UNASSIGNED: We mimicked NICS in vitro by applying a glutamate receptor agonist, kainic acid (KA) to organotypic cochlear explant cultures and experimentally manipulated cAMP signaling to determine whether PKA could promote synapse regeneration. We then delivered the cAMP phosphodiesterase inhibitor rolipram via implanted subcutaneous minipumps in noise-exposed CBA/CaJ mice to test the hypothesis that cAMP signaling could promote cochlear synapse regeneration in vivo.
UNASSIGNED: We showed that the application of the cell membrane-permeable cAMP agonist 8-cpt-cAMP or the cAMP phosphodiesterase inhibitor rolipram promotes significant regeneration of synapses in vitro within twelve hours after their destruction by KA. This is independent of neurotrophin-3, which also promotes synapse regeneration. Moreover, of the two independent signaling effectors activated by cAMP - the cAMP Exchange Protein Activated by cAMP and the cAMP-dependent protein kinase - it is the latter that mediates synapse regeneration. Finally, we showed that systemic delivery of rolipram promotes synapse regeneration in vivo following NICS.
UNASSIGNED: In vitro experiments show that cAMP signaling promotes synapse regeneration after excitotoxic destruction of cochlear synapses and does so via PKA signaling. The cAMP phosphodiesterase inhibitor rolipram promotes synapse regeneration in vivo in noise-exposed mice. Systemic administration of rolipram or similar compounds appears to provide a minimally invasive therapeutic approach to reversing synaptopathy post-noise.
■我们通过应用谷氨酸受体激动剂在体外模拟NICS,海藻酸(KA)用于器官型耳蜗外植体培养,并通过实验操纵cAMP信号传导来确定PKA是否可以促进突触再生。然后,我们通过植入皮下微型泵在噪声暴露的CBA/CaJ小鼠中递送cAMP磷酸二酯酶抑制剂rolipram,以检验cAMP信号传导可以促进体内耳蜗突触再生的假设。
■我们表明,细胞膜通透性cAMP激动剂8-cpt-cAMP或cAMP磷酸二酯酶抑制剂rolipram的应用在被KA破坏后12小时内促进了突触的体外再生。这与神经营养蛋白-3无关,神经营养蛋白-3也促进突触再生。此外,由cAMP激活的两个独立的信号效应物-由cAMP激活的cAMP交换蛋白和cAMP依赖性蛋白激酶-后者介导突触再生。最后,我们表明,全身递送咯利普兰促进NICS后体内突触再生。
■体外实验表明,cAMP信号传导在兴奋性毒性破坏耳蜗突触后促进突触再生,并通过PKA信号传导。cAMP磷酸二酯酶抑制剂罗利普兰促进噪声暴露小鼠体内突触再生。咯利普兰或类似化合物的全身给药似乎提供了一种微创治疗方法来逆转噪声后的突触病。