PM2.5 exposure induces systemic inflammation and oxidative stress in an intracranial atherosclerosis rat model.

OBJECTIVES: Exposure to airborne particle (PM2.5 ) is a risk factor for intracranial atherosclerosis (ICA). Because of the established role of systemic inflammation and oxidative stress by PM2.5 , we determined whether these processes account for PM2.5 -mediated ICA, and also whether omega-3 fatty acid (O3FA) dietary supplementation could attenuate them. METHODS: Adult Sprague-Dawley rats were exposed to filtered air (FA) or PM2.5 and fed either a normal chow diet (NCD) or a high-cholesterol diet (HCD), administered with or without O3FA (5 mg/kg/day by gavage) for 12 weeks. The lumen and thickness of the middle cerebral artery (MCA) were assessed. Serum tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin-1ß (IL-1ß), and interferon gamma (IFN-γ) were detected by ELISA. Reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) activity, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activity, mRNA levels of Nrf2, HO-1, NQO-1, and protein level of NOX subunit gp91 were quantified to determine the oxidative profile of brain vessels. RESULTS: PM2.5 increased (P < .05) ICA, especially in the HCD group; elevated serum TNF-α, IL-6, IL-1ß, and IFN-γ; increased cerebrovascular ROS, MDA, NOX activity, and gp91 protein levels; and decreased cerebrovascular SOD activity. Nrf2, HO-1, and NQO-1 mRNA levels were upregulated (P < .05) by PM2.5 exposure, especially in the HCD group. O3FA attenuated (P < .05) PM2.5 -induced systemic inflammation, vascular oxidative injury, and ICA. CONCLUSIONS: PM2.5 exposure induced systemic inflammation, cerebrovascular oxidative injury, and ICA in rats with HCD. O3FA prevented ICA development, and may therefore exert a protective effect against the atherogenic potential of PM2.5 .

Splenic responses play an important role in remote ischemic preconditioning-mediated neuroprotection against stroke.

BACKGROUND: Remote ischemic preconditioning (RIPC) of a limb has been reported to protect against ischemic stroke. Our previous results demonstrated that the RIPC-mediated neuroprotection is associated with alterations in circulating immune cell populations. Here, we evaluated the effect of the spleen, the largest reservoir of immune cells, on RIPC-mediated neuroprotection against stroke. METHODS: Noninvasive RIPC was achieved by four repeated cycles of 5-min blood flow constriction in the hindlimbs using a tourniquet. The blood and spleens were collected before and 1 h and 3 days after preconditioning to analyze the effect of RIPC on the spleen and the correlation between splenic and peripheral lymphocytes. Moreover, spleen weight and splenic lymphocytes were compared in stroke rats with or without RIPC. Finally, splenectomy was made 1 day or 2 weeks before RIPC and 90-min middle cerebral artery occlusion (MCAO). The infarct areas and deficits were assessed. Blood was collected 1 h after RIPC and 3 days after MCAO to explore the impact of splenectomy on RIPC-induced neuroprotection and immune changes. The contralateral and ipsilateral hemispheres were collected 3 days after MCAO to detect the infiltration of immune cells after RIPC and splenectomy. RESULTS: Flow cytometry analysis demonstrated that the RIPC promptly increased the percentages of CD3+CD8+ cytotoxic T (Tc) cells in the spleen with a relatively delayed elevation in CD3+CD161+ natural killer T (NKT) and CD3-CD45RA+ B lymphocytes. The percentages of circulating lymphocytes are positively correlated with the percentages of splenic lymphocytes in normal rats. Interestingly, RIPC resulted in negative correlations between the percentages of splenic and circulating T lymphocytes, while the correlation between splenic and circulating B lymphocytes remained positive. For animals subjected to RIPC followed by MCAO, RIPC increased splenic volume with an expansion of splenic lymphocytes 3 days after MCAO. Furthermore, the removal of the spleen 1 day or 2 weeks before RIPC and MCAO reduced the protective effect of RIPC on ischemic brain injury and reversed the effects of RIPC on circulating immune cell composition. RIPC significantly reduced brain infiltration of Tc and NKT cells. Prior splenectomy showed no effect on immune cell infiltration after RIPC and stroke. CONCLUSION: These results reveal an immunomodulatory effect of the spleen, effecting mainly the spleen-derived lymphocytes, during RIPC-afforded neuroprotection against cerebral ischemia.

Ethanol and normobaric oxygen: novel approach in modulating pyruvate dehydrogenase complex after severe transient and permanent ischemic stroke.

BACKGROUND AND PURPOSE: Ischemic stroke induces metabolic disarray. A central regulatory site, pyruvate dehydrogeanse complex (PDHC) sits at the cross-roads of 2 fundamental metabolic pathways: aerobic and anaerobic. In this study, we combined ethanol (EtOH) and normobaric oxygen (NBO) to develop a novel treatment to modulate PDHC and its regulatory proteins, namely pyruvate dehydrogenase phosphatase and pyruvate dehydrogenase kinase, leading to improved metabolism and reduced oxidative damage. METHODS: Sprague-Dawley rats were subjected to transient (2, 3, or 4 hours) middle cerebral artery occlusion followed by 3- or 24-hour reperfusion, or permanent (28 hours) middle cerebral artery occlusion without reperfusion. At 2 hours after the onset of ischemia, rats received either an intraperitoneal injection of saline, 1 dose of EtOH (1.5 g/kg) for 2- and 3-hour middle cerebral artery occlusion, 2 doses of EtOH (1.5 g/kg followed by 1.0 g/kg in 2 hours) in 4 hours or permanent middle cerebral artery occlusion, and EtOH+95% NBO (at 2 hours after the onset of ischemia for 6 hours) in permanent stroke. Infarct volumes and neurological deficits were examined. Oxidative metabolism and stress were determined by measuring ADP/ATP ratio and reactive oxygen species levels. Protein levels of PDHC, pyruvate dehydrogenase kinase, and pyruvate dehydrogenase phosphatase were assessed. RESULTS: EtOH induced dose-dependent neuroprotection in transient ischemia. Compared to EtOH or NBO alone, NBO+EtOH produced the best outcomes in permanent ischemia. These therapies improved brain oxidative metabolism by decreasing ADP/ATP ratios and reactive oxygen species levels, in association with significantly raised levels of PDHC and pyruvate dehydrogenase phosphatase, as well as decreased pyruvate dehydrogenase kinase. CONCLUSIONS: Both EtOH and EtOH+NBO treatments conferred neuroprotection in severe stroke by affecting brain metabolism. The treatment may modulate the damaging cascade of metabolic events by bringing the PDHC activity back to normal metabolic levels.

Comparison of self-expanding stents with distal embolic protection to balloon-expandable stents without a protection device in the treatment of symptomatic vertebral artery origin stenosis: a prospective randomized trial.

PURPOSE: To compare the angiographic and clinical outcomes of self-expanding stents (SES) with distal embolic protection devices (EPD) vs balloon-expandable stents (BES) without EPD in the treatment of symptomatic atherosclerotic vertebral artery ostial stenosis (VAOS). METHODS: Between July 2011 and March 2013, a prospective randomized trial was conducted involving 127 patients (mean age 67.3±10.2 years; 94 men) with symptomatic VAOS randomly assigned to treatment with SES + EPD (Precise RX or RX Acculink stent + Spider FX EPD; n=61) or BES (Palmaz Blue or Resolute RX; n=66) without EPD. In-stent restenosis (ISR) >50% detected by duplex ultrasound was the primary endpoint. Technical success, clinical success, complications within 30 days, and signal intensity abnormalities on diffusion weighted imaging (DWI) after stenting were compared. RESULTS: The 30-day technical success rate was 95.5% (63/66) for SES+EPD vs 100% (70/70) for BES without EPD (p=0.072). DWI at 24 hours poststenting showed 2 hyperintense lesions in 2 (3.3%) SES + EPD cases and 15 hyperintense lesions in 13 (18.6%) BES patients (p<0.01). At a mean 18-month follow-up, the clinical success rate was 93.9% (62/66) for the SES + EPD group vs 85.7% (60/70) for the BES group (p=0.115). The ISR was seen in 16/70 (22.9%) arteries in the BES group and 2/66 (3.1%) arteries in SES + EPD group (p<0.01). Target vessel revascularization was performed in 7 (10.0%) BES arteries vs none in the SES + EPD group (p<0.01). CONCLUSION: SES with EPD in the treatment of symptomatic VAOS is technically feasible and safe, with low rates of ISR and significantly reduced thromboembolic events on imaging when compared to BES without EPD.

Synergetic neuroprotection of normobaric oxygenation and ethanol in ischemic stroke through improved oxidative mechanism.

BACKGROUND AND PURPOSE: Normobaric oxygenation (NBO) and ethanol both provide neuroprotection in stroke. We evaluated the enhanced neuroprotective effect of combining these 2 treatments in a rat stroke model. METHODS: Sprague-Dawley rats were subjected to middle cerebral artery occlusion for 2 hours. Reperfusion was then established and followed by treatment with either (1) an intraperitoneal injection of ethanol (1.0 g/kg), (2) NBO treatment (2-hour duration), or (3) NBO plus ethanol. The extent of brain injury was determined by infarct volume and motor performance. Oxidative metabolism was determined by ADP/ATP ratios, reactive oxygen species levels, nicotinamide adenine dinucleotide phosphate oxidase activity, and pyruvate dehydrogenase activity. Protein expression of major nicotinamide adenine dinucleotide phosphate oxidase subunits (p47(phox), gp91(phox), and p67(phox)) and the enzyme pyruvate dehydrogenase was evaluated through Western immunoblotting. RESULTS: NBO and ethanol monotherapies each demonstrated reductions as compared to stroke without treatment in infarct volume (36.7% and 37.9% vs 48.4%) and neurological deficits (score of 6.4 and 6.5 vs 8.4); however, the greatest neuroprotection (18.8% of infarct volume and 4.4 neurological deficit) was found in animals treated with combination therapy. This neuroprotection was associated with the largest reductions in ADP/ATP ratios, reactive oxygen species levels, and nicotinamide adenine dinucleotide phosphate oxidase activity, and the largest increase in pyruvate dehydrogenase activity. CONCLUSIONS: Combination therapy with NBO and ethanol enhances the neuroprotective effect produced by each therapy alone. The mechanism behind this synergistic action is related to changes in cellular metabolism after ischemia reperfusion. NBO plus ethanol is attractive for clinical study because of its ease of use, tolerability, and tremendous neuroprotective potential in stroke.

Montelukast sodium protects against focal cerebral ischemic injury by regulating inflammatory reaction via promoting microglia polarization.

BACKGROUND: Neuroinflammation plays an important role in brain injury and repair. Regulation of post-stroke inflammation may be a reasonable strategy to treat ischemic stroke. The present study demonstrates that montelukast sodium protected brain tissue by regulating the post-stroke inflammatory reaction. METHODS: Adult male mice underwent distal occlusion of the middle cerebral artery (d-MCAO) surgery, followed by intraperitoneal injection of montelukast sodium or equivalent saline, from day 0-7 after the operation. On the 7th day, Rotarod and adhesive-removal test were performed. M AP2 staining, and Iba1, CD206, and CD16/32 co staining were performed. BV2 microglial cell lines were co-cultured with different concentrations of montelukast sodium with or without lipopolysaccharide (LPS). Real-time polymerase chain reaction (rt-PCR) and enzyme linked immunosorbent assay (ELISA) were used to detect the mRNA expression of M1 and M2 phenotypic microglia markers and the release of cytokines representing from different phenotypes of microglia cells. RESULTS: Montelukast sodium prolonged the time that d-MCAO mice remained on the rotating bar, shortened the time to remove the sticker on the opposite claw, and reduced the infarct volume, promoting the transformation of microglial cells/macrophages around the infarct to the M2 phenotype. Montelukast sodium increased the mRNA expression of Arg-1, CD206, TGF-ß, and IL-10 in BV2 microglial cell lines stimulated by LPS, while decreased the expression of iNOS, TNF-α, and CD16/32. CONCLUSION: Montelukast sodium can protect against focal cerebral ischemic injury by regulating inflammatory reaction via promoting microglia polarization.

Factors influencing the outcome of cardiogenic cerebral embolism: a literature review.

OBJECTIVE: The onset of cardiogenic cerebral embolism is sudden, dangerous, and often has high morbidity and mortality. Improving understanding of factors contributing to outcomes of cardiogenic cerebral embolism will improve prognostic and therapeutic capabilities. METHODS: Through PubMed and Google Scholar, this paper examined and analyzed the factors implicated in the outcome of patients with cardiogenic cerebral embolism using the key terms 'cardiogenic cerebral embolism', 'atrial fibrillation', 'stroke related diseases', 'collateral circulation', 'emboli profile', 'epigenetic' up to 28 February 2021. Full texts of the retrieved articles were accessed. In general, in these literatures, National Institute Health of Stroke Scale (NIHSS) score ≥ 17, modified Rankin Scale (mRS) score ≥ 2, stroke recurrence, death caused by stroke are regarded as the criteria of poor prognosis. As long as one of these conditions occurs, it is judged as poor prognosis. RESULTS: Factors influencing patient outcomes including patient outcome include severity of neurological impairment, types and severity of combined heart diseases, establishment of cerebral collateral circulation, treatments, components of emboli causing cardiogenic cerebral embolism, existence and control of other system complications, distribution and expression of inflammatory immune cells and molecules in the course of cardiogenic cerebral embolism, and epigenetic changes related to disease prognosis. CONCLUSION: Regarding to prevention and treatment of cardiogenic cerebral embolism, the related factors, such as clinical setting, emboli pathological profile, and epigenetic changes should be emphasized so that outcomes and recurrence of cardiogenic cerebral embolism can be improvised.

Neuroprotective Effects of Pharmacological Hypothermia on Hyperglycolysis and Gluconeogenesis in Rats after Ischemic Stroke.

Stroke is a leading threat to human life. Metabolic dysfunction of glucose may play a key role in stroke pathophysiology. Pharmacological hypothermia (PH) is a potential neuroprotective strategy for stroke, in which the temperature is decreased safely. The present study determined whether neuroprotective PH with chlorpromazine and promethazine (C + P), plus dihydrocapsaicin (DHC) improved glucose metabolism in acute ischemic stroke. A total of 208 adult male Sprague Dawley rats were randomly divided into the following groups: sham, stroke, and stroke with various treatments including C + P, DHC, C + P + DHC, phloretin (glucose transporter (GLUT)-1 inhibitor), cytochalasin B (GLUT-3 inhibitor), TZD (thiazolidinedione, phosphoenolpyruvate carboxykinase (PCK) inhibitor), and apocynin (nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor). Stroke was induced by middle cerebral artery occlusion (MCAO) for 2 h followed by 6 or 24 h of reperfusion. Rectal temperature was monitored before, during, and after PH. Infarct volume and neurological deficits were measured to assess the neuroprotective effects. Reactive oxygen species (ROS), NOX activity, lactate, apoptotic cell death, glucose, and ATP levels were measured. Protein expression of GLUT-1, GLUT-3, phosphofructokinase (PFK), lactate dehydrogenase (LDH), PCK1, PCK2, and NOX subunit gp91 was measured with Western blotting. PH with a combination of C + P and DHC induced faster, longer, and deeper hypothermia, as compared to each alone. PH significantly improved every measured outcome as compared to stroke and monotherapy. PH reduced brain infarction, neurological deficits, protein levels of glycolytic enzymes (GLUT-1, GLUT-3, PFK and LDH), gluconeogenic enzymes (PCK1 and PCK2), NOX activity and its subunit gp91, ROS, apoptotic cell death, glucose, and lactate, while raising ATP levels. In conclusion, stroke impaired glucose metabolism by enhancing hyperglycolysis and gluconeogenesis, which led to ischemic injury, all of which were reversed by PH induced by a combination of C + P and DHC.

NIHSS Consciousness Score Combined with ASPECTS is a Favorable Predictor of Functional Outcome post Endovascular Recanalization in Stroke Patients.

Although revascularization rates after endovascular thrombectomy for large vessel acute ischemic stroke (AIS) are high (71%), only 46% of patients achieve functional independence at 90 days. The present study was designed to explore a new method for predicting the functional prognosis of AIS patients after endovascular recanalization. A total of 200 anterior circulation stroke patients who received endovascular therapy were enrolled. Logistic regression analysis of clinical characteristics on functional independence were performed. The predictive power of sub-items in National Institute of Health stroke scale (NIHSS) and the combination of NIHSS consciousness and Alberta Stroke Program Early CT Score (ASPECTS) on functional independence were assessed by Receiver Operating Characteristic (ROC) curves and the latter was compared with 3 previously published prediction models by AUC (the area under ROC curve). The AUC for the NIHSS consciousness score to predict functional independence was higher than whole NIHSS and other sub-items (0.716 v 0.705, 0.586, 0.573, 0.552 and 0.559). Low NIHSS consciousness score, high ASPECTS score, short time from onset to recanalization, and high rate of successful recanalization were demonstrated to be significantly associated with the functional independence (OR 0.697, 2.226, 0.994 and 28.643). The prediction power of the combination was significantly better than NIHSS and ASPECTS alone (AUC 0.793 v 0.705 and 0.752). Compared with 3 other prediction models, the combination was found to be the strongest predictor for functional independence (AUC 0.793 v 0.791, 0.671 and 0.564). NIHSS which has been shown to be a strong predictor of functional outcomes after endovascular recanalization is largely dependent on the consciousness component. NIHSS consciousness score combined with ASPECTS appears to be a favorable predictor of functional independence. These findings may have broad reaching effects for isolated centers around the world without advanced imaging for triage and prognostication.

Adjuvant High-Flow Normobaric Oxygen After Mechanical Thrombectomy for Anterior Circulation Stroke: a Randomized Clinical Trial.

Adjuvant neuroprotective therapies for acute ischemic stroke (AIS) have demonstrated benefit in animal studies, albeit without human translation. We investigated the safety and efficacy of high-flow normobaric oxygen (NBO) after endovascular recanalization in anterior circulation stroke. This is a prospective randomized controlled study. Eligible patients were randomized to receive high-flow NBO by a Venturi mask (FiO2 50%, flow 15 L/min) or routine low-flow oxygen supplementation by nasal cannula (flow 3 L/min) after vessel recanalization for 6 h. Patient demographics, procedural metrics, complications, functional outcomes, symptomatic intracranial hemorrhage (sICH), and infarct volume were assessed. A total of 91 patients were treated with high-flow NBO. NBO treatment revealed a common odds ratio of 2.2 (95% CI, 1.26 to 3.87) favoring the distribution of global disability scores on the mRS at 90 days. The mortality at 90 days was significantly lower in the NBO group than in the control group, with an absolute difference of 13.86% (rate ratio, 0.35; 95% CI, 0.13-0.93). A significant reduction of infarct volume as determined by MRI was noted in the NBO group. The median infarct volume was 9.4 ml versus 20.5 ml in the control group (beta coefficient, - 20.24; 95% CI, - 35.93 to - 4.55). No significant differences were seen in the rate of sICH, pneumonia, urinary infection, and seizures between the 2 groups. This study suggests that high-flow NBO therapy after endovascular recanalization is safe and effective in improving functional outcomes, decreasing mortality, and reducing infarct volumes in anterior circulation stroke patients within 6 h from stroke onset.

Acute Anterior Choroidal Artery Territory Infarction: A Retrospective Study.

OBJECTIVES: To explore the clinical features, risk factors, etiopathogenesis, mechanism of progression, effect of intravenous thrombolysis therapy (IVT) and prognosis of acute ischemic stroke (AIS) in the anterior choroidal artery (AChA) territory. PATIENTS AND METHODS: A total of 113 AChA infarction patients were enrolled in the current study retrospectively. The demographic and clinical characteristics were collected and analyzed in all patients. The clinical characteristics were compared between clinical progression and no clinical progression groups, good and poor outcome groups, as well as with and without intravenous rt-PA groups. RESULTS: Hemiparesis was the most common clinical manifestation (92.9%), followed by dyslexia (54.9%), hemianesthesia (43.4%) and other syndromes. Forty-nine patients (43.4%) suffered from clinical progression and showed a higher rate with multiple risk factors together than patients without clinical progression (30.6% vs.14.1%, P = 0.039). Moreover, more patients with progression were found with carotid plaques (73.5% vs. 51.6%, P = 0.018) or carotid artery stenosis (18.4% vs. 6.3%, P = 0.045) than patients without progression. 69.9% of patients got good prognosis at 6-months. In good prognosis group, the proportion of patients with atrial fibrillation, clinical progression and large infarct size were significantly lower than in poor prognosis group (1.3% vs. 11.8%, P = 0.047; 23.9% vs. 67.6%, P = 0.001; 15.2% vs. 38.2%, P = 0.007). No significant difference was found on rate of clinical progression and good prognosis between patients with and without IVT. CONCLUSION: Motor deficits are the most frequent and typical symptoms in AChA infarcts. Although small artery disease was considered to be the important etiopathogenesis of the AChA infarcts, large vascular disease may be associated with clinical progression in AChA infarcts. Additionally, prognosis of AChA infarcts is correlated with clinical progression, infarct size and atrial fibrillation. IVT does not seem to prevent the clinical progression and improve prognosis of AChA infarcts.

Apolipoprotein E polymorphism carriers exhibit objective cognitive deficits: a single center trial.

OBJECTIVE: To assess the correlation between objectively measured cognitive function and apolipoprotein E polymorphism within one geographic region. METHODS: 61 patients, aged 55-90 years old, were enrolled in a memory clinic at the Beijing Luhe Hospital affiliated with Capital Medical University from September 2016 to September 2018. At this center, they were evaluated with neuropsychological scales to assess their memory and other aspects of cognitive function. Specific gene segments were extracted from venous blood by PCR amplification, and ApoE genotyping was carried out by chip hybridization. RESULTS: Among all patients, 0 had the genotype ε2/2, 7 had the genotype ε2/3, 0 had the genotype ε2/4, 40 had the genotype ε3/3, 12 had the genotype ε3/4, and 2 had the genotype ε4/4. The allele frequency ε2 accounted for 5.74%, ε3 accounted for 81.15% and ε4 accounted for 13.11%. The Mini-Mental State Examination (MMSE) scores of ε4 carriers (18.14 ± 0.39) were significantly lower than those of non-ε4 carriers (23.77 ± 6.29) (P < 0.05), and the Montreal Cognitive Assessment (MoCA) scores of ε4 carriers (14.36 ± 7.56) were also significantly lower than those of non-ε4 carriers (20.55 ± 8.08) (P < 0.05). CONCLUSION: The rate of the ε3/3 homozygous genotype was the highest, followed by the rates of the ε3/4 and ε2/3 genotypes. The rates of the ε2/4, ε4/4, and ε2/2 genotypes were the lowest. Deficits in memory and other cognitive processes were significantly more pronounced in ε4 carriers than in non-ε4 carriers.

Hypoxia-Inducible Factor 1α and 2α Have Beneficial Effects in Remote Ischemic Preconditioning Against Stroke by Modulating Inflammatory Responses in Aged Rats.

Limb remote ischemic preconditioning (RIPC) has been proven to alleviate stroke injury in young rats, but its protective effect and its mechanism in aged rats are still unclear. Hypoxia-inducible factor (HIF) is one of the important markers of stroke, and its high expression plays an important role in the pathogenesis of stroke. In this study, we tested the hypothesis that RIPC could regulate the expression of HIF, leading to reduced inflammatory responses in aged rats. Stroke was induced by transient middle cerebral artery occlusion (MCAo) in aged rats, and RIPC was conducted in both hind limbs. The HIF-1α and HIF-2α mRNA and protein were examined by real-time RT-PCR and western blotting (WB). Inflammatory cytokines in the peripheral blood and brain were measured using AimPlex multiplex immunoassays. The protein levels of p-Akt, Akt, p-ERK, and ERK were examined by WB. We investigated that RIPC reduced the infarct size, improved neurological functions, and decreased the expression of HIF-1α and HIF-2α in the ischemic brain. RIPC reduced the levels of IL-1ß, IL-6 and IFN-γ in the peripheral blood and the levels of IL-1ß and IFN-γ in the ischemic brain 48 h post-stroke. Moreover, intraperitoneal injection of the HIF inhibitor, acriflavine hydrochloride (ACF), abolished the protection of RIPC with respect to infarct size and neurological functions and neutralized the downregulation of pro-inflammatory IL-1ß, IL-6 and IFN-γ. ACF also reversed the activation of the Akt signaling pathway induced by RIPC following stroke. HIF may play a key role in RIPC, which was likely mediated by the Akt signaling pathway and systemic modulation of the inflammatory response in aged rats.

Remote ischemic preconditioning protects against ischemic stroke in streptozotocin-induced diabetic mice via anti-inflammatory response and anti-apoptosis.

OBJECTIVE: It has been shown that remote ischemic preconditioning (RIPreC) attenuates ischemic injury after stroke in healthy rats or mice. The present study aims to examine whether RIPreC offers neuroprotection against ischemic stroke in streptozotocin-induced diabetic mice. METHODS: Streptozotocin (STZ, 120 mg/kg) was intraperitoneally injected into the mice to induce type 1 diabetic model. The immune and inflammatory changes were analyzed 2 days after reperfusion by flow cytometry and multiplex cytokine assay analysis, respectively. RESULTS: We found that RIPreC reduced infarct sizes and alleviated neurological impairment in diabetic mice. RIPreC decreased CD8 T cells infiltrated into the brain, and attenuated the decreases of CD8 T cells in the blood, CD4 T cells and CD8 T cells in the spleen. Results from multiplex cytokine assay showed that RIPreC treatment decreased IL-6, IL-1 beta and TNF alpha levels in the cortex, while it inhibited IL-6 level in the hippocampus and striatum, and TNF alpha level in the hippocampus. RIPreC treatment also downregulated IL-6 and IFN gamma level in the blood, which increased after cerebral ischemic injury. In addition, RIPreC reduced pro-apoptotic protein BAX expression in the ischemic brain. CONCLUSIONS: Our results indicate that RIPreC attenuates cerebral injuries in streptozotocin-induced diabetic mice via anti-inflammatory response and anti-apoptosis in the ischemic brain.

Low dose concomitant treatment with chlorpromazine and promethazine is safe in acute ischemic stroke.

BACKGROUND: Acute ischemic stroke (AIS) is associated with significant morbidity and mortality and has a very narrow window of treatment with fibrinolytics. We investigated the safety and efficacy of combined chlorpromazine and promethazine (C+P) treatment in AIS. METHODS: A total of 64 consecutive patients diagnosed with AIS were selected and were randomly (double-blind) assigned into either the control group (standard of care [SOC] treatment) or the treatment group (SOC+C+P [12.5+12.5 mg BID or 25+25 mg BID]) which were treated for 2 weeks. The National Institutes of Health Stroke Scale (NIHSS) and Modified Rankin Scale (mRS) were computed prior to and after treatment to evaluate neurological deficits and daily functional status. RESULTS: In our study, 64 patients (males=81.3%) were divided into either the control (34 patients, 83.3% males, mean age=58.8±11.7 years) or the study group (30 patients, 79.4% males, mean age=62.3±9.1 years). While the NIHSS scores were not different between the control and treatment group at admission (P>0.05), a greater proportion of the cohort in both the groups (control group low NIHSS=79.4%, high NIHSS=20.6%, P<0.01) had a lower NIHSS at admission and (treatment group low NIHSS=83.3%, high NIHSS=16.7%, P<0.01). Interestingly, while both the control and treatment group had lower NIHSS and mRS scores at 90d post treatment compared to those at baseline, there were no significant differences in those scores between the two group (P>0.05) suggesting no improved benefit with C+P. Moreover, using C+P did not lead to any serious adverse effects when compared to the treatment group. CONCLUSIONS: While the addition of low dose chlorpromazine and promethazine to standard of care for acute ischemic stroke did not have any significant improvement in functional outcomes, there were no serious adverse effects. Thus, the use of chlorpromazine and promethazine in the acute ischemic stroke setting and future studies using higher doses of C+P are justified.

Brain ultrasound for diagnosis and prognosis in the neurological intensive care unit: a mini review for current development.

Objective: Transcranial doppler ultrasonography (TCD) is one of the few tools in the Neurological Intensive Care Unit (NICU) that allows for real-time monitoring of cerebral blood flow while also being non-invasive. This review examines the current use of TCD monitoring in the NICU. Method: We completed a literature review using Google Scholar and Pubmed. Relevant articles were included in this review. Results: The role of TCD in the NICU continues to evolve since its infancy in the 1980s. TCD use is now standard of care of for some neurological maladies. The significant advantages of TCD include convenience of use, non-invasive nature, bedside operation, high accuracy, and absence of interference from external factors such as temperature and sedatives. Conclusion: This review examines the current use of TCD monitoring in the NICU. Through review and continued development of similar non invasive technologies NICU care continues to innovate and evolve. Abbreviation: TCD: Transcranial Doppler.

MicroRNA-323 suppresses nerve cell toxicity in cerebral infarction via the transforming growth factor-ß1/SMAD3 signaling pathway.

In the present study, the aim was to investigate the function of microRNA­323 (miR­323) in cerebral infarction and its underlying mechanism. A rat model of cerebral infarction was established and hippocampal tissues were analyzed. In addition, to further understand the role of miR­323, PC12 cells were transfected with miR­323 mimics or inhibitors and subjected to hypoxia to model cerebral infarction. Reverse transcription­quantitative polymerase chain reaction was used to measure the expression of miR­323. A luciferase reporter assay was conducted to analyze miR­323 target sites the partial sequence of the 3'­untranslated region of SMAD3 mRNA in vitro. Western blot analysis was also used to analyze transforming growth factor­ß1 (TGF­ß1) and SMAD3 protein expression levels. It was observed that miR­323 expression was significantly upregulated in rats with cerebral infarction compared with rats in the sham­control group. In addition, overexpression of miR­323 induced nerve cell toxicity and reduced nerve cell growth in an in vitro model of cerebral infarction, whereas downregulation of miR­323 caused the opposite effects on nerve cell toxicity and growth in this model. In addition, overexpression of miR­323 directly targeted and suppressed SMAD3 expression in the in vitro model of cerebral infarction, while inhibition of miR­323 induced SMAD3 expression. The use of a SMAD3 inhibitor suppressed the effect of anti­miR­323 on nerve cell toxicity in the in vitro model of cerebral infarction. Collectively, these findings suggested that miR­323 suppresses nerve cell apoptosis in cerebral infarction via the TGF­ß1/SMAD3 signaling pathway.

High Intensity Physical Rehabilitation Later Than 24 h Post Stroke Is Beneficial in Patients: A Pilot Randomized Controlled Trial (RCT) Study in Mild to Moderate Ischemic Stroke.

Objective: Very early mobilization was thought to contribute to beneficial outcomes in stroke-unit care, but the optimal intervention strategy including initiation time and intensity of mobilization are unclear. In this study, we sought to confirm the rehabilitative effects of different initiation times (24 vs. 48 h) with different mobilization intensities (routine or intensive) in ischemic stroke patients within three groups. Materials and Methods: We conducted a randomized and controlled trial with a blinded follow-up assessment. Patients with ischemic stroke, first or recurrent, admitted to stroke unit within 24 h after stroke onset were recruited. Eligible subjects were randomly assigned (1:1:1) to 3 groups: Early Routine Mobilization in which patients received < 1.5 h/d out-of-bed mobilization within 24-48 h after stroke onset, Early Intensive Mobilization in which patients initiated ≥3 h/d mobilization at 24-48 h after the stroke onset, and Very Early Intensive Mobilization in which patients received≥3 h/d mobilization within 24 h. The modified Rankin Scale score of 0-2 was used as the primary favorable outcome. Results: We analyzed 248 of the 300 patients (80 in Early Routine Mobilization, 82 in Very Early Intensive Mobilization and 86 in Early Intensive Mobilization), with 52 dropping out (20 in Early Routine Mobilization, 18 in Very Early Intensive Mobilization and 14 in Early Intensive Mobilization). Among the three groups, the Early Intensive Mobilization group had the most favorable outcomes at 3-month follow-up, followed by patients in the Early Routine Mobilization group. Patients in Very Early Intensive Mobilization received the least odds of favorable outcomes. At 3 month follow up, 53.5%, (n = 46) of patients with Early Intensive Mobilization showed a favorable outcome (modified Rankin Scale 0-2) (p = 0.041) as compared to 37.8% (n = 31) of patients in the Very Early Intensive Mobilization. Conclusions: Post-stroke rehabilitation with high intensity physical exercise at 48 h may be beneficial. Very Early Intensive Mobilization did not lead to a favorable outcome at 3 months. Clinical Trial Registration: www.chictr.org.cn, identifier ChiCTR-ICR-15005992.

Intravenous Administration of Standard Dose Tirofiban after Mechanical Arterial Recanalization is Safe and Relatively Effective in Acute Ischemic Stroke.

To investigate the safety and efficacy of intravenous administration of a standard dose of glycoprotein-IIb/IIIa inhibitor tirofiban after vessel recanalization by mechanical thrombectomy in acute ischemic stroke. A consecutive series of patients (n=112) undergoing endovascular ischemic stroke intervention therapy were enrolled. 81 patients were eligible for intravenous (IV) tirofiban treatment for 24 hours after mechanical thrombectomy. The incidence of symptomatic intracranial hemorrhage (sICH), death, National Institutes of Health Stroke Scale (NIHSS) and modified Rankin scale (mRS) were assessed. In the 81 patients receiving tirofiban, 52 patients (64.2%) were treated with IV rt-PA before mechanical thrombectomy. sICH was found in 2 (2.5%) patients with no fatal ICH. Four patients died during 3 months after stroke onset. Successful recanalization with thrombolysis in cerebral infarction (TICI) score ≥2b was achieved in 75 of 81 patients (92.6%) after mechanical thrombectomy. The average number of passes with Solitaire stent retriever was 1.3. At 3 months, 55 of 81 patients (67.9%) had favorable outcomes (mRS<=2). The intravenous application of a standard dose of tirofiban post-Solitaire stent retriever thrombectomy and intravenous thrombolysis appears to be safe and relatively effective in acute ischemic stroke.

MicroRNA-132 modifies angiogenesis in patients with ischemic cerebrovascular disease by suppressing the NF­κB and VEGF pathway.

In the present study, the expression of microRNA (miR)­132 and the mechanism by which it modifies angiogenesis in patients with ischemic cerebrovascular disease (ICD) was investigated. RNA isolation and reverse transcription­quantitative polymerase chain reaction were used to measure miR­132 expression in patients with ICD. Inflammatory factors were measured using ELISA kits and western blotting measured B­cell lymphoma­2 (Bcl­2)­associated X/Bcl­2 ratio (Bax/Bcl­2 ratio), nuclear factor (NF)­κB p65, matrix metalloproteinase­9 (MMP­9), vascular cell adhesion molecule­1 (VCAM­1) and protein expression of inducible nitric oxide synthase (iNOS), and vascular endothelial growth factor (VEGF) protein expression. miR­132 expression in patients with ICD was lower compared with healthy volunteers. PC12 cells were used to create an oxygen glucose deprivation (OGD) model. miR­132 overexpression in an in vitro model was able to reduce tumor necrosis factor­a, interleukin (IL)­1ß, IL­6, IL­8, cyclooxygenase­2, caspase­3 and caspase­9 levels, suppress Bax/Bcl­2 ratio, NF­κB p65, MMP­9, VCAM­1, iNOS, VEGF protein expression. The results suggested that miR­132 may modify angiogenesis in patients with ICD by suppressing the NF­κB pathway and promoting the VEGF pathway, and may develop into a therapy for ICD in future research.