Low-Molecular-Weight Fucoidan Attenuates Mitochondrial Dysfunction and Improves Neurological Outcome After Traumatic Brain Injury in Aged Mice: Involvement of Sirt3
Low-Molecular-Weight Fucoidan Attenuates Mitochondrial Dysfunction and Improves Neurological Outcome After Traumatic Brain Injury in Aged Mice: Involvement of Sirt3
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DOI：
10.1007/s10571-015-0323-2
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发表时间：
2016-01
影响因子：
4
通讯作者：
Tao Wang;Mang Zhu;Zhong-Zheng He
中科院分区：
文献类型：
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作者：
Tao Wang;Mang Zhu;Zhong-Zheng He
创伤性脑损伤(TBI)是导致死亡和长期残疾的主要原因。褐藻多糖是从褐藻中提取的一种硫酸化多糖，具有很强的抗氧化和抗炎作用。考虑到脑外伤常发生在成人，尤其是老年个体，我们在此试图确定低分子岩藻糖胶(LMWF)对老年小鼠的保护作用。16-18月龄小鼠给予低分子肝素(1-50 mg/kg)或赋形剂，采用受控皮质撞击(CCI)模型进行脑创伤。LMWF 10 mg/kg和50 mg/kg剂量组大鼠大脑皮质和海马区病变体积均明显减少。这种保护作用与减少神经元凋亡有关，这一点从TUNEL染色中得到了证实。重要的是，低分子肝素即使在脑损伤后4小时内给药也是有效的。LMWF治疗改善了长期神经行为结果，包括感觉运动功能，以及与海马体相关的空间学习和记忆。此外，LMWF还能显著抑制蛋白质羰基、脂质过氧化、活性氧(ROS)的产生，以及线粒体功能障碍，表现为线粒体细胞色素c的释放和线粒体膜电位的崩溃。通过RT-PCR和Western印迹检测sirtuin3(SIRT3)的表达，探讨其可能的分子机制。结果表明，颅脑损伤后SIRT3的表达显著增加，LMWF处理后SIRT3的表达进一步增强。侧脑室注射小干扰RNA(SiRNA)阻断SIRT3基因，可部分阻断LMWF的治疗作用。综上所述，这些发现表明LMWF对老年脑损伤具有神经保护作用，这可能与通过激活SIRT3减轻线粒体功能障碍有关。
Traumatic brain injury (TBI) is a leading cause of death and long-term disability. Fucoidan, a sulfated polysaccharide extracted from brown algae, possesses potent anti-oxidative and anti-inflammatory effects. Considering TBI happens frequently in adults, especially in aged individuals, we herein sought to define the protective effects of low-molecular-weight fucoidan (LMWF) in the aged mice. 16- to 18-month-old mice administered with LMWF (1–50 mg/kg) or vehicle were subjected to TBI using a controlled cortical impact (CCI) model. LMWF at the doses of 10 and 50 mg/kg significantly reduced both cortical and hippocampal lesion volume. This protection was associated with reduced neuronal apoptosis, as evidenced by TUNEL staining. Importantly, LMWF was effective even when administered up to 4 h after TBI. Treatment with LMWF improved long-term neurobehavioral outcomes, including sensorimotor function, and hippocampus-associated spatial learning and memory. In addition, LMWF significantly suppressed protein carbonyl, lipid peroxidation, reactive oxygen species (ROS) generation, as well as mitochondrial dysfunction, which was evidenced by mitochondrial cytochrome c release and collapse of mitochondrial membrane potential (MMP). To evaluate the underlying molecular mechanisms, the expression of sirtuin 3 (Sirt3) was detected by RT-PCR and Western blot. The results showed that TBI significantly increased the expression of Sirt3, which was further elevated by LMWF treatment. Knockdown of Sirt3 using intracerebroventricular injection of small interfering RNA (siRNA) partially prevented the therapeutic effects of LMWF. Collectively, these findings demonstrated that LMWF exerts neuroprotection against TBI in the aged brain, which may be associated with the attenuation of mitochondrial dysfunction through Sirt3 activation.