salicylates and Brain-Ischemia

Excess activation of ionotropic glutamate receptors, primarily N-methyl-D-aspartate (NMDA) receptors and free radicals, evoke nerve cell death following hypoxic-ischemic brain injury in various animal models. However, clinical trials in stroke patients using NMDA receptor antagonists have failed to show efficacy primarily due to the limited therapeutic time window for neuroprotection and a narrow therapeutic index. In comparison, antioxidants prolonged the time window for neuroprotection in animal models of ischemic stroke and showed greater therapeutic potential in clinical trials for ischemic stroke. Excess activation of NMDA receptors and free radicals mediate the two separate pathways of nerve cell death in stroke and a safe and multifunctional drug that can block both routes in the brain will likely provide a better therapeutic outcome in patients with stroke. Derivatives of the lead structures of sulfasalazine and aspirin have led to the discovery of a new molecule, Neu2000, that has demonstrated excellent neuroprotection against NMDA- and free radical-induced cell death. Neu2000 is an NR2B-selective, moderate NMDA receptor antagonist with potent cell-permeable, spin trapping antioxidant action even at nanomolar concentrations. Nonclinical and human phase I studies demonstrated that Neu2000 can be translated to treat patients with stroke with better efficacy and therapeutic time window.

Topics: Animals; Antioxidants; Benzoates; Brain Ischemia; Drug Delivery Systems; Fluorobenzenes; Humans; meta-Aminobenzoates; Neuroprotective Agents; Receptors, N-Methyl-D-Aspartate; Salicylates; Spin Trapping; Stroke; Time Factors

Triflusal has demonstrated an efficacy similar to aspirin in the prevention of vascular events in patients with acute myocardial infarction (ΜΙ) and ischaemic stroke but with less bleeding events.. We performed a randomised, multicentre, phase 4 clinical trial to compare the clinical efficacy and safety of triflusal versus aspirin, administered for 12 months in patients eligible to receive a cyclooxygenase-1 (COX-1) inhibitor.. Patients with stable coronary artery disease or with a history of non-cardioembolic ischaemic stroke were randomly assigned to receive either triflusal 300 mg twice or 600 mg once daily or aspirin 100 mg once daily for 12 months. The primary efficacy endpoint was the composite of: (a) ΜΙ, (b) stroke (ischaemic or haemorrhagic), or, (c) death from vascular causes for the entire follow-up period. The primary safety endpoints were the rate of bleeding events as defined by Bleeding Academic Research Consortium (BARC) criteria.. At 12-month follow-up, an equivalent result was revealed between the triflusal (n=559) and aspirin (n=560) in primary efficacy endpoint. Specifically, the combined efficacy outcome rate (i.e. MI, stroke or death from vascular causes) difference was equal to -1.3% (95% confidence interval -1.1 to 3.5) and lied within the a-priori defined equivalence interval (p<0.001). Regarding the primary safety endpoints, patients on triflusal treatment were 50% less likely to develop bleeding events according to the BARC criteria, and especially any clinically overt sign of haemorrhage that requires diagnostic studies, hospitalisation or special treatment (BARC type 2).. The efficacy of triflusal in the secondary prevention of vascular events is similar to aspirin when administered for 12 months. Importantly, triflusal significantly reduced the incidence of ΜΙ and showed a better safety profile compared with aspirin. (ASpirin versus Triflusal for Event Reduction In Atherothrombosis Secondary prevention, ASTERIAS trial; Clinical Trials.gov Identifier: NCT02616497).

Topics: Aged; Aspirin; Brain Ischemia; Coronary Artery Disease; Cyclooxygenase Inhibitors; Female; Greece; Hemorrhage; Humans; Intracranial Embolism; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Recurrence; Risk Factors; Salicylates; Secondary Prevention; Stroke; Time Factors; Treatment Outcome

The potential of neuroprotective agents should be revisited in the era of endovascular thrombectomy (EVT) for acute large-artery occlusion because their preclinical effects have been optimized for ischemia and reperfusion injury. Neu2000, a derivative of sulfasalazine, is a multi-target neuroprotectant. It selectively blocks N-methyl-D-aspartate receptors and scavenges for free radicals. This trial aimed to determine whether neuroprotectant administration before EVT is safe and leads to a more favorable outcome.. This trial is a phase-II, multicenter, three-arm, randomized, double-blinded, placebo-controlled, blinded-endpoint drug trial that enrolled participants aged ≥ 19 years undergoing an EVT attempt less than 8 h from symptom onset, with baseline National Institutes of Health Stroke Scale (NIHSS) score ≥ 8, Alberta Stroke Program Early CT score ≥ 6, evidence of large-artery occlusion, and at least moderate collaterals on computed tomography angiography. EVT-attempted patients are randomized into control, low-dose (2.75 g), and high-dose (5.25 g) Neu2000KWL over 5 days. Seventy participants per group are enrolled for 90% power, assuming that the treatment group has a 28.4% higher proportion of participants with functional independence than the placebo group. The primary outcome, based on intention-to-treat criteria is the improvement of modified Rankin Scale (mRS) scores at 3 months using a dichotomized model. Safety outcomes include symptomatic intracranial hemorrhage within 5 days. Secondary outcomes are distributional change of mRS, mean differences in NIHSS score, proportion of NIHSS score 0-2, and Barthel Index > 90 at 1 and 4 weeks, and 3 months.. The trial results may provide information on new therapeutic options as multi-target neuroprotection might mitigate reperfusion injury in patients with acute ischemic stroke before EVT.. ClinicalTrials.gov, ID: NCT02831088 . Registered on 13 July 2016.

Topics: Brain Ischemia; Clinical Trials, Phase II as Topic; Disability Evaluation; Double-Blind Method; Endovascular Procedures; Fluorobenzenes; Humans; meta-Aminobenzoates; Multicenter Studies as Topic; Neuroprotective Agents; Prospective Studies; Randomized Controlled Trials as Topic; Recovery of Function; Republic of Korea; Salicylates; Stroke; Thrombectomy; Time Factors; Treatment Outcome

The antiplatelet effect of clopidogrel is reportedly influenced by cytochrome P450 2C19 (CYP2C19) polymorphisms. However, there is no data concerning the relationship between stroke recurrence and CYP2C19 polymorphisms in patients treated with clopidogrel for secondary prevention of ischemic stroke. Triflusal may be an alternative therapy for clopidogrel in patients with poor genotype. The Comparison of Triflusal and Clopidogrel Effects in Secondary Prevention of Stroke Based on Cytochrome P450 2C19 Genotyping (MAESTRO) study will investigate the effect of antiplatelet agents based on CYP2C19 polymorphisms in secondary prevention of ischemic stroke.. Assuming that 55% of patients belong to the poor genotype group, the required sample size is 1080 patients with at least 24 months of follow-up. This study is designed as a prospective, multicenter, randomized, parallel-group, open-label, and blind genotype trial. Patients who experience their first non-cardiogenic ischemic stroke within 30 days prior to screening are eligible. Patients received 300 mg triflusal twice a day or 75 mg clopidogrel once daily during the trial. The study is registered with ClinicalTrials.gov (NCT01174693).. The primary outcome is recurrent ischemic stroke or hemorrhagic stroke. Secondary outcomes consist of composite major vascular events including stroke, myocardial infarction, coronary revascularization, or vascular death.. Personalized medicine may be essential for patients according to individual drug metabolism abilities. MAESTRO is the first prospective study designed to evaluate the effect of CYP2C19 polymorphism in secondary stroke prevention and will resolve several questions regarding preventive antiplatelet agents for recurrent stroke.

Topics: Brain Ischemia; Cerebral Hemorrhage; Chemoprevention; Clopidogrel; Cytochrome P-450 CYP2C19; Follow-Up Studies; Genotype; Humans; Pharmacogenomic Variants; Platelet Aggregation Inhibitors; Recurrence; Salicylates; Secondary Prevention; Single-Blind Method; Stroke; Ticlopidine; Treatment Outcome

The mean follow-up in the clinical trials of antiplatelet drugs in the secondary prevention of ischemic atherothrombotic stroke ranges from 1 to 5.5 years. Thus, the safety and efficacy of these drugs in the very long term is not totally documented. We have assessed the safety and effectiveness of triflusal and aspirin for a very long-term period in the secondary prevention of patients with ischemic atherothrombotic stroke.. Patients with atherothrombotic ischemic stroke, including TIA, who participated in randomized clinical trials of triflusal versus aspirin were included in the study. The period of recruitment was between 1983 and 1999. After finishing their participation in the clinical trials, patients were followed up in the Neurology Department of our hospital. All patients were treated with aspirin or triflusal during a mean period of 17.2 years. Groups were comparable with respect to sex, age, risk factor and etiology of the stroke. Adverse events and vascular events (including stroke recurrence, ischemic heart disease and vascular death) that appeared throughout the study were registered. Statistical analysis was performed using the statistical package SPSS 15.0 for Windows. Kaplan-Meier curves and the log-rank test were used to compare treatments.. A total of 441 patients (305 men) with a mean age (±SD) of 51.1±12.4 years were included in the study; 288 patients (65.3%) were treated with triflusal and 153 with aspirin. There were no statistically significant differences between aspirin and triflusal concerning new vascular events (72.5 vs. 60.4%; p=0.28), stroke recurrence (49.7 vs. 46.5%; p=0.53), ischemic heart events (54.9 vs. 55.6%; p=0.90), vascular death (25.5 vs. 24%; p=0.73) and global mortality (42.5 vs. 42%; p=0.92). The incidence of serious bleeding (upper digestive tract hemorrhage and cerebral hemorrhage) was 18.3% in aspirin-treated patients and 5.5% in triflusal-treated patients (p<0.001). In reference to other adverse events, no significant differences were found between aspirin and triflusal.. In the secondary prevention of ischemic stroke, very long-term treatment with triflusal or aspirin seems to have a similar efficacy, but triflusal is safer with a lower hemorrhagic risk. Triflusal may be an alternative therapy, particularly in patients who present aspirin resistance.

Topics: Aged; Aspirin; Brain Ischemia; Dyspepsia; Female; Follow-Up Studies; Hemorrhage; Humans; Incidence; Intracranial Arteriosclerosis; Ischemic Attack, Transient; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Ischemia; Platelet Aggregation Inhibitors; Recurrence; Salicylates; Secondary Prevention; Vascular Diseases

The purpose of this study is to identify factors which predict adherence in stroke survivors.. This is a longitudinal study where 180 stroke survivors were assessed 1 year after their first ischaemic stroke. The relationship between adherence and illness and medication beliefs was tested at baseline (time 1) and again 5-6 weeks later (time 2).. The main outcome measures used in this study are Medication Adherence Report Scale and urinary salicylate levels.. Four variables predicted time 1 poor adherence: (1) younger age, (2) increased specific concerns about medications, (3) reduced cognitive functioning and (4) low perceived benefit of medication. Three out of these four variables were again predictive of time 2 adherence and accounted for 24% of the variance: (1) younger age, (2) increased specific concerns about medications and (3) low perceived benefit of medication. The urinary salicylate assay failed to differentiate between patients taking and not taking aspirin.. Interventions to improve adherence should target patients' beliefs about their medication.

Topics: Age Factors; Aged; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Attitude to Health; Brain Ischemia; Cognition; Female; Humans; Longitudinal Studies; Male; Medication Adherence; Psychiatric Status Rating Scales; Salicylates; Secondary Prevention; Severity of Illness Index; Stroke

Triflusal is a 4-fluoromethyl derivative of salicylic acid used for secondary prevention of ischemic stroke. Recent experimental data (permanent middle cerebral artery occlusion in rats) have shown a possible role of triflusal in neuroprotection through inhibition of inflammatory pathways.. To explore whether triflusal may modulate those pathways in human stroke, evolution of several inflammation markers (pro-inflammatory, adhesion molecules, chemokines, metalloproteinases, apoptosis and angiogenesis-related biomarkers) and neurological outcome were evaluated at baseline, and at days 1, 3, 7 and 90 in a pilot study in which 30 patients with acute ischemic stroke were randomly allocated to receive triflusal or aspirin.. An increase in IL-6 level was found in the aspirin group when compared to the triflusal group at the third and seventh day (p < 0.05). FGF-basic level was significantly increased at days 1 and 90 in the triflusal group (p = 0.040). The triflusal group also had higher levels of MIP-1alpha and MIP-1beta (p < 0.05) at day 1. Also among triflusal-treated patients, MCP-1 and TARC levels were increased as compared with the aspirin group at day 90 (p < 0.05). Interestingly, some of those markers modified by triflusal (MCP-1 and IL-6) were associated with neurological outcome: higher MCP-1 measured at day 3 among patients who improve at day 7 [462.3 (419.2-735.2) vs. 285 (242.1-428.2), p < 0.05], and lower levels of IL-6 at day 3 among patients who improve at day 90 [24.8 (5.6-77.3) vs. 5.4 (2.0-13.8), p < 0.05].. Triflusal modulates additional mechanisms to those of aspirin [pro-inflammatory (IL-6) and chemokine (MIP-1 and MCP-1) pathways] that could participate in the ischemic damage process following human acute stroke.

Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents; Aspirin; Biomarkers; Brain Ischemia; Female; Humans; Inflammation Mediators; Logistic Models; Male; Middle Aged; Neuroprotective Agents; Pilot Projects; Platelet Aggregation Inhibitors; Prospective Studies; Salicylates; Stroke; Time Factors; Treatment Outcome

The effectiveness of the low doses AAS in the prevention of the cerebral infarction has not been clearly still verified.. To compare the long term effectiveness of the treatment with low doses AAS in front of triflusal in the reduction of the stroke, ischemic cardiopathy, and cardiovascular death risks.. Of 386 patients with a first ischemic stroke, 217 were selected (106 triflusal, 111 AAS) that completed the approaches of atheromatous infarct (161 males, 72.2% and 58 female, 25.8%). The mean age was 43 years (standard deviation, SD 6.4, 95% CL 20-50). The patients received one of theses treatments: a) AAS (Sedergine) 330 mg/day (once a day); b) Triflusal (Disgren), 900 mg/day (300 mg 3 times a day). The mean time of follow-up for the group triflusal was of 48.3 months (20-94), while for the group AAS was of 46.3 months (2-84).. The combined incidence of cerebral infarcts, ischemic cardiopathy and vascular death was 19.8% in the patients treated with triflusal, and 28.8% in the patients treated with AAS what supposes a reduction of the risk of the 39% (OR 0.61; CL 0.30-2.01). In the subgroup of patients with carotid stenoses of more than 70% demonstrated by angiography, triflusal produces a significant reduction of risk (OR 0.30; CL 0.10-0.90). Also, triflusal reduced in 76% the risk of hemorrhagic complications in comparison of the AAS (OR 0.24; IC 0.06-0.94).. The study adds new doubts about the effectiveness of the low doses of AAS in the secondary prevention of the cerebral infarct. The triflusal shows effectiveness in subgroup of high risk and a significative reduction of the hemorrhagic complications that would be confirmed in controlled clinical trials with a greater number of patients.

Topics: Adult; Aspirin; Brain Ischemia; Cardiovascular Diseases; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Salicylates; Survival Rate

Background and Purpose- Although intracellular zinc accumulation has been shown to contribute to neuronal death after cerebral ischemia, the mechanism by which zinc keeps on accumulating to cause severe brain damage remains unclear. Herein the dynamic cause-effect relationships between zinc accumulation and reactive oxygen species (ROS) production during cerebral ischemia/reperfusion are investigated. Methods- Rats were treated with zinc chelator, ROS scavenger, mitochondria-targeted ROS inhibitor, or NADPH oxidase inhibitor during a 90-minute middle cerebral artery occlusion. Cytosolic labile zinc, ROS level, cerebral infarct volume, and neurological functions were assessed after ischemia/reperfusion. Results- Zinc and ROS were colocalized in neurons, leading to neuronal apoptotic death. Chelating zinc reduced ROS production at 6 and 24 hours after reperfusion, whereas eliminating ROS reduced zinc accumulation only at 24 hours. Furthermore, suppression of mitochondrial ROS production reduced the total ROS level and brain damage at 6 hours after reperfusion but did not change zinc accumulation, indicating that ROS is produced mainly from mitochondria during early reperfusion and the initial zinc release is upstream of ROS generation after ischemia. Suppression of NADPH oxidase decreased ROS generation, zinc accumulation, and brain damage only at 24 hours after reperfusion, indicating that the majority of ROS is produced by NADPH oxidase at later reperfusion time. Conclusions- This study provides the direct evidence that there exists a positive feedback loop between zinc accumulation and NADPH oxidase-induced ROS production, which greatly amplifies the damaging effects of both. These findings reveal that different ROS-generating source contributes to ischemia-generated ROS at different time, underscoring the critical importance of spatial and temporal factors in the interaction between ROS and zinc accumulation, and the consequent brain injury, after cerebral ischemia/reperfusion.

Topics: Animals; Antioxidants; Apoptosis; Biphenyl Compounds; Brain; Brain Ischemia; Chelating Agents; Ethylenediamines; Infarction, Middle Cerebral Artery; NADPH Oxidases; Neurons; Onium Compounds; Organometallic Compounds; Pramipexole; Rats; Reactive Oxygen Species; Salicylates; Zinc

2-Hydroxy-4-trifluoromethylbenzoic acid (HTB) is a metabolite of triflusal (TF), and has been reported to exert anti-inflammatory effect. In this study, the authors investigated whether HTB has a neuroprotective effect against ischemic brain injuries. We showed that intravenous administration of HTB (5mg/kg) 30min before or 1, 3, or 6h after middle cerebral artery occlusion (MCAO) reduced brain infarct to 10.4±3.3%, 16.9±2.3%, 22.2±1.5% and 40.7±7.5%, respectively, of that of treatment-naive MCAO controls, and the therapeutic time window extended to 9h after MCAO (40.7±7.5%). Furthermore, HTB suppressed infarct formation, protected motor activities, and ameliorated neurological deficits more effectively than by TF or salicylic acid (SA). HTB markedly suppressed microglial activation and proinflammatory cytokines expressions in the postischemic brain and in BV2 cells and suppressed LPS-induced nitrite production by inhibiting IkB degradation. In addition, HTB suppressed NMDA-induced neuronal cell death more effectively than TF or SA in primary cortical neuron cultures. Together, these results indicate that HTB has multi-modal protective effects against ischemic brain damage that encompass anti-inflammatory, anti-excitotoxicity, and anti-Zn

Topics: Animals; Anti-Inflammatory Agents; Aspirin; Brain; Brain Ischemia; Cytokines; Infarction, Middle Cerebral Artery; Male; Neurons; Neuroprotective Agents; Rats, Sprague-Dawley; Salicylates

Postischemic brain damage in stroke is proceded with complicated pathological events, and so multimodal drug treatments may offer better therapeutic means for improving clinical outcomes. Here, we report robust neuroprotective effects of a novel compound, 2-((2-oxopropanoyl)oxy)-4-(trifluoromethyl)benzoic acid (OPTBA), a 2-hydroxy-4-trifluoromethyl benzoic acid (HTB, a metabolite of triflusal)-pyruvate ester. Intravenous administration of OPTBA (5 mg/kg) 3 or 6 h after middle cerebral artery occlusion (MCAO) in Sprague-Dawley rats reduced infarct volumes to 38.5 ± 11.4% and 46.5 ± 15.3%, respectively, of that of MCAO controls, and ameliorated motor impairment and neurological deficits. Importantly, neuroprotective effects of OPTBA were far greater than those afforded by combined treatment of HTB and pyruvate. Furthermore, OPTBA suppressed microglial activation and proinflammatory cytokine inductions more effectively than HTB/pyruvate co-treatment in the postischemic brain and LPS-treated cortical slice cultures and also attenuated NMDA-induced neuronal death in hippocampal slice cultures. LC-MS analysis demonstrated that OPTBA was hydrolyzed to HTB and pyruvate with a t1/2 of 38.6 min in blood and 7.2 and 2.4 h in cortex and striatum, respectively, and HTB was maintained for more than 24 h both in blood and brain tissue. Together these results indicate OPTBA acts directly and via its hydrolysis products, thus acting as a multimodal neuroprotectant in the postischemic brain.

Topics: Animals; Benzoates; Blood-Brain Barrier; Brain Ischemia; Cytokines; Disease Models, Animal; Hydrolysis; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Salicylates; Stroke

Cerebral ischemia leads to brain injury via a complex series of pathophysiological events. Therefore, multidrug treatments or multitargeting drug treatments are attractive options in efficiently limiting brain damage. Here, we report a novel multifunctional compound oxopropanoyloxy benzoic acid (OBA-09), a simple ester of pyruvate and salicylic acid. This protective effect was manifested by recoveries from neurological and behavioral deficits. OBA-09 exhibited antioxidative effects in the postischemic brain, which was evidenced by remarkable reduction of lipid peroxidation and 4-hydroxy-2-nonenal staining in OBA-09-administered animals. Reactive oxygen species generation was markedly suppressed in primary cortical cultures under oxygen-glucose deprivation. More interestingly, OBA-09 was capable of scavenging hydroxyl radical in cell-free assays. High-performance liquid chromatography results demonstrated that OBA-09 was hydrolyzed to salicylic acid and pyruvate with t(1/2) = 43 min in serum and 4.2 h in brain parenchyma, indicating that antioxidative function of OBA-09 is executed by itself and also by salicylic acid after the hydrolysis. In addition to antioxidative function, OBA-09 exerts anti-excitotoxic and anti-Zn(2+)-toxic functions, which might be attributed to attenuation of ATP and nicotinamide adenine dinucleotide depletion and to the suppression of nuclear factor-κB activity induction. Together these results indicate that OBA-09 has a potent therapeutic potential as a multimodal neuroprotectant in the postischemic brain and these effects were conferred by OBA-09 itself and subsequently its hydrolyzed products.

Topics: Animals; Brain; Brain Ischemia; Cells, Cultured; Chromatography, High Pressure Liquid; Hydrolysis; Kinetics; L-Lactate Dehydrogenase; Mice; NAD; Neuroprotective Agents; Pyruvates; Reactive Oxygen Species; Salicylates; Spectrometry, Mass, Electrospray Ionization

Clinical data has shown that stroke exacerbates dementia in Alzheimer's disease (AD) patients. Previous work, combining rat models of AD and stroke have shown that neuroinflammation may be the common mediator between AD and stroke toxicity. This study examined the effects of triflusal (2-acetoxy-4-trifluoromethylbenzoic acid) in APP(23) transgenic mice receiving strokes. Six month-old APP(23) mice over-expressing mutant human amyloid precursor protein (APP) were used to model AD in this study. Unilateral injections of a potent vasoconstrictor, endothelin-1, into the striatum were used to mimic small lacunar infarcts. Immunohistochemical analysis was performed to examine AD-like pathology and inflammatory correlates of stroke and AD. APP(23) mice showed increases in AD-like pathology and inflammatory markers of AD in the cortex and hippocampus. Endothelin-induced ischemia triggered an inflammatory response along with increases in AD pathological markers in the region of the infarct. Triflusal reduced inflammation surrounding the endothelin-induced infarct only. At the dose used, anti-inflammatory treatment may be beneficial in reducing the AD and inflammatory correlates of stroke in a combined AD-stroke mouse model.

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Antigens, CD; Brain Ischemia; Disease Models, Animal; Endothelin-1; Humans; Inflammation; Mice; Mice, Inbred C57BL; Mice, Transgenic; NF-kappa B; Platelet Aggregation Inhibitors; Salicylates; Stroke; tau Proteins; Tumor Necrosis Factor-alpha

Excitotoxicity and oxidative stress mediate neuronal death after hypoxic-ischemic brain injury. We examined the possibility that targeting both N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity and oxidative stress would result in enhanced neuroprotection against hypoxic-ischemia. 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid (Neu2000) was derived from aspirin and sulfasalazine to prevent both NMDA neurotoxicity and oxidative stress. In cortical cell cultures, Neu2000 was shown to be an uncompetitive NMDA receptor antagonist and completely blocked free radical toxicity at doses as low as 0.3 micromol/L. Neu2000 showed marked neuroprotection in a masked fashion using histology and behavioral testing in two rodent models of focal cerebral ischemia without causing neurotoxic side effects. Neu2000 protected against the effects of middle cerebral artery occlusion, even when delivered 8 h after reperfusion. Single bolus administration of the drug prevented gray and white matter degeneration and spared neurologic function for over 28 days after MACO. Neu2000 may be a novel therapy for combating both NMDA receptor-mediated excitotoxicity and oxidative stress, the two major routes of neuronal death in ischemia, offering profound neuroprotection and an extended therapeutic window.

Topics: Animals; Antioxidants; Aspirin; Benzoates; Brain Ischemia; Cells, Cultured; Excitatory Amino Acid Antagonists; Fluorobenzenes; Infarction, Middle Cerebral Artery; meta-Aminobenzoates; Mice; N-Methylaspartate; Oxidative Stress; Receptors, N-Methyl-D-Aspartate; Salicylates; Sulfasalazine

Neuroinflammation plays a critical role in the pathogenesis of cerebral ischemia. Triflusal, a selective cyclooxygenase-2, and its active metabolite 3-hydroxy-4-trifluoromethylbenzoic acid may inhibit apoptosis and inflammation after cerebral ischemia. An in vivo model of cerebral ischemia was used to investigate the effects of triflusal and aspirin treatment on infarct volume, and inflammation after cerebral ischemia in the rat.. Male Wistar rats were subjected to a permanent right-sided middle cerebral artery occlusion. Rats received oral administration of either triflusal or aspirin. After 3 days after surgery, immunostaining was used to detect neuroinflammatory cells and molecules, and infarct volumes were measured.. Both triflusal and aspirin at a dose of 30 mg/kg but not 10 mg/kg significantly reduced infarct volume compared with vehicle treatment. Middle cerebral artery occlusion resulted in increased astrocyte and heat shock protein-27 (Hsp27) immunostaining in the ipsilateral cortex. Triflusal (30 mg/kg) or aspirin treatment (30 mg/kg) did not reduce the levels of GFAP or Hsp27 immunostaining. Triflusal (30 mg/kg) also significantly decreased the protein levels of IL-Ibeta but not nuclear factor kappa B or tumor necrosis factor-alpha in the cortex ipsilateral to the middle cerebral artery occlusion.. The results suggest that triflusal and aspirin appear to be equally neuroprotective against middle cerebral artery occlusion-induced cerebral ischemia. Therefore, strong rationale exists to continue the neuroprotective examination of triflusal in brain injury.

Topics: Animals; Aspirin; Brain Ischemia; Disease Models, Animal; Drug Therapy, Combination; Male; Rats; Rats, Wistar; Salicylates

Clinical data suggest that Alzheimer disease (AD) and stroke together potentiate cognitive impairment. Our rat model demonstrates that this interaction may be mediated through inflammatory cells and pathways. Thus, anti-inflammatory agents such as Triflusal, a nonsteroidal anti-inflammatory agent (NSAID), may provide neuroprotection for susceptible neurons in AD and cerebral ischemia.. AD was modeled by cerebroventricular injections of beta-amyloid (Abeta25-35) and subcortical lacunar infarcts by striatal endothelin injections. Inflammatory mechanisms were examined by immunohistochemical analysis. Behavioral tasks were assessed with the Montoya staircase test.. Triflusal reduced pathologic and inflammatory markers and functional deficits in rats receiving Abeta or endothelin alone but was less effective in the more severe pathology of the combined Abeta/endothelin model.. Higher doses or more prolonged treatment with NSAIDs may be required for more effective neuroprotection in combined AD and stroke conditions.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Astrocytes; Behavior, Animal; Brain; Brain Ischemia; Corpus Striatum; Cytokines; Disease Models, Animal; Endothelins; Glial Fibrillary Acidic Protein; Hippocampus; Immunohistochemistry; Inflammation; Microglia; Neurons; Peptides; Rats; Rats, Wistar; Salicylates; Temperature

Aspirin reduces the size of infarcts after ischaemic stroke. Although this fact has been attributed to its antiplatelet actions, direct neuroprotective effects have been also reported. We have demonstrated that aspirin is neuroprotective by inhibiting glutamate release in "in vitro" models of brain ischaemia. A pharmacological dissection of the components involved, using cell cortical culture exposed to oxygen-glucose deprivation, indicated that aspirin selectively inhibits the increase in extracellular glutamate concentration which results from reversal of the glutamate transporter, a component of release which is due to ATP depletion. Moreover, the neuroprotection afforded by aspirin occurred in parallel to a lesser decay in ATP levels after OGD. Aspirin not only elevated ATP levels in intact cortical neurones, but also in isolated brain mitochondria. On the other hand, using a whole-animal model of permanent focal brain ischaemia (MCAO; middle cerebral artery occlusion), wed have also demonstrated that aspirin (30 mg/Kg i.p. administered 2 h before the occlusion) produced a significant reduction in infarct volume, effect that correlated with the inhibition caused by aspirin on ischaemia-induced increase in brain and serum glutamate concentrations after the onset of the ischaemia. Aspirin also inhibited ischaemia-induced decrease in brain ATP levels. Finally, clinical studies showed that prior treatment with aspirin was associated with a lower risk of neurological deterioration after acute ischemic stroke which was related to a reduction of glutamate release. Our present findings show a novel mechanism for the neuroprotective effects of aspirin, that takes place at concentrations in the antiaggregant-analgesic range, useful in the management of patients with risk of ischaemic events.

Topics: Adenosine Triphosphate; Algorithms; Amino Acid Transport System X-AG; Animals; Aspirin; Brain Ischemia; Cell Death; Cerebrovascular Disorders; Clinical Trials as Topic; Disease Models, Animal; Glucose; Glutamic Acid; Humans; Indomethacin; Mitochondria; Neuroprotective Agents; Oxygen; Salicylates

Free radical-mediated damage during and/or after cerebral ischemia is thought to participate in the elaboration of stroke-related injury. To elucidate the role of this mechanism in cerebral damage, the study presented herein sought to clarify the spatial and temporal features of the free radical response to transient ischemia. With use of a reproducible model of in vivo focal ischemia/reperfusion, the time course of salicylate hydroxylation was measured in ischemic core and penumbra regions.. Transient focal cerebral ischemia was produced in Sprague-Dawley rats by occluding both carotid arteries and one middle cerebral artery for 3 hours, followed by reperfusion. Cerebral reperfusion was confirmed by visual inspection and iodo[14C]antipyrine autoradiography. A microdialysis probe was placed stereotactically in either the ischemic core or ischemic penumbra of the frontoparietal cortex; the probe was perfused with salicylate, and dialysate samples were analyzed by high-performance liquid chromatography for salicylate hydroxylation products.. Salicylate hydroxylation was significantly increased during ischemia and was further increased during 6 hours of reperfusion in the penumbra compared with sham controls. In comparison, a delayed increase in hydroxylation was observed within the ischemic core region only after 3 hours of reperfusion.. A differential generation of salicylate hydroxylation occurs in core and penumbra regions in association with focal ischemia/reperfusion of the rat neocortex. The early and progressive response in the penumbra suggests that free radical mechanisms may be continuously active in the aggravation of injury in the ischemic penumbra during ischemia and reperfusion. In contrast, the relatively delayed onset of hydroxylation in the core region indicates that this mechanism participates primarily in the late stages of ischemic injury in densely ischemic tissue. These findings are consistent with the concept that the role of free radicals in cerebral injury may differ qualitatively and/or quantitatively in areas of total and partial cerebral perfusion.

Topics: Animals; Antipyrine; Brain; Brain Ischemia; Coloring Agents; Hydroxylation; Male; Osmolar Concentration; Rats; Rats, Sprague-Dawley; Reperfusion; Salicylates; Salicylic Acid; Tetrazolium Salts; Tissue Distribution

We report the effects of the free radical scavengers, salicylic acid and bifemerane HC1, on the survival of hippocampal neurons in the Mongolin gerbil model of ischemia-reperfusion brain damage. In addition to performing histological examinations, we used the salicylate-trapping method to measure the amounts of hydroxyl radicals generated in the cerebral cortex and the hippocampus. Ischemia-reperfusion significantly reduced the number of neurons in the CA1 region of the hippocampus. The decrease was largely prevented by pretreating the animals with either salicylate, 20 mg/kg, or bifemerane HC1, 25 mg/kg. Administering salicylate to the animals 30 minutes after reperfusion was also effective, but bifemerane HC1 was ineffective when given after reperfusion. Two minutes after post-ischemic reperfusion, 2,3-dihydroxybenzoic acid levels were significantly elevated in the cerebral cortex and the hippocampus, and 2, 5-dihydroxybenzoic acid levels were significantly elevated in the hippocampus. The increase in 2,5-dyhydroxybenzoic acid in the hippocampus was suppressed by bifemerane HC1 given 30 minutes before exposure to ischemia. These results suggest that hydroxyl radicals are generated in the gerbil model of ischemia-reperfusion brain injury, and that salicylate and bifemerane HC1 partially prevent the loss of neurons in the hippocampus. Hydroxyl radical scavengers may be useful in reducing neuronal damage associated with ischemia-reperfusion injury.

Topics: Animals; Benzhydryl Compounds; Brain Ischemia; Cell Survival; Cerebral Cortex; Free Radical Scavengers; Gerbillinae; Hippocampus; Hydroxybenzoates; Hydroxyl Radical; Male; Neurons; Reperfusion Injury; Salicylates; Salicylic Acid

Topics: Brain Ischemia; Cerebral Hemorrhage; Female; Humans; Male; Platelet Aggregation Inhibitors; Salicylates

This follow-up study was designed to evaluate whether the use of aspirin either before or after aneurysm rupture affects the occurrence of delayed cerebral ischemia. Aspirin inhibits platelet function and thromboxane production and has been shown to reduce the risk of various cardiovascular and cerebrovascular ischemic diseases. Following admission, the patients in this study was interviewed regarding their use of aspirin and other medicines prior to and after hemorrhage, and their urine was screened qualitatively for salicylates. Patient outcome and the occurrence of hypodense lesions consistent with cerebral infarction on follow-up computerized tomography (CT) were studied prospectively up to 1 year after hemorrhage. Of 291 patients, 31 (11%) died because of the initial hemorrhage and 18 (6%) died due to rebleeding within 4 days after hemorrhage. Of the remaining 242 patients, 90 (37%) had delayed cerebral ischemia, which caused a permanent neurological deficit or death in 54 patients (22%). Of 195 patients undergoing follow-up CT, 85 (44%) had cerebral infarction that was not seen on the CT scan obtained on admission. Those who had salicylates in the urine on admission had a relative risk of 0.40 (95% confidence interval (CI), 0.15 to 1.10) of delayed ischemia with fixed deficit and a risk of 0.40 (95% CI, 0.18 to 0.93) of cerebral infarction compared with patients who did not have salicylates in their urine. This reduced risk of ischemic complications with aspirin use was restricted to those patients who used aspirin before hemorrhage, when the risk of ischemia was 0.21 (95% CI, 0.03 to 1.63) and the risk of infarct was 0.18 (95% CI, 0.04 to 0.84) compared with those who had not used aspirin. The reduced risk of cerebral infarction remained significant after adjustment for several potential confounding factors (adjusted risk 0.19; 95% CI, 0.04 to 0.89). These observations suggest that platelet function at the time of subarachnoid hemorrhage may be associated with delayed cerebral ischemia after aneurysm rupture.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Brain Ischemia; Cerebral Infarction; Female; Humans; Intracranial Aneurysm; Male; Middle Aged; Prospective Studies; Salicylates; Subarachnoid Hemorrhage; Time Factors; Tomography, X-Ray Computed

Systemic administration of salicylate (SA) to rats (100 mg kg-1 i.p. ) was used as an in vivo trap of hydroxyl radicals (.OH). In the brain SA reacts with hydroxyl radicals to form the stable adducts 2, 3- and 2,5 dihydroxybenzoic acid (DHBAs) which can thus be taken as an index of .OH formation. The DHBAs were recovered by intracerebral microdialysis in hippocampus or striatum and quantified by high pressure liquid chromatography (HPLC) with electrochemical detection. There were no peaks corresponding to 2,5-DHBA or 2,3-DHBA in the chromatograms from rats not receiving SA. A basal level of 2,5-DHBA was seen in the dialysates from all animals given SA whereas 2, 3-DHBA was not detected. In one group of rats generation of free oxygen radicals was induced in the striatum by adding Fe2+ and ascorbate to the perfusion fluid to test the sensitivity of the system. Addition of Fe2+ ascorbate to the perfusion fluid induced a significant 7-fold increase in 2,5-DHBA that gradually returned to baseline after removal of Fe2+/ascorbate. In two other groups the microdialysis probes were implanted in either the striatum or the hippocampus and the animals were subjected to 20 min of four-vessel occlusion + hypotension (4-VOH). Significant reductions in 2,5-DHBA were detected during ischaemia followed by significant increases of 5-fold and 3-fold in the striatum and hippocampus, respectively, beginning immediately upon reperfusion and lasting for the remainder of the observation period (160 min).

Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Gentisates; Hydroxybenzoates; Hydroxyl Radical; Male; Microdialysis; Monoamine Oxidase; Rats; Rats, Wistar; Reperfusion; Salicylates; Salicylic Acid

Oxygen free radicals have been implicated as a causal factor in posttraumatic neuronal cell loss following cerebral ischemia and head injury. The conversion of salicylate to dihydroxybenzoic acid (DHBA) in vivo was employed to study the formation of hydroxyl radical (.OH) following central nervous system (CNS) injury. Bilateral carotid occlusion (BCO) in gerbils and concussive head trauma in mice were selected as models of brain injury. The lipid peroxidation inhibitor, tirilazad mesylate (U-74006F), was tested for its ability to attenuate hydroxyl radical formation in these models. In addition, U-74006F was studied as a scavenger of hydroxyl radical in an in vitro assay based on the Fenton reaction. For in vivo experimentation, hydroxyl radical formation was expressed as the ratio of DHBA to salicylate (DHBA/SAL) measured in brain. In the BCO model, hydroxyl radical formation increased in whole brain with 10 min of occlusion followed by 1 min of reperfusion. DHBA/SAL was also found to increase in the mouse head injury model at 1 h postinjury. In both models, U-74006F (1 or 10 mg/kg) blocked the increase in DHBA/SAL following injury. In vitro, reaction of U-74006F with hydroxyl radical gave a product with a mol wt that was 16 greater than U-74006F, indicative of hydroxyl radical scavenging. We speculate that U-74006F may function by blocking oxyradical-dependent cell damage, and thereby maintaining free iron (which catalyzes hydroxyl radical formation) concentrations at normal levels.

Topics: Animals; Brain Injuries; Brain Ischemia; Free Radical Scavengers; Gentisates; Hydroxybenzoates; Hydroxyl Radical; Hydroxylation; Lipid Peroxides; Male; Mice; Pregnatrienes; Salicylates; Salicylic Acid

The salicylate trapping method was used to investigate the changes in hydroxyl radical (.OH) levels in the selectively vulnerable hippocampus compared to the cerebral cortex of gerbils subjected to a 10 min period of near complete forebrain ischemia. Salicylate-derived 2,5-dihydroxybenzoic acid (2,5-DHBA) was measured in sham-operated animals and at 1, 5, and 15 min of reperfusion. A basal level of 2,5-DHBA was also seen in non-ischemic gerbil brain, both in the hippocampus and cortex. The hippocampal basal level was 160% higher than in the cortex (P < .01). Treatment with the cytochrome P450 inhibitor SKF-525A (50 mg/kg s.c. 30 min before measurement) did not affect this basal level in either hippocampus or cortex, which argues against a contribution of metabolic salicylate hydroxylation as its source. In contrast, pretreatment with the arachidonic acid cyclo-oxygenase inhibitor ibuprofen (20 mg/kg s.c.) decreased (-68.8%) the level of salicylate hydroxylation in the hippocampus, but not the cortex. In animals subjected to 10 min of forebrain ischemia, a selective increase in 2,5-DHBA was observed in the hippocampus at 1 min of reperfusion which subsided by 5 min. No increase in salicylate hydroxylation was apparent in the cortex within the same time frame. The increase in .OH in the hippocampus at 1 min of reperfusion was accompanied by a significant decrease (-15.7%; P < .03) in the hippocampal levels of vitamin E. No loss of vitamin E was observed in the cortex at the same time.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain; Brain Ischemia; Cerebral Cortex; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Free Radicals; Gentisates; Gerbillinae; Hippocampus; Hydroxides; Hydroxybenzoates; Hydroxyl Radical; Ibuprofen; Lipid Peroxides; Male; Proadifen; Reperfusion; Salicylates; Salicylic Acid; Vitamin E

Ischemic cerebral infarcts induce hypercoagulation and microthrombosis, thus leading to vessel occlusion and reduction of local cerebral blood flow. Antiaggregant therapy can reduce the formation of microthrombi. We tested the effect of acetylsalicylic acid (ASA) and triflusal (2-acetoxy-4-tri-fluoromethylbenzonic acid) on the formation of microthrombi after middle cerebral artery (MCA) occlusion. Six groups of rats, each consisting of six animals received either ASA or triflusal at dosages of 12.5, 25 or 50 mg/1,000 g b.wt./day. One control group was sham-operated, in another control group MCA occlusion was performed; both groups received no therapy. The number of microthrombi was counted 7 days after MCA occlusion on paraffin sections. The highest number of microthrombi was found in the group with MCAO and without therapy (mean 28 microthrombi/animal). In treated groups a reduction of the number of microthrombi could be stated. The strongest reduction was achieved in the group treated with 12.5 mg triflusal (mean 5.2). No statistic significant difference in the number of microthrombi was found between the groups treated with 12.5 mg triflusal and 50 mg ASA (mean 8.7) compared to sham-operated control animals (mean 4.3, p greater than 0.05). Treatment with 12.5 mg triflusal was superior to 50 mg ASA in preventing microthrombi formation (p less than 0.05). These results indicate, that in experimental brain ischemia the number of microthrombi can be effectively reduced by application of antiaggregatory drugs.

Topics: Animals; Aspirin; Brain Ischemia; Cerebral Arteries; Intracranial Embolism and Thrombosis; Male; Platelet Aggregation Inhibitors; Rats; Rats, Inbred Strains; Salicylates

The aim of this study was to observe whether acetylsalicylic acid (ASA) had different effects in both sexes. Out of the ischemic stroke patients who were admitted to the National Taiwan University Hospital (NTUH), those who had not taken ASA or ASA-like drugs for more than 2 weeks were selected for this study. For the diagnosis of ischemic stroke, computed tomography (CT) of the brain was performed in all cases, and for differential diagnosis, other necessary procedures were employed in a few cases. The serum salicylate (SA) level was measured by Trinder's method, thromboxane B2 (TXB2) and 6-keto-PGF1 alpha by radioimmunoassay, threshold concentration of adenosine diphosphate (ADP) by Born's method, and circulating platelet aggregates (CPA) by Wu and Hoak's method. The present study showed that the means of serum SA levels after administration of the same dose of ASA were not significantly different between the two sexes. After ingestion of ASA, a single dose of 75 mg, 300 mg or 600 mg, or 300 mg 4 times a day, mean plasma TXB2 levels were significantly suppressed and mean threshold concentrations of ADP were significantly elevated in the two sexes. After administration of above-mentioned various doses of ASA, the abnormally high plasma TXB2 levels and abnormally low threshold concentrations of ADP and CPA ratios were significantly normalized in both male and female patients. Plasma 6-keto-PGF1 alpha levels were not influenced by ingestion of ASA 75 mg, but significantly depressed by administration of ASA 300 mg in both sexes. There were no sex differences in the antiplatelet effect of ASA in this experiment.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Aged; Aspirin; Blood Platelets; Brain Ischemia; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Platelet Aggregation; Salicylates; Salicylic Acid; Sex Factors; Thromboxane B2

Topics: Aged; Aspirin; Blood Platelets; Brain Ischemia; Female; Humans; Male; Middle Aged; Salicylates; Salicylic Acid; Thromboxane B2

The clinical picture of transient global amnesia (TGA) is discussed on the basis of the clinical findings in 19 patients. The central symptom is an acute memory loss, leading to disorientation, helplessness and pseudo-confusion. The symptoms last for several hours and then fade away. Pathogenetically a functional impairment of the limbic system is proposed. Most cases of TGA are due to ischaemic disease; rare causes are epileptic seizures, tumours, encephalitis and toxic or metabolic conditions. In order to clarify the aetiology and initiate appropriate therapy meticulous neurological investigation is necessary. The spontaneous prognosis of ischaemic forms is favourable, whilst in other cases it depends on the primary condition.

Topics: Adult; Amnesia; Brain Ischemia; Carbamazepine; Child; Female; Humans; Ischemic Attack, Transient; Limbic System; Male; Memory, Short-Term; Middle Aged; Platelet Aggregation; Salicylates