Sood Anika, Fernandes Valencia, Preeti Kumari, Khot Mayuri, 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.
Mol Neurobiol. 2023 Feb;60(2):901-922. doi: 10.1007/s12035-022-03120-x. Epub 2022 Nov 16.
Sphingosine receptors (S1PRs) are implicated in the progression of neurodegenerative diseases and metabolic disorders like obesity and type 2 diabetes (T2D). The link between S1PRs and cognition in type 2 diabetes, as well as the mechanisms that underpin it, are yet unknown. Neuroinflammation is the common pathology shared among T2D and cognitive impairment. However, the interplay between the M1 and M2 polarization state of microglia, a primary driver of neuroinflammation, could be the driving factor for impaired learning and memory in diabetes. In the present study, we investigated the effects of fingolimod (S1PR1 modulator) on cognition in high-fat diet and streptozotocin-induced diabetic mice. We further assessed the potential pathways linking microglial polarization and cognition in T2D. Fingolimod (0.5 mg/kg and 1 mg/kg) improved M2 polarization and synaptic plasticity while ameliorating cognitive decline and neuroinflammation. Sphingolipid dysregulation was mimicked in vitro using palmitate in BV2 cells, followed by conditioned media exposure to Neuro2A cells. Mechanistically, type 2 diabetes induced microglial activation, priming microglia towards the M1 phenotype. In the hippocampus and cortex of type 2 diabetic mice, there was a substantial drop in pSTAT3, which was reversed by fingolimod. This protective effect of fingolimod on microglial M2 polarization was primarily suppressed by selective jmjd3 blockade in vitro using GSK-J4, revealing that jmjd3 was involved downstream of STAT3 in the fingolimod-enabled shift of microglia from M1 to M2 polarization state. This study suggested that fingolimod might effectively improve cognition in type 2 diabetes by promoting M2 polarization.
鞘氨醇受体（S1PRs）与神经退行性疾病以及肥胖和2型糖尿病（T2D）等代谢紊乱的进展有关。S1PRs与2型糖尿病认知之间的联系及其潜在机制尚不清楚。神经炎症是T2D和认知障碍共有的常见病理特征。然而，作为神经炎症主要驱动因素的小胶质细胞M1和M2极化状态之间的相互作用可能是糖尿病患者学习和记忆受损的驱动因素。在本研究中，我们研究了芬戈莫德（S1PR1调节剂）对高脂饮食和链脲佐菌素诱导的糖尿病小鼠认知的影响。我们进一步评估了T2D中连接小胶质细胞极化与认知的潜在途径。芬戈莫德（0.5mg/kg和1mg/kg）改善了M2极化和突触可塑性，同时减轻了认知衰退和神经炎症。在BV2细胞中使用棕榈酸酯体外模拟鞘脂失调，然后将条件培养基暴露于Neuro2A细胞。从机制上讲，2型糖尿病诱导小胶质细胞活化，使小胶质细胞向M1表型极化。在2型糖尿病小鼠的海马体和皮质中，pSTAT3大幅下降，而芬戈莫德可使其逆转。芬戈莫德对小胶质细胞M2极化的这种保护作用在体外主要通过使用GSK-J4选择性阻断jmjd3来抑制，这表明jmjd3参与了STAT3下游在芬戈莫德促使小胶质细胞从M1极化状态转变为M2极化状态的过程。这项研究表明，芬戈莫德可能通过促进M2极化有效改善2型糖尿病患者的认知。
