Laboratory for Experimental Brain Research, Wallenberg Neuroscience Center, Lund University, BMCA13, 22184 Lund, Sweden.
Brain. 2011 Mar;134(Pt 3):732-46. doi: 10.1093/brain/awq367. Epub 2011 Jan 28.
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.
中风会导致脑损伤，随后大脑功能丧失的恢复缓慢且不完全。对中风大鼠进行丰富环境饲养可提供多模式感觉运动刺激，从而改善恢复，尽管涉及的具体机制尚未确定。在永久性大脑中动脉闭塞后两周内，对丰富环境中饲养的大鼠进行研究，我们发现梗塞周围区域的 sigma-1 受体表达增加。用 sigma-1 受体激动剂 1-(3,4-二甲氧基苯乙基)-4-(3-苯丙基)哌嗪二盐酸盐对永久性或短暂性大脑中动脉闭塞的大鼠进行治疗，从损伤后两天开始，可增强丧失的感觉运动功能的恢复，而不会减小梗塞面积。sigma-1 受体存在于反应性星形胶质细胞和神经元的半乳糖脑苷脂丰富的膜微区中。sigma-1 受体的激活增加了梗塞周围区膜筏中突触蛋白神经丝蛋白和神经连接蛋白的水平，而 sigma-1 受体沉默则阻止了 sigma-1 受体介导的原代皮质神经元培养物中的神经突生长。在星形胶质细胞培养物中，缺氧和葡萄糖剥夺诱导了 sigma-1 受体的表达和肌动蛋白依赖的膜筏形成，后者可被 sigma-1 受体小干扰 RNA 沉默和药理学抑制所阻断。我们得出的结论是，sigma-1 受体的激活通过增强大脑修复所需生物分子的细胞运输来刺激中风后的恢复，从而刺激大脑可塑性。sigma-1 受体的药理学靶向为中风治疗提供了超越神经保护治疗窗的新机会。
