Role of δ-opioid receptor function in neurogenesis and neuroprotection
Role of δ-opioid receptor function in neurogenesis and neuroprotection
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DOI：
10.1111/j.1471-4159.2006.03849.x
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发表时间：
2006-06-01
影响因子：
4.7
通讯作者：
Suzuki, T
中科院分区：
文献类型：
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作者：
Narita, M;Kuzumaki, N;Suzuki, T
本研究旨在评估 δ-阿片受体功能在神经发生和神经保护中的影响。我们发现选择性 δ-阿片受体激动剂 SNC80 [(+)-4-[(alpha R)-alpha-((2S,5R)-4-烯丙基-2,5-二甲基-1-哌嗪基)-3-甲氧基苯甲基]-N,N-二乙基苯甲酰胺] (10 nM) 刺激 δ-阿片受体可促进从 C3H 小鼠胚胎获得的多能神经干细胞的神经分化前脑。相比之下，选择性μ阿片受体激动剂[D-Ala(2)、N-Me-Phe(4)、Gly(5)-ol]-脑啡肽(DAMGO)或特异性κ阿片受体激动剂(-)-反式-(1S,2S)-U-50488盐酸盐(U50,488H)则没有这种作用。除了神经分化之外，在皮层神经元/神经胶质细胞共培养物中，用 SNC80 处理可抑制由 H2O2 (3 μM) 诱导的裂解 caspase 3 样免疫反应性的增加。 SNC80 的这些作用被 Trk 依赖性酪氨酸激酶抑制剂消除： (8R*,9S*,11S*)-(-)-9-羟基-9-甲氧基羰基-8-甲基-2,3,9,10-四氢-8,11-环氧-1H,8H,11H-2,7b,11a-三氮杂二苯并(a,g)环辛(cde)trinden-1-酮(K-252a)。 SNC80诱导的神经分化也可以通过蛋白激酶C（PKC）抑制剂、磷脂酰肌醇3激酶（PI3K）抑制剂、丝裂原激活蛋白激酶激酶（MEK）抑制剂或Ca2+/钙调蛋白依赖性蛋白激酶II（CaMKII）抑制剂的治疗得到抑制。这些发现提出了 δ-阿片受体在神经发生和神经保护中发挥关键作用的可能性，主要是通过激活 Trk 依赖性酪氨酸激酶，该激酶可能与 PI3K、PKC、CaMKII 和 MEK 相关。
The present study was undertaken to evaluate the implication of delta-opioid receptor function in neurogenesis and neuroprotection. We found that the stimulation of delta-opioid receptors by the selective delta-opioid receptor agonist SNC80 [(+)-4-[(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] (10 nM) promoted neural differentiation from multipotent neural stem cells obtained from embryonic C3H mouse forebrains. In contrast, either a selective mu-opioid receptor agonist, [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO), or a specific kappa-opioid receptor agonist, (-)-trans-(1S,2S)-U-50488 hydrochloride (U50,488H), had no such effect. In addition to neural differentiation, the increase in cleaved caspase 3-like immunoreactivity induced by H2O2 (3 mu M) was suppressed by treatment with SNC80 in cortical neuron/glia co-cultures. These effects of SNC80 were abolished by a Trk-dependent tyrosine kinase inhibitor: (8R*,9S*,11S*)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo(a,g)cycloocta(cde)trinden-1-one (K-252a). The SNC80-induced neural differentiation was also inhibited by treatment with the protein kinase C (PKC) inhibitor, phosphatidylinositol 3-kinase (PI3K) inhibitor, mitogen-activated protein kinase kinase (MEK) inhibitor or Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor. These findings raise the possibility that delta-opioid receptors play a crucial role in neurogenesis and neuroprotection, mainly through the activation of Trk-dependent tyrosine kinase, which could be linked to PI3K, PKC, CaMKII and MEK.