The role of metabolic diseases in ischemic stroke has become a primary concern in both research and clinical practice. Increasing evidence suggests that dysbiosis is associated with metabolic diseases. The aim of this study was to investigate whether the gut microbiota, as well as concentrations of organic acids, the major products of dietary fiber fermentation by the gut microbiota, are altered in patients with ischemic stroke, and to examine the association between these changes and host metabolism and inflammation. We analyzed the composition of the fecal gut microbiota and the concentrations of fecal organic acids in 41 ischemic stroke patients and 40 control subjects via 16S and 23S rRNA-targeted quantitative reverse transcription (qRT)-PCR and high-performance liquid chromatography analyses, respectively. Multivariable linear regression analysis was subsequently performed to evaluate the relationships between ischemic stroke and bacterial counts and organic acid concentrations. Correlations between bioclinical markers and bacterial counts and organic acids concentrations were also evaluated. Although only the bacterial counts of Lactobacillus ruminis were significantly higher in stroke patients compared to controls, multivariable analysis showed that ischemic stroke was independently associated with increased bacterial counts of Atopobium cluster and Lactobacillus ruminis, and decreased numbers of Lactobacillus sakei subgroup, independent of age, hypertension, and type 2 diabetes. Changes in the prevalence of Lactobacillus ruminis were positively correlated with serum interleukin-6 levels. In addition, ischemic stroke was associated with decreased and increased concentrations of acetic acid and valeric acid, respectively. Meanwhile, changes in acetic acid concentrations were negatively correlated with the levels of glycated hemoglobin and low-density lipoprotein cholesterol, whereas changes in valeric acid concentrations were positively correlated with the level of high sensitivity C-reactive protein and with white blood cell counts. Together, our findings suggest that gut dysbiosis in patients with ischemic stroke is associated with host metabolism and inflammation.

Increasing evidence shows that metabolic abnormalities in body fluids are distinguishing features of the pathophysiology of Parkinson’s disease. However, a non-invasive approach has not been established in the earliest or pre-symptomatic phases. Here, we report comprehensive double-cohort analyses of the metabolome using capillary electrophoresis/liquid chromatography mass-spectrometry. The plasma analyses identified 18 Parkinson’s disease-specific metabolites and revealed decreased levels of seven long-chain acylcarnitines in two Parkinson’s disease cohorts (n = 109, 145) compared with controls (n = 32, 45), respectively. Furthermore, statistically significant decreases in five long-chain acylcarnitines were detected in Hoehn and Yahr stage I. Likewise, decreased levels of acylcarnitine(16:0), a decreased ratio of acylcarnitine(16:0) to fatty acid(16:0), and an increased index of carnitine palmitoyltransferase 1 were identified in Hoehn and Yahr stage I of both cohorts, suggesting of initial β-oxidation suppression. Receiver operating characteristic curves produced using 12–14 long-chain acylcarnitines provided a large area of under the curve, high specificity and moderate sensitivity for diagnosing Parkinson’s disease. Our data demonstrate that a primary decrement of mitochondrial β-oxidation and that 12–14 long-chain acylcarnitines decreases would be promising diagnostic biomarkers for Parkinson’s disease.

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We report a long-term outcome on a large cohort of Japanese patients with Parkinson's disease (PD). A total of 1,768 (793 men, 975 women) consecutive patients visited our clinic from 1 January 1989 to 31 December 2002. Among them, 1,183 patients (531 men, 652 women) came to our clinic within 5 years from the onset of disease and at the Hoehn & Yahr Stage III or less at the first visit. Long-term outcome was evaluated in this subcohort of the patients. We examined the duration to reach Stage III, IV, and V, and the duration to develop wearing off and dyskinesia. Time to reach Stage III was slightly but significantly shorter in women, in that 23.8% of men and 35.3% of women reached Stage III by the end of the 5th year; 49.7% of men and 63.3% of women reached Stage III by the end of the 10th year, and 88.9% of men and 79.9% of women by the end of the 15th year (P < 0.001). Also, durations to develop wearing off and dyskinesia were shorter in women compared to men. These data suggest that the disease progression may be slightly faster for women. Young-onset patients showed significantly longer duration to reach Stage III, IV, and V but shorter duration to develop wearing off and dyskinesia. Not many studies are available in the literature on the long-term outcome of PD, and our data would be useful as a reference.

As oligodendrocyte precursor cells (OPCs) are vulnerable to ischemia, their differentiation to oligodendrocytes (OLG) is impaired in chronic cerebral hypoperfusion. Astrocyte–OLG interaction is important for white matter homeostasis. Recently, reactive astrocytes were separated into two types, A1 (cytotoxic) and A2 (neurotrophic). However, their role in prolonged cerebral hypoperfusion remains unclear. We analyzed the effects of interaction between A1–A2 astrocytes and OPC–OLG under hypoperfusion, focusing on mitochondrial migration. As an in vivo model, chronic hypoperfusion model mice were created by bilateral common carotid artery stenosis (BCAS) using microcoils. As a matching in vitro study, rat primary cells were cocultured with a nonlethal concentration of CoCl2. At 28 days after hypoperfusion, the number of OPC and astrocytes increased, whereas that of OLG decreased. Increased astrocytes were mainly A1‐like astrocytes; however, the number of A2‐like type decreased. In cell culture, OPC differentiation was interrupted under mimic chronic ischemia, but improved after astrocyte‐conditioned medium (ACM) was added. However, injured‐ACM was unable to improve OPC maturation. Incubation with CoCl2 changed astrocytes from A2‐like to A1‐like, and mitochondrial migration was also reduced. A Trkβ agonist was able to maintain astrocytes from A1‐like to A2‐like even under hyperperfused conditions, and aided in OPC maturation and memory impairment via mitochondrial migration and drug effects in cell culture study and BCAS model. The reduction of A1‐like astrocytes protects against white matter injury. Trkβ agonists may play an important role in the impairment under chronic ischemic conditions. Mitochondrial migration may be a broad therapeutic strategy for cerebrovascular diseases.Main pointsProlonged cerebral hypoperfusion leads to impaired oligodendrocyte (OLG) maturation and increased numbers of A1 astrocytes. Mitochondria migration maintained A2 astrocyte morphology, mature OLG, and myelinated white matter in vivo/vitro.

Background and Purpose— Exosomes play a pivotal role in neurogenesis. In the peri-infarct area after stroke, axons begin to regenerate but are inhibited by astrocyte scar formation. The direct effect and underlying molecular mechanisms of astrocyte-derived exosomes on axonal outgrowth after ischemia are not known. Methods— Using a semaphorin 3A (Sema3A) inhibitor, we explored neuronal signaling during axonal outgrowth after ischemia in rats subjected to middle cerebral artery occlusion and in cultured cortical neurons challenged with oxygen-glucose deprivation. Furthermore, we assessed whether this inhibitor suppressed astrocyte activation and regulated astrocyte-derived exosomes to enhance axonal outgrowth after ischemia. Results— In rats subjected to middle cerebral artery occlusion, we administered a Sema3A inhibitor into the peri-infarct area from 7 to 21 days after occlusion. We found that phosphorylated high-molecular weight neurofilament-immunoreactive axons were increased, glial fibrillary acidic protein–immunoreactive astrocytes were decreased, and functional recovery was promoted at 28 days after middle cerebral artery occlusion. In cultured neurons, the Sema3A inhibitor decreased Rho family GTPase 1, increased R-Ras, which phosphorylates Akt and glycogen synthase kinase 3β (GSK-3β), selectively increased phosphorylated GSK-3β in axons, and thereby enhanced phosphorylated high-molecular weight neurofilament-immunoreactive axons after oxygen-glucose deprivation. In cultured astrocytes, the Sema3A inhibitor suppressed activation of astrocytes induced by oxygen-glucose deprivation. Exosomes secreted from ischemic astrocytes treated with the Sema3A inhibitor further promoted axonal elongation and increased prostaglandin D 2 synthase expression on microarray analysis. GSK-3β + and prostaglandin D 2 synthase + neurons were robustly increased after treatment with the Sema3A inhibitor in the peri-infarct area. Conclusions— Neuronal Rho family GTPase 1/R-Ras/Akt/GSK-3β signaling, axonal GSK-3β expression, and astrocyte-derived exosomes with prostaglandin D 2 synthase expression contribute to axonal outgrowth and functional recovery after stroke.

Background and Purpose-Admission hyperglycemia is an independent risk factor for poor outcome of ischemic stroke. Amelioration of hyperglycemia by insulin has not been shown to improve the poststroke outcome. Glucagonlike peptide 1 receptor agonists, which modulate glucose levels by stimulating insulin secretion, have been shown to exert cytoprotective effects by inhibiting inflammation and oxidative stress. This study aimed to evaluate whether the glucagon-like peptide 1 receptor agonist exendin-4 could reduce glucose levels and exert protective effects after acute focal ischemia in hyperglycemic mice. Methods-Hyperglycemia was induced by intraperitoneal injection of dextrose 15 minutes before transient middle cerebral artery occlusion was performed for 60 minutes using an intraluminal thread. We assessed 4 groups: (1) normal glucose (vehicle control), (2) Key Words: brain ischemia ◼ glucagon-like peptide 1 ◼ hyperglycemia ◼ insulin ◼ matrix metalloproteinase 9 ◼ tumor necrosis factor-alpha

Background and Purpose-Neurogenesis has been observed in the dentate gyrus of the adult hippocampus; however, the mechanisms involved in this process are still only partly understood. In this study, we visualized the proliferation, migration, and differentiation of neuronal progenitor cells in the dentate gyrus induced by ischemic stress using improved retroviral vector. Methods-Improved retroviral vector expressing enhanced green fluorescent protein (EGFP) as a transgene was injected into the dentate gyrus of adult Mongolian gerbils. After 48 hours, transient global ischemia (TGI) was induced by bilateral common carotid artery occlusion for 5 minutes using aneurysm clips. The morphological and immunohistological features of newly-generated cells in the dentate gyrus were analyzed at various times thereafter. Results-At 48 hours after viral injection, almost all EGFP-positive dividing cells were found in the subgranule layer (SGL). These cells proliferated and migrated to the granule cell layer (GCL), expressing the developing neuronal markers polysialic acid and doublecortin, and differentiated to neuronal nuclei-positive or calbindin-positive mature granule cells at 30 days after TGI or sham-operation. The number of GFP-positive cells in the GCL was significantly higher (PϽ0.05) in the ischemic animals at 30 days than in sham-operated gerbils. Conclusions-We saw neurogenesis in the adult dentate gyrus. Furthermore, we showed that ischemic stress promoted the proliferation and normal development of neurons at this site.