in the hypothalamus. Interestingly, experiments with HU on primary cultures of rat microglia and astrocytes suggested that the increase in cytokine gene expression observed in hypothalamic explants is not accounted for by glial cells. Since both vasopressin and cytokines can activate the HPA axis, our present findings provide a reasonable explanation of the HPA activation elicited by HU in vivo in the rat.
Navarra
Pierluigi
P
Institute of Pharmacology, Catholic University Medical School, Largo Francesco Vito, Rome, Italy. pnavarra@rm.unicatt.it
Tringali
Giuseppe
G
Fabricio
Aline S C
AS
Proietti
Alessia
A
Vairano
Mauro
M
Pozzoli
Giacomo
G
Preziosi
Paolo
P
D000818:Animals; D001127:Arginine Vasopressin / Q000187:drug effects* / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006918:Hydroxyurea / Q000494:pharmacology*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D016207:Cytokines; D004791:Enzyme Inhibitors; D001127:Arginine Vasopressin; D003346:Corticotropin-Releasing Hormone; D006918:Hydroxyurea