Alexander J J, Banerjee P, Dawson G, Tonsgard J H
Dept. of Pediatrics, University of Chicago, IL 60637, USA.
J Neurosci Res. 1995 May 1;41(1):105-10. doi: 10.1002/jnr.490410112.
Hyperammonemia is an important cause of cerebral dysfunction in liver failure. We used two well-established models to induce hyperammonemia in rats, injection of urease and injection of methionine sulfoximine (MSO). Urease gave a 10-fold increase in blood ammonia while MSO, a glutamine synthetase inhibitor, gave a 4-fold increase in blood ammonia with no increase in brain glutamine levels. We observed a 2-fold increase in 5-HT1A receptor (5-HT1A-R) expression ([3H] 8-OH-DPAT binding) in hippocampus, and little change elsewhere, including thalamus in both models, thus eliminating a role for increased glutamine in the receptor induction. In contrast, a 4 to 8-fold increase in 5-HT1A-R mRNA was observed both in hippocampus and thalamus, suggesting some post-transcriptional regulation. In the absence of glutamine, ammonium acetate treatment of a hippocampal cell line which had been engineered to stably express the 5-HT1A-R (HN2-5) gave a 1.5-fold increase in [3H] 8-OH-DPAT binding and a 4-fold increase in the mRNA levels for the 5-HT1A-R. We conclude that the cell line HN2-5 is a good model for studying some of the biochemical sequelae of hyperammonemia and that changes in brain function are not only at the metabolic level, as thought earlier, but can also occur at the transcriptional level.
高氨血症是肝衰竭时脑功能障碍的一个重要原因。我们使用两种成熟的模型在大鼠中诱导高氨血症，即注射脲酶和注射蛋氨酸亚砜胺（MSO）。脲酶使血氨水平升高10倍，而MSO作为谷氨酰胺合成酶抑制剂，使血氨水平升高4倍，脑内谷氨酰胺水平未升高。在两种模型中，我们均观察到海马体中5-羟色胺1A受体（5-HT1A-R）表达（[3H] 8-羟基二丙胺基四氢萘结合）增加了2倍，而包括丘脑在内的其他部位几乎没有变化，从而排除了谷氨酰胺增加在受体诱导中的作用。相比之下，在海马体和丘脑中均观察到5-HT1A-R mRNA增加了4至8倍，提示存在一些转录后调控。在缺乏谷氨酰胺的情况下，用乙酸铵处理经基因工程改造以稳定表达5-HT1A-R的海马细胞系（HN2-5），[3H] 8-羟基二丙胺基四氢萘结合增加了1.5倍，5-HT1A-R的mRNA水平增加了4倍。我们得出结论，细胞系HN2-5是研究高氨血症某些生化后遗症的良好模型，并且脑功能的变化不仅如先前认为的那样发生在代谢水平，也可发生在转录水平。
