The development of new therapeutic approaches for stroke patients requires a detailed understanding of the mechanisms that enhance recovery of lost neurological functions. The efficacy to enhance homeostatic mechanisms during the first weeks after stroke will influence functional outcome. Thyroid hormones (TH) are essential regulators of neuronal plasticity, however, their role in recovery related mechanisms of neuronal plasticity after stroke remains unknown. This study addresses important findings of 3,5,3'-triiodo-L-thyronine (T3) in the regulation of homeostatic mechanisms that adjust excitability - inhibition ratio in the post-ischemic brain. This is valid during the first 2 weeks after experimental stroke induced by photothrombosis (PT) and in cultured neurons subjected to an in vitro model of acute cerebral ischemia. In the human post-stroke brain, we assessed the expression pattern of TH receptors (TR) protein levels, important for mediating T3 actions.Our results show that T3 modulates several plasticity mechanisms that may operate on different temporal and spatial scales as compensatory mechanisms to assure appropriate synaptic neurotransmission. We have shown in vivo that long-term administration of T3 after PT significantly (1) enhances lost sensorimotor function; (2) increases levels of synaptotagmin 1&2 and levels of the post-synaptic GluR2 subunit in AMPA receptors in the peri-infarct area; (3) increases dendritic spine density in the peri-infarct and contralateral region and (4) decreases tonic GABAergic signaling in the peri-infarct area by a reduced number of parvalbumin+ / c-fos+ neurons and glutamic acid decarboxylase 65/67 levels. In addition, we have shown that T3 modulates in vitro neuron membrane properties with the balance of inward glutamate ligand-gated channels currents and decreases synaptotagmin levels in conditions of deprived oxygen and glucose. Interestingly, we found increased levels of TRβ1 in the infarct core of post-mortem human stroke patients, which mediate T3 actions. Summarizing, our data identify T3 as a potential key therapeutic agent to enhance recovery of lost neurological functions after ischemic stroke.

中文翻译：

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Triiodothyronine调节神经元可塑性机制，以增强中风后的功能结局。

对中风患者的新治疗方法的发展需要对增强丧失的神经功能恢复的机制的详细了解。中风后最初几周内增强体内稳态机制的功效将影响功能预后。甲状腺激素（TH）是神经元可塑性的重要调节剂，但是，它们在中风后神经元可塑性的恢复相关机制中的作用仍然未知。这项研究解决了3,5,3'-triiodo-L-thyronine（T3）在调节稳态机制中的重要发现，该机制调节了缺血后脑的兴奋性-抑制率。这在由光血栓形成（PT）诱发的实验性中风后的前两周内有效，并在接受急性脑缺血的体外模型的培养神经元中有效。在人类中风后大脑中，我们评估了TH受体（TR）蛋白水平的表达模式，这对于介导T3动作很重要。确保适当的突触神经传递。我们已经在体内显示，PT后长期给予T3可以显着（1）增强丧失的感觉运动功能；（2）增加梗塞周围区域的AMPA受体中突触结合蛋白1和2的水平以及突触后GluR2亚基的水平；（3）通过减少小儿白蛋白+ / c-fos +神经元的数量和谷氨酸脱羧酶65/67的水平来增加梗塞周围和对侧区域的树突棘密度，并且（4）降低梗塞周围区域的补品GABA能信号。此外，我们已经表明，T3通过内向谷氨酸配体-门控通道电流的平衡来调节体外神经元膜的性能，并在缺乏氧气和葡萄糖的情况下降低突触结合蛋白的水平。有趣的是，我们发现在人类卒中后验尸的梗塞核心中TRβ1的水平升高，这介导了T3的作用。总之，我们的数据确定T3是增强缺血性中风后丧失的神经功能的恢复的潜在关键治疗药物。