Harrell Lindy E, Parsons Dee S, Kolasa Krystyna
Department of Neurology, VA Medical Center, University of Alabama at Birmingham, 975 Sparks Ctr, 1720 7th Avenue South, Birmingham, AL 35294, USA.
Exp Neurol. 2005 Jul;194(1):182-90. doi: 10.1016/j.expneurol.2005.02.009.
In rat, injection of the specific cholinotoxin, 192 IgG-saporin, into the medial septum results not only in a selective cholinergic denervation of hippocampus, but in an ingrowth of peripheral sympathetic fibers, originating from the superior cervical ganglion, into the hippocampus. A similar process, in which peripheral noradrenergic axons invade hippocampus, may also occur in Alzheimer's disease. Since apoptotic cell death has been demonstrated in the selective neuronal loss found in Alzheimer's disease, the aim of this study was to measure apoptotic protein expression and DNA fragmentation in hippocampal sympathetic ingrowth and cholinergic denervation. Western blot, TdT-mediated dUTP nick end labeling, and oligo ligation techniques were used. Choline acetyltransferase activity and norepinephrine concentrations were also measured. As seen in our previous results, an increase in apoptotic markers was induced by cholinergic denervation alone (medial septum lesion + ganglionectomy), while hippocampal sympathetic ingrowth (medial septum + sham ganglionectomy) reduced or normalized apoptotic effects to control group levels. A decrease in choline acetyltransferase activity was also found in the dorsal hippocampus of hippocampal sympathetic ingrowth and cholinergic denervation groups. An increase in norepinephrine concentration was found in hippocampal sympathetic ingrowth but not in cholinergic denervation group. Results of this study suggest that cholinergic denervation is responsible for most of the proapoptotic responses, while hippocampal sympathetic ingrowth produces a protective effect in the process of programmed cell death in rat dorsal hippocampus. This effect may be a secondary to an altered relationship between norepinephrine-acetylcholine.
在大鼠中，向内侧隔区注射特异性胆碱能毒素192 IgG-皂草素，不仅会导致海马体选择性胆碱能去神经支配，还会使源自颈上神经节的外周交感神经纤维长入海马体。在阿尔茨海默病中可能也会发生类似的过程，即外周去甲肾上腺素能轴突侵入海马体。由于在阿尔茨海默病中发现的选择性神经元丢失已证实存在凋亡性细胞死亡，本研究的目的是测量海马体交感神经长入和胆碱能去神经支配中的凋亡蛋白表达和DNA片段化。使用了蛋白质免疫印迹法、末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法和寡核苷酸连接技术。还测量了胆碱乙酰转移酶活性和去甲肾上腺素浓度。正如我们之前的结果所示，仅胆碱能去神经支配（内侧隔区损伤+神经节切除术）就会诱导凋亡标志物增加，而海马体交感神经长入（内侧隔区+假神经节切除术）会将凋亡效应降低或恢复到对照组水平。在海马体交感神经长入和胆碱能去神经支配组的背侧海马体中也发现胆碱乙酰转移酶活性降低。在海马体交感神经长入组中发现去甲肾上腺素浓度增加，但胆碱能去神经支配组未发现。本研究结果表明，胆碱能去神经支配是大多数促凋亡反应的原因，而海马体交感神经长入在大鼠背侧海马体程序性细胞死亡过程中产生保护作用。这种效应可能是去甲肾上腺素-乙酰胆碱之间关系改变的继发结果。
