Institute of Neurosciences, CSIC-Universidad Miguel Hernández, Avenida Ramon y Cajal, 03550 San Juan de Alicante, Spain.
Exp Neurol. 2012 Jul;236(1):28-33. doi: 10.1016/j.expneurol.2012.03.020. Epub 2012 Apr 5.
Cognitive impairment is common in patients with chronic kidney disease. Brain nicotinic acetylcholine receptors modulate cognitive functions, such as learning and memory. Pharmacological cholinergic enhancement is useful in patients with cognitive dysfunction. The major nicotinic acetylcholine receptor subtypes in the brain are heteromeric α4β2 and homomeric α7 receptors. To study the involvement of neuronal acetylcholine receptors in cognitive impairment in uremic rats, bilateral nephrectomy was performed. 24 weeks after nephrectomy, memory was assessed using the one trial step-down inhibitory avoidance test. Neuronal nicotinic acetylcholine receptors in the brain were studied by radioligand binding, immunoprecipitation, Western blot and sucrose gradient experiments. We demonstrated that rats with severe renal failure show disorders of short term memory. Long term memory was not altered in these rats. The number of functional α4β2 heteromeric neuronal nicotinic receptors was decreased in the brains of rats with severe renal failure. There was a significant correlation between the degree of renal impairment and the number of heteromeric nicotinic acetylcholine receptors in the brain. The down-regulation of functional α4β2 receptors in the brains of rats with severe renal failure was not due to a reduction of α4 or β2 subunit proteins. The number of α7 homomeric neuronal nicotinic acetylcholine receptors was not altered. These findings may have important clinical significance for the management of cognitive impairment in patients with chronic kidney disease.
认知障碍在慢性肾脏病患者中很常见。脑烟碱型乙酰胆碱受体调节认知功能，如学习和记忆。药物增强胆碱能在认知功能障碍患者中很有用。脑中主要的烟碱型乙酰胆碱受体亚型是异源四聚体α4β2 和同源α7 受体。为了研究神经元烟碱型乙酰胆碱受体在尿毒症大鼠认知障碍中的作用，进行了双侧肾切除术。肾切除 24 周后，使用单次试验阶梯式回避测试评估记忆。通过放射性配体结合、免疫沉淀、Western blot 和蔗糖梯度实验研究脑内神经元烟碱型乙酰胆碱受体。我们证明严重肾功能衰竭的大鼠表现出短期记忆障碍。这些大鼠的长期记忆没有改变。严重肾功能衰竭大鼠脑中功能性α4β2 异源神经元烟碱型乙酰胆碱受体的数量减少。肾功能衰竭大鼠脑内异源烟碱型乙酰胆碱受体的数量与肾功能损害的程度之间存在显著相关性。严重肾功能衰竭大鼠脑中功能性α4β2 受体的下调不是由于α4 或β2 亚基蛋白减少所致。α7 同源神经元烟碱型乙酰胆碱受体的数量没有改变。这些发现可能对慢性肾脏病患者认知障碍的治疗具有重要的临床意义。
