Substrates for hypothalamic PGE2 synthesis are not decreased in cholestatic rats.

Abstract

We have recently described impaired IL-1 beta-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis in cholestatic rats and have implicated defective IL-1 beta-mediated hypothalamic generation of PGE2 in this finding. Since patients with obstructive cholestasis have decreased levels of PGE2 precursor fatty acids in their red blood cell membranes (arachidonic acid) we speculated that a similar deficiency of membrane prostaglandin percursor fatty acids in the hypothalamus of cholestatic rats may contribute to the defective cytokine-mediated PGE2 generation we have previously described. Therefore, in this study we determined red blood cell and hypothalamic membrane fatty acid composition in rats with obstructive cholestasis due to bile duct resection and in non-cholestatic sham resected controls 5 days after operation. To do this red blood cell membrane and hypothalamic membrane fatty acids were extracted, methyl esterified and quantified by gas liquid chromatography. Similar to results found in patients with obstructive cholestasis, bile duct resected rats had significantly reduced levels of red blood cell membrane arachidonic acid compared to levels in sham resected controls (p < or = 0.02). However, bile duct resected and sham resected rats had similar levels of hypothalamic membrane arachidonic acid. Therefore, these results suggest that the impaired IL-1 beta-induced HPA axis activation in cholestatic rats cannot be explained by lower hypothalamic membrane levels of the PGE2 substrate arachidonic acid in these animals. Furthermore, our results suggest that the brain in cholestasis appears to be protected from membrane fatty acid composition alterations which are seen outside the blood-brain-barrier.