Activation of signaling pathways following localized delivery of systemically administered neurotrophic factors across the blood-brain barrier using focused ultrasound and microbubbles.
Activation of signaling pathways following localized delivery of systemically administered neurotrophic factors across the blood-brain barrier using focused ultrasound and microbubbles.
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DOI：
10.1088/0031-9155/57/7/n65
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发表时间：
2012-04-07
影响因子：
3.5
通讯作者：
Konofagou EE
中科院分区：
文献类型：
--
作者：
Baseri B;Choi JJ;Deffieux T;Samiotaki G;Tung YS;Olumolade O;Small SA;Morrison B;Konofagou EE
脑源性神经营养因子 (BDNF) 除了在神经退行性疾病中发挥治疗作用外，还被证明具有广泛的神经保护作用。在这项研究中，通过使用聚焦超声非侵入性破坏血脑屏障 (BBB)，在野生型小鼠 (n=7) 中证明了将外源性 BDNF 递送至左侧海马体的功效。通过免疫组织化学检测海马神经元中的 pTrkB 受体和激活的 pAkt、pMAPK 和 pCREB 进行定量评估，发现 BDNF 生物活性在递送后得以保留。因此，首次证明系统施用的神经营养因子可以穿过非侵入性破坏的血脑屏障，并在大脑高度局部化的区域触发神经元下游信号传导效应。这是首次追踪所施用的分子穿过血脑屏障（BBB）并定位于神经元触发分子效应。其他初步结果显示在具有两种额外神经营养因子的野生型小鼠中，例如神经胶质源性神经营养因子 (GDNF) (n=12) 和神经营养因子 (NTN) (n=2)。这进一步证明了FUS在细胞和分子水平上对中枢神经系统疾病早期治疗的影响，并强化了FUS辅助药物递送和疗效的前提。
The brain-derived neurotrophic factor (BDNF) has been shown to have broad neuroprotective effects in addition to its therapeutic role in neurodegenerative disease. In this study, the efficacy of delivering exogenous BDNF to the left hippocampus is demonstrated in wild-type mice (n=7) through the noninvasively disrupted blood-brain barrier (BBB) using focused ultrasound. The BDNF bioactivity was found to be preserved following delivery as assessed quantitatively by immunohistochemical detection of the pTrkB receptor and activated pAkt, pMAPK, and pCREB in the hippocampal neurons. It was therefore shown for the first time that systemically administered neurotrophic factors can cross the noninvasively disrupted BBB and trigger neuronal downstream signaling effects in a highly localized region in the brain. This is the first time that the administered molecule is tracked through the blood-brain barrier (BBB) and localized in the neuron triggering molecular effects. Additional preliminary findings are shown in wild-type mice with two additional neurotrophic factors such as the glia-derived neurotrophic factor (GDNF) (n=12) and neurturin (NTN) (n=2). This further demonstrates the impact of FUS for the early treatment of CNS diseases at the cellular and molecular level and strengthens its premise for FUS-assisted drug delivery and efficacy.