Neurobiology Division, Defence Institute of Physiology and Allied Sciences, Defence Research and Development Organization, Ministry of Defence, Govt. of India, Lucknow Road, Timarpur, Delhi, India.
Eur J Pharmacol. 2011 Dec 15;672(1-3):96-105. doi: 10.1016/j.ejphar.2011.08.023. Epub 2011 Sep 5.
Hypobaric hypoxia is encountered at high altitude. It has a deleterious effect on cognitive functions. An important cause of memory impairment at high altitude is the impairment of neurotransmission. The present study investigates the role of cholinergic markers in hypobaric hypoxia-induced memory impairment. Rats were exposed to hypobaric hypoxia at 6,100 m for 7 days in a simulated-decompression chamber. Memory performance was assessed using the Morris water maze task. Cholinergic markers such as acetylcholine, acetylcholinesterase, choline acetyltransferase, α-7-nicotinic acetylcholine receptor and M(1) muscarinic acetylcholine receptor were also evaluated along with neuronal morphology and DNA fragmentation. We found impairment in memory function along with a decrease in acetylcholine levels, increase in acetylcholinesterase activity, down regulation of choline acetyltransferase, α-7-nicotinic acetylcholine receptor and M(1) muscarinic acetylcholine receptor. We also found that cellular damage is associated with a significant increase in DNA fragmentation. However, administration of acetylcholinesterase inhibitors, such as physostigmine and galantamine, resulted in amelioration of the hypobaric hypoxia induced deleterious effects. It improved acetylcholine level, decreased acetylcholinesterase activity and increased the synthesis of acetylcholine by increasing choline acetyltransferase activity. Also, the acetylcholinesterase inhibitors improved neuronal morphology, perhaps by increasing the expression of α-7-nicotinic acetylcholine receptor and by reducing the acetylcholinesterase level in the cortex and the hippocampus. Therefore, our results suggest cholinergic dysfunction is one of the mechanisms involved in hypobaric hypoxia-induced memory impairment and that acetylcholinesterase inhibitors were able to restore cholinergic function and thus improve memory function.
低压缺氧发生在高海拔地区。它对认知功能有有害影响。高原记忆障碍的一个重要原因是神经递质传递受损。本研究探讨了胆碱能标志物在低压缺氧引起的记忆障碍中的作用。将大鼠置于模拟减压室中，在 6100 米的高度暴露于低压缺氧 7 天。使用 Morris 水迷宫任务评估记忆性能。还评估了乙酰胆碱、乙酰胆碱酯酶、胆碱乙酰转移酶、α-7-烟碱型乙酰胆碱受体和 M1 毒蕈碱型乙酰胆碱受体等胆碱能标志物，以及神经元形态和 DNA 片段化。我们发现记忆功能受损，乙酰胆碱水平降低，乙酰胆碱酯酶活性增加，胆碱乙酰转移酶、α-7-烟碱型乙酰胆碱受体和 M1 毒蕈碱型乙酰胆碱受体下调。我们还发现细胞损伤与 DNA 片段化的显著增加有关。然而，乙酰胆碱酯酶抑制剂（如毒扁豆碱和加兰他敏）的给药导致低压缺氧诱导的有害作用得到改善。它通过增加胆碱乙酰转移酶活性来提高乙酰胆碱水平，降低乙酰胆碱酯酶活性并增加乙酰胆碱的合成。此外，乙酰胆碱酯酶抑制剂改善了神经元形态，这可能是通过增加α-7-烟碱型乙酰胆碱受体的表达和减少皮质和海马中的乙酰胆碱酯酶水平来实现的。因此，我们的结果表明，胆碱能功能障碍是低压缺氧引起记忆障碍的机制之一，而乙酰胆碱酯酶抑制剂能够恢复胆碱能功能，从而改善记忆功能。
