S1PR2 inhibition mitigates cognitive deficit in diabetic mice by modulating microglial activation via Akt-p53-TIGAR pathway.

Cognitive deficit is one of the challenging complications of type 2 diabetes. Sphingosine 1- phosphate receptors (S1PRs) have been implicated in various neurodegenerative and metabolic disorders. The association of S1PRs and cognition in type 2 diabetes remains elusive. Microglia-mediated neuronal damage could be the thread propagating cognitive deficit. The effects of S1PR2 inhibition on cognition in high-fat diet and streptozotocin-induced diabetic mice were examined in this work. We further assessed microglial activation and putative microglial polarisation routes. Cognitive function loss was observed after four months of diabetes induction in Type 2 diabetes animal model. JTE013, an S1PR2 inhibitor, was used to assess neuroprotection against cognitive decline and neuroinflammation in vitro and in vivo diabetes model. JTE013 (10 mg/kg) improved synaptic plasticity by upregulating psd95 and synaptophysin while reducing cognitive decline and neuroinflammation. It further enhanced anti-inflammatory microglia in the hippocampus and prefrontal cortex (PFC), as evidenced by increased Arg-1, CD206, and YM-1 levels and decreased iNOS, CD16, and MHCII levels. TIGAR, TP53-induced glycolysis and apoptosis regulator, might facilitate the anti-inflammatory microglial phenotype by promoting oxidative phosphorylation and decreasing apoptosis. However, since p53 is a TIGAR suppressor, inhibiting p53 could be beneficial. S1PR2 inhibition increased p-Akt and TIGAR levels and reduced the levels of p53 in the PFC and hippocampus of type 2 diabetic mice, thereby decreasing apoptosis. In vitro, palmitate was used to imitate sphingolipid dysregulation in BV2 cells, followed by conditioned media exposure to Neuro2A cells. JTE013 rescued the palmitate-induced neuronal apoptosis by promoting the anti-inflammatory microglia. In the present study, we demonstrate that the inhibition of S1PR2 improves cognitive function and skews microglia toward anti-inflammatory phenotype in type 2 diabetic mice, thereby promising to be a potential therapy for neuroinflammation.

Alterations in brain white matter microstructural properties in patients with Crohn's disease in remission.

Patients with inflammatory bowel disease have been shown to have abnormal brain morphometry or function, which are associated with psychological symptoms such as stress, depression or anxiety. The present work recruited 20 Crohn's disease patients in remission (CDs) and 20 age-gender-handedness-education matched healthy controls (HCs) and compared their brain white matter microstructural properties using Diffusion Tensor Imaging (DTI). Additionally, we examined the correlations between the microstructural properties and cognition (verbal fluency language task, VF) and affect (anxiety) in both groups as well as disease duration in CDs. Results showed that CDs exhibited significant alterations in microstructural properties compared to HCs in various white matter tracts relevant to language function despite no significant difference in VF scores. Furthermore, CDs' microstructural changes exhibited correlations with anxiety level and disease duration. These findings suggest that CD patients may experience changes in white matter microstructural properties which may be a biomarker of neuropsychiatric comorbidities of CD.

A Verbal Fluency Task-Based Brain Activation fMRI Study in Patients with Crohn's Disease in Remission.

BACKGROUND AND PURPOSE: In this pilot study, we investigated functional brain activation changes in patients with Crohn's disease (CD) in remission compared to age and gender-matched healthy controls (HCs). METHODS: Data from 20 patients with CD in remission (age range 19-63 years) and 20 HCs (matched in age and gender) were analyzed. Task functional MRI (fMRI) data were collected while participants performed a cognitive (phonemic verbal fluency) task in the scanner. All participants also performed the same task outside the scanner. RESULTS: Task fMRI results showed greater bi-hemispheric activation in CD patients compared to controls. Because this pattern is commonly reported with normal aging, we performed further analyses to investigate fMRI responses in a subset of the younger CD patients (N = 12, age < = 35 years) compared to matched young HCs (age < = 35 years), and an older cohort of HCs (age > = 50 years). Results showed that task activation patterns were similar between young CD patients and older HCs, and that both groups differed significantly from younger HCs. Activation intensity in specific brain regions for patients was associated with disease duration. CONCLUSIONS: These results suggest that CD patients in remission may show accelerated signs of aging in terms of brain responses to a typical cognitive task. Future work with larger sample size will need to replicate these results as well as investigate the influence of factors, such as chronicity of the disease and medication effects on task-associated brain activation patterns in this patient population.