title: Manifestation of psychiatric behaviors in a mouse model of griseofulvin-induced hepatic porphyria.
abstract: Most patients with hepatic porphyria exhibit neuropsychiatric symptoms, including abdominal pain, peripheral neuropathy, confusion, insomnia and mental disturbances such as anxiety and depression. Although heme deficiency and accumulation of heme precursors are thought to be responsible for neuropsychiatric manifestations in patients with acute porphyria, the pathogenetic mechanisms remain poorly understood. In the present study, we observed psychiatric behaviors in mice with hepatic porphyria induced by the ingestion of a griseofulvin (GF)-containing diet over a period of 12 weeks. GF ingestion by the mice caused an accumulation of porphyrins in the feces and a decrease in heme in the liver; these effects were observed throughout the entire duration of the experiment, with maximum levels observed after circa 1 week of ingestion of this diet. In addition, the mice developed enlargement of the liver, hepatocyte injury, and cholestasis. Mice with hepatic porphyria manifested an anxiety-like behavior by the long-term treatment (over 5 weeks) in a GF-dose and duration dependent manner. The hepatic porphyria mice also manifested depression-like behaviors by the short-term treatment (3 weeks) of GF2.0, which was reversed by administration of anti-depressant, imipramine. In conclusion, this study for the first time demonstrated psychiatric manifestations in GF-induced hepatic porphyria mice. The present results suggest that model animals could be useful for elucidating the mechanisms underlying psychiatric manifestations in syndromes such as hepatic porphyria and hepatic encephalopathy that are associated with the impairment of hepatic function.
authors.affiliation: Josai International University, Togane, Chiba, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Satoh
authors.forename: Reiko
authors.initials: R
authors.lastname: Iwadate
authors.forename: Yukino
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawai
authors.forename: Naomi
authors.initials: N
authors.lastname: Kudo
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Kawashima
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mitsumoto
mesh_terms: D000818:Animals; D001007:Anxiety / Q000209:etiology / Q000378:metabolism / Q000523:psychology*; D001522:Behavior, Animal / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003863:Depression / Q000209:etiology / Q000378:metabolism / Q000523:psychology*; D004195:Disease Models, Animal; D004798:Enzymes / Q000097:blood; D005243:Feces / Q000737:chemistry; D006118:Griseofulvin / Q000633:toxicity*; D006418:Heme / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D017094:Porphyrias, Hepatic / Q000139:chemically induced / Q000150:complications / Q000378:metabolism / Q000523:psychology*; D013550:Swimming
chemical_list: D004798:Enzymes; D006118:Griseofulvin; D006418:Heme; D003577:Cytochrome P-450 Enzyme System