Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid with strong neuroprotective properties that is important for normal excitability and synaptic transmission in the hippocampal neurons. Considering the above, the aim of the present study was to determine whether increasing brain S1P level is able to reverse spatial memory impairment in streptozotocin-diabetic rats. The experiment was carried out on diabetic (n = 22) and nondiabetic (n = 10) male Wistar rats. Diabetes was induced by a single injection of streptozotocin. Eleven weeks later, 11 diabetic animals received injections of THI (S1P lyase inhibitor) for seven days. During the last five days of the experiment spatial reference memory acquisition and retention were tested in the Morris water maze task. The animals were then anaesthetized and samples of the hippocampus, prefrontal cortex, striatum, and cerebellum were excised. The content of S1P and related sphingolipids was measured using a HPLC method. Diabetes induced a depletion of ceramide in the hippocampus and cerebellum that was associated with impaired spatial memory and learning. Administration of THI to the diabetic animals prevented ceramide depletion in the hippocampus and cerebellum, and induced an increase in S1P content in all examined brain structures. These effects were associated with an improvement in spatial memory. We conclude that pharmacological inhibition of S1P lyase partially reverses the impairment in spatial memory induced by chronic hyperglycemia, and that this effect may be related to the prevention of ceramide depletion in the hippocampus and cerebellum, the increase in brain S1P level, or both.

1-磷酸鞘氨醇 (S1P) 是一种生物活性鞘脂，具有很强的神经保护特性，对海马神经元的正常兴奋性和突触传递很重要。考虑到上述情况，本研究的目的是确定增加脑 S1P 水平是否能够逆转链脲佐菌素 - 糖尿病大鼠的空间记忆障碍。对糖尿病患者（n  = 22）和非糖尿病患者（n = 10) 雄性 Wistar 大鼠。单次注射链脲佐菌素诱发糖尿病。11 周后，11 只糖尿病动物接受了为期 7 天的 THI（S1P 裂解酶抑制剂）注射。在实验的最后五天期间，在 Morris 水迷宫任务中测试了空间参考记忆的获取和保留。然后将动物麻醉并切除海马、前额叶皮层、纹状体和小脑的样本。S1P 和相关鞘脂的含量使用 HPLC 方法测量。糖尿病会导致海马体和小脑中神经酰胺的消耗，这与空间记忆和学习受损有关。对糖尿病动物施用 THI 可防止海马和小脑中神经酰胺的消耗，并诱导所有检查的大脑结构中 S1P 含量的增加。这些效果与空间记忆的改善有关。我们得出结论，S1P 裂解酶的药理学抑制部分逆转了由慢性高血糖引起的空间记忆障碍，这种作用可能与防止海马和小脑神经酰胺耗竭、脑 S1P 水平增加或两者有关。