Expression of GTP cyclohydrolase I in murine locus ceruleus is enhanced byperipheral administration of lipopolysaccharide

Among the enzymes involved in the system for catecholamine biosynthesis, GT P cyclohydrolase I (GCH) contributes to the system as the first and rate-li miting enzyme for the de novo biosynthesis of tetrahydrobiopterin (BH4), wh ich is the cofactor for tyrosine hydroxylase (TH). Therefore, we investigat ed whether the endotoxemia caused by an intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) can modulate BH4 production in the norepinephrine nuclei, i.e. the locus ceruleus (LC; A6) and central caudal pens (A5), in C3H/HeN mice and whether such a change in BH4, if any, can result in the mo dification of norepinephrine production in these nuclei. After a 5-mug i.p. injection of LPS, the protein expression of GCH and TH in both nuclei was examined by immunohistochemistry. The staining intensity of GCH-positive ce lls increased at 6 h, whereas no significant change in the staining intensi ty of TH-positive cells was detected. Next, we measured the contents of BH4 , norepinephrine, and its metabolites 4-hydroxy-3-methoxyphenylglycol (MHPG ) and DL-4-hydroxy-3-methoxymandelic acid (VMA) in these nuclei after LPS i .p. injection. The BH4 content increased to a statistically significant lev el at 2 and 4 h after the injection. The contents of MHPG and VMA also show ed a time-course similar to that of BH4. These data can be rationalized to indicate that an increased supply of BH4 in the LC increased TH activity an d resulted in an increase in norepinephrine production rate at the site. Th is is the first report that sheds light on BH4 as a molecule that intervene s during endotoxemia to increase norepinephrine production rate in the LC. (C) 2001 Elsevier Science B.V. All rights reserved.