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

• Published in: Brain research Vol. 890; no. 2; pp. 203 - 210
• Main Authors: Kaneko, Yoko S., Ikemoto, Keiko, Mori, Keiji, Nakashima, Akira, Nagatsu, Ikuko, Ota, Akira
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 02.02.2001; Amsterdam Elsevier; New York, NY
• Subjects: Animals; Biochemistry and metabolism; Biological and medical sciences; Biopterins - analogs & derivatives; Biopterins - biosynthesis; Central nervous system; Endotoxemia - enzymology; Endotoxemia - physiopathology; Fundamental and applied biological sciences. Psychology; GTP Cyclohydrolase - drug effects; GTP Cyclohydrolase - metabolism; GTP cyclohydrolase I; Hypothalamo-Hypophyseal System - enzymology; Hypothalamo-Hypophyseal System - physiopathology; Immunohistochemistry; Injections, Intraperitoneal; Lipopolysaccharide; Lipopolysaccharides - pharmacology; Locus ceruleus; Locus Coeruleus - cytology; Locus Coeruleus - drug effects; Locus Coeruleus - enzymology; Male; Mice; Mice, Inbred C3H; Neurons - drug effects; Neurons - enzymology; Norepinephrine; Norepinephrine - biosynthesis; Stress, Physiological - enzymology; Stress, Physiological - physiopathology; Tetrahydrobiopterin; Tyrosine 3-Monooxygenase - metabolism; Tyrosine hydroxylase; Vertebrates: nervous system and sense organs; IL, Interleukin; NO, Nitric oxide; BH4, (6 R)- l- erythro-dihydroxypropyl-2-amino-4-hydroxy-5,6,7,8-tetrahydropteridine; NF, Nuclear factor; NOS, Nitric oxide synthase; i.p., Intraperitoneal; MHPG, 4-hydroxy-3-methoxyphenylglycol; Tyrosine hydroxylase; LC, Locus ceruleus; Neurotransmitters, modulators, transporters, and receptors; TH, Tyrosine hydroxylase; EDTA, Ethylenediaminetetra-acetic acid; GTP cyclohydrolase I; Tetrahydrobiopterin; Tris, 2-amino-2-hydroxymethyl-1,3-propanediol; VMA, dl-4-hydroxy-3-methoxymandelic acid; Lipopolysaccharide; GCH, GTP cyclohydrolase I; Norepinephrine; CNS, Central nervous system; TNF, Tumor necrosis factor; LPS, Lipopolysaccharide; Locus ceruleus; Enzyme; Rodentia; Central nervous system; Gene expression; Tyrosine 3-monooxygenase; Vertebrata; Mammalia; Mouse; Hydrolases; Oxidoreductases; Locus coeruleus; Brain (vertebrata)
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(00)03161-9

Among the enzymes involved in the system for catecholamine biosynthesis, GTP cyclohydrolase I (GCH) contributes to the system as the first and rate-limiting enzyme for the de novo biosynthesis of tetrahydrobiopterin (BH4), which is the cofactor for tyrosine hydroxylase (TH). Therefore, we investigated 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 pons (A5), in C3H/HeN mice and whether such a change in BH4, if any, can result in the modification of norepinephrine production in these nuclei. After a 5-μg 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 cells increased at 6 h, whereas no significant change in the staining intensity 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 level at 2 and 4 h after the injection. The contents of MHPG and VMA also showed 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 and resulted in an increase in norepinephrine production rate at the site. This is the first report that sheds light on BH4 as a molecule that intervenes during endotoxemia to increase norepinephrine production rate in the LC.