Xyloketal B alleviates cerebral infarction and neurologic deficits in a mouse stroke model by suppressing the ROS/TLR4/NF-KB inflammatory signaling pathway

• Published in: 中国药理学报：英文版 2017, Vol.38 (9), p.1236-1247
• Main Author: Ni PAN Liu-yi LU Mei LI Guo-hao WANG Fang-yu n SUN Hong-shuo SUN Xue-jun WEN Jian-ding CHENG Jian- wen CHEN Ji-yan PANG Jie LIU Yong-yuan GUAN Li-yan ZHAO Wen-liang CHEN Guan-lei WANG
• Format: Article
• Language: English
• Subjects: NF-κB; TLR4; 信号通路; 局灶性脑缺血; 成年小鼠; 模型; 神经功能; 缺损
• ISSN: 1671-4083; 1745-7254

Xyloketal B （Xyl-B） is a novel marine compound isolated from mangrove fungus Xylaria sp. We previously demonstrated that pretreatment with XyI-B exerted neuroprotective effects and attenuated hypoxic-ischemic brain injury in neonatal mice. In the present study we investigated the neuroprotective effects of pre- and post-treatment with XyI-B in adult mice using a transient middle cerebral artery occlusion （tMCAO） model, and explored the underlying mechanisms. Adult male C57 mice were subjected to tMCAO surgery. For the pre-treatment, XyI-B was given via multiple injections （12.5, 25, and 50 mg.kgl-d1, ip） 48 h, 24 h and 30 min before ischemia. For the post-treatment, a single dose of XyI-B （50 mg/kg, ip） was injected at 0, 1 or 2 h after the onset of ischemia. The regional cerebral perfusion was monitored using a laser-Doppler flowmeter. TTC staining was performed to determine the brain infarction volume. We found that both pre-treatment with XyI-B （50 mg/kg） and post-treatment with XyI-B （50 mg/kg） significantly reduced the infarct volume, but had no significant hemodynamic effects. Treatment with Xyl-B also significantly alleviated the neurological deficits in tMCAO mice. Furthermore, treatment with XyI-B significantly attenuated ROS overproduction in brain tissues; increased the MnSOD protein levels, suppressed TLR4, NF-KB and iNOS protein levels; and downregulated the mRNA levels of proinflammatory cytokines, including IL-1β, TNF-α IL-6 and IFN-y. Moreover, XyI-B also protected blood-brain barrier integrity in tMCAO mice. In conclusion, XyI-B administered within 2 h after the onset of stroke effectively protects against focal cerebral ischemia; the underlying mechanism may be related to suppressing the ROS/TLR4/NF-KB inflammatory signaling pathway.