Synapto-protective drugs evaluation in reconstructed neuronal network.
Synapto-protective drugs evaluation in reconstructed neuronal network.
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DOI：
10.1371/journal.pone.0071103
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Peyrin JM
中科院分区：
文献类型：
--
作者：
Deleglise B;Lassus B;Soubeyre V;Alleaume-Butaux A;Hjorth JJ;Vignes M;Schneider B;Brugg B;Viovy JL;Peyrin JM
慢性神经退行性综合征，如阿尔茨海默病和帕金森病，或急性综合征，如缺血性中风或创伤性脑损伤，其特征是早期突触崩溃，先于轴突和神经元胞体退化，并促进患者的早期认知功能障碍。到目前为止，神经保护策略未能阻止神经退行性综合征的进展。阻止细胞体丢失的药物无法阻止认知能力的下降，可能是因为它们缺乏突触保护作用。缺乏易于操作的生理上真实的神经元网络模型阻碍了适用于治疗的突触保护药物的开发。在这里，我们描述了一个新的微流控平台，它使得研究重建的定向小鼠神经元网络的轴突损伤的后果成为可能。每个神经元群体和亚室都可以单独进行化学处理。因此，局部病理性应激或假定的保护性分子对躯体、中轴突、突触前和突触后的影响可以借助这一多功能的“片上脑”平台进行评估。我们表明，突触前丢失是在皮质纤维切断后观察到的最早事件，在轴突碎裂或突触后脊椎改变的任何迹象之前。该平台可用于筛选和评估几种药物的突触保护潜力。例如，NAD+和Rho-Kinase抑制剂Y27632可以有效地防止突触断开，而广谱caspase抑制剂zVAD-fmk和二苯乙烯类白藜芦醇不能防止突触前变性。因此，该平台是发育和神经退行性神经科学领域基础研究的一个有前途的工具，也为建立轴突保护和突触保护药物的药理筛选提供了机会。
Chronic neurodegenerative syndromes such as Alzheimer’s and Parkinson’s diseases, or acute syndromes such as ischemic stroke or traumatic brain injuries are characterized by early synaptic collapse which precedes axonal and neuronal cell body degeneration and promotes early cognitive impairment in patients. Until now, neuroprotective strategies have failed to impede the progression of neurodegenerative syndromes. Drugs preventing the loss of cell body do not prevent the cognitive decline, probably because they lack synapto-protective effects. The absence of physiologically realistic neuronal network models which can be easily handled has hindered the development of synapto-protective drugs suitable for therapies. Here we describe a new microfluidic platform which makes it possible to study the consequences of axonal trauma of reconstructed oriented mouse neuronal networks. Each neuronal population and sub-compartment can be chemically addressed individually. The somatic, mid axon, presynaptic and postsynaptic effects of local pathological stresses or putative protective molecules can thus be evaluated with the help of this versatile “brain on chip” platform. We show that presynaptic loss is the earliest event observed following axotomy of cortical fibers, before any sign of axonal fragmentation or post-synaptic spine alteration. This platform can be used to screen and evaluate the synapto-protective potential of several drugs. For instance, NAD+ and the Rho-kinase inhibitor Y27632 can efficiently prevent synaptic disconnection, whereas the broad-spectrum caspase inhibitor zVAD-fmk and the stilbenoid resveratrol do not prevent presynaptic degeneration. Hence, this platform is a promising tool for fundamental research in the field of developmental and neurodegenerative neurosciences, and also offers the opportunity to set up pharmacological screening of axon-protective and synapto-protective drugs.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
16.2
作者：
Jagust W
通讯作者：
Jagust W
DOI：
10.1007/978-3-7091-0932-8_25
发表时间：
2012-01-01
期刊：
SYNAPTIC PLASTICITY: DYNAMICS, DEVELOPMENT AND DISEASE
影响因子：
--
作者：
Marcello, Elena;Epis, Roberta;Di Luca, Monica
通讯作者：
Di Luca, Monica
影响因子：
2.6
作者：
Hadjantonakis, AK;Gertsenstein, M;Nagy, A
通讯作者：
Nagy, A
影响因子：
64.5
作者：
Li Z;Jo J;Jia JM;Lo SC;Whitcomb DJ;Jiao S;Cho K;Sheng M
通讯作者：
Sheng M