ß-Caryophyllene Liposomes Attenuate Neurovascular Unit Damage After Subarachnoid Hemorrhage in Rats.

This study was conducted to prepare ß-caryophyllene loaded liposomes (BCP-LP) and investigated their effects on neurovascular unit (NVU) damage after subarachnoid hemorrhage (SAH) in rats. A blood injection into the pre-chiasmatic cistern was used to achieve SAH. BCP-LP were prepared, characterized and administrated to rats with SAH. The prepared BCP-LP were spherical with a size distribution of approximately 189.3 nm and Zeta potential of - 13.9 mV. Neurological scoring, the balance beam test, cerebral blood flow monitoring, brain edema and biochemical analyses were applied to evaluate the effects of BCP-LP on rat NVU damage after SAH. The results demonstrated that BCP-LP treatment improved neurological function disorder, balance ability and cerebral blood perfusion in rats. Brain edema detection and blood-brain barrier permeability detection revealed that BCP-LP could reduce brain edema and promote repairment of blood-brain barrier after SAH. Using the western blot experiments, we demonstrated that BCP-LP attenuated the loss of tight junction proteins Occludin and Zonula occludens-1, inhibit the high expression of VEGFR-2 and GFAP, and promote the repair of laminin. These results demonstrate the protective effect BCP-LP exert in the NVU after SAH in rats, and supports the use of BCP-LP for future study and therapy of SAH.

Intracranial biodegradable silica-based nimodipine drug release implant for treating vasospasm in subarachnoid hemorrhage in an experimental healthy pig and dog model.

Nimodipine is a widely used medication for treating delayed cerebral ischemia (DCI) after subarachnoid hemorrhage. When administrated orally or intravenously, systemic hypotension is an undesirable side effect. Intracranial subarachnoid delivery of nimodipine during aneurysm clipping may be more efficient way of preventing vasospasm and DCI due to higher concentration of nimodipine in cerebrospinal fluid (CSF). The risk of systemic hypotension may also be decreased with intracranial delivery. We used animal models to evaluate the feasibility of surgically implanting a silica-based nimodipine releasing implant into the subarachnoid space through a frontotemporal craniotomy. Concentrations of released nimodipine were measured from plasma samples and CSF samples. Implant degradation was followed using CT imaging. After completing the recovery period, full histological examination was performed on the brain and meninges. The in vitro characteristics of the implant were determined. Our results show that the biodegradable silica-based implant can be used for an intracranial drug delivery system and no major histopathological foreign body reactions were observed. CT imaging is a feasible method for determining the degradation of silica implants in vivo. The sustained release profiles of nimodipine in CSF were achieved. Compared to a traditional treatment, higher nimodipine CSF/plasma ratios can be obtained with the implant.

Trigger factors and their attributable risk for rupture of intracranial aneurysms: a case-crossover study.

BACKGROUND AND PURPOSE: Little is known about activities that trigger rupture of an intracranial aneurysm. Knowledge on what triggers aneurysmal rupture increases insight into the pathophysiology and facilitates development of prevention strategies. We therefore aimed to identify and quantify trigger factors for aneurysmal rupture and to gain insight into the pathophysiology. METHODS: During a 3-year period, 250 patients with aneurysmal subarachnoid hemorrhage completed a structured questionnaire regarding exposure to 30 potential trigger factors in the period soon before subarachnoid hemorrhage (hazard period) and for usual frequency and intensity of exposure. We assessed relative risks (RR) of rupture after exposure to triggers with the case-crossover design comparing exposure in the hazard period with the usual frequency of exposure. Additionally, we calculated population-attributable risks. RESULTS: Eight triggers increased the risk for subarachnoid hemorrhage: coffee consumption (RR, 1.7; 95% CI, 1.2-2.4), cola consumption (RR, 3.4; 95% CI,1.5-7.9), anger (RR, 6.3; 95% CI, 4.6-25), startling (RR, 23.3; 95% CI, 4.2-128), straining for defecation (RR, 7.3; 95% CI, 2.9-19), sexual intercourse (RR, 11.2; 95% CI, 5.3-24), nose blowing (RR, 2.4; 95% CI, 1.3-4.5), and vigorous physical exercise (RR, 2.4; 95% CI, 1.2-4.2). The highest population-attributable risks were found for coffee consumption (10.6%) and vigorous physical exercise (7.9%). CONCLUSIONS: We identified and quantified 8 trigger factors for aneurysmal rupture. All triggers induce a sudden and short increase in blood pressure, which seems a possible common cause for aneurysmal rupture. Some triggers are modifiable, and further studies should assess whether reduction of exposure to these factors or measures preventing sudden increase in blood pressure decrease the risk of rupture in patients known to have an intracranial aneurysm.

Medidas protectoras frente a la isquemia cerebral tras hemorragia subaracnoidea (I) / Protective measures against cerebral ischemia following subarachnoid hemorrhage: part 1

Objetivos: La presencia de vasoespasmo cerebral tras hemorragia subaracnoidea aneurismática contribuye a la importante morbimortalidad de esta entidad. Por ello, se han desarrollado múltiples estudios con diferentes tratamientos dirigidos a su prevención, aunque la evidencia sobre su eficacia es limitada. Nuestro objetivo fue realizar una revisión bibliográfica de las diferentes terapias con evidencia científica para la prevención del vasoespasmo cerebral posthemorragia subaracnoidea aneurismática. Métodos: Búsqueda en MEDLINE (desde 1950 hasta octubre 2009) y revisión bibliográfica de las publicaciones halladas sobre prevención del vasoespasmo cerebral posthemorragia subaracnoidea aneurismática. Se restringió la búsqueda a artículos en inglés, francés y español. Se emplearon las palabras clave [cerebral vasospasm, subarachnoid hemorrhage, therapy, nimodipine, triple h, clazosentan, statins, magnesium] y sus combinaciones. Además se llevó a cabo una búsqueda manual en las referencias de los artículos seleccionados. Se incluyeron artículos que reunieran las siguientes condiciones: estudios controlados aleatorizados, metaanálisis, estudios clínicos no aleatorizados, estudios descriptivos, estudios analíticos observacionales, artículos de opinión y revisión. Resultados: La parte 1 analiza el tratamiento con calcioantagonistas y la triple terapia (hipertensión, hemodilución e hipervolemia) y la parte 2 analiza nuevas terapias como son el clazosentán, el magnesio y las estatinas. Hallamos 597 referencias de las cuales 283 fueron seleccionadas. Se incluyeron finalmente 61, las cuales se distribuyeron en 2 artículos de opinión, 21 estudios controlados aleatorizados, 22 artículos de revisión, 3 metaanálisis, 4 estudios clínicos no aleatorizados, 1 estudio descriptivo y 5 estudios analíticos observacionales. Tres estudios (2 metaanálisis y un estudio controlado aleatorizado) demostraron un beneficio en términos de morbimortalidad del uso del nimodipino en pacientes con hemorragia subaracnoidea aneurismática. Por el contrario en el análisis del resto de fármacos (clazosentán, estatinas y magnesio) no se objetivó un beneficio clínico estadísticamente significativo. Conclusiones: En la actualidad no hay suficiente evidencia para apoyar la utilización de triple terapia, clazosentán, estatinas y sulfato de magnesio para la prevención del vasoespasmo cerebral posthemorragia subaracnoidea aneurismática. El único tratamiento preventivo recomendado es el nimodipino(AU)

Background and objectives: Cerebral vasospasm following aneurysmal subarachnoid hemorrhage contributes significantly to morbidity and mortality. Many studies on the various treatments aimed at preventing cerebral vasospasm have been carried out, but evidence of efficacy is limited. Our aim was to review the literature on the various therapies for which there is scientific evidence of protection against cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Methods: MEDLINE search (1950 to the october 2009) and review of articles found on the prevention of cerebral vasospasm following aneurysmal subarachnoid hemorrhage. The search was restricted to articles in English, French, and Spanish. The keywords were cerebral vasospasm, subarachnoid hemorrhage, therapy, nimodipine, triple H, clazosentan, statins, and magnesium in addition to the word forms derived from them. We also searched manually for references cited in the selected articles. A title was included if it was a randomized controlled trial, meta-analysis, nonrandomized clinical trial, descriptive study, observational study with statistical analysis, opinion article, or expert review. Results: Part 1 analyzed treatment with calcium antagonists and triple-H therapy (hypertension, hemodilution, and hypervolemia). Part 2 analyzed new therapies such as clazosentan, magnesium, and statins. A total of 597 titles were located; 283 were initially selected. The 61 articles finally selected for review were of the following types: 2 opinion articles, 21 randomized controlled trials, 22 expert review articles, 3 meta-analyses, 4 nonrandomized clinical trials, 1 descriptive study, and 5 observational studies with statistical analysis. Three studies (2 meta-analyses and 1 randomized controlled trial) demonstrated that nimodipine use confers benefits (reduced morbidity and mortality) for patients with aneurysmatic subarachnoid hemorrhage. Statistically significant clinical benefits ould not be demonstrated for the other drugs (clazosentan, statins, and magnesium). Conclusions: Insufficient evidence is available to support the use of the triple-H therapy, clazosentan, statins, or magnesium sulfate for the prevention of cerebral vasospasm following subarachnoid hemorrhage. Nimodipine is the only preventative treatment that can be recommended(AU)

Coffee consumption and risk of stroke in women.

BACKGROUND AND PURPOSE: Coffee consumption has been inconsistently associated with stroke incidence and mortality in previous studies. We investigated the association between coffee consumption and stroke incidence in the Swedish Mammography Cohort. METHODS: We prospectively followed of 34,670 women without a history of cardiovascular disease or cancer at baseline in 1997. Coffee consumption was assessed in 1997 using a self-administered questionnaire. Incident stroke cases were ascertained from the Swedish Hospital Discharge Registry. RESULTS: During a mean follow-up of 10.4 years, we ascertained 1680 stroke events, including 1310 cerebral infarctions, 154 intracerebral hemorrhages, 79 subarachnoid hemorrhages, and 137 unspecified strokes. After adjustment for other risk factors, coffee consumption was associated with a statistically significant lower risk of total stroke, cerebral infarction, and subarachnoid hemorrhage but not intracerebral hemorrhage. The multivariable relative risks of total stroke across categories of coffee consumption (<1 cup/day, 1 to 2 cups/day, 3 to 4 cups/day, and ≥5 cups/day) were 1.00, 0.78 (95% CI, 0.66 to 0.91), 0.75 (95% CI, 0.64 to 0.88), and 0.77 (95% CI, 0.63 to 0.92, respectively; P for trend=0.02). The association between coffee consumption and cerebral infarction was not modified by smoking status, body mass index, history of diabetes or hypertension, or alcohol consumption. CONCLUSIONS: These findings suggest that low or no coffee consumption is associated with an increased risk of stroke in women.

Melatonin decreases mortality following severe subarachnoid hemorrhage.

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease that is associated with significant morbidity and mortality. There is substantial evidence to suggest that oxidative stress is significant in the development of acute brain injury following SAH. Melatonin is a strong antioxidant that has low toxicity and easily passes through the blood-brain barrier. Previous studies have shown that melatonin provides neuroprotection in animal models of ischemic stroke. This study hypothesizes that melatonin will provide neuroprotection when administered 2 hr after SAH. The filament perforation model of SAH was performed in male Sprague-Dawley rats weighing between 300 and 380 g. Melatonin (15 or 150 mg/kg), or vehicle was given via intraperitoneal injection 2 hr after SAH. Mortality and neurologic deficits were assessed 24 hr after SAH. A significant reduction in 24-hr mortality was seen following treatment with high dose melatonin. There was no improvement in neurologic scores with treatment. Brain water content and lipid peroxidation were measured following the administration of high dose melatonin to identify a mechanism for the increased survival. High dose melatonin tended to reduce brain water content following SAH, but had no effect on the lipid peroxidation of brain samples. Large doses of melatonin significantly reduces mortality and brain water content in rats following SAH through a mechanism unrelated to oxidative stress.

Habitual green tea consumption and risk of an aneurysmal rupture subarachnoid hemorrhage: a case-control study in Nagoya, Japan.

BACKGROUND: Green tea, a popular beverage in Japan, contains many polyphenolic antioxidants, which might prevent cardiovascular disease. This study is designed to determine whether the consumption of green tea is associated with a reduced risk for subarachnoid hemorrhage (SAH) using a case-control study. METHODS: Incident SAH cases (n=201) were identified and individually matched by age (+/-2 years) and gender to hospital (n=201) and community controls (n=201) from April 1992 to March 1997. Habitual regular tea consumption was assessed with a structured questionnaire. Conditional logistic regression models were used to compute odds ratios adjusted for smoking, history of hypertension, and educational levels. RESULTS: The proportion of the consumption of one time or more of tea per day was higher in controls (70.9%) than in SAH patients (60.3%). Multivariate analyses showed that green tea consumption was inversely associated with SAH risk. Subjects consuming <1, and >or=1 time per day had adjusted ORs of 0.74 (CI: 0.34-1.58), and 0.56 (CI: 0.32-0.98) in comparison with non daily green tea drinkers, respectively (p-trend <0.001). CONCLUSION: In a case-control study in Japan, we found that habitual green tea consumption may be strongly associated with a reduced risk for SAH. Our findings will be useful in targeting individuals and populations for the primary prevention of SAH.

Controlled trial of alpha-tocopherol and beta-carotene supplements on stroke incidence and mortality in male smokers.

Observational data suggest that diets rich in fruits and vegetables and with high serum levels of antioxidants are associated with decreased incidence and mortality of stroke. We studied the effects of alpha-tocopherol and beta-carotene supplementation. The incidence and mortality of stroke were examined in 28 519 male cigarette smokers aged 50 to 69 years without history of stroke who participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study). The daily supplementation was 50 mg alpha-tocopherol, 20 mg beta-carotene, both, or placebo. The median follow-up was 6.0 years. A total of 1057 men suffered from incident stroke: 85 men had subarachnoid hemorrhage; 112, intracerebral hemorrhage; 807, cerebral infarction; and 53, unspecified stroke. Deaths due to stroke within 3 months numbered 38, 50, 65, and 7, respectively (total 160). alpha-Tocopherol supplementation increased the risk of subarachnoid hemorrhage 50% (95% CI -3% to 132%, P=0.07) but decreased that of cerebral infarction 14% (95% CI -25% to -1%, P=0.03), whereas beta-carotene supplementation increased the risk of intracerebral hemorrhage 62% (95% CI 10% to 136%, P=0.01). alpha-Tocopherol supplementation also increased the risk of fatal subarachnoid hemorrhage 181% (95% CI 37% to 479%, P=0.01). The overall net effects of either supplementation on the incidence and mortality from total stroke were nonsignificant. alpha-Tocopherol supplementation increases the risk of fatal hemorrhagic strokes but prevents cerebral infarction. The effects may be due to the antiplatelet actions of alpha-tocopherol. beta-Carotene supplementation increases the risk of intracerebral hemorrhage, but no obvious mechanism is available.

The association of tranexamic acid and nimodipine in the pre-operative treatment of ruptured intracranial aneurysms.

In the scope of a late intervention policy on ruptured intracranial aneurysms, on D.+12 on an average, we first used tranexamic acid, at moderate doses: 3 g orally or 1.5 g intravenously per day. We, subsequently, added nimodipine, usually 240 mg orally per day or 2 mg intravenously per hour. The medical treatment consisted of amply sufficient hydration, and in systematic and regular administration of analgesics and sedatives. Hypotension was absolutely avoided; if necessary, an antihypertensive treatment was prescribed very cautiously. Phenytoin was regularly given. In the present study, we try to answer the following questions: (1) Can we confirm that the preventive action of tranexamic acid remains as effective, when doses, markedly lower than usually recommended, are used? (2) Does nimodipine prevent the increase of pre-operative ischaemic complications, which should be expected when tranexamic acid is administered? Amongst 101 patients with SAH of proven aneurysmal origin, 84 were treated with tranexamic acid and nimodipine. In 25 patients, an aneurysm was not visualised; 21 received this treatment. For several reasons, only a retrospective study was possible, to evaluate the results of our antifibrinolytic and calcium-blocking therapies, on rebleeding and pre-operative delayed ischaemia. We compared, therefore, similar cases from the literature, with our own cases, taking into consideration the clinical grades, the days of admission and of intervention, the moment of rebleeding and of delayed pre-operative ischaemia, etc. The following impressions emerge: (1) same effectiveness of moderate doses of tranexamic acid; (2) no increase of pre-operative delayed ischaemic complications, in comparison with patients not receiving antifibrinolytics but nimodipine; (3) important role of a devastating initial bleed and of operative complications; (4) difficulty of avoiding rebleeding at D.0, whatever the therapeutic measures, medical and/or surgical.

Identification, characterization, and functional role of phosphodiesterase type IV in cerebral vessels: effects of selective phosphodiesterase inhibitors.

The role of the phosphodiesterase type IV isozyme (PDE IV) in the regulation of cerebrovascular tone was investigated in the canine basilar artery in vitro and in vivo. The PDE isozymes extracted from the canine basilar artery were isolated by diethylaminoethanol (DEAE)-Sepharose affinity chromatography and identified based on sensitivity to isozyme-selective PDE inhibitors. [3H]cAMP hydrolysis was observed in one major and one minor peak of activity. The predominant peak was inhibited by the addition of cGMP (25%), siguazodan (26%), rolipram (39%), and the combination of siguazodan and rolipram (95%). Selective PDE IV inhibitors BRL 61063, rolipram, and denbufylline were equieffective inhibitors of [3H]-ccAMP hydrolysis mediated by PDE IV isolated from the canine basilar artery [concentrations producing 50% inhibition (IC50S) = 0.21 +/- 0.05 microM, 0.67 +/- 0.23 microM, and 0.73 +/- 0.16 microM, respectively]. In precontracted isolated ring segments of the canine basilar artery, selective PDE IV inhibitors produced potent and complete relaxation (IC50S < 150 nM). In contrast, zaprinast (a selective PDE V inhibitor) and siguazodan (a selective PDE III inhibitor) produced only weak relaxation of the basilar artery (IC50S = 4.5 microM and > 10 microM, respectively). Vasorelaxation produced by PDE IV inhibitors was not altered by removing the endothelium, 1-NAME, or adenosine receptor antagonism. In a canine model of acute cerebral vasospasm, all three selective PDE IV inhibitors reversed basilar artery spasm produced by autologous blood without altering mean arterial blood pressure. In contrast, prolonged treatment with BRL 61063 failed to alter the development of basilar spasm in the two hemorrhage canine models of chronic cerebral vasospasm. Denbufylline-induced relaxation in vitro was also significantly impaired in basilar arteries obtained from the model of chronic vasospasm. In conclusion, PDE IV appears to be the predominant isozyme regulating vascular tone mediated by cAMP hydrolysis in cerebral vessels. In addition, vasorelaxation modulated by PDE IV is compromised in chronic cerebral vasospasm associated with subarachnoid hemorrhage.