Therapeutic window for cinnamophilin following oxygen-glucose deprivation and transient focal cerebral ischemia.
Cinnamophilin (CINN, (8R, 8'S)-4, 4'-dihydroxy-3, 3'-dimethoxy-7-oxo-8, 8'-neolignan) protects against ischemic stroke in mice. While some anti-oxidative effects of CINN have been characterized, its therapeutic window and molecular basis for neuroprotection remain unclear. We evaluated antioxidant and anti-inflammatory properties and therapeutic window of CINN against brain ischemia using a panel of in vitro and in vivo assays. Data from lipid peroxidation and radical scavenging assays showed that CINN was a robust antioxidant and radical scavenger. CINN effectively inhibited the production of tumor necrosis factor alpha (TNF-alpha), nitrite/nitrate, interleukin-6 (IL-6) in lipopolysaccharide (LPS)-stimulated RAW 264.7 and BV2 cells (P<0.05, respectively). Relative to controls, CINN, administrated at 80 mg/kg, 2, 4, or 6 h postinsult, but not 12 h, significantly reduced brain infarction by 34-43% (P<0.05) and improved neurobehavioral outcome (P<0.05) following transient focal cerebral ischemia in rats. CINN (10-30 microM) also significantly reduced oxygen-glucose deprivation-induced neuronal damage (P<0.05) in rat organotypic hippocampal slices, even when it was administrated 2, 4, or 6 h postinsult. Together, CINN protects against ischemic brain damage with a therapeutic window up to 6 h in vivo and in vitro, which may, at least in part, be attributed by its direct antioxidant and anti-inflammatory effects.
Lee
E-Jian
EJ
Department of Surgery, Neurophysiology Laboratory, Neurosurgical Service, National Cheng Kung University Medical Center and Medical School, Tainan, Taiwan. ejian@mail.ncku.edu.tw
Chen
Hung-Yi
HY
Hung
Yu-Chang
YC
Chen
Tsung-Ying
TY
Lee
Ming-Yang
MY
Yu
Shu-Ching
SC
Chen
Ying-Hsin
YH
Chuang
I-Chuan
IC
Wu
Tian-Shung
TS
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000627:therapeutic use*; D052160:Benzothiazoles / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000172:deficiency*; D006139:Guaiacol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D000860:Hypoxia / Q000188:drug therapy*; D015850:Interleukin-6 / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology; D017705:Lignans / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009924:Organ Culture Techniques; D009195:Peroxidase / Q000378:metabolism; D010627:Phenethylamines / Q000378:metabolism; D011134:Polysaccharides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy; D013451:Sulfonic Acids / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000975:Antioxidants; D052160:Benzothiazoles; D015850:Interleukin-6; D017705:Lignans; D009566:Nitrates; D009573:Nitrites; D010627:Phenethylamines; D011134:Polysaccharides; D013451:Sulfonic Acids; D014409:Tumor Necrosis Factor-alpha; C057485:1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane; C088121:cinnamophilin; C002502:2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid; D006139:Guaiacol; D009195:Peroxidase; D005947:Glucose