NR AUDT
AU Sakurai-Yamashita,Y.; Sakaguchi,S.; Yoshikawa,D.; Okimura,N.; Masuda,Y.; Katamine,S.; Niwa,M.
TI Female-specific neuroprotection against transient brain ischemia observed in mice devoid of prion protein is abolished by ectopic expression of prion protein-like protein
QU Neuroscience 2005; 136(1): 281-7
PT journal article
AB 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.
MH Amyloid/deficiency/genetics/*metabolism; Animals; Brain/*metabolism; Calcium Channel Blockers/pharmacology; Cell Death/drug effects; Estradiol/pharmacology; Female; Flunarizine/pharmacology; Hippocampus/drug effects/metabolism/pathology/physiopathology; In Situ Nick-End Labeling; Ischemic Attack, Transient/metabolism/pathology/*physiopathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons/drug effects/metabolism; Neuroprotective Agents/*metabolism; Prions/genetics/*metabolism; Protein Precursors/deficiency/genetics/*metabolism; Research Support, Non-U.S. Gov't; *Sex Characteristics
AD 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
SP englisch
PO USA