Sigma receptor activation reduces infarct size at 24 hours after permanent middle cerebral artery occlusion in rats
Sigma receptor activation reduces infarct size at 24 hours after permanent middle cerebral artery occlusion in rats
复制标题
DOI：
10.2174/156720206776875849
复制
发表时间：
2006-05-01
影响因子：
2.1
通讯作者：
Cuevas, Javier
中科院分区：
文献类型：
--
作者：
Ajmo, Craig T., Jr.;Vernon, Dionne O. L.;Cuevas, Javier
栓塞性卒中唯一可用的治疗方法是重组组织纤溶酶原激活剂，必须在卒中发作后3小时内给予。我们研究了1，3-二-邻甲苯胍（DTG）（一种高亲和力σ受体激动剂）作为在延迟时间点减少梗死面积的潜在治疗的作用。大鼠进行永久性栓塞大脑中动脉闭塞（MCAO），并允许恢复，然后在24，48和72小时接受皮下注射15 mg/kg的DTG。在96小时时，对大鼠实施安乐死，收获脑并切片。使用神经变性标记物Fluoro-Jade在对照（仅MCAO）和DTG处理的动物中在皮质/纹状体和皮质/海马区域的水平上定量海马区。DTG治疗显著减少皮质/纹状体和皮质/海马区的梗死面积> 80%。相对于对照组大鼠。这些发现证实了免疫组化实验，使用神经元标记物，小鼠抗神经元核单克隆抗体（NeuN），这表明DTG的应用显着增加了这些地区的存活神经元的数量。此外，DTG阻断MCAO引起的炎症反应，如通过免疫染色胶质细胞酸性蛋白（GFAP）和isolectin IB 4的结合分别检测到的反应性星形胶质细胞和活化的小胶质细胞/巨噬细胞的数量减少所示。因此，我们的研究结果表明，σ受体选择性激动剂，DTG，可以提高神经元的存活时，缺血性中风后24小时。此外，σ受体在延迟时间点用于中风治疗的功效可能是这些受体的神经保护和抗炎特性组合的结果。
The only available treatment for embolic stroke is recombinant tissue plasminogen activator, which must be administered within three hours of stroke onset. We examined the effects of 1,3-di-o-tolyguanidine (DTG), a high affinity sigma receptor agonist, as a potential treatment for decreasing infarct area at delayed time points. Rats were subjected to permanent embolic middle cerebral artery occlusion (MCAO) and allowed to recover before receiving subcutaneous injections of 15 mg/kg of DTG at 24, 48, and 72 hours. At 96 hours the rats were euthanized, and brains harvested and sectioned. Infarct areas were quantified at the level of the cortical/striatal and cortical/hippocampal regions in control (MCAO-only) and DTG treated animals using a marker for neurodegeneration, Fluoro-Jade. DTG treatment significantly reduced infarct area in both cortical/striatal and cortical/hippocampal regions by > 80%. relative to control rats. These findings were confirmed by immunohistochemical experiments using the neuronal marker, mouse anti-neuronal nuclei monoclonal antibody (NeuN), which showed that application of DTG significantly increased the number of viable neurons in these regions. Furthermore, DTG blocked the inflammatory response evoked by MCAO, as indicated by decreases in the number of reactive astrocytes and activated microglia/macrophages detected by immunostaining for glial fibrillary acidic protein (GFAP) and binding of isolectin IB4, respectively. Thus, our results demonstrate that the sigma receptorselective agonist, DTG, can enhance neuronal survival when administered 24 hr after an ischemic stroke. In addition, the efficacy of sigma receptors for stroke treatment at delayed time points is likely the result of combined neuroprotective and anti-inflammatory properties of these receptors.