Sood Anika, Fernandes Valencia, Preeti Kumari, Khatri Dharmendra Kumar, Singh Shashi Bala
Molecular & Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana 500037, Hyderabad, India.
Molecular & Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana 500037, Hyderabad, India.
Behav Brain Res. 2023 May 28;446:114415. doi: 10.1016/j.bbr.2023.114415. Epub 2023 Mar 29.
Sphingosine-1-phosphate (S1P) is emerging as a crucial sphingolipid modulating neuroinflammation and cognition. S1P levels in the brain have been found to be decreased in cognitive impairment. S1P lyase (S1PL) is the key enzyme in metabolizing S1P and has been implicated in neuroinflammation. This study evaluated the effect of S1PL inhibition on cognition in type 2 diabetic mice. Fingolimod (0.5 mg/kg and 1 mg/kg) rescued cognition in high-fat diet and streptozotocin-induced diabetic mice, as evident in the Y maze and passive avoidance test. We further evaluated the effect of fingolimod on the activation of microglia in the pre-frontal cortex (PFC) and hippocampus of diabetic mice. Our study revealed that fingolimod inhibited S1PL and promoted anti-inflammatory microglia in both PFC and hippocampus of diabetic mice as it increased Ym-1 and arginase-1. The levels of p53 and apoptotic proteins (Bax and caspase-3) were elevated in the PFC and hippocampus of type 2 diabetic mice which fingolimod reversed. The underlying mechanism promoting anti-inflammatory microglial phenotype was also explored in this study. TIGAR, TP53-associated glycolysis and apoptosis regulator, is known to foster anti-inflammatory microglia and was found to be downregulated in the brain of type 2 diabetic mice. S1PL inhibition decreased the levels of p53 and promoted TIGAR, thereby increasing anti-inflammatory microglial phenotype and inhibiting apoptosis in the brain of diabetic mice. Our study reveals that S1PL inhibition could be beneficial in mitigating cognitive deficits in diabetic mice.
鞘氨醇-1-磷酸（S1P）正逐渐成为一种调节神经炎症和认知的关键鞘脂。研究发现，认知障碍患者大脑中的S1P水平会降低。S1P裂解酶（S1PL）是代谢S1P的关键酶，与神经炎症有关。本研究评估了抑制S1PL对2型糖尿病小鼠认知的影响。芬戈莫德（0.5mg/kg和1mg/kg）改善了高脂饮食和链脲佐菌素诱导的糖尿病小鼠的认知，这在Y迷宫和被动回避试验中得到了证实。我们进一步评估了芬戈莫德对糖尿病小鼠前额叶皮质（PFC）和海马体中微胶质细胞激活的影响。我们的研究表明，芬戈莫德抑制了S1PL，并促进了糖尿病小鼠PFC和海马体中的抗炎性微胶质细胞，因为它增加了Ym-1和精氨酸酶-1。2型糖尿病小鼠PFC和海马体中p53和凋亡蛋白（Bax和caspase-3）的水平升高，而芬戈莫德可使其逆转。本研究还探讨了促进抗炎性微胶质细胞表型的潜在机制。TP53相关糖酵解和凋亡调节因子TIGAR已知可促进抗炎性微胶质细胞，且在2型糖尿病小鼠的大脑中被发现下调。抑制S1PL可降低p53水平并促进TIGAR，从而增加糖尿病小鼠大脑中的抗炎性微胶质细胞表型并抑制细胞凋亡。我们的研究表明，抑制S1PL可能有助于减轻糖尿病小鼠的认知缺陷。
