Honokiol protects rat brain from focal cerebral ischemia-reperfusion injury by inhibiting neutrophil infiltration and reactive oxygen species production.
We have previously shown that honokiol, an active component of Magnolia officinalis, displayed protective effect against focal cerebral ischemia-reperfusion (FCI/R) injury in rats. Production of reactive oxygen species (ROS) and infiltration of neutrophils to injured tissue play deleterious roles during cerebral ischemia. To study the mechanism(s) in mediating neuroprotective effect of honokiol, FCI/R-induced neutrophil infiltration and lipid peroxidation in brain tissue, and activation of neutrophils in-vitro were examined. Intravenous administration of honokiol (0.01-1.0 microg/kg) 15 min before (pretreatment) or 60 min after (post-treatment) middle cerebral artery occlusion reduced the total infarcted volume by 20-70% in dose-dependent manner. Pretreatment or post-treatment of honokiol at concentration of 0.1 and 1.0 microg/kg significantly decreased the neutrophil infiltration in the infarcted brain. Time course of neutrophil infiltration was performed in parallel with the lipid peroxidation in infracted brain tissue during FCI/R injury. The results indicate that honokiol can protect brain tissue against lipid peroxidation and neutrophil infiltration during FCI/R injury and cerebral infarction induced by FCI/R is accompanied with a prominent neutrophil infiltration to the infarcted area during FCI/R course. In-vitro, honokiol (0.1-10 microM) significantly diminished fMLP (N-formyl-methionyl-leucyl-phenylalanine)- or PMA (phorbol-12-myristate-13-acetate)-induced neutrophil firm adhesion, a prerequisite step behind neutrophil infiltration, and ROS production in neutrophils. Intracellular calcium overloading activates calcium-stimulated enzymes and further exaggerates FCI/R injury. Honokiol (0.1-10 microM) impeded the calcium influx induced by fMLP (a receptor agonist), AlF(4)(-) (a G-protein activator) or thapsigargin (an intracellular calcium pool releaser). Therefore, we conclude that the amelioration of FCI/R injury by honokiol can be attributed to its anti-oxidative and anti-inflammatory actions through, at least in part, limiting lipid peroxidation and reducing neutrophil activation/infiltration by interfering firm adhesion, ROS production, and calcium overloading that may be primed/activated during FCI/R injury.
Liou
Kuo-Tong
KT
Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
Shen
Yuh-Chiang
YC
Chen
Chieh-Fu
CF
Tsao
Cheng-Ming
CM
Tsai
Shen-Kou
SK
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002544:Cerebral Infarction / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D017705:Lignans; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D000498:Allyl Compounds; D010636:Phenols
D001713:Biphenyl Compounds; D002118:Calcium; D017705:Lignans; D009240:N-Formylmethionine Leucyl-Phenylalanine; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D013755:Tetradecanoylphorbol Acetate; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C042932:formylmethionyl-leucyl-phenylalanine methyl ester