Long-term intermittent fasting improves neurological function by promoting angiogenesis after cerebral ischemia via growth differentiation factor 11 signaling activation.

Intermittent fasting (IF), an alternative to caloric restriction, is a form of time restricted eating. IF conditioning has been suggested to have neuroprotective effects and potential long-term brain health benefits. But the mechanism underlying remains unclear. The present study focused on the cerebral angiogenesis effect of IF on ischemic rats. Using a rat middle cerebral artery occlusion model, we assessed neurological outcomes and various vascular parameters such as microvessel density (MVD), regional cerebral blood flow (rCBF), proliferation of endothelial cells (ECs), and functional vessels in the peri-infarct area. IF conditioning ameliorated the modified neurological severity score and adhesive removal test, increased MVD, and activated growth differentiation factor 11 (GDF11)/activin-like kinase 5 (ALK5) pathways in a time-dependent manner. In addition, long-term IF conditioning stimulated proliferation of ECs, promoted rCBF, and upregulated the total vessel surface area as well as the number of microvessel branch points through GDF11/ALK5 pathways. These data suggest that long-term IF conditioning improves neurological outcomes after cerebral ischemia, and that this positive effect is mediated partly by angiogenesis in the peri-infarct area and improvement of functional perfusion microvessels in part by activating the GDF11/ALK5 signaling pathway.

Contribution of intracranial artery stenosis to white matter hyperintensities progression in elderly Chinese patients: A 3-year retrospective longitudinal study.

Background and purpose: There have been controversial results in previous studies for the association between intracranial artery stenosis (ICAS) and white matter hyperintensities (WMHs), and the correlation of ICAS with the progression of WMHs is uncertain. The aim of this study was to investigate the association between ICAS and the progression of WMHs. Methods: In this retrospective longitudinal study, we enrolled 302 patients aged 60 years and older who had received two brain MRI scans with a 3-year interval and was examined by CTA in the first MRI scan. We measured the stenosis of major intracranial arteries by CTA and assessed the progression of WMHs using the modified Rotterdam Progression scale (mRPS). We performed binary logistic regression analyses and established linear regression model to determine the relationship between the degree of ICAS and the progression of WMHs. Results: A total of 302 patients were enrolled, of which 48.3% experienced WMHs progression. After adjustment for confounding factors, the patients with Grade 2 ICAS had an OR of 2.8 (95% CI 1.4-5.5), and those with Grade 3 ICAS had an OR of 3.0 (95% CI 1.2-7.3) for the progression of WMHs. The ICAS degree remained associated with PVWMHs but had an attenuated relation to SCWMHs. ICAS severity was significantly associated with WMHs progression scores, higher for Grade 3 ICAS [ß (SE) = 0.18 (0.18)] followed by Grade 2 ICAS [ß (SE) = 0.10 (0.15)] compared with Grade 1 ICAS. Conclusions: Patients with more severe ICAS are more likely to have WMHs progression and have distinct relevancy to PVWMHs and SCWMHs, which may provide clues for understanding mechanisms of WMHs progression.

Status epilepticus with focal neurologic deficits: a rare presentation of Neurosyphilis.

Neurosyphilis is a late complication of primary syphilis and occurs with a multitude of vague symptoms. In this study, we report a patient with neurosyphilis who presented with status epilepticus, hemiplegia, and aphasia, which may be easily misdiagnosed. After performing the reactive serum test, including the toluidine red unheated serum test and the Treponema pallidum particle agglutination assay test, and cerebrospinal fluid analysis, as well as the brain Magnetic Resonance Imaging (MRI) results, we consider it general paresis of the insane, also known as dementia paralytica. The patient was started on a 14-day course with high-dose intravenous penicillin. After this treatment, the patient made significant recovery with improved cognitive function, evidenced by his Mini-mental State Examination score of 21. However, before this treatment, he could not cooperate with this exam. General paresis of the insane typically has a progressive course and normally presents 10 to 30 years after the initial infection. The manifestations of this patient and his suspicious history of transient ischemic attacks may mislead to the diagnosis of Todd's paresis or stroke. The prevalence of syphilis has been rising again in recent years. To date, there is no gold standard for the diagnosis of neurosyphilis. Early diagnosis is of great importance, as penicillin therapy is highly effective.

Circulating Soluble CD163: A Potential Predictor for the Functional Outcome of Acute Ischemic Stroke.

Background: CD163 is a transmembrane glycoprotein receptor expressed on innate immune cells that sheds from the cell membrane and circulates as a soluble form (sCD163). This study aimed to investigate the circulating levels and clinical relevance of soluble CD163 (sCD163) in acute ischemic stroke (AIS). Methods: This study recruited 300 patients with AIS and 78 healthy controls. The patients were followed up for 1 month to observe the functional outcomes. The neurological functions of the patients were assessed using the NIH Stroke Scale (NIHSS) and the modified Rankin Scale (mRS). The plasma concentrations of sCD163 at the baseline (patient admission) were determined by ELISA. Results: We found that patients with AIS had significantly higher plasma sCD163 concentrations than the healthy control. Patients with high sCD163 concentrations had better functional outcomes than patients with low sCD163 concentrations. The plasma sCD163 concentrations were positively associated with the NIHSS scores and infarction volume at the baseline. The plasma sCD163 was positively associated with the improvement of the NIHSS scores but was negatively associated with the risk of poor functional outcomes during follow-up. Conclusions: These findings indicate that circulating sCD163 is a potential biomarker that is associated with disease severity and the functional outcome of AIS.

Hydrogen sulfide down-regulates BACE1 and PS1 via activating PI3K/Akt pathway in the brain of APP/PS1 transgenic mouse.

BACKGROUND: Endogenous hydrogen sulfide (H2S) may have multiple physiological functions in brain. Our previous study showed that H2S improved spatial memory impairment and decreased the production of Aß in APP/PS1 transgenic mice. However, many of the underlying mechanisms are not still being elucidated. The aim of the present study is to investigate the neuroprotective mechanisms of H2S involving in the activity of ß-secretase (BACE1), γ-secretase (PS1) and α-secretase (ADAM17). METHODS: Morris water maze was used to measure the behavior change. The levels of Aß40 and Aß42 were quantified using colorimetric ELISA kits and immunohistochemical analysis. The levels of BACE1, PS1, ADAM17, pAkt, pp38MAPK, pERK and pJNK were tested by Western blot analysis in normal mice, APP/PS1 transgenic mice and 50µmol/kg-NaHS-treated transgenic mice. On the basis of exogenous H2S treatment, LY294002 (inhibitors of PI3K/Akt) or PD98059 (inhibitors of MAPK/ERK) was injected into lateral cerebral ventricle. RESULTS: The levels of BACE1, PS1 and pp38MAPK were increased and ADAM17 were decreased in the APP/PS1 transgenic mice. After intraperitoneal administration of an H2S donor (NaHS) into APP/PS1 mice, the levels of BACE1, PS1 and pp38MAPK were reduced and ADAM17 increased. The level of pp38 MAPKs, pAkt and pERK1/2 was increased in APP/PS1 transgenic mice compared with normal mice (p<0.05). There was no difference in the expression of pJNK between AD transgenic mice and normal mice (p>0.05). These results demonstrated that LY294002 inhibited the effect of H2S on decreasing the BACE1 and PS1, reducing the level of Aß and improving memory impairment in APP/PS1 transgenic mice. PD98059 had no influence on the expression of BACE1 and PS1. CONCLUSIONS: H2S inhibits the expression of BACE1 and PS1 by activating PI3K/Akt pathway in AD.

[Effect of exogenous hydrogen sulfide on BACE-1 enzyme expression and ß-amyloid peptide metabolism in high-glucose primary neuronal culture].

OBJECTIVE: To investigate the effects of exogenous hydrogen sulfide (H2S) on ß-site APP cleaving enzyme 1 (BACE-1) and ß-amyloid peptide (Aß) metabolism in primary culture of neurons under high-glucose condition. METHODS: The cortical neurons in primary culture under normal and high glucose (60 mmol/L) conditions for 24 h were exposed to 25, 50 and 100 µmol/L NaHS. Aß1-42 concentration in the cell culture was measured by ELISA, and BACE-1 mRNA and protein levels were detected by fluorescent quantitative real-time PCR and Western blotting, respectively. RESULTS: Compared with the neurons cultured in normal glucose, the neurons exposed to high glucose showed significantly increased Aß1-42 concentration and BACE-1 mRNA and protein expressions (P<0.05). Exposure to 25, 50 and 100 µmol/L NaHS significantly decreased Aß1-42 concentration and BACE-1 mRNA and protein expressions in the high-glucose cell culture (P<0.05). CONCLUSION: Neurons exposed to high glucose exhibit increased Aß1-42 levels and BACE-1 mRNA and protein expressions, which can be concentration-dependently decreased by NaHS.

Hydrogen sulfide improves spatial memory impairment and decreases production of Aß in APP/PS1 transgenic mice.

Alzheimer's disease (AD) is defined both by its progressive cognitive deterioration and hallmark increase in neuronal Aß plaque formation. However, many of the underlying neurobiological facets of this disease are still being elucidated. Previous research has demonstrated that production of neuronal hydrogen sulfide (H2S) is significantly decreased in patients with AD. Moreover, systemic plasma H2S levels are negatively correlated with its severity. However, how a decrease in H2S production might be correlated with either the etiology or pathophysiology of AD remains unknown. To better understand the role of H2S in AD, we examined both levels of H2S and the expression and activity H2S-synthesizing enzyme (cystathionine beta synthase or CBS) in an APP/PS1 transgenic mouse line at 3, 6, 9 and 12 months. After intraperitoneal (i.p.) administration of an H2S donor (NaHS) into APP/PS1 mice, application of exogenous H2S resulted in improved spatial learning and memory acquisition in APP/PS1 mice. H2S administration also led to significant decrease in extracellular levels of Aß40 and Aß42, the expression of BACE1 and PS1, and a significant increase of ADAM17 expression. Similarly, an increase in non-amyloidogenic C83 fragment generation and a decrease in amyloidogenic C99 fragment generation were also observed. Thus, NaHS application resulted in a shift from the plaque-forming beta pathway to the non-plaque forming alpha pathway of APP cleavage in 6 and 12 month APP/PS1 mice. These results indicate the importance of H2S to AD severity and that administration of exogenous H2S can promote a non-amyloidogenic processing of APP.