Evaluation of Metformin on Cognitive Improvement in Patients With Non-dementia Vascular Cognitive Impairment and Abnormal Glucose Metabolism

Objective: Recent studies have suggested that metformin can penetrate the blood–brain barrier, protecting neurons via anti-inflammatory action and improvement of brain energy metabolism. In this study, we aim to investigate the effect of metformin on cognitive function in patients with abnormal glucose metabolism and non-dementia vascular cognitive impairment (NDVCI).Methods: One hundred patients with NDVCI and abnormal glucose metabolism were randomly allocated into two groups: metformin and donepezil (n = 50) or acarbose and donepezil (n = 50). The neuropsychological status, glucose metabolism, and common carotid arteries intima–media thickness (CCA-IMT) before and after a year of treatment, were measured and compared between the groups.Results: Ninety four patients completed all the assessment and follow-up. After a year of treatment, there was a decrease in Alzheimer’s disease Assessment Scale-Cognitive Subscale scores and the duration of the Trail Making Test in the metformin-donepezil group. Furthermore, these patients showed a significant increase in World Health Organization–University of California–Los Angeles Auditory Verbal Learning Test scores after treatment (all P < 0.05). However, there was no obvious improvement in cognitive function in the acarbose-donepezil group. We also observed a significant decrease in the level of fasting insulin and insulin resistance (IR) index in the metformin-donepezil group, with a lower CCA-IMT value than that in the acarbose-donepezil group after a year of treatment (P < 0.05).Conclusion: We conclude that metformin can improve cognitive function in patients with NDVCI and abnormal glucose metabolism, especially in terms of performance function. Improved cognitive function may be related to improvement of IR and the attenuated progression of IMT.Trial Registration:ChiCTR-IPR-17011855

B7-H4 Treatment of T Cells Inhibits ERK, JNK, p38, and AKT Activation

B7-H4 is a newly identified B7 homolog that plays an important role in maintaining T-cell homeostasis by inhibiting T-cell proliferation and lymphokine-secretion. In this study, we investigated the signal transduction pathways inhibited by B7-H4 engagement in mouse T cells. We found that treatment of CD3+ T cells with a B7-H4.Ig fusion protein inhibits anti-CD3 elicited T-cell receptor (TCR)/CD28 signaling events, including phosphorylation of the MAP kinases, ERK, p38, and JNK. B7-H4.Ig treatment also inhibited the phosphorylation of AKT kinase and impaired its kinase activity as assessed by the phosphorylation of its endogenous substrate GSK-3. Expression of IL-2 is also reduced by B7-H4. In contrast, the phosphorylation state of the TCR proximal tyrosine kinases ZAP70 and lymphocyte-specific protein tyrosine kinase (LCK) are not affected by B7-H4 ligation. These results indicate that B7-H4 inhibits T-cell proliferation and IL-2 production through interfering with activation of ERK, JNK, and AKT, but not of ZAP70 or LCK

The neuron regrowth is associated with the proliferation of neural precursor cells after leukemia inhibitory factor administration following spinal cord injury in mice.

To explore whether LIF could promote the proliferation of neural precursor cells (NPCs) and to analyze the correlation between increased NPCs and FluoroGold (FG) labeled neurons in mice after spinal cord injury (SCI).Motor behavior was assessed using Rotarod and Platform Hang tests; neurons in the corticospinal and rubrospinal systems were labeled with FG, NPCs were immustained with nestin-FITC conjugate. The numbers of FG-labeled neurons and NPCs were estimated, and the correlation between FG-labeled neurons and NPCs was assessed.Mice in the SCI group showed negligible recovery of locomotor behavior; in contrast, mice in the LIF group showed a statically significant improvement. Both FG-labeled neurons and NPCs were significantly increased in the LIF group compared to the SCI group, and this increase in FG-labeled neurons and NPCs showed a clear association above the lesion level.LIF could promote locomotive behaviors in mice post-SCI by encouraging the proliferation of NPCs; LIF may in fact be a potential cytokine for the induction of NPCs post-SCI

Elevated Levels of IFN-γ in CSF and Serum of Patients with Amyotrophic Lateral Sclerosis.

To explore whether the levels of IFN-γ in cerebral spinal fluid (CSF) and serum are elevated in ALS patients and to analyze the correlations between the IFN-γ levels and disease progression.CSF and serum samples were obtained from 52 ALS patients and 31 non-ALS patients. The levels of IFN-γ in CSF and serum were assessed, and disease progression parameters, including the disease interval (months from onset, MFO), the revised ALS Functional Rating Scale (ALSFRS-r) score and the disease progression rate (DPR) were analyzed by registered neurologists. All samples were measured using a commercial enzyme-linked immunosorbent assay. Statistical analyses were performed using Prism software.Compared to the non-ALS patients, the ALS patients displayed significantly increased levels of IFN-γ in both CSF and serum, and these values consistently correlated with disease progression.These results demonstrated that IFN-γ in CSF may serve as a biomarker of ALS differentiation and progression. CSF IFN-γ was a more reliable biomarker of disease diagnosis and progression than serum IFN-γ

Locomotor behavior analysis of mice in the Nor, SCI, LIF and sham groups using the Rotarod and the Platform Hang tests.

<p>Fig. 1A showed a permanent hind limb paralysis in Rotarod analysis in the SCI group. A significant improvement was detected on the Rotarod in the LIF group compared to the SCI group; a statistical difference was found after the fourth day and the maximal response was achieved by the sixth day, despite continuous treatment for 14 days. A similar significant (<i>p<</i>0.05) improvement was observed in the Platform Hang test (Fig. 1B) in LIF group. The locomotor behavior of the Nor and Sham groups was not affected in both Rotarod and Platform Hang tests.</p

Analysis of FG-labeled neurons in the corticospinal and rubrospinal systems in the Nor, SCI, LIF and Sham groups.

<p>Fig. 2A–D showed the FG-labeled neurons in the corticospinal system in the Nor (2A), SCI (2B), LIF (2C) and Sham (2D) groups. Fig. 2E summarized the number of FG-labeled neurons in the corticospinal system. The number of FG-labeled neurons in the LIF group decreased compared to the Nor group, but increased compared to SCI group. Fig. 2F–I showed the FG-labeled neurons in the rubrospinal system in the Nor (2F), SCI (2G), LIF (2H) and Sham (2I) groups. Fig. 2J showed a similar pattern to that shown in Fig. 2E in the rubrospinal system. * Indicates comparison with the Nor group. # Indicates comparison with the SCI group. Cor: Corticospinal; Rub: Rubrospinal. Bar =  100 µm.</p

The correlation between NPCs and FG-labeled neurons.

<p>Fig. 4A–B showed that the number of NPCs above the lesion level, but not below the lesion level (Fig. 4C–D), was positively correlated with the number of FG-labeled neurons in both the corticospinal and rubrospinal systems in the LIF group. There was no any positive correlation detected between the number of NPCs and the number of FG-labeled neurons above (Fig. 4E–F) and below (Fig. 4G–H) the lesion level of spinal cord in both the corticospinal and rubrospinal systems in the SCI group.</p

Experimental design showing the number of mice allocated to the Nor, SCI, LIF and Sham groups.

<p>Experimental design showing the number of mice allocated to the Nor, SCI, LIF and Sham groups.</p

NPCs in spinal cord above and below the lesion level.

<p>Fig. 3A–E showed the NPCs in spinal cord above the lesion level. Fig. 3A–D showed the NPCs above the lesion level in the Nor (3A), SCI (3B), LIF (3C) and Sham (3D) groups. Fig. 3E showed that the number of NPCs above the lesion level in the LIF group increased compared to the SCI group, but they were rare in the Nor and Sham groups. Fig. 3F–J showed the NPCs in the spinal cord below the lesion level. Fig. 3F–I showed the NPCs below the lesion level in the Nor (3F), SCI (3G), LIF (3H) and Sham (3I) groups. Fig. 3J showed the number of NPCs below the lesion level in LIF group increased compared to the SCI group, but they were rare in the Nor and Sham groups. * indicates comparison with the Nor and Sham groups. # Indicates comparison with the SCI group. Bar  = 50 µm.</p