Neuroprotective role of transgenic PAF-acetylhydrolase II in mouse models of focal cerebral ischemia.
OBJECTIVE
Platelet-activating factor (PAF) and oxidized unsaturated free fatty acids have been postulated to aggravate neuronal damage in the postischemic brain. Type II PAF-acetylhydrolase (PAF-AH II) not only terminates signals by PAF by its PAF-hydrolyzing activity but also protects cells against oxidative stress. We examined whether PAF-AH II can rescue cerebral neurons against ischemic insults.


METHODS
Transgenic mice overexpressing human PAF-AH II in neurons were generated and enzyme expressions were examined biochemically and histochemically. The mice were subjected to 60 minutes of transient middle cerebral artery occlusion followed by reperfusion for 24 hours. The infarction and apoptosis were estimated by TTC staining and fluorescence TUNEL staining, respectively.


RESULTS
Overexpression of PAF-AH II was found in brains of transgenic mice by Western blot and enzymatic activity analyses. In immunohistochemistry, human PAF-AH II expression was found throughout the central nervous system, especially in neurons of neocortex, hippocampus, and basal ganglia. The neurological deficit scores, cerebral edema index, and relative infarction volume were all significantly (P<0.05) lower in transgenic mice (1.30+/-0.72, 1.12+/-0.04, and 14.0+/-7.7%, respectively) than in wild-type mice (2.56+/-0.93, 1.23+/-0.12, and 31.9+/-9.7%, respectively). Percentages of apoptotic cells were also significantly (P<0.001) lower in transgenic mice (cortex, 5.2+/-3.3%; hippocampus, 3.4+/-7.0%) than in wild-type mice (cortex, 41.1+/-16.9%; hippocampus, 58.9+/-15.3%).


CONCLUSIONS
These results indicate that PAF-AH II exerts strong neuroprotective effects against ischemic injury and suggest a possibility for clinical use of this enzyme in cerebral ischemia.
Umemura
Kimiko
K
Department of Neurosurgery, University of Toyama Faculty of Medicine, Toyama, Japan.
Kato
Ichiro
I
Hirashima
Yutaka
Y
Ishii
Yoko
Y
Inoue
Takao
T
Aoki
Junken
J
Kono
Nozomu
N
Oya
Takeshi
T
Hayashi
Nakamasa
N
Hamada
Hideo
H
Endo
Shunro
S
Oda
Masaya
M
Arai
Hiroyuki
H
Kinouchi
Hiroyuki
H
Hiraga
Koichi
K
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000378:metabolism
D018696:Neuroprotective Agents; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase