Stroke

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Effect of intravenous ethanol on cerebral vasospasm produced by subarachnoid blood.
Stroke - Tập 10 Số 5 - Trang 535-537 - 1979
Kevin J. Barry, R. Michael Scott
The cat basilar artery was exposed using the transclival approach. After administration of 5% ethanol via intravenous infusion, vasospasm was produced by applying the animal's fresh arterial blood to the exposed artery. The resultant vasospasm was of markedly reduced intensity and duration as compared to vasospasm in control animals. In ethanol-treated animals with spasm induced from non-autogenous fresh arterial bloof free of ethanol, a reduction in the duration of vasospasm was noted although the initial intensity of spasm was similar to control animals. There was no anti-spasm effect if the ethanol infusion followed the production of vasospasm.
Retinal Artery Occlusion and the Risk of Stroke Development
Stroke - Tập 47 Số 2 - Trang 376-382 - 2016
Tyler Hyungtaek Rim, Jinu Han, Yoon Seong Choi, Seung-Sik Hwang, Christopher Seungkyu Lee, Sung Chul Lee, Sung Soo Kim
Background and Purpose— Our aim was to evaluate the risk of subsequent stroke development after retinal artery occlusion (RAO). Methods— National registry data were collected from the Korean National Health Insurance Service, comprised 1 025 340 random subjects. Patients diagnosed with RAO in 2002 and 2003 were excluded. The RAO group was composed of patients with an initial diagnosis of either central or other RAO between January 2004 and December 2013 (n=401). The comparison group was composed of randomly selected patients (5 per RAO patient; n=2003) who were matched to the RAO group according to sociodemographic factors and year of RAO diagnosis. Each sampled patient was tracked until 2013. Cox proportional hazard regression was used. Results— Stroke occurred in 15.0% of the RAO group and in 8.0% of the comparison group ( P < 0.001). RAO was associated with an increased risk of stroke occurrence (hazard ratio, 1.78; 95% confidence interval, 1.32–2.41). The magnitude of the RAO effect for stroke was larger among younger adults aged <65 years (hazard ratio, 3.11) than older adults aged ≥65 years (hazard ratio, 1.26). However, the risk of subsequent stroke was significantly increased in older adults aged ≥65 years at the 4-year follow-up (hazard ratio, 1.58; 95% confidence interval, 1.01–2.48). Conclusions— RAO was significantly associated with subsequent stroke after adjusting for comorbidities and sociodemographic factors. These findings are limited by uncontrolled confounding factors and need to be replicated by other observational studies.
Comparison of Risk Factors in Patients With Transient and Prolonged Eye and Brain Ischemic Syndromes
Stroke - Tập 33 Số 10 - Trang 2383-2390 - 2002
Gillian Mead, Steff Lewis, Joanna M. Wardlaw, Martin Dennis
Background and Purpose— Patients with ischemic stroke, cerebral transient ischemic attacks (TIAs), retinal artery occlusion (RAO), and amaurosis fugax are thought to have similar risk factors and underlying vascular disease. However, if risk factors are different in patients with eye compared with brain symptoms and in those whose symptoms last <24 hours (transient) compared with those lasting >24 hours (prolonged), more focused prevention strategies are possible in the future. Methods— All patients with ischemic stroke, cerebral TIA, RAO, and amaurosis fugax presenting to our hospital from 1994 to 1999 were examined by a stroke physician. Risk factors were documented, and patients underwent carotid Doppler ultrasound. Results— We registered 1491 patients with ischemic stroke, 580 with cerebral TIA, 79 with RAO, and 138 with amaurosis fugax. Atrial fibrillation was more common in brain than eye events, whether prolonged [ischemic stroke versus RAO: odds ratio (OR), 3.6; 95% confidence interval (CI), 1.1 to 12] or transient (cerebral TIA versus amaurosis fugax: OR, 2.9; 95% CI, 0.7 to 13), and more common in prolonged than transient events, whether brain (stroke versus cerebral TIA: OR, 3.3; 95% CI, 2.1 to 5.1) or eye (RAO versus amaurosis fugax: OR, 2.7; 95% CI, 0.4 to 16). Severe ipsilateral carotid disease was less common in brain than eye events, whether prolonged (ischemic stroke versus RAO: OR, 0.6; 95% CI, 0.3 to 1.0) or transient (cerebral TIA versus amaurosis fugax: OR, 0.4; 95% CI, 0.2 to 0.6). Conclusions— These data suggest that there are pathogenetic differences between transient and permanent eye and brain ischemic syndromes. Improved understanding of these mechanisms could lead to more effective stroke prevention.
Ca <sup>2+</sup> Sparks and Their Function in Human Cerebral Arteries
Stroke - Tập 33 Số 3 - Trang 802-808 - 2002
George C. Wellman, David J. Nathan, Christine M. Saundry, Guillermo J. Pérez, Adrian D. Bonev, Paul L. Penar, Bruce I. Tranmer, Mark T. Nelson
Background and Purpose — Local Ca 2+ release events (Ca 2+ sparks) caused by the opening of ryanodine-sensitive Ca 2+ channels in the sarcoplasmic reticulum have been suggested to oppose constriction in cerebral arteries through the activation of large-conductance Ca 2+ -activated K + (BK) channels. We report the first identification and characterization of Ca 2+ sparks and associated BK channel currents in smooth muscle cells isolated from human cerebral arteries. Methods — Membrane currents and intracellular Ca 2+ were measured with the use of the patch-clamp technique and laser scanning confocal microscopy. Results — Ca 2+ sparks with a peak fractional fluorescence change (F/F 0 ) of 2.02±0.04 and size of 8.2±0.5 μm 2 (n=108) occurred at a frequency of approximately 1 Hz in freshly isolated, cerebral artery myocytes from humans. At a holding potential of −40 mV, the majority of, but not all, Ca 2+ sparks (61 of 85 sparks) were associated with transient BK currents. Consistent with a role for Ca 2+ sparks in the control of cerebral artery diameter, agents that block Ca 2+ sparks (ryanodine) or BK channels (iberiotoxin) were found to contract human cerebral arteries. Conclusions — This study provides evidence for local Ca 2+ signaling in human arterial myocytes and suggests that these events may play an important role in control of cerebral artery diameter in humans.
Resveratrol Preconditioning Protects Against Cerebral Ischemic Injury via Nuclear Erythroid 2–Related Factor 2
Stroke - Tập 46 Số 6 - Trang 1626-1632 - 2015
Srinivasan Narayanan, Kunjan R. Dave, Isa Saul, Miguel A. Pérez‐Pinzón
Background and Purpose— Nuclear erythroid 2 related factor 2 (Nrf2) is an astrocyte-enriched transcription factor that has previously been shown to upregulate cellular antioxidant systems in response to ischemia. Although resveratrol preconditioning (RPC) has emerged as a potential neuroprotective therapy, the involvement of Nrf2 in RPC-induced neuroprotection and mitochondrial reactive oxygen species production after cerebral ischemia remains unclear. The goal of our study was to study the contribution of Nrf2 to RPC and its effects on mitochondrial function. Methods— We used rodent astrocyte cultures and an in vivo stroke model with RPC. An Nrf2 DNA binding ELISA and protein analysis via Western blotting of downstream Nrf2 targets were performed to determine RPC-induced activation of Nrf2 in rat and mouse astrocytes. After RPC, mitochondrial function was determined by measuring reactive oxygen species production and mitochondrial respiration in both wild-type and Nrf2 −/− mice. Infarct volume was measured to determine neuroprotection, whereas protein levels were measured by immunoblotting. Results— We report that Nrf2 is activated by RPC in rodent astrocyte cultures, and that loss of Nrf2 reduced RPC-mediated neuroprotection in a mouse model of focal cerebral ischemia. In addition, we observed that wild-type and Nrf2 −/− cortical mitochondria exhibited increased uncoupling and reactive oxygen species production after RPC treatments. Finally, Nrf2 −/− astrocytes exhibited decreased mitochondrial antioxidant expression and were unable to upregulate cellular antioxidants after RPC treatment. Conclusions— Nrf2 contributes to RPC-induced neuroprotection through maintaining mitochondrial coupling and antioxidant protein expression.
Pharmacological Induction of Heme Oxygenase-1 by a Triterpenoid Protects Neurons Against Ischemic Injury
Stroke - Tập 43 Số 5 - Trang 1390-1397 - 2012
Feng Zhang, Suping Wang, Meijuan Zhang, Zhongfang Weng, Peiying Li, Yu Gan, Lili Zhang, Guodong Cao, Yanqin Gao, Rehana K. Leak, Michael B. Sporn, Jun Chen
Background and Purpose— Heme oxygenase-1 (HO-1) is an inducible Phase 2 enzyme that degrades toxic heme; its role in cerebral ischemia is not fully understood. We hypothesize that chemically induced HO-1 upregulation with the novel triterpenoid CDDO-Im (2-cyano-3,12 dioxooleana-1,9 dien-28-oyl imidazoline), a robust inducer of Phase 2 genes, protects neurons against ischemic injury. Methods— Using 3 different models of ischemia, including oxygen–glucose deprivation in neuronal cultures, global ischemia in rats, and focal ischemia in mice, we determined (1) whether CDDO-Im induces HO-1 expression and protects against ischemic injury; and (2) whether HO-1 inhibition disrupts the neuroprotective effect of CDDO-Im. Results— CDDO-Im treatment (50–300 nmol/L) resulted in 8-fold HO-1 upregulation in cultured neurons and protected against oxygen–glucose deprivation. The protection was abolished when the cultures were transfected with nuclear factor (erythroid-derived 2) like-2–shRNA or coincubated with tin protoporphyrin IX, a specific HO-1 inhibitor. In the rat model of global ischemia, intracerebroventricular infusion of CDDO-Im (0.5–1.5 μg) augmented HO-1 expression in hippocampal neurons and resulted in significant increases in CA1 neuronal survival after global ischemia. To further strengthen the clinical relevance of the CDDO-Im treatment, we tested its effects in the mouse model of temporary focal ischemia (60 minutes). Postischemic intraperitoneal injection of CDDO-Im (10–100 μg) enhanced HO-1 expression and significantly reduced neurological dysfunction and infarct volume. Intracerebroventricular infusion of tin protoporphyrin IX reduced the neuroprotective effect of CDDO-Im against global and focal ischemia. Conclusions— CDDO-Im confers neuroprotection against ischemic injury by upregulating HO-1, suggesting that enhance of HO-1 expression may be a legitimate strategy for therapeutic intervention of stroke.
β-Cell Function and Clinical Outcome in Nondiabetic Patients With Acute Ischemic Stroke
Stroke - Tập 52 Số 8 - Trang 2621-2628 - 2021
Takuya Kiyohara, Ryu Matsuo, Jun Hata, Kuniyuki Nakamura, Yoshinobu Wakisaka, Masahiro Kamouchi, Takanari Kitazono, Tetsuro Ago, Takao Ishitsuka, Setsuro Ibayashi, Kenji Kusuda, Kenichiro Fujii, T Nagao, Yasushi Okada, Masahiro Yasaka, Hiroaki Ooboshi, Tsuyoshi Omae, Ḱazunori Toyoda, Hiroshi Nakane, Hiroshi Sugimori, Shuji Arakawa, Kenji Fukuda, Jiro Kitayama, Shigeru Fujimoto, Shoji Arihiro, Junya Kuroda, Yoshihisa Fukushima, Yasuhiro Kumai
Background and Purpose: Little is known about how β-cell dysfunction affects clinical outcome after ischemic stroke. We examined whether β-cell function is associated with clinical outcome after acute ischemic stroke and if so, whether insulin resistance influences this association in a prospective study of patients with acute stroke. Methods: A total of 3590 nondiabetic patients with acute ischemic stroke (mean age, 71 years) were followed up for 3 months. β-Cell function was assessed using the homeostasis model assessment for β-cell function (HOMA-β). Study outcomes were poor functional outcome (modified Rankin Scale score, 3–6) and stroke recurrence at 3 months after stroke onset and neurological deterioration (≥2-point increase in the National Institutes of Health Stroke Scale score) at discharge. Logistic regression analysis was used to evaluate the association between quintile levels of serum HOMA-β and clinical outcomes. Results: The age- and sex-adjusted odds ratios for poor functional outcome and neurological deterioration increased significantly with decreasing HOMA-β levels ( P for trend, <0.001 and 0.001, respectively). These associations became more prominent after adjustment for HOMA-insulin resistance and were substantially unchanged even after further adjustment for other confounders, namely, body mass index, dyslipidemia, hypertension, estimated glomerular filtration rate, stroke subtype, National Institutes of Health Stroke Scale score on admission, and reperfusion therapy (odds ratio [95% CI] for the first versus fifth quintile of HOMA-β, 3.30 [2.15–5.08] for poor functional outcome and 10.69 [4.99–22.90] for neurological deterioration). Such associations were not observed for stroke recurrence. In stratified analysis for the combination of HOMA-β and HOMA-insulin resistance levels, lower HOMA-β and higher HOMA-insulin resistance levels were independently associated with increased risks of poor functional outcome and neurological deterioration. Conclusions: Our findings suggest that β-cell dysfunction is significantly associated with poor short-term clinical outcome independently of insulin resistance in nondiabetic patients with acute ischemic stroke.
Asiatic Acid Attenuates Infarct Volume, Mitochondrial Dysfunction, and Matrix Metalloproteinase-9 Induction After Focal Cerebral Ischemia
Stroke - Tập 43 Số 6 - Trang 1632-1638 - 2012
Ki Yong Lee, Ok‐Nam Bae, Kelsey Serfozo, Siamk Hejabian, Ahmad Moussa, Mathew J. Reeves, Wilson K. Rumbeiha, Scott D. Fitzgerald, Gary R Stein, Seung‐Hoon Baek, John L. Goudreau, Mounzer Kassab, Arshad Majid
Background and Purpose— Asiatic acid (AA) has been shown to attenuate cerebral infarction in a mouse model of focal ischemia and shows promise as a neuroprotective stroke therapy. To facilitate translation of these findings to clinical studies, we determined pharmacokinetics, a dose–response relationship, the therapeutic time window, and efficacy using multiple stroke models. We also explored potential mechanisms of action. Methods— Escalating doses of intravenous AA were administered and serum concentrations were measured at multiple time points for the pharmacokinetic studies. Subsequently, a dose–response relationship was determined followed by administration at different intervals after the onset of ischemia to establish a therapeutic time window for neuroprotection. Outcome measurements included both histological and behavioral. Mitochondrial function and matrix metalloproteinase activity in controls and treated rats were also determined. Results— The pharmacokinetic studies showed that AA (75 mg/kg) has a half-life of 2.0 hours. AA significantly decreased infarct volume and improved neurological outcome even when administration was at time points up to 12 hours after the onset of ischemia. Infarct volume was also significantly decreased in female rats and spontaneously hypertensive rats. AA attenuated mitochondrial dysfunction and reduced matrix metalloproteinase-9 induction. Conclusions— Our study shows AA is effective against multiple models of focal ischemia, has a long therapeutic time window, and is also effective in females and hypertensive animals. AA may mediate neuroprotection by protecting mitochondria and inhibiting matrix metalloproteinase-9 induction and activation. Taken together these data suggest that AA is an excellent candidate for development as a stroke therapy.
White Matter Injury After Subarachnoid Hemorrhage
Stroke - Tập 46 Số 10 - Trang 2909-2915 - 2015
Yusuke Egashira, Hao Zhao, Ya Hua, Richard F. Keep, Guohua Xi
Background and Purpose— We recently observed early white matter injury after experimental subarachnoid hemorrhage (SAH), but the underlying mechanisms are uncertain. This study investigated the potential role of matrix metalloproteinase (MMP)-9 in blood–brain barrier (BBB) disruption and consequent white matter injury. Methods— SAH was induced by endovascular perforation in adult male mice. The following 3 experiments were devised: (1) mice underwent magnetic resonance imaging at 24 h after SAH and were euthanized to determine BBB disruption and MMP-9 activation in white matter; (2) to investigate the role of MMP-9 in BBB disruption, lesion volumes on magnetic resonance imaging were compared between wild-type (WT) and MMP-9 knockout (MMP-9 −/− ) mice at 24 h after SAH; (3) WT and MMP-9 −/− mice underwent magnetic resonance imaging at 1 and 8 days after SAH to detect time-dependent changes in brain injury. Brains were used to investigate myelin integrity in white matter. Results— In WT mice with SAH, white matter showed BBB disruption (albumin leakage) and T2 hyperintensity on magnetic resonance imaging. MMP-9 activity was elevated at 24 h after SAH. MMP-9 −/− mice had less white matter T2 hyperintensity after SAH than WT mice. At 8 days after SAH, WT mice had decreased myelin integrity and MMP-9 −/− mice developed less white matter injury. Conclusions— SAH causes BBB disruption and consequent injury in white matter. MMP-9 plays an important role in those pathologies and could be a therapeutic target for SAH-induced white matter injury.
Estradiol Regulates Angiopoietin-1 mRNA Expression Through Estrogen Receptor-α in a Rodent Experimental Stroke Model
Stroke - Tập 36 Số 2 - Trang 337-341 - 2005
Agnieszka Ardelt, Louise D. McCullough, Kenneth S. Korach, Michael M. Wang, Diane H. Munzenmaier, Patricia D. Hurn
Background and Purpose— Female, compared with male, animals are protected from cerebral ischemic injury. Physiological concentrations of 17β-estradiol (E2) reduce damage in experimental stroke. E2 augments angiogenesis in reproductive organs and noncerebral vascular beds. We hypothesized that E2 protects brain in stroke through modulation of angiogenesis. We quantified molecular markers of angiogenesis and capillary density before and after unilateral middle cerebral artery occlusion (MCAO). Methods— Female animals were ovariectomized, treated with 25 μg E2 or placebo implants, and subjected to 2-hour MCAO and 22 hours of reperfusion. Brain angiopoietin-1 (Ang-1), Ang-2, Tie-1, Tie-2, vascular endothelial growth factor (VEGF), VEGF R1, and VEGF R2 mRNA levels were determined by RNAse protection assays, and CD31-positive vessels were counted. Results— E2, but not ischemia, upregulated cerebral Ang-1 mRNA by 49%. Capillary density was higher in the brains of E2-treated animals. In estrogen receptor-α knockout (ERKO) mice, E2-mediated induction of Ang-1 mRNA was absent relative to wild-type littermates. Conclusions— These results suggest that E2 increases Ang-1 and enhances capillary density in brain under basal conditions, priming the MCA territory for survival after experimental focal ischemia.
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