title: Cerebral oxidative stress induces spatial working memory dysfunction in uremic mice: neuroprotective effect of tempol.
abstract: BACKGROUND
  Chronic kidney disease (CKD) is frequently associated with uremic encephalopathy and cognitive impairment. Recent studies have demonstrated that cerebral oxidative stress contributes to cognitive dysfunction. Although oxidative stress has been reported to increase in the uremic rat brain, the relationship between increased oxidative stress and cognitive impairment in uremia is unclear. In the present study, the effects of tempol (TMP), an antioxidant drug, were investigated in uremic mice.
  
  
  METHODS
  CKD was induced in male C57BL/6 mice (n = 8) by left nephrectomy and 2/3 electrocoagulation of the right renal cortex. Working memory performance was tested by the radial arm water maze test. We have prepared two protocols ('time course study' and 'treatment study'). First, we examined the working memory test and histological examination of mouse brains after 4 and 8 weeks. Next, we investigated the effect of TMP (3 mM) against uremia-induced neurodegeneration and oxidative stress in the mouse brain.
  
  
  RESULTS
  Eight weeks after CKD induction, vehicle-treated mice made significantly more errors than sham-operated control mice, while TMP improved working memory performance in CKD mice. CKD was associated with accumulation of 8-hydroxy-2'-deoxyguanosine in the hippocampal neuronal cells, but not in TMP-treated CKD mice. Increased numbers of pyknotic neuronal cells were observed in the hippocampus of CKD mice at 8 weeks, but pyknotic neuronal cell numbers were decreased under the influence of TMP in uremic mice.
  
  
  CONCLUSIONS
  The present study provided evidence that uremia is associated with spatial working memory dysfunction in mice and that treatment with TMP protects against cerebral oxidative stress and improves cognitive dysfunction in uremic mice, suggesting their potential usefulness for the treatment of cognitive dysfunction in uremia.
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Fujisaki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tsuruya
authors.forename: Mayumi
authors.initials: M
authors.lastname: Yamato
authors.forename: Jiro
authors.initials: J
authors.lastname: Toyonaga
authors.forename: Hideko
authors.initials: H
authors.lastname: Noguchi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakano
authors.forename: Masatomo
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Masanori
authors.initials: M
authors.lastname: Tokumoto
authors.forename: Hideki
authors.initials: H
authors.lastname: Hirakata
authors.forename: Takanari
authors.initials: T
authors.lastname: Kitazono
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D003497:Cyclic N-Oxides / Q000627:therapeutic use*; D003849:Deoxyguanosine / Q000031:analogs & derivatives; D004353:Drug Evaluation, Preclinical; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology; D008570:Memory, Short-Term / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress; D051436:Renal Insufficiency, Chronic / Q000150:complications; D065852:Spatial Memory / Q000187:drug effects; D013113:Spin Labels; D014511:Uremia / Q000150:complications*
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D018696:Neuroprotective Agents; D013113:Spin Labels; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; C001803:tempol
keywords: chronic kidney disease; cognitive dysfunction; oxidative stress; uremia