The non-peptidic δ-opioid receptor agonist Tan-67 mediates neuroprotection post-ischemically and is associated with altered amyloid precursor protein expression, maturation and processing in mice.
The non-peptidic δ-opioid receptor agonist Tan-67 mediates neuroprotection post-ischemically and is associated with altered amyloid precursor protein expression, maturation and processing in mice.
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非肽δ-阿片受体激动剂TAN-67在异化后介导神经保护作用，并与小鼠中淀粉样蛋白前体蛋白的表达，成熟和加工有关。
DOI：
10.1111/jnc.14265
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发表时间：
2018-03
影响因子：
4.7
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Min JW;Liu Y;Wang D;Qiao F;Wang H
Tan-67是一种选择性的非肽类δ-阿片受体（DOR）激动剂，可在预处理动物中对脑缺血/再灌注（I/R）引起的神经元损伤提供神经保护。在这项研究中，我们研究了在中风小鼠中缺血后给予Tan-67是否也具有神经保护作用，以及治疗是否影响淀粉样前体蛋白（APP）的表达，成熟和加工。通过大脑中动脉闭塞1小时（h）诱导小鼠局灶性脑I/R模型，并在再灌注后1小时经尾静脉给予Tan-67（1.5、3或4.5mg/kg）。或者，纳曲吲哚，选择性DOR拮抗剂（5 mg/kg），在Tan-67治疗前1 h给药。我们的结果表明，缺血后给予Tan-67（3 mg/kg或4.5 mg/kg）具有神经保护作用，表现为I/R后梗死体积减少和神经元丢失。重要的是，Tan-67改善了动物的存活率和神经行为结果。相反，纳曲吲哚废除了梗死体积中的Tan-67神经保护作用。Tan-67治疗还增加了缺血再灌注后6小时同侧半影区APP的表达、成熟和加工，但在缺血再灌注后24小时减少了同一脑区APP的表达和成熟。Tan-67诱导的APP表达增加也见于I/R后24 h的缺血皮质。此外，Tan-67可抑制缺血再灌注后24 h脑皮质BACE-1表达、β-分泌酶活性和APP的BACE裂解，纳曲吲哚可阻断上述作用。我们的数据表明，Tan-67是一种有前途的DOR依赖性治疗药物，用于治疗I/R引起的疾病，Tan-67介导的神经保护作用可能是通过调节APP表达，成熟和加工介导的，尽管改变的APP和观察到的结果之间的因果关系不确定。我们提出，缺血后给予δ-阿片受体（DOR）激动剂Tan-67可抑制缺血性卒中引起的神经元损伤。Tan-67介导的神经保护作用依赖于DOR激活，并与抑制缺血性卒中引起的淀粉样前体蛋白（APP）表达、成熟和加工以及β-分泌酶活性的改变有关。我们的研究结果表明，Tan-67作为一种有前途的治疗剂，用于治疗缺血性中风引起的疾病。
Tan-67 is a selective non-peptidic δ-opioid receptor (DOR) agonist that confers neuroprotection against cerebral ischemia/reperfusion (I/R)-caused neuronal injury in pre-treated animals. In this study, we examined whether post-ischemic administration of Tan-67 in stroke mice is also neuroprotective and whether the treatment affects expression, maturation and processing of the amyloid precursor protein (APP). A focal cerebral I/R model in mice was induced by middle cerebral artery occlusion for 1 hour (h) and Tan-67 ( 1.5, 3 or 4.5 mg/kg) was administered via the tail vein at 1 h after reperfusion. Alternatively, naltrindole, a selective DOR antagonist (5 mg/kg), was administered 1 h before Tan-67 treatment. Our results showed that post-ischemic administration of Tan-67 (3 mg/kg or 4.5 mg/kg) was neuroprotective as shown by decreased infarct volume and neuronal loss following I/R. Importantly, Tan-67 improved animal survival and neurobehavioral outcomes. Conversely, naltrindole abolished Tan-67 neuroprotection in infarct volume. Tan-67 treatment also increased APP expression, maturation and processing in the ipsilateral penumbral area at 6 h but decreased APP expression and maturation in the same brain area at 24 h after I/R. Tan-67-induced increase of APP expression was also seen in the ischemic cortex at 24 h following I/R. Moreover, Tan-67 attenuated BACE-1 expression, β-secretase activity and the BACE cleavage of APP in the ischemic cortex at 24 h after I/R, which was abolished by naltrindole. Our data suggest that Tan-67 is a promising DOR-dependent therapeutic agent for treating I/R-caused disorder and that Tan-67-mediated neuroprotection may be mediated via modulating APP expression, maturation and processing, despite an uncertain causative relationship between the altered APP and the outcomes observed. We proposed that post-ischemic administration of Tan-67, a δ-opioid receptor (DOR), agonist, inhibits neuronal injury caused by ischemic stroke. Tan-67-mediated neuroprotection is dependent on DOR activation and is associated with suppression of ischemic stroke-caused alterations of amyloid precursor protein (APP) expression, maturation and processing as well as β-secretase activity. Our results suggest Tan-67 as a promising therapeutic agent for treating ischemic stroke-caused disorder.
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影响因子：
4.7
作者：
Min JW;Lü L;Freeling JL;Martin DS;Wang H
通讯作者：
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Irizarry, MC
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通讯作者：
Chopp, M