Harrell Lindy E, Parsons Dee S, Kolasa Krystyna
Department of Neurology, VA Medical Center, University of Alabama at Birmingham, 975 Sparks Center, 1720 7th Avenue South, Birmingham, AL 35294, USA.
Brain Res. 2005 Feb 1;1033(1):68-77. doi: 10.1016/j.brainres.2004.11.021.
In this study, the effect of intraseptal injection of specific cholinotoxin 192-IgG saporin (SAP) +/- intraperitoneal injection of N-[chloroethyl]-N-ethyl-2-bromobenzylamine (DSP-4) (noradrenergic fiber neurotoxin) was examined in rat hippocampus. Medial septal lesions resulted not only in selective cholinergic denervation of hippocampus (Medial septal lesion + ganglionectomy; SAP + Gx) but also in hippocampal sympathetic ingrowth (IG) of adrenergic fibers (Medial septal lesion + sham ganglionectomy; SAP + IG). Saporin-induced septal lesions produced a significant reduction in hippocampal choline acetyltransferase activity in all tested groups (SAP + IG +/- DSP-4 and SAP + Gx +/- DSP-4), and an increase in noradrenaline concentration in the SAP + IG group. Visualization of noradrenergic fibers by histofluorescence revealed a mixture of fine and thick varicosities in the SAP + IG but only fine fibers in control and SAP + Gx animals. SAP + IG + DSP-4 lesions produced significant reduction in noradrenaline concentration in all groups with a concomitant decrease in visualization of central noradrenergic fibers in dorsal and ventral hippocampus. Treatment of SAP + IG animals with DSP-4 left mostly thick fibers, probably derived from peripheral sympathetic ingrowth. No fluorescence was seen in either the control + DSP-4 or SAP + Gx + DSP-4 animals. Apoptotic-like changes, using in situ oligonucleotide ligation techniques, were also assessed. Proapoptotic changes were seen in the SAP + Gx +/- DSP-4 group as compared to CON +/- DSP-4 groups. SAP + IG regardless of DSP-4 treatment protected hippocampal cells from apoptotic cell death when compared to positive control and SAP + Gx +/- DSP-4 groups. In summary, elevated noradrenaline concentration following specific cholinergic denervation probably reflects compensatory hippocampal ingrowth originating from the peripheral sympathetic system which may be responsible for neuroprotective effects, i.e., antiapoptosis-like effect. Since cholinergic and noradrenergic systems are known to be involved in Alzheimer's disease and related cognitive function, knowing how these neurotransmitters work after specific lesions may be of importance as an animal model of Alzheimer's disease and as a potential target for Alzheimer's disease drug therapies.
在本研究中，检测了在大鼠海马体内注射特定胆碱毒素192-IgG皂草素（SAP）±腹腔注射N-氯乙基-N-乙基-2-溴苄胺（DSP-4，去甲肾上腺素能纤维神经毒素）的效果。内侧隔区损伤不仅导致海马体选择性胆碱能去神经支配（内侧隔区损伤+神经节切除术；SAP+Gx），还导致肾上腺素能纤维的海马体交感神经长入（IG）（内侧隔区损伤+假神经节切除术；SAP+IG）。皂草素诱导的隔区损伤在所有测试组（SAP+IG±DSP-4和SAP+Gx±DSP-4）中均导致海马胆碱乙酰转移酶活性显著降低，而在SAP+IG组中去甲肾上腺素浓度升高。通过组织荧光法对去甲肾上腺素能纤维进行可视化观察发现，SAP+IG组中既有细小的曲张体，也有粗大的曲张体，而对照组和SAP+Gx组动物中只有细小纤维。SAP+IG+DSP-4损伤使所有组的去甲肾上腺素浓度显著降低，同时背侧和腹侧海马体中中枢去甲肾上腺素能纤维的可视化程度也随之降低。用DSP-4处理SAP+IG动物后，大多留下粗大纤维，可能来自外周交感神经长入。在对照组+DSP-4或SAP+Gx+DSP-4动物中均未观察到荧光。还使用原位寡核苷酸连接技术评估了凋亡样变化。与CON±DSP-4组相比，在SAP+Gx±DSP-4组中观察到促凋亡变化。与阳性对照组和SAP+Gx±DSP-4组相比，无论是否用DSP-4处理，SAP+IG均可保护海马细胞免于凋亡性细胞死亡。总之，特定胆碱能去神经支配后去甲肾上腺素浓度升高可能反映了源自外周交感神经系统的代偿性海马长入，这可能是神经保护作用（即抗凋亡样作用）的原因。由于已知胆碱能和去甲肾上腺素能系统与阿尔茨海默病及相关认知功能有关，了解这些神经递质在特定损伤后的作用方式，对于作为阿尔茨海默病动物模型以及作为阿尔茨海默病药物治疗的潜在靶点可能具有重要意义。
