title: Altered histamine neurotransmission in HPRT-deficient mice.
abstract: Lesch-Nyhan syndrome (LNS) is an X-chromosomal disorder with congenital deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) as underlying defect. We determined the concentrations of dopamine, histamine and their metabolites in brains of HPRT knockout mice, which serve as an animal model for LNS, and compared the results to those obtained from wild-type controls. Analyses were performed by high performance liquid chromatography (HPLC)-coupled tandem mass spectrometry (MS/MS). Besides a decrease of dopamine and 3-methoxytyramine (3-MT) concentrations in the cerebral hemisphere, HPRT-deficient mice also exhibited significantly reduced 1-methylhistamine (1-MH) and 1-methylimidazole-4-acetic acid (1-MI4AA) concentrations in the brain hemisphere and medulla. Moreover, the amount of 1-MI4AA was significantly decreased in the cerebellum. Our findings show that neuronal perturbations caused by HPRT deficiency are not restricted to the dopamine system but also affect histaminergic neurotransmission. These new insights into the brain metabolism of an LNS mouse model may help to find new therapeutic strategies to improve the quality of life of LNS patients.
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: tschirner.sarah@mh-hannover.de.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Tschirner
authors.affiliation: Research Core Unit Metabolomics, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: gutzki.frank@mh-hannover.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Gutzki
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany; Research Core Unit Metabolomics, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: kaever.volkhard@mh-hannover.de.
authors.forename: Volkhard
authors.initials: V
authors.lastname: Kaever
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: seifert.roland@mh-hannover.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: schneider.erich@mh-hannover.de.
authors.forename: Erich H
authors.initials: EH
authors.lastname: Schneider
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism; D006632:Histamine / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D007093:Imidazoles / Q000378:metabolism; D007926:Lesch-Nyhan Syndrome / Q000235:genetics; D008761:Methylhistamines / Q000378:metabolism; D018345:Mice, Knockout; D009435:Synaptic Transmission
chemical_list: D007093:Imidazoles; D008761:Methylhistamines; D015102:3,4-Dihydroxyphenylacetic Acid; C002667:methylimidazoleacetic acid; D006632:Histamine; D007041:Hypoxanthine Phosphoribosyltransferase; C005954:imidazoleacetic acid; C001746:3-methoxytyramine; C020404:tele-methylhistamine; D004298:Dopamine; D006719:Homovanillic Acid
keywords: Dopamine; HPLC; HPRT knockout mice; Histamine; Lesch–Nyhan syndrome; Mass spectrometry