Tenecteplase thrombolysis for stroke up to 24 hours after onset with perfusion imaging selection: the umbrella phase IIa CHABLIS-T randomised clinical trial.

BACKGROUND: The performance of intravenous tenecteplase in patients who had an acute ischaemic stroke with large/medium vessel occlusion or severe stenosis in an extended time window remains unknown. We investigated the promise of efficacy and safety of different doses of tenecteplase manufactured in China, in patients who had an acute ischaemic stroke with large/medium vessel occlusion beyond 4.5-hour time window. METHODS: The CHinese Acute tissue-Based imaging selection for Lysis In Stroke-Tenecteplase was an investigator-initiated, umbrella phase IIa, open-label, blinded-endpoint, Simon's two-stage randomised clinical trial in 13 centres across mainland China. Participants who had salvageable brain tissue on automated perfusion imaging and presented within 4.5-24 hours from time of last seen well were randomised to receive 0.25 mg/kg tenecteplase or 0.32 mg/kg tenecteplase, both with a bolus infusion over 5-10 s. The primary outcome was proportion of patients with promise of efficacy and safety defined as reaching major reperfusion without symptomatic intracranial haemorrhage at 24-48 hours after thrombolysis. Assessors were blinded to treatment allocation. All participants who received tenecteplase were included in the analysis. RESULTS: A total of 86 patients who had an acute ischaemic stroke identified with anterior large/medium vessel occlusion or severe stenosis were included in this study from November 2019 to December 2021. All of the 86 patients enrolled either received 0.25 mg/kg (n=43) or 0.32 mg/kg (n=43) tenecteplase, and were available for primary outcome analysis. Fourteen out of 43 patients in the 0.25 mg/kg tenecteplase group and 10 out of 43 patients in the 0.32 mg/kg tenecteplase group reached the primary outcome, providing promise of efficacy and safety for both doses based on Simon's two-stage design. DISCUSSION: Among patients with anterior large/medium vessel occlusion and significant penumbral mismatch presented within 4.5-24 hours from time of last seen well, tenecteplase 0.25 mg/kg and 0.32 mg/kg both provided sufficient promise of efficacy and safety. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04086147, https://clinicaltrials.gov/ct2/show/NCT04086147).

Thrombolysis with Recombinant Human Prourokinase 4.5-6 h After Acute Ischemic Stroke: A Phase IIa, Randomized, and Open-Label Multicenter Clinical Trial.

BACKGROUND: Ischemic stroke is a major cause of disability and death worldwide. A narrow therapeutic window profoundly constrained the utilization of alteplase. OBJECTIVES: To investigate therapeutic effects and safety of intravenous recombinant human prourokinase (rhPro-UK) in patients with acute ischemic stroke (AIS) in the 4.5-6 h therapeutic time windows. METHODS: We conducted a phase IIa, randomized, and open-label multicenter clinical trial. Between 4.5 and 6 h after the onset of AIS, patients were randomly administrated to receive intravenous rhPro-UK at a 50 mg or 35 mg dose. The primary endpoint was excellent functional outcome defined as modified Rankin scale (mRS) score of 1 or less at 90 days. The secondary outcome was the treatment response, which was based on an at least 4-point improvement from baseline National Institutes of Health stroke scale (NIHSS) score at 24 h after drug administration. Safety endpoints included death, symptomatic intracerebral hemorrhage (sICH), and other serious adverse events. RESULTS: We enrolled 80 patients in the 4.5-6 h therapeutic time windows at 17 medical centers in China from December 2016 to November 2017. A total of 39 patients were treated with 50 mg rhPro-UK, and 39 were treated with 35 mg rhPro-UK. Compared with the baseline, the NIHSS score at 24 h and days 7, 14, 30, and 90 was decreased significantly among patients treated with either rhPro-UK 50 mg or 35 mg. The mean reduction in the NIHSS from baseline to 90 days after the onset was 3.56 and 5.79 in the rhPro-UK 50 mg group and the rhPro-UK 35 mg group, respectively. The rates of functional independence at 90 days of rhPro-UK 50 mg and 35 mg were 61.54% and 69.23%, respectively (P = 0.475), and the proportion of patients with functional response to treatment at 24 h were 28.21% and 33.33% (P = 0.624). No sICH occurred in the two groups, and death occurred in only one patient in the rhPro-UK 50 mg group. There was no significant difference in mortality at 90 days and the rate of other serious adverse events between two groups. CONCLUSION: In the 4.5-6 h time window, more than 60% of patients at either dose of rhPro-UK (50 mg or 35 mg) achieved functional independence at 90 days without increased mortality and sICH risk. Thus, intravenous rhPro-UK was effective and safe for patients with AIS within 4.5-6 h after stroke onset. While no significant differences were identified between different dosages of rhPro-UK regarding clinical outcomes, it is a logical step to further test the safety and efficacy of the low dose of rhPro-UK in a well-powered phase III study. TRIAL REGISTRATION: http://www.chictr.org.cn . Identifier: ChiCTR1800016519. Date of registration: 6 June 2018.

Association of atherogenic index of plasma with early neurological deterioration in patients with acute ischemic stroke.

PURPOSE: To explore the correlation between Atherogenic Index of Plasma (AIP) and early neurological deterioration (END) in patients with acute ischemic stroke (AIS). METHODS: A retrospective analysis of 334 patients diagnosed with AIS between January 2021 and May 2023 at the Affiliated Huai'an Hospital of Xuzhou Medical University. Patients were divided into END and non-END groups based on changes in National Institutes of Health Stroke Scale scores (NIHSS) within 7 days of admission, and the differences in the indicators between the two groups were examined using univariate analysis. The patients were then divided into three groups based on the tertile of the AIP (T1: AIP≤ -0.01; T2: 0 ≤AIP≤0.16; AIP≥0.17), and logistic regression analysis was used to examine the association between the AIP and END. Finally, the predictive ability of the AIP was evaluated using the receiver operating characteristic (ROC) curve. RESULTS: A total of 334 patients were included, of which 64 (19.20%) had END. The results of the analysis showed that the AIP was significantly higher in the END group compared to the non-END group. Multivariable logistic regression analysis showed that higher AIP was associated with END in AIS patients (OR=3.259, 95%CI, 1.490-7.125, P = 0.003), especially in large-artery atherosclerosis (LAA) subtype (OR=4.240, 95%CI,1.30-13.87, P = 0.017). ROC analysis revealed that the best predictive cutoff value of AIP was 0.115, and the area under the ROC curves for AIP was 0.681(0.604-0.758). CONCLUSION: Our study uncovered that higher AIP levels were associated with END development in AIS patients.

Higher serum lipocalin 2 is associated with post-stroke depression at discharge.

BACKGROUND AND AIMS: Post-stroke depression (PSD), as one of the common complications after stroke, seriously affects the physical and mental health and functional prognosis of patients. Previous studies have shown that the increase of inflammatory mediators is associated with the occurrence of PSD. Lipocalin 2 (LCN2), as an acute phase protein, is involved in the development of acute ischemic stroke (AIS), and its expression is up-regulated in patients with depression, suggesting that there is a potential correlation between serum LCN2 and depression. The aim of this study was to explore the relationship between serum LCN2 at admission and PSD at discharge. METHODS: A total of 358 AIS patients were retrospectively included. All patients had fasting venous blood taken within 24 h of admission to detect serum LCN2. The patients were evaluated by 17-item Hamilton Depression Scale (HAMD) before discharge. Patients with HAMD score > 7 were diagnosed with PSD. The correlation between serum LCN2 and PSD was tested using binary logistic regression analysis. RESULTS: In our study, 92 (25.7%) patients were diagnosed with PSD at discharge. According to the serum LCN2 value, the patients were divided into three layers (Tertile1 ≤ 105.24ng/ml; Tertile2: 105.24-140.12ng/ml; Tertile3 ≥ 140.12ng/ml), with T1 layer (the lowest levels) as a reference, after adjusting for multiple potential confounding factors, T3 layer (the highest levels) was independently associated with the occurrence of PSD (odds ratio [OR] = 2.639, 95% confidence interval [CI]: 1.317-5.287, P = 0.006). Similar results were found when the serum LCN2 was analyzed as a continuous variable. The optimal cut-off value of serum LCN2 at admission to predict PSD at discharge was 117.60ng/ml, at this threshold, the sensitivity was 77.2%, and the specificity was 53.4%. CONCLUSIONS: High serum LCN2 levels at admission are an independent risk factor for PSD in patients with AIS at discharge.

Plasma Lipoprotein-Associated Phospholipase A2 Affects Cognitive Impairment in Patients with Cerebral Microbleeds.

Purpose: The plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory biomarker of cerebral microbleeds (CMBs) and may be related to the occurrence, development, and prognosis of cognitive impairment. The present study aimed to investigate the impact of plasma Lp-PLA2 level on the cognitive impairment in patients with CMBs. Methods: In this study, 213 patients with CMBs confirmed by 3.0 T brain magnetic resonance imaging (MRI) were analyzed. Lp-PLA2 levels were determined by magnetic particle chemiluminescence immunoassay technology, and cognitive function was assessed using the Montreal Cognitive Assessment Scale (MoCA). The cognitive functions of patients with CMBs were divided into three groups according to the MoCA scale, including normal cognition (NC), mild cognitive impairment (MCI), and moderate-severe cognitive impairment (MSCI). Clinical, laboratory and radiological data of the three groups were analysed. The relationship between plasma Lp-PLA2 and MoCA score in patients with CMBs was investigated through rank correlation analysis and multivariate regression analysis, and receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of Lp-PLA2. Results: CMBs were detected in 213 (30.2%) of 705 patients who underwent 3.0 T MRI. Multiple comparisons showed that plasma Lp-PLA2 in patients with CMBs with normal cognitive scores was significantly lower than that in the other two groups with cognitive impairment (p < 0.05). In the single factor correlation analysis, high level of plasma Lp-PLA2 was negatively correlated with the decrease of MoCA score in patients with CMBs (r =-0.389, p < 0.01). Multivariate regression analysis showed that high plasma Lp-PLA2 was an independent risk factor for a low MoCA score in patients with CMBs (odds ratio [OR]=1.014; 95% confidence interval [CI], 1.002-1.026; p=0.025). Conclusion: A high level of plasma Lp-PLA2 is positively correlated with the generation of cognitive impairment in patients with CMBs and negatively correlated with the degree of impairment. Plasma Lp-PLA2 is an important indicator of cognitive impairment in patients with CMBs and may provide a therapeutic target for preventing CMB-induced cognitive impairment.

Correlation of lipoprotein-associated phospholipase A2 and cerebral microbleeds in patients with acute ischaemic stroke.

BACKGROUND AND AIMS: Cerebral microbleeds (CMBs) increase the risk of stroke occurrence and recurrence,and affect the prognosis of stroke patients. Therefore, identifying biological markers that predict CMBs after stroke is urgently needed. This study explored whether high levels of lipoprotein-associated phospholipase A2(Lp-PLA2) are associated with an increased risk of CMBs in patients with acute ischaemic stroke (AIS). METHODS: From April 2020 to October 2021, we enrolled 242 patients with AIS. At admission, the plasma levels of Lp-PLA2 were measured in all patients as well as the number of CMBs and white matter lesions. According to the results of the Susceptibility Weighted Imaging (SWI), the patients were divided into a CMB group and a no-CMB group. The groups were compared with univariate and multivariate analyses to clarify the correlation between Lp-PLA2 levels and CMBs, and the optimal cut-off value of Lp-PLA2 that predicted CMBs was determined from the receiver-operating characteristic curve. RESULTS: CMBs were detected in 71 (29.3%) of the 242 AIS patients. The median Lp-PLA2 level was 182.79 ng/ml. Using the 1st quartile of Lp-PLA2 levels (the lowest levels) as the reference group, univariate logistic regression analysis showed that individuals in the 4th quartile (the highest levels) had a higher risk of CMBs (odds ratio [OR] = 1.460, 95% confidence interval [CI]: 1.188-1.795, P = 0.000). This correlation persisted after adjusting for relevant risk factors (OR = 1.370, 95% CI: 1.096-1.713, P = 0.006). The optimal cut-off value of Lp-PLA2 that predicted the occurrence of CMBs was 184.36 ng/ml; at this threshold, the sensitivity was 69.0%, and the specificity was 60.2%. CONCLUSIONS: Our data suggest that a high level of Lp-PLA2 in patients with AIS is a potential risk factor for CMBs.

Efficacy and Safety of Recombinant Human Prourokinase in Acute Ischemic Stroke: A Phase IIa Randomized Clinical Trial.

Recombinant human prourokinase (rhPro-UK) is a novel thrombolytic that has been approved to treat patients with acute myocardial infarction. However, the safety and efficacy of intravenous rhPro-UK in patients with acute ischemic stroke (AIS) has not been well established. We aimed to investigate the safety and preliminary efficacy of rhPro-UK in patients with AIS in a multi-center phase IIa trial setting. One hundred nineteen patients within 4.5 h of AIS onset were enrolled in this randomized, open-label, 23-center phase IIa clinical trial. Patients were randomly assigned to 35 mg (n = 40) or 50 mg (n = 39) intravenous rhPro-UK or 0.9 mg/kg recombinant tissue plasminogen activator (r-tPA; n = 40). The primary endpoint was functional independence defined as a modified Rankin scale (mRS) score of 0 or 1 at 90 days. The secondary outcome was early neurological improvement defined as a reduction of ≥ 4 points on the National Institutes of Health Stroke Scale (NIHSS) score from baseline to 24 h after drug administration. Safety endpoints included death due to any cause, symptomatic intracerebral hemorrhage (sICH), and other serious adverse events (SAEs). The proportion of patients with an mRS score of ≤ 1 at 90 days did not differ significantly among three groups (35 mg rhPro-UK: 55.56% vs. 50 mg rhPro-UK: 57.89% vs. vs. r-tPA: 52.63%; P = 0.92). The rates of treatment response, referring to early neurological improvement, were similar among these three groups (36.11% vs. 31.58% vs. 28.95%, respectively; P = 0.85). There was no difference in mortality at 90 days or in the rate of other SAEs among the three groups. One patient in the 50 mg rhPro-UK group suffered sICH. While neither the primary efficacy outcomes nor safety profile differed significantly among the low, high rhPro-UK and control groups, it is a logical step to further test the low-dose rhPro-UK group versus the control group in a well-powered phase III study.Trial Registration: http://www.chictr.org.cn . Identifier: ChiCTR1800016519. Date of registration: June 6 2018.

Use of Diterpene Ginkgolides Meglumine Injection to Regulate Plasma Levels of PAI-1 and t-PA in Patients With Acute Atherosclerotic Cerebral Infarction.

BACKGROUND: To: (i) explore the effect of diterpene ginkgolides meglumine injection (DGMI) on neurological deficit symptoms in acute atherosclerotic cerebral infarction (AACI) patients; (ii) measure the level of plasma plasminogen activator inhibitor (PAI)-1 and tissue plasminogen activator (t-PA). METHODS: Eighty AACI patients were divided equally and randomly into the DGMI group and control group. In addition to basic treatment, the DGMI group was treated with DGMI (25 mg/d) for 14 days. The control group had basic treatment without DGMI. Before and after treatment, the degree of neurological deficit was assessed, thromboelastography undertaken, and plasma levels of PAI-1 and t-PA measured. RESULTS: The National Institutes of Health Stroke Scale score of patients in the DGMI group after treatment was lower than that in the control group, and the Barthel Index was higher than that in the control group ( P <0.05). Thromboelastography revealed that, in the DGMI group, the R value and K value after treatment were higher than before treatment, the angle and maximum amplitude value were lower than before treatment, and both were significant ( P <0.05). Compared with the control group, the plasma PAI-1 level of patients in the DGMI group was lower than that in the control group, and the t-PA level was higher than that in the control group ( P <0.05) after 14 days of treatment. CONCLUSIONS: DGMI may affect the activity of the blood coagulation and fibrinolysis system by regulating the plasma level of PAI-1 and t-PA, and improving neurological deficit symptoms. DGMI is important for improving the prognosis of patients with AACI.

The Relationship Between APOE Gene Polymorphism and In-stent Restenosis After Stenting at the Beginning of the Vertebral Artery.

OBJECTIVE: To retrospectively investigate the relationship between apolipoprotein E (APOE) gene polymorphism and in-stent restenosis (ISR) after stenting at the beginning of the vertebral artery. METHODS: The study included 155 patients who successfully underwent stenting at the beginning of the vertebral artery and had postoperative digital subtraction angiography or computed tomography angiography. Based on the follow-up results, they were divided into the restenosis (ISR) group and non-restenosis (non-ISR) group. The clinical information and APOE genotypes of both groups were analyzed. A binary logistic regression model was used to analyze independent risk factors for ISR. RESULTS: After 1 year of follow-up, 49 (31.6%) patients had ISR and 106 (68.4%) did not. Binary logistic regression analysis showed that serum low-density lipoprotein cholesterol (LDL-C), serum lipoprotein-related phospholipase A2 (Lp-PLA2), and E3/E4 genotype were independent risk factors for ISR after stenting at the beginning of the vertebral artery. In addition, the LDL-C level of patients with the E3/E4 genotype was higher compared with the E3/E3 genotype group (P < 0.05). CONCLUSIONS: APOE gene polymorphism is associated with ISR, and the E3/E4 genotype is an independent risk factor for ISR after stenting at the beginning of the vertebral artery. Further genetic studies can identify risk genotypes to facilitate the early prediction and identification of high-risk patients with ISR.

Effects of cerebral artery thrombectomy on efficacy, safety, cognitive function and peripheral blood Aß, IL-6 and TNF-α levels in patients with acute cerebral infarction.

OBJECTIVE: Acute cerebral infarction (ACI) can lead to death or disability, posing a serious threat to human health. This study aimed to investigate the effects of cerebral artery thrombectomy on the efficacy, safety, cognitive function and peripheral blood amyloid-ß (Aß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels in patients with ACI. METHODS: The clinical data of 169 patients with ACI admitted to our hospital from April 2019 to September 2020 were analyzed retrospectively. Among them, 100 patients were treated with cerebral artery thrombectomy and assigned to the research group, and the other 69 patients were intervened by conventional treatment and assigned to the control group. The clinical effects in the two groups were observed and compared. The cognitive function was evaluated by the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment Scale (MoCA), the neurological dysfunction was assessed by the National Institutes of Health Stroke Scale (NIHSS), and the prognosis was determined by the Modified Rankin Scale (mRS). Peripheral blood Aß1-40, Aß1-42, IL-6 and TNF-α levels were determined using the enzyme-linked immunosorbent assay (ELISA). The incidence of adverse reactions and complications was statistically analyzed. RESULTS: The overall response rate (ORR) was notably higher in the research group compared with the control group. Aß1-40, Aß1-42, IL-6 and TNF-α levels showed no significant difference between the two groups before treatment (P>0.05). After treatment, serum Aß1-40 level was lower and Aß1-42 was higher in the research group compared with the control group at each time point. Serum IL-6 level was markedly higher within 24 h while it was dramatically lower 24 h after treatment in the research group as compared with the control group. At 24 h, 7 d and 14 d after treatment, serum TNF-α level in the research group was lower than that in the control group (P<0.05). The MMSE and MoCA scores showed no significant differences between the two groups before treatment; however, the two scores in the research group were statistically higher than those in the control group after treatment. In addition, lower NIHSS and mRS scores were determined in the research group compared with the control group after treatment. Moreover, except for the statistically significant difference in the number of cases with cognitive dysfunction (P<0.05), there was no significant difference in the incidence of other adverse reactions between the research group and the control group (P>0.05). CONCLUSIONS: Cerebral artery thrombectomy is effective in the treatment of ACI, which can improve the cognitive function of patients and alleviate the high Aß accumulation and inflammation in the central nervous system, with a high safety profile.

Neuroprotective Effect of S-trans, Trans-farnesylthiosalicylic Acid via Inhibition of RAS/ERK Pathway for the Treatment of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD), a leading cause of dementia, becomes a serious health issue for individuals and society around the world. AD is a neurodegenerative disease characterized by the deposition of amyloid-ß (Aß) peptides and neurofibrillary tangles (NFT) and the loss of large numbers of neurons. To date, there is no effective treatment for AD, and thus, to enhance neurogenesis in the AD brain may be a therapeutic strategy. RAS signaling pathway involves in synaptic plasticity and memory formation, which is overexpressed in brains with AD. This study used Aß1-42-injected mice (Aß1-42-mice) as the AD model to investigate the effects of S-trans, trans-farnesylthiosalicylic acid (FTS), a synthetic Ras inhibitor, on the impairment of neurogenesis and the spatial cognitive deficits. MATERIALS AND METHODS: AD model mice were manufactured through intracerebroventricular injection of Aß1-42. Morris water maze (MWM) was performed to evaluate the capacity of spatial memory, and Nissl staining was applied to assess neuronal damage in the hippocampus CA1. Immunohistochemistry of 5-bromo-2-deoxyuridine (BrdU), BrdU/neuronal nuclei (NeuN), and doublecortin (DCX) were used to detect progenitor cell proliferation, maturation, and neurite growth, respectively. And the expression levels of RAS, ERK/ERK phosphorylation (p-ERK) and CREB/CREB phosphorylation (p-CREB) were detected by Western blot. RESULTS: The results demonstrated that FTS could prevent Aß1-42 to impair survival and neurite growth of newborn neurons in the hippocampal dentate gyrus (DG) in Aß1-42-mice. Furthermore, behavioral indexes and morphological findings showed that FTS improved the learning and spatial memory abilities of Aß1-42-mice. In addition, FTS could inhibit the levels of hippocampal p-ERK and p-CREB activated by Aß, which is the underlying molecular mechanism. CONCLUSION: In conclusion, these findings suggest that FTS as a RAS inhibitor could be a potential therapeutic agent for the treatment of AD.

Role of plasminogen activator inhibitor-1 in the diagnosis and prognosis of patients with Parkinson's disease.

Parkinson's disease is a neurodegenerative disease that frequently results in memory disorders, cognitive decline and dementia. Previous studies have reported that plasminogen activator inhibitor-1 (PAI-1) serves an important role in cardiovascular disease risk, adiposity, insulin resistance and inflammation. However, the role of PAI-1 in diagnosis and prognosis of patients with Parkinson's disease following deep brain stimulation (DBS) has not reported, to the best of our knowledge. Therefore, the purpose of the present study was to investigate the clinical significance of PAI-1 in patients with Parkinson's disease. Plasma PAI-1 levels were measured in 102 patients with Parkinson's disease who underwent DBS. It was demonstrated that plasma PAI-1 levels were significantly increased in patients with Parkinson's disease compared with healthy individuals (P<0.01). Patients with Parkinson's disease received DBS presented significantly improved cognitive competence compared with controls (P<0.01). DBS significantly decreased plasma PAI-1 levels in patients with Parkinson's disease compared with controls (P<0.05). It was also observed that plasma PAI-1 levels were significantly negatively associated with cognitive function for patients with Parkinson's disease (P<0.01). In conclusion, these findings demonstrated that the degree of Parkinson's disease severity is positively associated with circulating levels of plasma PAI-1 levels, which suggests that PAI-1 may be a potential diagnostic and prognostic marker for patients with Parkinson's disease.

Simvastatin Enhances Activity and Trafficking of α7 Nicotinic Acetylcholine Receptor in Hippocampal Neurons Through PKC and CaMKII Signaling Pathways.

Simvastatin (SV) enhances glutamate release and synaptic plasticity in hippocampal CA1 region upon activation of α7 nicotinic acetylcholine receptor (α7nAChR). In this study, we examined the effects of SV on the functional activity of α7nAChR on CA1 pyramidal cells using patch-clamp recording and explored the underlying mechanisms. We found that the treatment of hippocampal slices with SV for 2 h induced a dose-dependent increase in the amplitude of ACh-evoked inward currents (IACh) and the level of α7nAChR protein on the cell membrane without change in the level of α7nAChR phosphorylation. These SV-induced phenotypes were suppressed by addition of farnesol (FOH) that converts farnesyl pyrophosphate, but not geranylgeraniol. Similarly, the farnesyl transferase inhibitor FTI277 was able to increase the amplitude of IACh and enhance the trafficking of α7nAChR. The treatment with SV enhanced phosphorylation of CaMKII and PKC. The SV-enhanced phosphorylation of CaMKII rather than PKC was blocked by FOH, Src inhibitor PP2 or NMDA receptor antagonist MK801 and mimicked by FTI. The SV-enhanced phosphorylation of PKC was sensitive to the IP3R antagonist 2-APB. The SV-increased amplitude of IACh was suppressed by PKC inhibitor GF109203X and Go6983, or CaMKII inhibitor KN93. The SV- and FTI-enhanced trafficking of α7nAChR was sensitive to KN93, but not GF109203X or Go6983. The PKC activator PMA increased α7nAChR activity, but had no effect on trafficking of α7nAChR. Collectively, these results indicate that acute treatment with SV enhances the activity and trafficking of α7nAChR by increasing PKC phosphorylation and reducing farnesyl-pyrophosphate to trigger NMDA receptor-mediated CaMKII activation.

Ras inhibitor S-trans, trans-farnesylthiosalicylic acid enhances spatial memory and hippocampal long-term potentiation via up-regulation of NMDA receptor.

Statins by reducing farnesyl-pyrophosphate or farnesyl transferase inhibitors have been demonstrated to enhance spatial memory and long-term potentiation (LTP). The objective of this study was to investigate effects of the synthetic Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS) on spatial cognitive function in adult mice, synaptic plasticity in hippocampal CA1 regions, and NMDA receptor (NMDAr) activity of pyramidal cells. Here, we show that administering FTS (5 mg/kg, i.p.) enhanced spatial cognitive performance, as assessed via Morris water maze and Y-maze tests. Treating hippocampal slices with FTS (5 µM) for 2 h enhanced selectively NMDAr-dependent LTP without changing the synaptic properties. In comparison with the controls, the FTS-treated slices showed increases in the amplitude of NMDA-evoked currents (INMDA) and the phosphorylation of NMDAr GluN2A/GluN2B subunits and Src. The Src inhibitor PP2 blocked the enhancing effects of FTS on the activity and phosphorylation of NMDAr. In FTS-treated slices, basal levels of CaMKII, ERK2 and CREB phosphorylation did not differ significantly from those of controls; however, high-frequency stimulation-induced increases in CaMKII, ERK2 and CREB phosphorylation were more significant than in the controls, which were sensitive to PP2 and NMDAr antagonist MK801. Furthermore, the phosphorylation of AMPA receptor GluR1 during LTP was higher in FTS-treated slices compared with the control, which depended on Src and ERK1/2 signaling. The results indicate that the Ras inhibition by FTS can enhance NMDAr-dependent LTP by increasing Src activity to promote NMDAr GluN2A/GluN2B phosphorylation, which then leads to spatial memory potentiation.

2-(2-benzofuranyl)-2-imidazoline (2-BFI) improved the impairments in AD rat models by inhibiting oxidative stress, inflammation and apoptosis.

Alzheimer's Disease (AD) is one of the commonest neural degeneration in aging population, and has become a global health challenge. 2-(2-benzofuranyl)-2-imidazoline (2-BFI) was reported to effectively improved the damage of patients with neuropathological disorders. In the present study, we investigated the effect of 2-BFI on the improvement of antioxidative, inflammation, and apoptosis in AD rats. Sprague-Dawley rats (2 months old, n=40) were used in this study and after injection of Aß1-42 into hippocampal CA1 (Cornu Ammonis) region, the rats were given high, moderate and low dose of 2-BFI though intraperitoneal (i.p.) injection. Then spatial memory and navigation ability were analyzed by Morrize Water Maze. For the molecular testing, chemical colorimetry, ELISA and immunoblotting were performed to measure the activities of antioxidative enzymes, the abundance of immune cytokines and expression of apoptotic proteins, respectively. Hematoxylin and Eosin staining was used to analyze the pathological changes. We observed that 2-BFI significantly ameliorated the learning and memory abilities in rat models with AD by dosage treatment, as demonstrated by the shorten learning latency and greater times of travel across the platform quadrant. Additionally, reactive oxygen species (ROS) and malondialdehyde (MDA), were decreased after treatment of 2-BFI with dosage dependency, while the activities of superoxidase dismutase (SOD) and (GPX) Glutathione peroxidase were in turn enhanced, suggesting that 2-BFI could protect the antioxidative enzymes and reduce the oxidative stress in the hippocampus. Moreover, the expression of inflammatory factors including TNF-a and IL-1ß were decreased after 2-BFI treatment. Additionally, the neuronal apoptosis was also attenuated, as shown by Western blot results. Taken together, the cognitive impairment in AD rats could be significantly improved by 2-BFI in a dose-dependent manner through suppressing oxidants accumulation, inhibiting of inflammatory response, as well as enhancing the neural viability.

Simvastatin ameliorate memory deficits and inflammation in clinical and mouse model of Alzheimer's disease via modulating the expression of miR-106b.

BACKGROUND: Alzheimer's disease (AD) as a neurodegenerative brain disorder is a devastating pathology leading to disastrous cognitive impairments and dementia, and several studies have shown that AD is closely related to the inflammation, so anti-inflammatory treatment may provide therapeutic benefits. In this study, the effect of simvastatin on inflammation was investigated and the underlying mechanisms were explored. METHODS: First, we tested the effect of simvastatin on AD in clinical research. The fasting venous blood was collected in order to evaluate the levels of interleukin-6 (IL-6), interleukine-1 beta (IL-1ß), antichymotrypsin (ACT) and human tumor necrosis factor α (TNF-α), which were measured with the enzyme-linked immunosorbent assay (ELISA) kits. Amyloid-ß (Aß), amyloid-ß precursor protein (APP) and ß-site APP-cleaving enzyme 1(BACE1) were tested by western blotting. Second, we used an APPswe/PS1E9 (APP/PS1) double transgenic mice to evaluate the amelioration ability of simvastatin against the memory impairment in vivo. Spatial learning and memory of mice were investigated by the Morris water maze test (MWM). The mRNA of inflammatory cytokines were measured using real-time PCR. Third, the phospho-proteome profile of SH-SY5Y human neuroblastoma cells treated with simvastatin was used to investigate the possible mechanisms. RESULTS: The results showed that simvastatin ameliorated the memory deficits both in clinical AD patients and animal model of AD. Simvastatin could reduce the mRNA expression of inflammatory cytokines and mediators, suppress the apoptosis of neural stem cells and improve the survival rate of neurons. Moreover, long non-coding RNA (lnc RNA) n336694 and miR-106b was overexpressed in APP/PS1 mice brain tissues, the relationship between lnc RNA n336694 and miR-106b was explored using the method of Target Scan bioinformatics predictions, the results revealed that miR-106b might be a potential target of lnc RNA n336694. Furthermore, miR-106b mediated apoptosis in SH-SY5Y cell and simvastatin could suppressed this process. CONCLUSION: Our results suggested that simvastatin could be of benefit in preventing the progression of AD and expected to be potentially used as a lead drug for further anti-AD treatment.

Fluoride Induces Neuroinflammation and Alters Wnt Signaling Pathway in BV2 Microglial Cells.

Fluoride is a common element in nature and our daily life, and excessive intake of this element can cause fluorosis and irreversible brain damage. The toxic effects of fluoride on the central nervous system may be attributed to the release of inflammatory cytokines and ROS. GSK3ß is a key protein that modulates NF-κB activity and inflammatory cytokine levels and plays an important role in the Wnt signaling pathway. In this study, we found that fluoride altered the inflammatory status and oxidative stress by inhibiting Wnt signaling pathway activity. This study thus provides a valid basis for the fluorine-induced neuroinflammation injury theory.

Atorvastatin in improvement of cognitive impairments caused by amyloid ß in mice: involvement of inflammatory reaction.

BACKGROUND: The production of inflammatory cytokines resulting from amyloid ß (Aß) is associated with the initiation of Alzheimer's disease (AD). Atorvastatin (ATV) has been reported to improve AD, however, it is unclear how the anti-inflammatory mechanism is linked with its protection against the impairment of spatial cognitive function in AD. The present study was designed to explore what mechanism was possibly involved in the anti-inflammatory pathway in regard to the ATV treatment of AD. METHODS: We used an AD model induced by the administration of Aß(25-35) in male C57BL/6 mice and an in vitro culture system to study the protective effects of ATV on the spatial cognitive deficits, hippocampal long-term potentiation (LTP) impairment and inflammatory reaction. RESULTS: The intragastric administration of ATV (5 mg/kg) in Aß(25-35)-treated mice significantly ameliorated the spatial cognitive deficits and prevented the LTP impairment in hippocampal CA1. The increased Iba-1 positive cells and inflammatory components in the hippocampus were reduced after the ATV treatment. The anti-inflammatory and LTP protection of ATV were abolished using the replenishment of farnesyl pyrophosphate by the administration of farnesol (FOH). The hippocampal slices culture showed Aß(25-35)-induced neurotoxicity in the absence of the presence of ATV. Treatment with ATV (0.5, 1, 2.5 µmol/L) dose-dependently prevented the cell damage in hippocampus induced by Aß25-35. CONCLUSION: The administration of ATV ameliorated the cognitive deficits, depressed the inflammatory responses, improved the LTP impairment, and prevents Aß25-35-induced neurotoxicity in cultured hippocampal neurons. These protective functions of ATV involved the pathway of reducing farnesyl pyrophosphate (FPP).

Atorvastatin May Correct Dyslipidemia in Adult Patients at Risk for Alzheimer's Disease Through an Anti-Inflammatory Pathway.

BACKGROUND: Dyslipidemia is a risk factor for the pathogenesis of Alzheimer's disease. Although, atorvastatin is a well-accepted lipid-lowering agent, the benefits of atorvastatin treatment through an anti-inflammatory mechanism are still unclear. OBJECTIVE: The present study was designed to examine changes in inflammatory markers following administration of atorvastatin in dyslipidemic patients with a parental history of Alzheimer's disease. METHODS: Dyslipidemic adults with a parental history of Alzheimer's disease were administered either 40 mg of atorvastatin or placebo for 18 months. Before and after the study, lpid levels, blood pressure, body weight and body mass index, and the inflammatory markers hs-Creactive protein, serum monocyte chemoattractant protien-1, interleukin-1ß, interleukin-6, and tumor necrosis factor-α were tested. RESULTS: Baseline levels of lipids, body mass index, hs-Creactive protein, monocyte chemoattractant protien-1, interleukin- 1ß, interleukin-6 and tumor necrosis factor-α did not show any difference between the two groups. However, after 18 months of atorvastatin treatment, all inflammatory markers significantly decreased in association with a reduction of lipid profiles, body mass index, bodyweight, and blood pressure, compared with those patients treated with placebo. CONCLUSION: Administration of atorvastatin corrected dyslipidemia in association with a reduction in inflammatory markers. Our results suggest that the therapeutic benefits of atorvastatin possibly involve an anti-inflammatory pathway.

Urinary kallidinogenase for the treatment of cerebral arterial stenosis.

AIM: Urinary kallidinogenase (UK) has shown promise in improving cerebral perfusion. This study aimed to examine how UK affects cognitive status and serum levels of amyloid betas (Aßs) 1-40 and 1-42 in patients with cerebral arterial stenosis. METHODS: Ninety patients with cerebral arterial stenosis were enrolled, of whom 45 patients received UK + conventional treatment (UK group), and 45 patients received conventional treatment alone as control group. Cognitive status and Aß1-40 and Aß1-42 serum levels were determined before treatment and at 4 weeks and 8 weeks after treatment. RESULTS: At 4 weeks after treatment, cognitive status in patients treated with UK clearly improved accompanied by Aß1-40 serum levels decreasing while there was no change of Aß1-42. Cognitive status in patients receiving UK continued to improve, Aß1-40 serum levels declined further as well as Aß1-42 serum levels began to decrease dramatically at 8 weeks after treatment. CONCLUSION: UK could improve cognitive status and decrease both Aß1-40 and Aß1-42 serum levels to prevent ischemic cerebral injury, which represents a good option for patients with cerebral arterial stenosis.