Lange-Asschenfeldt Christian, Schäble Sandra, Suvorava Tatsiana, Fahimi Ehsan Gholamreza, Bisha Marion, Stermann Torben, Henning Uwe, Kojda Georg
Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Comparative Psychology, Institute of Experimental Psychology, Heinrich-Heine-University, Düsseldorf, Germany.
Neuropharmacology. 2016 Aug;107:100-110. doi: 10.1016/j.neuropharm.2016.03.025. Epub 2016 Mar 21.
Nicotinic acetylcholine receptor (nAChR) subtypes containing the α4 subunit, particularly α4β2 nAChRs, play an important role in cognitive functioning. The impact of the smoking cessation aid varenicline, a selective partial α4β2 nAChR agonist, on (1) changes of central protein and mRNA expression of this receptor and (2) on memory deficits in a mouse model of cognitive impairment was investigated. Protein and mRNA expression of both the α4 and β2 receptor subunits in mouse brain endothelial and hippocampal cells as well as hippocampus and neocortex tissues were determined by western blot and realtime PCR, respectively. The β2 antibody showed low specificity, though. Tissues were examined following a 2-week oral treatment with various doses of varenicline (0.01, 0.1, 1, 3 mg/kg/day) or vehicle. In addition, episodic memory of mice was assessed following this treatment with an object recognition task using (1) normal mice and (2) animals with anticholinergic-induced memory impairment (i.p. injection of 0.5 mg/kg scopolamine). Varenicline dose-dependently increased protein expression of both the α4 and β2 subunit in cell cultures and brain tissues, respectively, but had no effect on mRNA expression of both subunits. Scopolamine injection induced a significant reduction of object memory in vehicle-treated mice. By contrast, cognitive performance was not altered by scopolamine in varenicline-treated mice. In conclusion, a 2-week oral treatment with varenicline prevented memory impairment in the scopolamine mouse model. In parallel, protein, but not mRNA expression was upregulated, suggesting a posttranscriptional mechanism. Our findings suggest a beneficial effect of varenicline on cognitive dysfunction.
含有α4亚基的烟碱型乙酰胆碱受体（nAChR）亚型，尤其是α4β2 nAChRs，在认知功能中起重要作用。研究了戒烟辅助药物伐尼克兰（一种选择性部分α4β2 nAChR激动剂）对（1）该受体的中枢蛋白和mRNA表达变化以及（2）认知障碍小鼠模型中记忆缺陷的影响。分别通过蛋白质印迹法和实时PCR测定小鼠脑内皮细胞和海马细胞以及海马和新皮质组织中α4和β2受体亚基的蛋白质和mRNA表达。不过，β2抗体显示出低特异性。在用不同剂量的伐尼克兰（0.01、0.1、1、3mg/kg/天）或赋形剂进行2周口服治疗后检查组织。此外，在这种治疗后，使用（1）正常小鼠和（2）抗胆碱能诱导记忆障碍的动物（腹腔注射0.5mg/kg东莨菪碱）通过物体识别任务评估小鼠的情景记忆。伐尼克兰分别在细胞培养物和脑组织中剂量依赖性地增加α4和β2亚基的蛋白质表达，但对两个亚基的mRNA表达没有影响。注射东莨菪碱导致赋形剂处理小鼠的物体记忆显著降低。相比之下，在伐尼克兰处理的小鼠中，东莨菪碱并未改变认知表现。总之，伐尼克兰2周口服治疗可预防东莨菪碱小鼠模型中的记忆障碍。同时，蛋白质表达上调，但mRNA表达未上调，提示存在转录后机制。我们的研究结果表明伐尼克兰对认知功能障碍具有有益作用。
