Inhibition of neutrophil migration by a protein kinase inhibitor for the treatment of ischemic brain infarction.
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 inhibiting neutrophil infiltration may provide an effective therapeutic intervention to reduce ischemic injury.
Satoh
S
S
Laboratory for Pharmacology, Asahi Chemical Industry, Shizuoka, Japan.
Kobayashi
T
T
Hitomi
A
A
Ikegaki
I
I
Suzuki
Y
Y
Shibuya
M
M
Yoshida
J
J
Asano
T
T
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D018994:Myosin Light Chains / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D051381:Rats
D004791:Enzyme Inhibitors; D018994:Myosin Light Chains; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C049347:fasudil