右美托咪定通过阻断TLR-4/nf-κb通路抑制炎症反应对大鼠短暂性全脑缺血/再灌注损伤具有神经保护作用
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Dexmedetomidine confers neuroprotection against transient global cerebral ischemia/reperfusion injury in rats by inhibiting inflammation through inactivation of the TLR-4/NF-κB pathway
背景与目的：右美托咪定(DXM)的抗炎作用被认为是其脑缺血再灌注损伤神经保护作用的重要机制。
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方法：在大鼠短暂性全脑缺血/再灌注损伤模型中，我们研究了DXM的抗炎作用是否与抑制Toll样受体(TLR)-4/核因子κb(nf-κb)通路有关。将50只大鼠随机分为5组(10只/组)：S组不予治疗；C组短暂性全脑缺血（10 min）；D组缺血前30 min给予DXM治疗；R组于缺血前30 min给予选择性TLR-4阻断剂resatorvid；RD组在缺血前30 min给予resatorvid和DXM。
结果：缺血1d后检测坏死细胞数、凋亡细胞数、TLR-4、nf-κb、caspase-3水平并在缺血前及2、6、24h后分别测定促炎细胞因子TNF-α、白细胞介素1β(IL-1β)和白细胞介素6(IL-6)。C组坏死、凋亡细胞计数及TLR-4、nf-κb、caspase-3水平均高于其他各组。缺血2h后，C组TNF-α明显高于其他各组；缺血后6h，C组IL-6升高。缺血后6、24h，C组IL-1β高于D组。
结论：我们的研究提示DXM通过阻断TLR-4/nf-κb通路而发挥抗炎作用，这可能部分解释了DXM对脑缺血后的神经保护作用。
Kim E, Kim HC, Lee S
Dexmedetomidine confers neuroprotection against transient global cerebral ischemia/reperfusion injury in rats by inhibiting inflammation through inactivation of the TLR-4/NF-κB pathway
Neurosci Lett.May 10，2017 ;649:20-27. doi: 10.1016/j.neulet.2017.04.011.
BACKGROUND: Dexmedetomidine (DXM) has anti-inflammatory effects, which is considered an important mechanism of DXM-induced neuroprotection from cerebral ischemia/reperfusion injury.
METHODS:We determined whether the anti-inflammatory effects of DXM are associated with inhibition of the toll-like receptor (TLR)-4/nuclear factor kappa B (NF-κB) pathway in a rat model of transient global cerebral ischemia/reperfusion injury. Fifty rats were randomly assigned to one of five groups (10 rats/group): Group S received no treatment; Group C underwent transient global ischemia (10min); Group D received DXM 30min before ischemia; Group R received resatorvid, a selective TLR-4 antagonist, 30min before ischemia; and Group RD received resatorvid and DXM 30min before ischemia.
RESULTS:The numbers of necrotic and apoptotic cells and the levels of TLR-4, NF-κB, and caspase-3 were assessed 1day after ischemia, and pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) were measured before ischemia and 2, 6, and 24h thereafter. The necrotic and apoptotic cell counts and levels of TLR-4, NF-κB, and caspase-3 were higher in Group C than in other groups. TNF-α were higher in Group C than in other groups 2h after ischemia, whereas IL-6 were higher in Group C 6h after ischemia. IL-1β was higher in Group C than in Group D 6 and 24h after ischemia.
CONCLUSIONS:Our findings suggest that the anti-inflammatory action of DXM via inactivation of the TLR-4/NF-κB pathway, in part, may explain DXM-induced neuroprotection after cerebral ischemia.
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