The PKC-β selective inhibitor, Enzastaurin, impairs memory in middle-aged rats.
The PKC-β selective inhibitor, Enzastaurin, impairs memory in middle-aged rats.
复制标题
DOI：
10.1371/journal.pone.0198256
复制
发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Huentelman MJ
中科院分区：
文献类型：
--
作者：
Willeman MN;Mennenga SE;Siniard AL;Corneveaux JJ;De Both M;Hewitt LT;Tsang CWS;Caselli J;Braden BB;Bimonte-Nelson HA;Huentelman MJ
恩扎他林是一种蛋白激酶C-β选择性抑制剂，是为治疗癌症而开发的。蛋白激酶C-β是一种对多种神经功能起重要作用的酶；特别是以往的啮齿动物研究报告，在空间和恐惧条件下的学习和记忆中存在缺陷，蛋白激酶C-β水平较低。根据苯扎托林的作用机制，本研究研究了苯扎托林对12月龄Fischer-344雄性大鼠学习记忆的影响。每天给大鼠皮下注射赋形剂或苯扎托林，并使用空间参考记忆Morris水迷宫进行行为测试。服用苯扎托林的大鼠表现出过夜保持能力下降，在后一测试日表现较差，这表明记忆损伤轻微但严重。在探测器试验期间没有差异，表明所有动物在测试结束时都能够在空间上将平台定位到适当的象限。用下一代测序(Illumina)对从海马区提取的RNA进行分析。未发现有统计学意义的转录差异。我们的研究结果表明，急性苯并司他汀治疗可以损害基于海马区的学习和记忆表现，而对海马区的转录没有影响。我们建议，在未来的临床试验中，应注意使用蛋白激酶C-ü抑制剂，以监测可能的认知影响，未来的研究应检查这些影响是否完全可逆。
Enzastaurin is a Protein Kinase C-β selective inhibitor that was developed to treat cancers. Protein Kinase C-β is an important enzyme for a variety of neuronal functions; in particular, previous rodent studies have reported deficits in spatial and fear-conditioned learning and memory with lower levels of Protein Kinase C-β. Due to Enzastaurin’s mechanism of action, the present study investigated the consequences of Enzastaurin exposure on learning and memory in 12-month-old Fischer-344 male rats. Rats were treated daily with subcutaneous injections of either vehicle or Enzastaurin, and behaviorally tested using the spatial reference memory Morris Water Maze. Rats treated with Enzastaurin exhibited decreased overnight retention and poorer performance on the latter testing day, indicating a mild, but significant, memory impairment. There were no differences during the probe trial indicating that all animals were able to spatially localize the platform to the proper quadrant by the end of testing. RNA isolated from the hippocampus was analyzed using Next Generation Sequencing (Illumina). No statistically significant transcriptional differences were noted. Our findings suggest that acute Enzastaurin treatment can impair hippocampal-based learning and memory performance, with no effects on transcription in the hippocampus. We propose that care should be taken in future clinical trials that utilize Protein Kinase C-ß inhibitors, to monitor for possible cognitive effects, future research should examine if these effects are fully reversible.
登录
查看更多内容
影响因子：
5.7
作者：
Jian, Weiguo;Yamashita, Hideyuki;Sonpavde, Guru
通讯作者：
Sonpavde, Guru
影响因子：
4.2
作者：
Engler-Chiurazzi E;Tsang C;Nonnenmacher S;Liang WS;Corneveaux JJ;Prokai L;Huentelman MJ;Bimonte-Nelson HA
通讯作者：
Bimonte-Nelson HA
影响因子：
2.9
作者：
Paratcha, G;Furman, M;Medina, JH
通讯作者：
Medina, JH
DOI：
10.1073/pnas.1302569110
发表时间：
2013-09-03
影响因子：
11.1
作者：
Lanz, Tobias V.;Becker, Simon;Platten, Michael
通讯作者：
Platten, Michael
DOI：
10.1073/pnas.98.4.1930
发表时间：
2001-02-13
影响因子：
11.1
作者：
Jiang, CH;Tsien, JZ;Hu, YH
通讯作者：
Hu, YH