Increasing pro-survival factors within whole brain tissue of Sprague Dawley rats via intracerebral administration of modified valproic acid.
Increasing pro-survival factors within whole brain tissue of Sprague Dawley rats via intracerebral administration of modified valproic acid.
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DOI：
10.1016/j.jphs.2015.07.003
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发表时间：
2015-08
影响因子：
3.5
通讯作者：
R. Bates;B. Stith;K. Stevens
中科院分区：
文献类型：
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作者：
R. Bates;B. Stith;K. Stevens
神经组织暴露于丙戊酸可增加几种促进生存的磷酸蛋白，这些蛋白可用作指示有益药物反应的生物标志物(pAktSer473，pGSK3TyrSer9，pErk1/2Thr202/β204)。不幸的是，VPA靶向神经组织是一个问题，因为严重的不对称分布，药物往往留在外周血液中，而不是定位在大脑内。脑内注射酰胺连接的VPA-聚乙二醇偶联物可以通过增强保留力和促进有利于生存的磷酸蛋白在大脑中的全球增加来解决这些问题。有必要检测聚乙二醇化丙戊酸分子的保留生物活性，同时定位颅内插管位置，以优化慢性丙戊酸暴露的已知下游生物标志物的增加。在这里，我们展示了在脑组织内急性注射VPA-聚乙二醇偶联物几乎增加了所有被检测的磷酸化蛋白，包括众所周知的促进生存的因子。相比之下，急性注射VPA意外地减少了整个小时的信号传递。针刺入整个脑组织是这一过程中故意造成创伤的原因。对脑组织的创伤被观察到克服了已知的注射溶液中未修饰的VPA的磷酸化蛋白增加，而VPA-聚乙二醇偶联物似乎诱导了促进生存的磷酸化蛋白的显著增加，尽管有程序性创伤。
Neural tissue exposure to valproic acid (VPA) increases several pro-survival phospho-proteins that can be used as biomarkers for indicating a beneficial drug response (pAktSer473, pGSK3βSer9, pErk1/2Thr202/Tyr204). Unfortunately, targeting VPA to neural tissue is a problem due to severe asymmetrical distribution, wherein the drug tends to remain in peripheral blood rather than localizing within the brain. Intracerebral delivery of an amide-linked VPA–PEG conjugate could address these issues by enhancing retention and promoting cerebro-global increases in pro-survival phospho-proteins. It is necessary to assay for the retained bioactivity of a PEGylated valproic acid molecule, along with locating an intracranial cannula placement that optimizes the increase of a known downstream biomarker for chronic VPA exposure. Here we show an acute injection of VPA–PEG conjugate within brain tissue increased virtually all of the assayed phospho-proteins, including well-known pro-survival factors. In contrast, an acute injection of VPA expectedly decreased signaling throughout the hour. Needle penetration into whole brain tissue is the intentional cause of trauma in this procedure. The trauma to brain tissue was observed to overcome known phospho-protein increases for unmodified VPA in the injected solution, while VPA–PEG conjugate appeared to induce significant increases in pro-survival phospho-proteins, despite the procedural trauma.