title: Female-specific neuroprotection against transient brain ischemia observed in mice devoid of prion protein is abolished by ectopic expression of prion protein-like protein.
abstract: This study was designed to examine the function of cellular prion protein and prion protein-like protein/Doppel, in transient ischemia-related neuronal death in the hippocampus. Two different lines of mice devoid of cellular prion protein, Zrch I Prnp(0/0) and Ngsk Prnp(0/0), were used. The former lacks cellular prion protein whereas the latter ectopically expresses prion protein-like protein/Doppel in the brain in the absence of cellular prion protein. Mice were subjected to 10 min-occlusion of the bilateral common carotid arteries with recovery for 14 days. Less than 10% of the pyramidal neurons in the CA1 subfield were degenerated in male and female wild-type mice. In contrast, more than half of the neurons were lost in male Zrch I Prnp(0/0) and Ngsk Prnp(0/0) mice. Such severe neuronal loss was also observed in female Ngsk Prnp(0/0) mice. However, female Zrch I Prnp(0/0) mice showed mild neuronal loss similar to wild-type mice. Flunarizine, a T- and L-type Ca(2+)-channel antagonist, significantly reduced the neuronal loss in female but not in male Ngsk Prnp(0/0) mice. These results indicate that loss of cellular prion protein renders hippocampal neurons susceptible to ischemic insult specifically in male but not female mice and the ectopic expression of prion protein-like protein/Doppel aggravates the ischemic neuronal death in female prion protein-null mice probably via overloading of Ca(2+)-dependent signaling.
authors.affiliation: Department of Pharmacology 1, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. yasukosy@net.nagasaki-u.ac.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Sakurai-Yamashita
authors.forename: S
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: D
authors.initials: D
authors.lastname: Yoshikawa
authors.forename: N
authors.initials: N
authors.lastname: Okimura
authors.forename: Y
authors.initials: Y
authors.lastname: Masuda
authors.forename: S
authors.initials: S
authors.lastname: Katamine
authors.forename: M
authors.initials: M
authors.lastname: Niwa
mesh_terms: D000682:Amyloid / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005444:Flunarizine / Q000494:pharmacology; D058851:GPI-Linked Proteins; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D002546:Ischemic Attack, Transient / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012727:Sex Characteristics
chemical_list: D000682:Amyloid; D002121:Calcium Channel Blockers; D058851:GPI-Linked Proteins; D018696:Neuroprotective Agents; D000072002:Prion Proteins; D011328:Prions; C122036:Prnd protein, mouse; C512657:Prnp protein, mouse; D011498:Protein Precursors; D004958:Estradiol; D005444:Flunarizine