Neuroprotective role of transgenic PAF-acetylhydrolase II in mouse models of focal cerebral ischemia

Kimiko Umemura, Ichiro Kato, Yutaka Hirashima, Yoko Ishii, Takao Inoue, Junken Aoki, Nozomu Kono, Takeshi Oya, Nakamasa Hayashi, Hideo Hamada, Shunro Endo, Masaya Oda, Hiroyuki Arai, Hiroyuki Kinouchi, Koichi Hiraga

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE - 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.

Original languageEnglish
Pages (from-to)1063-1068
Number of pages6
JournalStroke
Volume38
Issue number3
DOIs
Publication statusPublished - 2007 Mar

Keywords

  • Apoptosis
  • Focal ischemia
  • Neuroprotection
  • PAF-acetylhydrolase
  • Transgenic mice

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialised Nursing

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