Zileuton reduces inflammatory reaction and brain damage following permanent cerebral ischemia in rats.
5-Lipoxygenase inhibitor zileuton has been demonstrated to attenuate ischemic brain damage in rats of permanent focal cerebral ischemia in previous work. To further investigate the mechanism underlying zileuton's neuroprotection, adult male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (MCAO), then received treatment with zileuton or vehicle after the onset of ischemia. Neurological deficit, cerebral infarction, and morphological characteristic were measured 6 and 24 h after MCAO. The enzymatic activity of myeloperoxidase (MPO) was assessed 6 and 24 h after MCAO and the lipid peroxidation levels were evaluated by malondialdehyde assay. Expression of nuclear factor-kappa B (NF-kappaB) p65 in rat brain was detected by immunohistochemistry and Western blot. Expression of inducible nitric oxide synthase (iNOS) in rat brain was determined by RT-PCR and Western blot. Nitric oxide production in rat brain was also measured 24 h after MCAO. The concentration of TNF-alpha and IL-1beta in serum were detected by ELISA. Zileuton significantly reduced neurological deficit scores, cerebral infarct volume, MPO activity, and the lipid peroxidation levels. It also inhibited the expression of NF-kappaB and decreased the expression and activity of iNOS in rat brain. In addition, zileuton attenuated the release of TNF-alpha and IL-1beta in serum. Our results suggest that zileuton reduces inflammatory reaction and brain damage in a rat model of permanent focal cerebral ischemia. The neuroprotective effect of zileuton in cerebral ischemia might be associated with the inhibition of inflammatory reaction.
Tu
Xian-kun
XK
Department of Neurosurgery, Affiliated Union Hospital of Fujian Medical University, 29# Xinquan Road, Fuzhou, Fujian 350001, China.
Yang
Wei-zhong
WZ
Wang
Chun-hua
CH
Shi
Song-sheng
SS
Zhang
Yong-liang
YL
Chen
Chun-mei
CM
Yang
Yi-kun
YK
Jin
Chang-dan
CD
Wen
Shuai
S
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002544:Cerebral Infarction / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000097:blood; D015227:Lipid Peroxidation / Q000187:drug effects; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020556:Neutrophil Infiltration / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D000893:Anti-Inflammatory Agents; D053583:Interleukin-1beta; D016859:Lipoxygenase Inhibitors; D018696:Neuroprotective Agents; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D008315:Malondialdehyde; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C063449:zileuton; D006918:Hydroxyurea