Promoting hematoma absorption is a novel therapeutic strategy for intracerebral hemorrhage (ICH); however, the mechanism of hematoma absorption is unclear. The present study explored the function and potential mechanism of CD36 in hematoma absorption using in vitro and in vivo ICH models. Hematoma absorption in CD36-deficient ICH patients was examined. Compared with patients with normal CD36 expression, CD36-deficient ICH patients had slower hematoma adsorption and aggravated neurologic deficits. CD36 expression in perihematomal tissues in wild-type mice following ICH was increased, whereas the hematoma absorption in CD36−/− mice was decreased. CD36−/− mice also showed aggravated neurologic deficits and increased TNF-α and IL-1β expression levels. The phagocytic capacity of CD36−/− microglia for RBCs was also decreased. Additionally, the CD36 expression in the perihematoma area after ICH in TLR4−/− and MyD88−/− mice was significantly increased, and hematoma absorption was significantly promoted, which was significantly inhibited by an anti-CD36 Ab. In vitro, TNF-α and IL-1β significantly inhibited the microglia expression of CD36 and reduced the microglia phagocytosis of RBCs. Finally, the TLR4 inhibitor TAK-242 upregulated CD36 expression in microglia, promoted hematoma absorption, increased catalase expression, and decreased the H2O2 content. These results suggested that CD36 mediated hematoma absorption after ICH, and TLR4 signaling inhibited CD36 expression to slow hematoma absorption. TLR4 inhibition could promote hematoma absorption and significantly improve neurologic deficits following ICH.

High-mobility group protein box-1 (HMGB1) has recently been recognized as a novel candidate in a specific upstream pathway promoting inflammation after brain ischemia. However, its downstream pathway and underlying mechanism have yet to be elucidated. The HMGB1 level in the acute cerebral infarct (ACI) group was significantly increased compared with that of control group, and correlated with the severity of neurologic impairment of ACI patients. Further, recombinant human HMGB1 (rhHMGB1) had no effect on microglia derived from mice lacking the Toll-like receptor 4 (TLR4 À/À ). Intracerebroventricular injection of rhHMGB1 in TLR4 + / + mice cause significantly more injury after cerebral ischemia-reperfusion than control group. But, TLR4À/À mice administered with rhHMGB1 showed moderate impairment after ischemia-reperfusion than TLR4 + / + mice. To determine the potential downstream signaling of HMGB1/TLR4 in cerebral ischemic injury, we used the ischemic-reperfusion model with Toll/interleukin-1 receptor domain-containing adaptorinducing interferon-b knockout mice (TRIF À/À ) and evaluated the activity and expression of TRIF pathway-related kinases. The results suggest that the TRIF pathway is not likely to be involved in TLR4-mediated ischemia brain injury. Finally, we found that TLR4 expressed by immigrant macrophages was involved in the development of ischemic brain damage. These results suggest that HMBG1 mediates ischemia-reperfusion injury by TRIF-adaptor independent Toll-like receptor 4 signaling. The TLR4 expressed by immigrant macrophages may be involved in the development of ischemic brain damage.

Cerebral ischemia triggers acute inflammation, which has been associated with an increase in brain damage. The mechanisms that regulate the inflammatory response after cerebral ischemia are multifaceted. An important component of this response is the activation of the innate immune system. However, details of the role of the innate immune system within the complex array of mechanisms in cerebral ischemia remain unclear. There have been recent great strides in our understanding of the innate immune system, particularly in regard to the signaling mechanisms of Toll-like receptors (TLRs), whose primary role is the initial activation of immune cell responses. So far, few studies have examined the role of TLRs in cerebral ischemia. However, work with experimental models of ischemia suggests that TLRs are involved in the enhancement of cell damage following ischemia, and their absence is associated with lower infarct volumes. It may be possible that therapeutic targets could be designed to modulate activities of the innate immune system that would attenuate cerebral brain damage. Ischemic tolerance is a protective mechanism induced by a variety of preconditioning stimuli. Interpreting the molecular mechanism of ischemic tolerance will open investigative avenues into the treatment of cerebral ischemia. In this review, we discuss the critical role of TLRs in mediating cerebral ischemic injury. We also summarize evidence demonstrating that cerebral preconditioning downregulates pro-inflammatory TLR signaling, thus reducing the inflammation that exacerbates ischemic brain injury.

Recent reports have shown that preconditioning with the TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)) protects against cerebral ischemia/reperfusion (I/R) injury. However, it is unclear whether poly(I:C) treatment after cerebral I/R injury is also effective. We used mouse/rat middle cerebral artery occlusion and cell oxygen-glucose deprivation models to evaluate the therapeutic effects and mechanisms of poly(I:C) treatment. Poly(I:C) was i.p. injected 3 h after ischemia (treatment group). Cerebral infarct volumes and brain edemas were significantly reduced, and neurologic scores were significantly increased. TNF-α and IL-1β levels were markedly decreased, whereas IFN-β levels were greatly increased, in the ischemic brain tissues, cerebral spinal fluid, and serum. Injuries to hippocampal neurons and mitochondria were greatly reduced. The numbers of TUNEL-positive and Fluoro-Jade B+ cells also decreased significantly in the ischemic brain tissues. Poly(I:C) treatment increased the levels of Hsp27, Hsp70, and Bcl2 and decreased the level of Bax in the ischemic brain tissues. Moreover, poly(I:C) treatment attenuated the levels of TNF-α and IL-1β in serum and cerebral spinal fluid of mice stimulated by LPS. However, the protective effects of poly(I:C) against cerebral ischemia were abolished in TLR3−/− and TLR4−/−mice. Poly(I:C) downregulated TLR4 signaling via TLR3. Poly(I:C) treatment exhibited obvious protective effects 14 d after ischemia and was also effective in the rat permanent middle cerebral artery occlusion model. The results suggest that poly(I:C) exerts therapeutic effects against cerebral I/R injury through the downregulation of TLR4 signaling via TLR3. Poly(I:C) is a promising new drug candidate for the treatment of cerebral infarcts.

Background: There is scant information on characteristics, treatment, functional outcome and case fatality of ischemic stroke with atrial fibrillation (AF) in China. Methods: For this study, first-ever ischemic stroke patients who were admitted within 1 month of stroke onset during the period of March 2002 through December 2008 were included. Data on ischemic stroke patients were collected which included: demographics, risk factors, treatment administered, stroke-related complications and 3-month, 6-month and 1-year death and disability. Multivariate regression models were used to analyze predictors for death and disability. Results: Of the 2,683 patients included in this study, 366 (13.6%) had AF. In this group, valvular AF was observed in 153 (41.8%) patients. Compared to patients without AF, patients with AF were older (66.1 vs. 63.6, p = 0.001) and had a higher NIHSS score on admission (median 10 vs. 4, p < 0.001) and more frequently suffered from hemorrhagic transformation (7.3 vs. 2.8%, p < 0.001), pulmonary infection (27 vs. 10.6%, p < 0.001), urinary tract infection (8.5 vs. 3.0%, p < 0.001), acute gastrointestinal tract hemorrhage (4.1 vs. 1.9%, p = 0.008), electrolyte disturbance (5.2 vs. 1.8%, p < 0.001), acute renal failure (1.1 vs. 0.5%, p = 0.005) and urinary incontinence (3.8 vs. 0.6%, p < 0.001) during hospitalization. The percentages of patients with AF who received oral anticoagulants were 3.3% before stroke onset and 14.2% at discharge. Moreover, patients with AF had a higher proportion of disability (determined as modified Rankin Scale score 3–5) in 3-month, 6-month and 1-year follow-ups (46.6, 41.9 and 37.6 vs. 29.1, 24.0 and 19.3%, respectively, p < 0.001) and higher case fatality in hospitalization, 3-month, 6-month and 1-year follow-ups (10.1, 25.5, 29.1 and 34.0 vs. 2.0, 7.4, 8.8 and 11.6%, respectively, p < 0.001). Multivariate logistic regression determined that AF, age and NIHSS score were the independent predictors for the 3-month, 6-month and 1-year death. Conclusions: Ischemic stroke patients with AF have a poorer outcome, a higher frequency of stroke-related complications and a higher case fatality than patients without AF. Oral anticoagulants were underused in AF patients.

No abstract

Background and Purpose: Data on the association between renal dysfunction and outcome in patients with stroke are controversial and scarce. We investigated the predictors of renal dysfunction upon admission and the association between renal dysfunction and clinical outcome in patients with acute stroke in a hospitalized Chinese population. Methods: 1,758 acute stroke patients were consecutively enrolled into the study. The estimated glomerular filtration rate (eGFR) was calculated by the Modification of Diet in Renal Disease equation. Reduced estimate of the glomerular filtration rate was defined as eGFR <60 ml/min/1.73 m². Multivariate logistical regression was used to evaluate the predictors of renal dysfunction upon admission and to examine the association between renal dysfunction and outcomes. The main outcome measures were death and death/disability (disability defined as modified Rankin Scale score >2) at 12 months after stroke. Results: Of the included 1,758 cases (ischemic stroke: n = 1,192; hemorrhagic stroke: n = 566), 463 cases had reduced eGFR, which accounted for 26.3% of the total number. The distribution of eGFR upon admission was normal and the mean was 75.87 ± 38.31 ml/min/1.73 m² (ischemic stroke: 75.07 ± 29.89 ml/min/1.73 m²; hemorrhagic stroke: 77.57 ± 51.73 ml/min/1.73 m²). There was no significant difference between the two groups (p = 0.285). The independent predictors of eGFR upon admission were age (OR = 1.039, 95% CI = 1.028–1.050), male gender (OR = 0.658, 95% CI = 0.504–0.859), hematocrit on admission (OR = 1.008, 95% CI = 1.003–1.013), history of hypertension (OR = 1.307, 95% CI = 1.034–1.653), history of diabetes (OR = 1.411, 95% CI = 1.012–1.967) and NIHSS scores upon admission (OR = 1.497, 95% CI = 1.286–1.743). After adjustment for confounders, the patients with renal dysfunction had a significantly higher risk of death/disability (OR = 1.864, 95% CI = 1.170–2.970) compared with patients whose eGFR was more than 90 ml/min/1.73 m² at the end of the 12th month. Further analysis on type of stroke showed that reduced eGFR was an independent predictor of death/disability at the end of the 12th month in patients with hemorrhagic stroke (OR = 2.353, 95% CI = 1.063–5.209), but not for ischemic stroke (OR = 1.625, 95% CI = 0.881–2.999). Conclusions: Our study indicated that more than 1/4 of all patients with acute stroke presented with renal dysfunction. Reduced eGFR on admission is a strong predictor of poor outcome for hemorrhagic stroke but not for ischemic stroke.

Background and Purpose-Distinguishing between symptoms of posterior circulation infarction (PCI) and anterior circulation infarction (ACI) can be challenging. This study evaluated the frequency of symptoms/signs in the 2 vascular territories to determine the diagnostic value of particular symptoms/signs for PCI. Methods-Neurological deficits were reviewed and compared from 1174 consecutive patients with a diagnosis of PCI or ACI confirmed by magnetic resonance imaging in the Chengdu Stroke Registry. The diagnostic value of specific symptoms/signs for PCI was determined by measuring their sensitivity, specificity, positive predictive value (PPV), and the OR.