Tenecteplase Plus Butyphthalide for Stroke Within 4.5-6 Hours of Onset (EXIT-BT): a Phase 2 Study.

To date, the benefit of intravenous thrombolysis is confined to within 4.5 h of onset for acute ischemic stroke (AIS) without advanced neuroimaging selection. The current trial aimed to investigate the safety and efficacy of intravenous tenecteplase (TNK) plus Dl-3-n-Butylphthalide (NBP) in AIS within 4.5 to 6 h of onset. In this randomized, multicenter trial, eligible AIS patients were randomly assigned to receive intravenous TNK (0.25 mg/kg) plus NBP or NBP within 4.5 to 6 h of onset. The primary endpoint was symptomatic intracranial hemorrhage (sICH). Secondary endpoints included excellent functional outcome defined as a modified Rankin Scale score of 0 to 1 at 90 days. 100 patients diagnosed by non-contrast CT (NCCT) were enrolled, including 50 in TNK group and 50 in control group. sICH occurred in 2.0% (1/50) in TNK group and 0.0% (0/49) in control group with no difference (unadjusted P = 0.998). The proportion of excellent functional outcome was 77.6% (38/49) in TNK group and 69.4% (34/49) in control group with non-significance (absolute difference 8.2%, P = 0.36). A significant decrease in NIHSS score at 24 h (P = 0.004) and more early neurological improvement (20.4% vs 4.1%; P = 0.026) was observed in TNK vs control group, but there was no difference in other secondary outcomes. This phase 2 study suggests that intravenous TNK with adjuvant NBP seems safe, feasible and may improve early neurological function in AIS patients within 4.5 to 6 h of symptom onset selected using NCCT.Clinical Trials Registration: This trial was registered with ClinicalTrials.gov (NCT05189509).

Fingolimod protects against neurovascular unit injury in a rat model of focal cerebral ischemia/reperfusion injury.

Recent research on the underlying mechanisms of cerebral ischemia indicates that the neurovascular unit can be used as a novel subject for general surveys of neuronal damage and protein mechanisms. Fingolimod (FTY-720) is a newly developed immunosuppressant isolated from Cordyceps sinensis that exhibits a wide range of biological activities, and has recently attracted much attention for the treatment of ischemic cerebrovascular diseases. In the current research, the role of FTY-720 and its possible mechanisms were assessed from an neurovascular unit perspective using a rat cerebral ischemia model. Our results revealed that FTY-720 markedly decreased infarct volume, promoted neurological function recovery, and weakened the blood-brain barrier permeability of ischemic rats. The protective roles of FTY-720 in ischemic stroke are ascribed to a combination of sphingosin-1-phosphate receptor-1 and reduced expression of sphingosin-1-phosphate receptor-1 in microvessels and reduction of interleukin-17A protein levels. These findings indicate that FTY-720 has promise as a new therapy for neurovascular protection and functional recovery after ischemic stroke.

Protective effect of 2-deoxy-D-glucose on the brain tissue in rat cerebral ischemia-reperfusion models by inhibiting Caspase-apoptotic pathway.

We observed the effect of 2-deoxy-D-glucose (2-DG) on the brain tissue in rat cerebral ischemia-reperfusion (I/R) and explored its mechanism. After observing the effect of 2-DG on endoplasmic reticulum stress (ERS), rats were randomly divided into sham-operation group, I/R group and I/R+2-DG group (each group with 60 rats). I/R models were prepared by middle cerebral artery occlusion. In I/R+2-DG group, each rat was given intraperitoneal 2-DG of 100 mg/kg once a day for 7 days before brain ischemia. According to different time points (3h, 6h, 12h, 24h and 48h) after I/R, each group was divided into 5 subgroups (each subgroup with 12 rats). Nerve cell apoptosis, and the expressions of mRNA and protein of glucose regulated protein 78 (GRP78), cleaved-caspase-9 and cleaved-caspase-3 were determined with TUNEL, Western blotting and RT-PCR, respectively, in rat cerebral hippocampal CA1 area at each time point. TUNEL-positive cells were significantly less in I/R+2-DG group than in I/R group at each time point (all P<0.01). In I/R and I/R+2-DG groups, the expressions of mRNA and protein of GRP78 reached the maximum 12 h after I/R, and cleaved-caspase-9 and cleaved-caspase-3 reached the maximum 24 h after I/R. Compared with sham-operation group, the expressions of mRNA and protein of GRP78, cleaved-caspase-9 and cleaved-caspase-3 were all significantly increased (all P<0.01) in I/R and I/R+2-DG groups. However, the expressions of mRNA and protein of GRP78 were significantly higher in I/R+2-DG group than in I/R group (all P<0.05), but the expressions of mRNA and protein of cleaved-caspase-9 and cleaved-caspase-3 were all significantly lower in I/R+2-DG group than in I/R group (all P<0.05). We conclude that 2-DG has a neuroprotective effect on the brain tissue in rat cerebral ischemia-reperfusion models. The mechanism may be that 2-DG starts ERS followed by up-regulation of mRNA and protein of GRP78 and down-regulation of mRNA and protein of cleaved-caspase-9 and cleaved-caspase-3, which blocks the apoptotic pathway.

Effects of Ginkgo biloba extract on the apoptosis of oxygen and glucose-deprived SH-SY5Y cells and its mechanism.

OBJECTIVE: The aim was to observe the effects of the extract of Ginkgo biloba (EGb761) on the apoptosis of oxygen and glucose-deprived (OGD) human neuroblastoma cells (SH-SY5Y) cells and explore its mechanism. MATERIALS AND METHODS: SH-SY5Y cells were divided into normal control group, OGD group, OGD for 4 h and EGb761-pretreated groups including very low-concentration (20 µg/ml), low-concentration group (25 µg/ml), moderate-concentration group (50 µg/ml) and high-concentration group (100 µg/ml). Twenty four hours after reoxygenation, cell viability was determined with 3-[4, 5-dimehyl-2-thiazolyl]-2, 5-diphenyl-2H-tetrazolium bromide assay, apoptosis rate was detected with annexin V-fluorescein isothiocyanate/propidium iodide double staining flow cytometry and the protein level of apoptosis-inducing factor (AIF) was observed with immunofluorescence technique in each group. RESULTS: Cell viability was significantly lower in OGD group than in EGb761-pretreated groups, especially in moderate-concentration group (50 µg/ml) (P < 0.005). Apoptosis rate was significantly lower in EGb761-pretreated groups than in OGD group (P < 0.001). Immunofluorescent staining showed that there was AIF nuclear translocation in both EGb761-pretreated groups and OGD group, but AIF nuclear translocation was less in EGb761-pretreated groups than in OGD group. CONCLUSION: EGb761 can reduce the apoptosis of OGD SH-SY5Y cells probably through inhibiting AIF nuclear translocation. This study provides a theoretical basis for the application of EGb761 in clinical practice.

The effect of procyanidin on expression of STAT1 in type 2 diabetes mellitus SD rats with focal cerebral ischemia.

OBJECTIVES: Diabetes with cerebral infarction is a common disease that severely impacts health. This study investigated the effect of procyanidin (PC) on the expression of signal transducers and activators of transcription (STAT1) in type 2 diabetes mellitus SD rats with focal cerebral ischemia. We then explored the protective mechanisms of PC in type 2 diabetes mellitus SD rats with focal cerebral ischemia, to provide theory evidence for its clinical application. METHODS: We set up a type 2 diabetes mellitus-MCAO model, evaluated neurological function, and used immunohistochemistry methods to measure the activity of STAT1. RESULTS: The brain expression of STAT1 in rats of the sham-operation group was low, but more STAT1 positive cells were found in normal rats with ischemia and in rats with both type 2 diabetes and ischemia when groups were compared with the sham-operation group (p<0.01). Compared with rats that had type 2 diabetes and ischemia, the numbers of STAT1 positive cells after low, medium and high-doses of PC were all decreased (p<0.01), whereby the mid and high-dose groups showed a more substantial decrease (p<0.01) and with no variance between the two groups (p>0.05). CONCLUSIONS: These results indicate that PC has a neuroprotective effect on type 2 diabetes mellitus-MCAO; this may be through decreasing the expression of STAT1, which influences the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway that may inhibit apoptosis to relieve neurological impairment.

Analysis on 85 case reports of adverse drug reactions.

This study investigated the occurrence and characteristics of adverse drug reactions (ADR) in our hospital and provide references for clinical rational drug use. We collected the 85 case reports of adverse drug reactions in our hospital in 2010 and made retrospective statistical analysis on them. The varieties of anti-infective drugs used are the most used. It also had the highest proportion of adverse drug reactions; the common symptom of adverse drug reactions is skin and accessory damage. Adverse drug reactions are affected by many factors, and relevant departments should strengthen ADR monitoring, to reduce or avoid the occurrence of adverse drug reactions.

Chronic caffeine treatment reverses memory impairment and the expression of brain BNDF and TrkB in the PS1/APP double transgenic mouse model of Alzheimer's disease.

The objective of this study was to investigate the effects of varying doses of caffeine on memory impairment and the expression of brain neurotrophic derived factor (BNDF) and TrkB in PS1/APP double transgenic mouse models. PS1/APP double transgenic mice were administered 0.3 ml/day of saline, 1.5 mg/day of caffeine or 0.75 mg/day of caffeine for eight weeks. A water maze test and western blotting were used to determine the memory capability and expression of hippocampal BNDF and TrkB of the mice. The results demonstrated that 0.75 mg/day and 1.5 mg/day doses of caffeine significantly increased memory capability and the expression of hippocampal BDNF and TrkB in PS1/APP mice with a dose-response effect. The results suggested that chronic caffeine treatment may reverse memory impairment in PS1/APP transgenic mice, and BDNF and its receptor TrkB, may be involved in this process.

Correlation between ischemia-modified albumin and lipid levels in patients with acute cerebrovascular disease.

Acute cerebrovascular disease (ACVD) is associated with high morbidity and mortality rates, however, molecular markers to aid in its early detection are lacking. In this study, we examined the correlation between serum ischemia-modified albumin (IMA), a marker used to identify ischemic events in the heart, and blood lipids in patients with ACVD. Serum IMA levels were determined by enzyme-linked immuno-sorbent assay, and total cholesterol (TC), low-density lipoprotein (LDL), high­density lipoprotein cholesterol (HDL) and triglyceride (TG) levels were determined biochemically in 62 patients with cerebral infarction (CI), 40 patients with intracerebral hemorrhage (ICH), 18 patients with subarachnoid hemorrhage (SAH) and 100 healthy individuals (controls). Serum IMA levels were significantly higher in each of the ACVD groups compared to the control group (CI, 80.81±11.97 U/ml; ICH, 80.25±10.91 U/ml; SAH, 74.43±11.39 U/ml and control, 41.08±5.10 U/ml; P<0.05). Additionally, serum TC, LDL and TG levels significantly increased, while serum HDL significantly decreased in the ACVD groups compared to the control group (P<0.05). A positive correlation was found between serum IMA levels and serum TC, LDL and TG levels in the ACVD patients, while serum IMA levels were negatively correlated with serum HDL levels (P<0.05). Thus, serum IMA increased following an ACVD event and was closely correlated with changes in the blood lipid levels. These factors, when combined, may allow the development of molecular markers for an earlier diagnosis of ACVD.

[Clinical study on effect and therapeutical mechanism of composite Salvia injection on acute cerebral infarction].

OBJECTIVE: To investigate the curative effect and therapeutical mechanism of composite salvia injection (CSI) in treating ischemic cerebral infarction in the respect of oxygen free radical and apolipoprotein. METHODS: Sixty-eight cases of ischemic cerebral infarction within the first 72 hrs after onset were divided randomly into the CSI group (treated with CSI) and the control group (treated with Xueshuantong). Serum lipid peroxide (LPO) and superoxide dismutase (SOD) were measured by colorimetry and apolipoprotein A1 (ApoA1) and ApoB100 were measured with unidirectional immune diffusion method. RESULTS: Serum levels of LPO and ApoB100 were obviously lower, and levels of SOD and ApoA1 significantly higher in the CSI group than those in the control group (P < 0.05 or P < 0.01). The total effective rate of CSI in treating cerebral infarction was 88.24%, which was significantly higher than that of the control (P < 0.05). CONCLUSION: CSI shows definite effect in treating cerebral infarction, to reduce the oxygen free radical damage and regulate the apolipoprotein metabolism possibly was the important therapeutical mechanism.