Department of Pharmacology, Medical University of Bialystok, Poland.
Department of Physiology, Medical University of Bialystok, Poland.
Mol Cell Neurosci. 2020 Sep;107:103526. doi: 10.1016/j.mcn.2020.103526. Epub 2020 Jul 3.
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.
鞘氨醇-1-磷酸（S1P）是一种具有强大神经保护特性的生物活性鞘脂，对海马神经元的正常兴奋性和突触传递很重要。有鉴于此，本研究旨在确定增加大脑 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。该实验在雄性 Wistar 糖尿病（n=22）和非糖尿病（n=10）大鼠中进行。糖尿病通过单次注射链脲佐菌素诱导。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 5 天，使用 Morris 水迷宫任务测试了空间参考记忆的获得和保留。然后将动物麻醉并取出海马体、前额叶皮层、纹状体和小脑的样本。使用 HPLC 法测量 S1P 和相关鞘脂的含量。糖尿病导致海马体和小脑中的神经酰胺耗竭，与空间记忆和学习受损有关。向糖尿病动物给予 THI 可防止海马体和小脑中的神经酰胺耗竭，并诱导所有检查的大脑结构中 S1P 含量增加。这些影响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慢性高血糖引起的空间记忆障碍，并且这种作用可能与海马体和小脑的神经酰胺耗竭的预防、大脑 S1P 水平的增加或两者都有关。
