The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke
The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke
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DOI：
10.1093/brain/awq367
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发表时间：
2011-03-01
期刊：
影响因子：
14.5
通讯作者：
Wieloch, Tadeusz
中科院分区：
文献类型：
--
作者：
Ruscher, Karsten;Shamloo, Mehrdad;Wieloch, Tadeusz
中风导致脑损伤，随后缓慢和不完全恢复失去的脑功能。丰富的住房中风受伤的大鼠提供多模式的感觉运动刺激，这有助于恢复，但涉及的具体机制尚未确定。在永久性大脑中动脉闭塞后，在丰富的环境中生活两周的大鼠中，我们发现梗死周围区域的sigma-1受体表达增加。在损伤后2天开始，用1-（3，4-二甲氧基苯乙基）-4-（3-苯丙基）哌嗪二盐酸盐（一种sigma-1受体激动剂）治疗永久性或短暂性大脑中动脉闭塞的大鼠，增强了失去的感觉运动功能的恢复，而不减少梗死面积。在反应性星形胶质细胞和神经元的半乳糖苷富集膜微区中发现了sigma-1受体。σ-1受体激活增加了梗死周围区域膜筏中突触蛋白neurabin和neurexin的水平，而σ-1受体沉默阻止了原代皮层神经元培养物中σ-1受体介导的神经突生长。在星形胶质细胞培养中，氧和葡萄糖剥夺诱导sigma-1受体表达和肌动蛋白依赖性膜筏形成，后者被sigma-1受体小干扰RNA沉默和药理学抑制阻断。我们的结论是，σ-1受体激活刺激恢复中风后，通过增强细胞运输的生物分子所需的大脑修复，从而刺激大脑的可塑性。σ-1受体的药理学靶向为脑卒中治疗提供了超越神经保护治疗窗的新机会。
Stroke leads to brain damage with subsequent slow and incomplete recovery of lost brain functions. Enriched housing of stroke-injured rats provides multi-modal sensorimotor stimulation, which improves recovery, although the specific mechanisms involved have not been identified. In rats housed in an enriched environment for two weeks after permanent middle cerebral artery occlusion, we found increased sigma-1 receptor expression in peri-infarct areas. Treatment of rats subjected to permanent or transient middle cerebral artery occlusion with 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride, an agonist of the sigma-1 receptor, starting two days after injury, enhanced the recovery of lost sensorimotor function without decreasing infarct size. The sigma-1 receptor was found in the galactocerebroside enriched membrane microdomains of reactive astrocytes and in neurons. Sigma-1 receptor activation increased the levels of the synaptic protein neurabin and neurexin in membrane rafts in the peri-infarct area, while sigma-1 receptor silencing prevented sigma-1 receptor-mediated neurite outgrowth in primary cortical neuronal cultures. In astrocytic cultures, oxygen and glucose deprivation induced sigma-1 receptor expression and actin dependent membrane raft formation, the latter blocked by sigma-1 receptor small interfering RNA silencing and pharmacological inhibition. We conclude that sigma-1 receptor activation stimulates recovery after stroke by enhancing cellular transport of biomolecules required for brain repair, thereby stimulating brain plasticity. Pharmacological targeting of the sigma-1 receptor provides new opportunities for stroke treatment beyond the therapeutic window of neuroprotection.