Search

BACKGROUND A growing body of experimental evidence suggests that hemin released from heme is a potent oxidant and accumulates in intracranial hematomas. Hemopexin (Hpx) decreases hemin accumulation and catabolism by nerve cells. In previous study, we observed that Hpx gene knockout aggravated striatal injury and worsened behavioral deficits of mice subjected to intracerebral hemorrhage. AIM To examine the effect of Hpx on oxidative damage and apoptosis in cultured nerve cells with blood clot. METHODS Neuron and glial cells were transfected with adenoviral Hpx gene. Transfected primary neuron-glial cells were co-cultured with 50 μl of arterial blood clot using insert transwells. The sham group was co-coulture with 50 μl of DMEM/F12, which contained 28 μl of serum; the control group was transfected with adenoviral vector. At 12 and 24 h, the level of malonaldehyde (MDA), surperoxide dismutase (SOD) concentration, glutathione (GSH), apoptosis, expression of HO-1 and caspase-3 were detected. RESULTS MDA level was decreased (P < 0.01) whereas SOD and GSH concentration were increased in the Hpx group (P < 0.05 and P < 0.01, respectively). Results of flow cytometry revealed no significant difference in apoptosis between the Hpx group and model group at 12 h. However, the percentage of cells undergoing apoptosis in the Hpx group was decreased at 24 h compared with the model group (P < 0.01). HO-1 expression decreased in the Hpx group at 24 h (P < 0.01) while caspase-3 expression decreased at both 12 and 24 h (P < 0.011 and P < 0.05, respectively) compared with the model group. CONCLUSION Hpx protected nerve cells exposed to blood from injury by anti-oxidation and a decrease in the expression of HO-1 and caspase-3.

Cerebral ischemia-reperfusion (I/R) is associated with increased levels of reactive oxygen species (ROS) and brain edema, which lead to the deterioration of patient prognosis. Resveratrol serves a neuroprotective role in I/R injury, and this role may be associated with its anti‑oxidative effects. However, resveratrol's mechanism of action in cerebral I/R injury remains to be fully understood. In order to investigate the effect of resveratrol in cerebral I/R‑induced injury, male Sprague‑Dawley rats were randomly assigned to four groups: The sham‑operation group, the I/R group and the edaravone and resveratrol groups (I/R + E and I/R + R groups). Infarct volume was evaluated by 2,3,5‑tripenyltetrazolium chloride staining, brain edema was evaluated by the water content in the reperfused brain and malondialdehyde (MDA) was measured by the thiobarbituric acid method. Superoxide dismutase (SOD) levels were measured using the Total Superoxide Dismutase Assay kit. Inducible nitric oxide synthase (iNOS) levels in the hippocampus and cortex were measured by ELISA, and aquaporin 4 (AQP4) expression was measured by immunohistochemical staining and western blot analysis. The results demonstrated that resveratrol reduced the infarct volume and the incidence of brain edema and reduced neurological deficits. These outcomes were accompanied by reduced levels of MDA, iNOS and AQP4, and increased SOD levels in cerebral I/R injury. In conclusion, resveratrol protected against cerebral I/R injury by ameliorating oxidative stress and reducing AQP4 expression.

Object Deep brain stimulation (DBS) is the surgical procedure of choice for patients with advanced Parkinson disease (PD). The globus pallidus internus (GPi) and the subthalamic nucleus (STN) are commonly targeted by this procedure. The purpose of this meta-analysis was to compare the efficacy of DBS in each region. Methods MEDLINE/PubMed, EMBASE, Web of Knowledge, and the Cochrane Library were searched for English-language studies published before April 2013. Results of studies investigating the efficacy and clinical outcomes of DBS of the GPi and STN for PD were analyzed. Results Six eligible trials containing a total of 563 patients were included in the analysis. Deep brain stimulation of the GPi or STN equally improved motor function, measured by the Unified Parkinson's Disease Rating Scale Section III (UPDRSIII) (motor section, for patients in on- and off-medication phases), within 1 year postsurgery. The change score for the on-medication phase was 0.68 (95% CI – 2.12 to 3.47, p > 0.05; 5 studies, 518 patients) and for the off-medication phase was 1.83 (95% CI – 3.12 to 6.77, p > 0.05; 5 studies, 518 patients). The UPDRS Section II (activities of daily living) scores for patients on medication improved equally in both DBS groups (p = 0.97). STN DBS allowed medication dosages to be reduced more than GPi DBS (95% CI 129.27–316.64, p < 0.00001; 5 studies, 540 patients). Psychiatric symptoms, measured by Beck Depression Inventory, 2nd edition scores, showed greater improvement from baseline after GPi DBS than after STN DBS (standardized mean difference −2.28, 95% CI −3.73 to −0.84, p = 0.002; 3 studies, 382 patients). Conclusions GPi and STN DBS improve motor function and activities of daily living for PD patients. Differences in therapeutic efficacy for PD were not observed between the 2 procedures. STN DBS allowed greater reduction in medication for patients, whereas GPi DBS provided greater relief from psychiatric symptoms. An understanding of other symptomatic aspects of targeting each region and long-term observations on therapeutic effects are needed.

We aimed to develop a double-injection model of intracerebral hemorrhage (ICH) in rabbits and to evaluate it as a tool for investigating post-ICH brain injury. Rabbits were injected with 300 μL fresh autologous whole blood into the right basal ganglia. Behavioral changes were rated, brain water content (BWC) was measured and brain tissue morphology was also examined. ICH was established in 93.5% of the blood injection group. At 1, 3 and 7 days after ICH, there were significant differences in the total neurological scores (p < 0.01) and BWC (p < 0.01) between a sham-operated group and the ICH group. These findings suggest that the model produces a persistent neurological deficit, hematoma volume and perihematomal edema and closely mimics human hypertensive basal ganglia ICH; it is a controllable and reproducible hematoma that lends itself to quantitative investigation.

Background/Aims: HIF-1α is accumulated in the cellular nucleus and cytoplasm under conditions of oxygen deprivation and engaged in pathophysiologic changes of homeostasis by modulating the expression of several target genes. As an endogenous signaling protein, HIF-1α contributes to in neuroprotection, erythropoiesis, and apoptosis modulation. The purpose of this study was to examine the role played by HIF-1α in regulating neurological injury evoked by intracerebral hemorrhage (ICH) through its downstream product, namely vascular endothelial growth factor (VEGF). In particular, we examined the effects of diabetic hyperglycemia on HIF-1α response in the processing of ICH. Methods: ELISA was used to measure HIF-1α and VEGF; and Western Blot analysis to examine the protein expression of VEGFR-2 and Caspase-3. Neurological Severity Score and brain water content were used to indicate neurological function and brain edema. Results: HIF-1α and VEGF were significantly increased in the brain after induction of ICH in non-diabetic control rats and diabetic rats; however, the amplified levels of HIF-1α and VEGF were attenuated in diabetic rats (P

Capillarisin, one of the major bioactive compounds derived from Artemisia capillaries Thunb, has been reported to have extensive pharmacological properties, such as ant-inflammatory and anti-nociceptive activities. However, the molecular mechanisms responsible for the anti-inflammatory activity of capillarisin have not been elucidated in microglia. In the present study, we investigated the anti-inflammatory effects and molecular mechanisms of capillarisin on LPS-stimulated BV2 microglial cells. The effects of capillarisin on inflammatory mediators TNF-α, IL-6, IL-1β, NO and PGE2 were detected. The effects of capillarisin on NF-κB and MAPK activation were detected by western blotting. The results showed that capillarisin suppressed LPS-induced TNF-α, IL-6, IL-1β, NO and PGE2 production in a dose-dependent manner. Capillarisin also inhibited LPS-induced TLR4 expression, NF-κB and MAPKs activation in BV2 microglia. In conclusion, capillarisin inhibited LPS-induced inflammation by blocking TLR4-mediated NF-κB and MAPKs activation in BV2 microglia.

Background and Purpose— We aimed to develop a risk score (intracerebral hemorrhage–associated pneumonia score, ICH-APS) for predicting hospital-acquired stroke-associated pneumonia (SAP) after ICH. Methods— The ICH-APS was developed based on the China National Stroke Registry (CNSR), in which eligible patients were randomly divided into derivation (60%) and validation (40%) cohorts. Variables routinely collected at presentation were used for predicting SAP after ICH. For testing the added value of hematoma volume measure, we separately developed 2 models with (ICH-APS-B) and without (ICH-APS-A) hematoma volume included. Multivariable logistic regression was performed to identify independent predictors. The area under the receiver operating characteristic curve (AUROC), Hosmer–Lemeshow goodness-of-fit test, and integrated discrimination index were used to assess model discrimination, calibration, and reclassification, respectively. Results— The SAP was 16.4% and 17.7% in the overall derivation (n=2998) and validation (n=2000) cohorts, respectively. A 23-point ICH-APS-A was developed based on a set of predictors and showed good discrimination in the overall derivation (AUROC, 0.75; 95% confidence interval, 0.72–0.77) and validation (AUROC, 0.76; 95% confidence interval, 0.71–0.79) cohorts. The ICH-APS-A was more sensitive for patients with length of stay >48 hours (AUROC, 0.78; 95% confidence interval, 0.75–0.81) than those with length of stay P =0.20) and validation ( P =0.66) cohorts. Similarly, a 26-point ICH-APS-B was established. The ICH-APS-A and ICH-APS-B were not significantly different in discrimination and reclassification for SAP after ICH. Conclusion— The ICH-APSs are valid risk scores for predicting SAP after ICH, especially for patients with length of stay >48 hours.

Endothelin-1 (ET-1)-induced cell damage is commonly involved in ischemia/hypoxia-associated diseases. PD155080 [sodium 2-benzo (1.3)dioxol-5-yl-3-benzyl-4-(4‑metho-xyphenyl)-4-oxobut-2-enoate] is a selective endothelin A receptor (ETAR) antagonist that inhibits ET-1‑induced cell damage. The aim of this study was to investigate the effects of PD155080 on hypoxia-induced rat brain microvascular endothelial cell (BMEC) injury. BMECs were isolated from the cerebral cortex of Wistar rats and cultured in an anoxia chamber, containing 95% N(2) and 5% CO(2) for 12 h. BMEC injury was assessed by determining cellular ultra-microstructural changes and cell viability by MTT assay, trypan blue (TB) staining and measuring the lactate dehydrogenase (LDH) levels. ET-1 mRNA expression was detected by in situ hybridization and reverse transcription PCR (RT-PCR); the ET-1 protein level was measured by radioimmunoassay. Following exposure to hypoxic conditions, the viability of the BMECs was markedly decreased and the ultrastructure of the BMECs was damaged, as demonstrated by chromatin margination, chromatin agglutination, plasma edema, the increased number of intracellular liposomes and vacuoles, mitochondrial swelling and the expansion of a rough surfaced endoplasmic reticulum. The levels of ET-1 and ET-1 mRNA expression in the BMECs were increased following exposure to hypoxic conditions. Of note, the administration of PD155080 greatly enhanced the viability of the BMECs and ameliorated hypoxia-induced cellular injury. PD155080 also inhibited hypoxia-induced ET-1 production by the BMECs. In conclusion, PD155080 exerts protective effects against hypoxia-induced BMEC injury.

Purpose To examine associations of matrix metalloproteinase-9 (MMP-9) and monocyte chemoattractant protein-1 (MCP-1) concentrations with the severity of carotid atherosclerosis, based on measurements of carotid plaque and intima–media thickness (IMT). Methods This cross-sectional study included 116 stroke-free participants (45.7% males, 54.3% females; mean age, 64.73 ± 14.53 years). Serum MMP-9 and MCP-1 concentrations were measured, and plaque morphology, including total plaque score (PS), plaque stability, and IMT, was assessed ultrasonographically. Participants were grouped according to total PS (0, 1–2, ≥3), plaque stability (no plaque, stable, unstable) and IMT tertiles ( 1 mm). Multinomial logistic regression models were used to assess the associations of MMP-9 and MCP-1 concentrations with plaque and IMT values after adjusting for vascular risk factors. Results MMP-9 quartiles ( vs . quartile 1) were significantly associated with a greater prevalence of plaque instability [Q2: odds ratio (OR) = 5.13, 95% confidence interval (CI) = 1.01–24.9, p = 0.042; Q3: OR = 15.5, 95% CI = 3.1–78.1, p = 0.001; Q4: OR = 13.2, 95% CI = 2.7–64.97, p = 0.001] and high total PS (Q3: OR = 10.02, 95% CI = 1.5–65.33, p = 0.016; Q4: OR = 21.5, 95% CI = 3.5–132.1, p = 0.001). MCP-1 concentration was significantly associated with IMT (OR = 22.94, 95% CI = 2.14–245.66, p = 0.01). Conclusions Elevated serum MMP-9 concentration was independently associated with high total carotid artery PS, plaque instability, and large IMT value. MCP-1 concentration was independently associated with IMT, but not with plaque morphology.

Erythropoietin (EPO) has been shown to be neuroprotective in various models of neuronal injury. The aim of the present study was to investigate the beneficial effect of recombinant human EPO (rhEPO) following intracerebral hemorrhage (ICH) and the underlying molecular and cellular mechanisms. ICH was induced using autologous blood injection in adult rats. rhEPO (5000 IU/kg) or vehicle was administered to rats with ICH 2 h following surgery and every 24 h for 1 or 3 days. To study the involvement of the PI3K signaling pathway in the rhEPO‑mediated effect, the PI3K inhibitor wortmannin (15 µg/kg), was intravenously administered to rats with ICH 90 min prior to rhEPO treatment. Brain edema was measured 3 days following ICH and behavioral outcomes were measured at 1, 7, 14, 21 and 28 days following ICH using the modified neurological severity score (mNSS) and the corner turn test. Proinflammatory cytokines, including tumor necrosis factor (TNF)‑α, interleukin (IL)-1β and IL-6, in the ipsilateral striatum were analyzed using an enzyme-linked immunosorbent assay 24 h following ICH. Neuronal apoptosis in the perihematomal area was determined by NeuN and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) double-staining. The results showed that rhEPO treatment reversed ICH, increased brain water content, upregulated proinflammatory cytokines, neuronal loss and apoptosis in the perihematomal area and rescued behavioral deficits in injured rats. Inhibiting the PI3K pathway with wortmannin abolished the rhEPO‑mediated neuroprotective effects. Moreover, western blot analysis showed that rhEPO induced the upregulation of Akt phosphorylation and downregulation of glycogen synthase kinase (GSK)‑3β phosphorylation, which were reversed by pretreatment with wortmannin, indicating the involvement of PI3K signaling in rhEPO-mediated anti-apoptotic and anti-inflammatory effects following ICH. In conclusion, these results suggested that rhEPO may exert its beneficial effects in ICH through the activation of the PI3K signaling pathway.

We explored the possibility that hypoxia-inducible factor-1alpha (HIF-1alpha) might contribute to the therapeutic effect of neural stem cell (NSC) transplantation in cerebral ischemia. The relative efficacy of modified NSC to promote behavioral recovery was investigated in a rat model of stroke induced by a transient middle cerebral artery occlusion (MCAO). A recombinant adenovirus (Ad-HIF-1alpha) was engineered to express HIF-1alpha. Control NSC infected with control adenovirus (NSC-Ad), recombinant adenovirus Ad-HIF-1alpha, or NSC infected by Ad-HIF-1alpha (NSC-Ad-HIF-1alpha), were used for intraventricular transplantion into rat brain 24 hours after MCAO. Neurological deficits were assessed over 4 weeks using the modified neurological severity scale (NSS) score. Long-term in vivo expression of HIF-1alpha was demonstrated by Western blotting and immunocytochemistry, and derivatives of nestin-positive transplanted cells contributed to both neuronal (neurofilament-positive) and astroglial (glial fibrillary acidic protein-positive) lineages. All animals showed functional improvement. Improvement was accelerated in animals receiving either NSC-Ad or Ad-HIF-1alpha, while improvement at all times between 7 days and 28 days post MCAO was significantly greater in animals transplanted with NSC-Ad-HIF-1alpha than for other treated animals. NSC-Ad-HIF-1alpha cells also increased the number of factor VIII-positive cells in the region of ischemic injury, indicating that HIF-1alpha expression can promote angiogenesis. Gene-modified NSC expressing HIF-1alpha have therapeutic potential in ischemic stroke.

ObjectiveTo investigate the effects of adenovirus (Ad)-mediated hypoxia-inducible factor-1alpha (HIF-1α) gene on proliferation and differentiation of endogenous neural stem cells (NSCs) in rats following intracerebral hemorrhage (ICH) and the underlying mechanisms.MethodsA total of 120 specific pathogen-free, adult, male Sprague-Dawley rats were included in this study. After establishment of ICH models in rats, PBS, Ad, or Ad-HIF-1α was administered via the ischemic ventricle. On the 1st, 7th, 14th, 21st and 28th d after ICH, rat neurological deficits were scored, doublecortin (DCX) expression in the subventricular zone cells was detected by immunohistochemical staining, and 5-bromo-2'-deoxyuridine (BrdU)-, BrdU/DCX-, and BrdU/glial fibrillary acidic protein-positive cells in the subventricular zone were counted using immumofluorescence method among PBS, Ad, and Ad-HIF-1α groups.ResultsOn the 7th, 14th, 21st and 28th d after ICH, neurological deficit scores in the Ad-HIF-1α group were significantly lower than in the PBS and Ad groups (P