Shin-ichi Satoh (1), Teruki Kobayashi (1), Asako Hitomi (1), Ichiro Ikegaki
(1), Yoshio Suzuki (2), Masato Shibuya (3), Jun Yoshida (2) and Toshio Asano
(1)
(1) Laboratory for Pharmacology, Asahi Chemical Industry, 632-1, Mifuku,
Ohito-cho, Tagata-gun, Shizuoka 410-2321, Japan
(2) Department of Neurosurgery, Nagoyo University School of Medicine, Tsurumai,
Nagoya 466-0065, Japan
(3) Department of Neurosurgery, Chukyo Hospital, Sanjyo, Nagoya 457-0866,
Japan
Abstract: This study investigated the therapeutic potential of
agents that inhibited neutrophil infiltration in cerebral ischemic infarction.
The migration of neutrophils elicited by N-formyl-methionyl-leucyl-phenylalanine,
tumor necrosis factor, C5a or platelet-activating factor was potently inhibited
by fasudil, an inhibitor of protein kinases including rho kinase, protein
kinase C and myosin light chain kinase, and hydroxy fasudil, a metabolite
of fasudil, in vitro. In a microembolism model in rats, myeloperoxidase-quantified
neutrophil accumulation in the ischemic brain was observed 24 hr after embolization.
Intravenous administration of fasudil prevented the accumulation of neutrophils.
In rats given fasudil, myeloperoxidase activity in the ipsilateral hemisphere
(0.04+/-0.01 unit/g wet tissue) was significantly lower than that in ischemic
rats (0.11+/-0.02 unit/g wet tissue). Fasudil also significantly reduced
the size of the infarct area and improved neurological functions. These
results suggest that neutrophil infiltration into the ischemic brain is
involved in the pathogenesis of ischemic injury and that neutrophil infiltration
may provide an effective therapeutic intervention to reduce ischemic injury.
Keywords: Cerebral ischemia, Neutrophil, Migration, Fasudil, Protein
kinase inhibitor