Lev-Lehman E, el-Tamer A, Yaron A, Grifman M, Ginzberg D, Hanin I, Soreq H
Department of Biological Chemistry, Life Sciences Institute, Hebrew University, Jerusalem, Israel.
Brain Res. 1994 Oct 24;661(1-2):75-82. doi: 10.1016/0006-8993(94)91183-5.
To study the mechanisms underlying cholinotoxic brain damage, we examined ethylcholine aziridinium (AF64A) effects on cholinesterase genes. In vitro, AF64A hardly affected cholinesterase activities yet inhibited transcription of the G,C-rich AChE DNA encoding acetylcholinesterase (AChE) more than the A,T-rich butyrylcholinesterase (BChE) DNA. In vivo, intracerebroventricular injection of 2 nmol of AF64A decreased AChE mRNA in striatum and septum by 3- and 25-fold by day 7, with no change in BChE mRNA or AChE activity. In contrast, hippocampal AChE mRNA increased 10-fold by day 7 and BChE mRNA and AChE activity decreased 2-fold. By day 60 post-treatment, both AChE mRNA and AChE levels returned to normal in all regions except hippocampus, where AChE activity and BChE mRNA were decreased by 2-fold. Moreover, differential PCR displays revealed persistent induction, specific to the hippocampus of treated rats, of several unidentified G,C-rich transcripts, suggesting particular responsiveness of hippocampal G,C-rich genes to cholinotoxicity.
为研究胆碱毒性脑损伤的潜在机制，我们检测了氮丙啶乙基胆碱（AF64A）对胆碱酯酶基因的影响。在体外，AF64A对胆碱酯酶活性影响不大，但对富含G、C的乙酰胆碱酯酶（AChE）DNA转录的抑制作用比对富含A、T的丁酰胆碱酯酶（BChE）DNA更强。在体内，脑室内注射2 nmol的AF64A，到第7天时纹状体和隔区的AChE mRNA分别下降了3倍和25倍，而BChE mRNA和AChE活性无变化。相反，海马体的AChE mRNA在第7天时增加了10倍，BChE mRNA和AChE活性下降了2倍。治疗后60天时，除海马体外所有区域的AChE mRNA和AChE水平均恢复正常，海马体中的AChE活性和BChE mRNA下降了2倍。此外，差异PCR显示，处理过的大鼠海马体中持续诱导出几种未鉴定的富含G、C的转录本，表明海马体中富含G、C的基因对胆碱毒性具有特殊的反应性。
