A Novel Small Molecule Neurotrophin-3 Analogue Promotes Inner Ear Neurite Outgrowth and Synaptogenesis In vitro.
A Novel Small Molecule Neurotrophin-3 Analogue Promotes Inner Ear Neurite Outgrowth and Synaptogenesis In vitro.
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一种新型小分子 Neurotropin-3 类似物在体外促进内耳神经突生长和突触发生。
DOI：
10.3389/fncel.2021.666706
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发表时间：
2021
影响因子：
5.3
通讯作者：
Jung DH
中科院分区：
文献类型：
--
作者：
Kempfle JS;Duro MV;Zhang A;Amador CD;Kuang R;Lu R;Kashemirov BA;Edge AS;McKenna CE;Jung DH
感音神经性听力损失是不可逆的，与内耳内螺旋神经节神经元 (SGN) 和感觉毛细胞的丧失有关。改善螺旋神经节神经元 (SGN) 的存活率、神经突生长和突触发生可能会给听力受损患者带来显着的效果。因此，人们对在内耳中使用神经营养因子来促进 SGN 的存活以及通过存活的 SGN 来重新连接感觉毛细胞产生了浓厚的兴趣。神经营养蛋白-3 (NT-3) 和脑源性神经营养因子 (BDNF) 代表发育期间和整个成年期内耳中的主要神经营养蛋白，并已证明具有 SGN 存活和神经突生长的潜力。我们开创了一种混合分子方法，可最大限度地提高体内 SGN 刺激，其中神经营养素的小分子类似物与双磷酸盐连接，而双磷酸盐又与耳蜗骨结合。我们之前已经证明，与利塞膦酸盐偶联的小分子 BDNF 类似物与骨基质结合，并在体外促进 SGN 神经突生长和突触发生。由于 NT-3 在多种情况下已被证明比 BDNF 具有更强的耳蜗再生能力，因此我们试图为 NT-3 开发类似的方法。 1Aa 是 NT-3 的小分子类似物，已被证明可以通过 NT-3 受体 TrkC 激活细胞，尽管之前尚未描述其对 SGN 的活性。在此，我们描述了 1Aa 以及 1Aa 与利塞膦酸盐 Ris-1Aa 的共价缀合物的设计和合成。我们证明，与对照组相比，1Aa 和 Ris-1Aa 均以显着更高的水平刺激 SGN 培养物中的神经突生长。 Ris-1Aa 在与骨的主要矿物质成分羟基磷灰石结合时保持其神经营养活性。 1Aa 和 Ris-1Aa 在耳蜗外植体培养中均促进显着的突触再生，并且 1Aa 和 Ris-1Aa 似乎至少部分通过 TrkC 发挥作用。我们的结果提供了第一个证据，证明 NT-3 的小分子类似物可以刺激 SGN 并促进 SGN 和内毛细胞之间的突触再生。我们的研究结果支持了羟基磷灰石靶向双膦酸盐缀合作为一种新策略，将神经营养剂递送至包裹在耳蜗骨内的 SGN 的前景。
Sensorineural hearing loss is irreversible and is associated with the loss of spiral ganglion neurons (SGNs) and sensory hair cells within the inner ear. Improving spiral ganglion neuron (SGN) survival, neurite outgrowth, and synaptogenesis could lead to significant gains for hearing-impaired patients. There has therefore been intense interest in the use of neurotrophic factors in the inner ear to promote both survival of SGNs and re-wiring of sensory hair cells by surviving SGNs. Neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) represent the primary neurotrophins in the inner ear during development and throughout adulthood, and have demonstrated potential for SGN survival and neurite outgrowth. We have pioneered a hybrid molecule approach to maximize SGN stimulation in vivo, in which small molecule analogues of neurotrophins are linked to bisphosphonates, which in turn bind to cochlear bone. We have previously shown that a small molecule BDNF analogue coupled to risedronate binds to bone matrix and promotes SGN neurite outgrowth and synaptogenesis in vitro. Because NT-3 has been shown in a variety of contexts to have a greater regenerative capacity in the cochlea than BDNF, we sought to develop a similar approach for NT-3. 1Aa is a small molecule analogue of NT-3 that has been shown to activate cells through TrkC, the NT-3 receptor, although its activity on SGNs has not previously been described. Herein we describe the design and synthesis of 1Aa and a covalent conjugate of 1Aa with risedronate, Ris-1Aa. We demonstrate that both 1Aa and Ris-1Aa stimulate neurite outgrowth in SGN cultures at a significantly higher level compared to controls. Ris-1Aa maintained its neurotrophic activity when bound to hydroxyapatite, the primary mineral component of bone. Both 1Aa and Ris-1Aa promote significant synaptic regeneration in cochlear explant cultures, and both 1Aa and Ris-1Aa appear to act at least partly through TrkC. Our results provide the first evidence that a small molecule analogue of NT-3 can stimulate SGNs and promote regeneration of synapses between SGNs and inner hair cells. Our findings support the promise of hydroxyapatite-targeting bisphosphonate conjugation as a novel strategy to deliver neurotrophic agents to SGNs encased within cochlear bone.
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影响因子：
2.5
作者：
Farrell KB;Karpeisky A;Thamm DH;Zinnen S
通讯作者：
Zinnen S
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16.2
作者：
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影响因子：
5.3
作者：
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影响因子：
4.7
作者：
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通讯作者：
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影响因子：
5
作者：
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通讯作者：
Dedeoglu A