dinoprost and Brain-Ischemia

Methylene blue (MB), generic name methylthioninium (C(16)H(18)ClN(3) S . 3H(2)O), is a blue dye synthesized in 1876 by Heinrich Caro for use as a textile dye and used in the laboratory and clinically since the 1890s, with well-known toxicity and pharmacokinetics. It has experimentally proven neuroprotective and cardioprotective effects in a porcine model of global ischemia-reperfusion in experimental cardiac arrest. This effect has been attributed to MB's blocking effect on nitric oxide synthase and guanylyl cyclase, the latter blocking the synthesis of the second messenger of nitric oxide. The physiological effects during reperfusion include stabilization of the systemic circulation without significantly increased total peripheral resistance, moderately increased cerebral cortical blood flow, a decrease of lipid peroxidation and inflammation, and less anoxic tissue injury in the brain and the heart. The last two effects are recorded as less increase in plasma concentrations of astroglial protein S-100beta, as well as troponin I and creatine kinase isoenzyme MB, respectively.

Topics: Animals; Blood Pressure; Brain Ischemia; Cerebrovascular Circulation; Creatine Kinase, MB Form; Dinoprost; Disease Models, Animal; Enzyme Inhibitors; History, 19th Century; Methylene Blue; Myocardial Ischemia; Myocardial Reperfusion; Nerve Growth Factors; Nitric Oxide; Random Allocation; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Survival Analysis; Swine; Time Factors; Troponin I

Ischaemic stroke represents one of the main causes of disability. According to the broad investigations, it is widely assumed that the contribution of inflammatory mediators is strongly involved in its pathogenesis. Hence, it seems that stroke treatment needs more efficient and inflammatory-targeted compounds to modulate inflammatory-related pathways. Such strategies paved the way to achieve better clinical outcomes along with conventional therapies. Boswellic acids (BAs), the main bioactive compounds of Boswellia sp. resin; are triterpenoids with well-documented anti-inflammatory properties. Compared with NSAIDs, BAs cross blood-brain barrier yet they do not cause serious gastrointestinal adverse effects. Considering BAs anti-inflammatory features, we conducted a randomized double-blind placebo-controlled pilot trial of these compounds as a supplementary therapy. This trial randomized 80 ischaemic stroke patients (40-80-years old) with a 4-20 score according to the National Institutes of Health Stroke Scale (NIHSS), within 72 h of neurological sign onset, in 1-month follow-up period. We assessed NIHSS as primary and plasma levels of TNF-α, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IFN-γ, IP-10, MCP-1, 8-isoprostane, and PGE2 as secondary outcomes. According to NIHSS evaluation, patients who were allocated to BA group had a significant recovery in neurological function during the 1-month follow-up, compared with the placebo. The levels of plasma inflammatory markers were significantly decreased in BA group after 7 days of intervention in TNF-α, IL-1β, IL-6, IL-8, and PGE2. As a preliminary controlled trial in ischaemic stroke, BAs could improve clinical outcome in the early phases of stroke along with promising changes in plasma inflammatory factors.Clinical trial registrationhttps://www.irct.ir Unique identifier: IRCT20170315033086N5. IRCT is a primary registry in the WHO registry network (https://www.who.int/ictrp/network/primary/en/).

Topics: Adult; Aged; Aged, 80 and over; Brain Ischemia; Chemokines; Cytokines; Dinoprost; Double-Blind Method; Female; Humans; Male; Middle Aged; Pilot Projects; Stroke; Triterpenes

Inflammatory response is a critical component of the complex pathophysiological response to stroke. Vitamin C has been shown to have important roles in cell performance and vascular function. In this study, we compared the nutritional status and levels of inflammatory markers between stroke cases and controls and assessed which antioxidant was associated with levels of inflammatory markers and oxidative stress among cases and controls.. We evaluated the nutritional status and measured plasma levels of vitamins C and E, uric acid, serum levels of C-reactive protein (CRP), the cytokines tumor necrosis factor-alpha and interleukin-1beta, intercellular adhesion molecule-1 (ICAM-1) and chemokine monocyte chemoattractant protein-1 (MCP-1), prostaglandins PGE2 and PGI2, and 8-isoprostanes (8-epiPGF2alpha) for 15 patients with ischemic stroke within 2 to 5 days after stroke onset and for 24 control subjects.. Stroke patients had significantly lower plasma levels of vitamin C than did controls. Among stroke patients, CRP was significantly elevated, as were the ICAM-1, MCP-1, and 8-epiPGF2alpha, but the prostaglandins PGE2 and PGI2 were significantly reduced. Interestingly, vitamin C concentration was significantly inversely correlated with the levels of CRP and 8-epiPGF2alpha among stroke patients, and 8-epiPGF2alpha was significantly associated with the levels of CRP. Uric acid was also elevated among stroke patients.. Lower vitamin C concentration, higher serum levels of inflammatory (CRP, ICAM-1, MCP-1) and oxidative stress (8-epiPGF2alpha) markers, and lower PGI2 and PGE2 concentrations among stroke patients indicate the presence of an inflammatory response associated with stroke.

Topics: Aged; Antioxidants; Ascorbic Acid; Biomarkers; Brain Ischemia; C-Reactive Protein; Chemokine CCL2; Cytokines; Diet; Dinoprost; Humans; Inflammation Mediators; Intercellular Adhesion Molecule-1; Middle Aged; Neuropsychological Tests; Nutritional Status; Oxidative Stress; Prostaglandins; Reference Values; Stroke; Time Factors; Uric Acid; Vitamin E

Delayed cerebral ischemia (DCI) is a serious complication of aneurysmal subarachnoid hemorrhage (aSAH), which is responsible for significant death and disability. The dynamic balance between the production and elimination of reactive oxygen species (ROS) in patients with DCI is suspected be shifted to favor ROS formation. The authors assessed the relationship between F2-isoprostanes (F2-IsoPs), oxidative stress biomarkers, and glucose-6-phosphate dehydrogenase (G6PD), which are responsible for nicotinamide adenine dinucleotide phosphate (NADPH) production for glutathione system function, with post-aSAH DCI.. The authors assessed 45 aSAH patients for F2-IsoP and G6PD concentration using commercial ELISA on days 2, 4, and 6 after aSAH. The authors examined the correlation between plasma F2-IsoP and G6PD concentrations and clinical factors with DCI occurrence and aSAH outcome.. Expectedly, the most important clinical predictors of DCI were Hunt and Hess grade and modified Fisher (mFisher) grade. Plasma F2-IsoP and G6PD concentrations were greater in aSAH patients than the control group (p < 0.01). F2-IsoP concentrations were greater and G6PD concentrations were lower in patients with DCI than those without (p < 0.01). Plasma F2-IsoP and G6PD concentrations on day 2 were correlated with DCI occurrence (p < 0.01). Plasma F2-IsoP concentrations on days 2 and 6 were correlated with outcome at 1 and 12 months (p < 0.01).. Decreased G6PD indirectly informs the reduced antioxidant response, especially for the glutathione system. G6PD concentration was lower in patients with DCI than those without, which may explain the increased F2-IsoP concentrations. mFisher grade, plasma F2-IsoP concentration, and G6PD concentration on day 2 after aSAH, in combination, may serve as predictors of DCI. Further research is necessary to investigate the therapeutic utility of F2-IsoPs and antioxidants in clinical practice.

Topics: Brain Ischemia; Cerebral Infarction; Dinoprost; Glucosephosphate Dehydrogenase; Glutathione; Humans; Prospective Studies; Reactive Oxygen Species; Subarachnoid Hemorrhage

Spontaneous, recurrent spreading depolarizations (SD) are increasingly more appreciated as a pathomechanism behind ischemic brain injuries. Although the prostaglandin F2α - FP receptor signaling pathway has been proposed to contribute to neurodegeneration, it has remained unexplored whether FP receptors are implicated in SD or the coupled cerebral blood flow (CBF) response. We set out here to test the hypothesis that FP receptor blockade may achieve neuroprotection by the inhibition of SD. Global forebrain ischemia/reperfusion was induced in anesthetized rats by the bilateral occlusion and later release of the common carotid arteries. An FP receptor antagonist (AL-8810; 1 mg/bwkg) or its vehicle were administered via the femoral vein 10 min later. Two open craniotomies on the right parietal bone served the elicitation of SD with 1 M KCl, and the acquisition of local field potential. CBF was monitored with laser speckle contrast imaging over the thinned parietal bone. Apoptosis and microglia activation, as well as FP receptor localization were evaluated with immunohistochemistry. The data demonstrate that the antagonism of FP receptors suppressed SD in the ischemic rat cerebral cortex and reduced the duration of recurrent SDs by facilitating repolarization. In parallel, FP receptor antagonism improved perfusion in the ischemic cerebral cortex, and attenuated hypoemic CBF responses associated with SD. Further, FP receptor antagonism appeared to restrain apoptotic cell death related to SD recurrence. In summary, the antagonism of FP receptors (located at the neuro-vascular unit, neurons, astrocytes and microglia) emerges as a promising approach to inhibit the evolution of SDs in cerebral ischemia.

Topics: Animals; Brain Ischemia; Cerebral Cortex; Cerebral Infarction; Cerebrovascular Circulation; Cortical Spreading Depression; Dinoprost; Male; Prosencephalon; Prostaglandins; Rats, Sprague-Dawley; Signal Transduction

There are limited prospective data evaluating the role of urinary F2-IsoP and NOX2 as predictive markers in atrial fibrillation (AF). The aim of this study was to analyse the role of urinary prostaglandin PGF2alpha (8-iso-PGF2α) and NOX2, markers of systemic oxidative stress, in predicting cardiovascular (CV) events and mortality in anticoagulated non-valvular AF patients. This was a prospective study including 1,002 anticoagulated AF patients, followed for a median time of 25.7 months (interquartile range: 14.8-50.9). All major CV events, CV deaths and all-cause deaths were considered as primary outcomes of the study. CV events included fatal/nonfatal ischaemic stroke, fatal/nonfatal myocardial infarction (MI), cardiac revascularisation and transient ischaemic attack (TIA). Oxidative stress biomarkers, such as urinary 8-iso-PGF2α and serum sNOX2-dp, a marker of NOX2 activation, were measured. A CV event occurred in 125 patients (12.5 %); 78 CV deaths and 31 non-CV deaths were registered. 8-iso-PGF2α and sNOX2-dp were correlated (Rs=0.765 p< 0.001). A significant increased cumulative incidence of CV events and CV deaths was observed across tertiles for 8-iso-PGF2α and sNOX2-dp. An increased rate of all-cause death was observed across tertiles of urinary 8-iso-PGF2α. In Cox or Fine and Gray models, 8-iso-PGF2α predicted CV events and CV and non-CV deaths. The addition of tertiles of 8-iso-PGF2α to CHA2DS2-VASc score improved ROC curves for each outcome and NRI for CV events (0.24 [0.06-0.53] p=0.0067). The study shows that in AF patients 8-iso-PGF2α and NOX2 levels are predictive of CV events and total mortality. F2-IsoP may complement conventional risk factors in prediction of CV events.

Topics: Aged; Aged, 80 and over; Area Under Curve; Atrial Fibrillation; Biomarkers; Brain Ischemia; Cause of Death; Cerebrovascular Disorders; Dinoprost; Female; Humans; Incidence; Ischemic Attack, Transient; Kaplan-Meier Estimate; Male; Membrane Glycoproteins; Middle Aged; Myocardial Infarction; NADPH Oxidase 2; NADPH Oxidases; Oxidative Stress; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Risk Factors; ROC Curve; Rome; Stroke; Time Factors

Bioactive lipids such as the prostaglandins have been reported to have various cytoprotective or toxic properties in acute and chronic neurological conditions. The roles of PGF(2α) and its receptor (FP) are not clear in the pathogenesis of ischemic brain injury. Considering that this G-protein coupled receptor has been linked to intracellular calcium regulation, we hypothesized that its blockade would be protective. We used FP antagonist (AL-8810) and FP receptor knockout (FP(-/-)) mice in in vivo and in vitro stroke models. Mice that were treated with AL-8810 had 35.7±6.3% less neurologic dysfunction and 36.4±6.0% smaller infarct volumes than did vehicle-treated mice after 48h of permanent middle cerebral artery occlusion (pMCAO); FP(-/-) mice also had improved outcomes after pMCAO. Blockade of the FP receptor also protected against oxygen-glucose deprivation (OGD)-induced cell death and reactive oxygen species formation in slice cultures. Finally, we found that an FP receptor agonist dose dependently increased intracellular Ca(2+) levels in cultured neurons and established that FP-related Ca(2+) signaling is related to ryanodine receptor signaling. These results indicate that the FP receptor is involved in cerebral ischemia-induced damage and could promote development of drugs for treatment of stroke and acute neurodegenerative disorders.

Topics: Animals; Brain; Brain Ischemia; Calcium; Cell Death; Cells, Cultured; Dinoprost; Dose-Response Relationship, Drug; Male; Mice; Mice, Knockout; Neurons; Neuroprotective Agents; Reactive Oxygen Species; Receptors, Prostaglandin

Arachidonic acid (AA) and its vasoactive metabolites have been implicated in the pathogenesis of brain damage induced by cerebral ischemia. The membrane AA concentrations can be reduced by changes in dietary fatty acid intake. The purpose of the present study was to investigate the effects of chronic ethyl docosahexaenoate (E-DHA) administration on the generation of eicosanoids of AA metabolism during the period of reperfusion after ischemia in gerbils. Weanling male gerbils were orally pretreated with either E-DHA (100, 200 mg/kg) or vehicle, once a day, for 10 weeks, and subjected to transient forebrain ischemia by bilateral common carotid occlusion for 10 min. E-DHA (200 mg/kg) pretreatment significantly decreased the content of brain lipid AA at the termination of treatment, prevented postischemic impaired regional cerebral blood flow (rCBF) and reduced the levels of brain prostaglandin (PG) PGF(2alpha) and 6-keto-PGF(1alpha), and thromboxane B(2) (TXB(2)), as well as leukotriene (LT) LTB(4) and LTC(4) at 30 and 60 min of reperfusion compared with the vehicle, which was well associated with the attenuated cerebral edema in the E-DHA-treated brain after 48 h of reperfusion. These data suggest that the E-DHA (200 mg/kg) pretreatment reduces the postischemic eicosanoid productions, which may be due to its reduction of the brain lipid AA content.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Brain; Brain Chemistry; Brain Edema; Brain Ischemia; Cerebrovascular Circulation; Dinoprost; Docosahexaenoic Acids; Eicosanoids; Fatty Acids; Gerbillinae; Leukotriene B4; Leukotriene C4; Lipids; Male; Reperfusion; Thromboxane B2

Free radical-induced peroxidation is an important factor in the genesis of hypoxic-ischemic encephalopathy, including that of the preterm infant. Isoprostanes are major peroxidation products. Since microvascular dysfunction seems to contribute to ischemic encephalopathies, we studied the cytotoxicity of 8-iso-prostaglandin F2alpha (PGF2alpha) on cerebral microvascular cells.. Microvascular endothelial, astroglial, and smooth muscle cells from newborn brain were cultured. The cytotoxicity of 8-iso-PGF2alpha on these cells was determined by MTT assays and lactate dehydrogenase (LDH) release, propidium iodide incorporation, and DNA fragmentation (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling [TUNEL]). In addition, effects of intraventricular injections of 8-iso-PGF2alpha and possible involvement of thromboxane in 8-iso-PGF2alpha-induced cytotoxicity were determined.. 8-Iso-PGF2alpha induced time- and concentration-dependent endothelial cell death (EC50=0.1 nmol/L) but exerted little effect on smooth muscle and astroglial cells; endothelial cell death seemed mostly of oncotic nature (propidium iodide incorporation and LDH release). Cell death was associated with increased endothelial thromboxane A2 (TXA2) formation and was prevented by TXA2 synthase inhibitors (CGS12970 and U63557A); TXA2 mimetics U46619 and I-BOP also caused endothelial cell death. Intraventricular injection of 8-iso-PGF2alpha induced periventricular damage, which was attenuated by CGS12970 pretreatment.. These data disclose a novel action of 8-iso-PGF2alpha involving TXA2 in oxidant stress-induced cerebral microvascular injury and brain damage.

Topics: Animals; Astrocytes; Brain; Brain Ischemia; Cell Death; Cell Survival; Cells, Cultured; Dinoprost; Dinoprostone; DNA Fragmentation; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Inhibitors; F2-Isoprostanes; In Vitro Techniques; Injections, Intraventricular; Isoprostanes; L-Lactate Dehydrogenase; Microcirculation; Muscle, Smooth, Vascular; Necrosis; Rats; Rats, Sprague-Dawley; Swine; Thromboxane A2; Thromboxane-A Synthase

Short episodes of ischemia and reperfusion in various organs may protect the organ itself, and the heart both as an immediate and a delayed effect. The present study investigates whether a systemic protection of vascular function occurs during adaption to ischemia. Brain ischemia was induced by bilateral ligation of the internal carotid arteries in C57BL6 mice, and 24-36 hours later rings of the thoracic aorta were mounted to study in vitro relaxation and contraction, or proteins were extracted for immunoblotting for endothelial nitric oxide synthase (eNOS) or inducible NOS (iNOS). eNOS decreased, while iNOS increased in the aortic wall after carotid artery ligation. In vitro contraction to increasing concentrations of prostaglandin F(2alpha) (PGF(2alpha)) was attenuated, while relaxation to acetylcholine (ACh) was enhanced. The latter was abolished by the iNOS-inhibitor aminoguanidine. When brain ischemia was induced in iNOS deficient mice, an increase of aortic eNOS was found 24 hours later. The ischemia-induced attenuated relaxation to PGF(2alpha) and enhanced relaxation to ACh were abolished. Aortic rings from mice with severe atherosclerosis (apolipoprotein E and low density lipoprotein receptor double knockout (ApoE/LDLr KO) mice) and spontaneous ischemic events in the heart or brain in vivo were also studied. Spontaneous ischemic events in ApoE/LDLr KO animals did not influence iNOS and eNOS in the vessel wall. A reduced contraction to PGF(2alpha) was observed, but relaxation to ACh was unchanged. These findings suggest that induced brain ischemia as a model of delayed, remote preconditioning protects vessel reactivity, and this protection is mediated by iNOS.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Brain Ischemia; Dinoprost; Disease Models, Animal; In Vitro Techniques; Ischemic Attack, Transient; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Myocardial Ischemia; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phenylephrine; Reference Values

Formation of the lipid peroxidation product 8-epi-prostaglandin2alpha (8-epi-PGF2alpha) a bioactive marker of oxidative stress, was quantified in in vitro and in vivo models of neuronal death. In culture media of primary rat cortical neurones exposed to hypoxia followed by reoxygenation, a 3.7-fold increase of 8-epi-PGF2alpha concentration was observed in comparison to control cells. In rats submitted to 2h middle cerebral artery occlusion followed by a 22h reperfusion period, a 27-fold increase of 8-epi-PGF2alpha was observed in the ischaemic hemisphere compared with the corresponding hemisphere of sham-operated rats. Treatment with the neuroprotective agent BN 80933 significantly reduced both 8-epi-PGF2alpha elevations in vitro and in vivo. These data suggest that 8-epi-PGF2alpha elevations might reflect the damaging free radical overproduction and subsequent lipid peroxidation during neuronal injury induced by hypoxia and ischaemia. Inhibition of 8-epi-PGF2alpha elevations participates to the neuroprotective effects of BN 80933.

Topics: Animals; Brain Ischemia; Cells, Cultured; Cerebral Cortex; Culture Media, Conditioned; Dinoprost; Enzyme Inhibitors; F2-Isoprostanes; Hypoxia, Brain; Infarction, Middle Cerebral Artery; L-Lactate Dehydrogenase; Neuroprotective Agents; Pyrazines; Rats; Rats, Wistar; Reperfusion Injury; Thiophenes

Experiments compared the hemispheric neural damage resulting from global hemispheric hypoxic ischemia (GHHI, ligation of right common carotid artery plus 35 min of 12% O2) in groups of anesthetized, male Long Evans rats, 9-10 weeks of age, kept at 37 degrees C, and previously given an intracerebroventricular (i.c.v., 2.5 microl) injection of 28 or 70 pmoles of PGE2, PGF2alpha or PGD2 or sterile saline (SS) 30 min beforehand. Mean arterial pressure (MAP), ipsilateral cortical capillary blood flow (CBF), colonic (Tc), ipsilateral (Tipsi) and contralateral (Tcontra), temporalis muscle temperatures were measured before, during and for 15 min after GHHI. Necrotic neural damage was assessed 7 days post-GHHI. All groups given GHHI + PGs showed increased ipsilateral hemispheric damage to GHHI especially due to enhanced neocortical damage, compared to the saline control group given the same insult. PGD2 was the most potent PG to cause further damage to the global insult. Tc, Tipsi, Tcontra and MAP increased following the i.c.v. injection of PGE2. I.c.v. PGF2alpha transiently decreased MAP, PGD2 tended to decrease cerebral blood flow and neither evoked changes in temperature compared to respective pre-injection control values. Results demonstrate increased neural damage to GHHI with prior i.c.v. PGE2, PGF2alpha or PGD2 administration.

Topics: Animals; Body Temperature; Brain; Brain Ischemia; Dinoprost; Dinoprostone; Fever; Hemodynamics; Hypoxia, Brain; Male; Prostaglandin D2; Rats

The effects of ZK-118.182, a stable analogue of PGD2, were evaluated in an endothelin-1-induced cerebral ischemia rabbit model. Ischemia was induced by endothelin-1 injection (0.25 ng bolus) into subcavian artery and ischemic changes were assessed histologically by the number of ischemic neurons in the brain stem. ZK-118.182 (2 micrograms/kg, bolus into subclavian artery) reduced the number of ischemic neurons when injected 20 min after endothelin-1 injection, Iloprost, a stable analogue of PGI2, was also effective in reducing the number of ischemic neurons in a dose of 0.5 microgram/kg (bolus into subclavian artery). The results suggested that ZK-118.182 has a potent antiischemic effect which is comparable to that of iloprost in rabbits.

Topics: Animals; Brain Ischemia; Dinoprost; Disease Models, Animal; Endothelin-1; Iloprost; Neurons; Platelet Aggregation Inhibitors; Rabbits

Both platelet activation and lipid peroxidation are potential sources of vasoactive eicosanoids that can be produced via the cyclooxygenase pathway, ie, thromboxane (TX) A2, or by free radical-catalyzed peroxidation of arachidonic acid, ie, isoprostanes. We investigated the biosynthesis of TXA2 and F2-isoprostanes, as reflected by the urinary excretion of 11-dehydro-TXB2 and 8-epi-prostaglandin (PG) F2 alpha respectively, in 62 consecutive patients (30 men, 32 women; mean age, 67 +/- 14 years) with acute ischemic stroke.. At least two consecutive 6-hour urine samples were obtained during the first 72 hours after onset of symptoms. Urinary eicosanoids were measured by previously described radioimmunoassays.. Repeated periods of enhanced thromboxane biosynthesis were found in 52% of patients. Urinary 11-dehydro-TXB2 averaged 221 +/- 207 (mean +/- SD; n = 197; range, 13 to 967) pmol/mmol creatinine in 30 patients treated with cyclooxygenase inhibitors (mostly aspirin) at the time of study versus 392 +/- 392 (n = 186; range, 26 to 2533) in 32 untreated patients (P < .001). The corresponding values for 8-epi-PGF2 alpha excretion were 74 +/- 42 (range, 14 to 206) and 83 +/- 65 (range, 24 to 570) pmol/mmol creatinine (P > .05). The correlation between the two metabolites was moderate in both untreated patients (r = .41, P < .001) and patients with cyclooxygenase inhibitors (r = .31, P < .001). In a multiple regression analysis, increased thromboxane production was independently associated with severity of stroke on admission, atrial fibrillation, and treatment with cyclooxygenase-inhibiting drugs.. We conclude that during the first few days after an acute ischemic stroke (1) platelet activation occurs repeatedly in a cyclooxygenase-dependent fashion; (2) platelet activation is not associated with concurrent changes in isoprostane biosynthesis; (3) platelet activation is independently associated with stroke severity and atrial fibrillation; and (4) isoprostane biosynthesis is largely independent of platelet cyclooxygenase activity.

Topics: Acute Disease; Aged; Atrial Fibrillation; Brain Ischemia; Cerebrovascular Disorders; Cyclooxygenase Inhibitors; Dinoprost; Female; Humans; Lipid Peroxides; Male; Middle Aged; Platelet Activation; Reference Values; Thromboxane B2

The effect of mild and moderate hypothermia on ischemia-induced glutamate release and eicosanoid production was evaluated in WKY rats subjected to incomplete forebrain ischemia. Under isoflurane anesthesia, microdialysis probes were inserted into the hippocampus and caudate nucleus. In four groups of rats, the intraischemic temperature was maintained at either 38 degrees C (normothermia), 36 degrees C, 34 degrees C (mild hypothermia) and 30 degrees C (moderate hypothermia). In these groups, normothermia was restored immediately upon reperfusion. In two additional groups, both intra- and post-ischemic temperatures were maintained at either 34 degrees C or 30 degrees C. The levels of glutamate were measured in the dialysate collected during ischemia and the levels of TxB2, 6-keto-PGF1 alpha and PGF2 alpha were measured in dialysate collected prior to and after ischemia. As expected, hypothermia reduced ischemia-induced glutamate release in both structures. However, the application of mild hypothermia did not attenuate post-ischemic levels of all eicosanoids measured. Moderate hypothermia (30 degrees C) attenuated the post-ischemic increase in the levels of PGF2 alpha. The data suggest that the processes that lead to eicosanoid formation are less sensitive to temperature reduction than those that lead to glutamate release.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Temperature; Brain Chemistry; Brain Ischemia; Caudate Nucleus; Dinoprost; Eicosanoids; Glutamic Acid; Hippocampus; Hypothermia; Microdialysis; Rats; Rats, Inbred WKY; Reperfusion; Thromboxane B2

Post-ischemic metabolism of arachidonic acid by cyclooxygenase results in the elaboration of numerous eicosanoids and in the generation of free radicals. Accordingly, the effect of cyclooxygenase inhibition by ibuprofen on post-ischemic eicosanoid production and delayed neuronal death was evaluated in Wistar-Kyoto rats subjected to incomplete forebrain ischemia. In control (C) and ibuprofen-treated groups (n = 5 each), pre- and post-ischemic eicosanoid production in the caudate nucleus (CN) and dorsal hippocampus (HPC) were evaluated by microdialysis. The ibuprofen-treated animals were given ibuprofen, 15 mg/kg i.v., prior to insertion of microdialysis probes. Forebrain ischemia was induced by bilateral carotid artery occlusion (BCAO) for 10 min with simultaneous hypotension to 35 Torr. The concentrations of thromboxane B2 (TxB2), 6-keto-PGF1 alpha and PGF2 alpha in the microdialysate were measured by radioimmunoassay. In two additional concurrent groups of rats (n = 10 each), neuronal injury in the HPC, CN and cortex (parietal, temporal and entorhinal regions) was evaluated histologically three days after 10 min of forebrain ischemia with and without pre-ischemic ibuprofen administration. In the control microdialysis group, levels of TxB2, 6-keto-PGF1 alpha and PGF2 alpha increased in both CN and HPC after probe insertion. These probe related increases were substantially reduced in the ibuprofen group. After ischemia and reperfusion in the control group, the levels of TxB2 and PGF2 alpha increased in both CN and HPC. Levels of 6-keto-PGF1 alpha increased in the CN but not in the HPC. The administration of ibuprofen substantially reduced post-ischemic TxB2 and PGF2 alpha levels in both CN and HPC and decreased 6-keto-PGF1 alpha levels in the CN. The results of these initial microdialysis studies left the possibility that, in the ibuprofen group, the reduction in eicosanoid levels after probe penetration might have influenced the subsequent post-ischemic eicosanoid production. Therefore, in an additional group of animals (n = 5), ibuprofen was administered after probe insertion. Only PGF2 alpha levels were measured in this group. Increased levels of PGF2 alpha comparable to the original control group were detected after probe penetration. Nonetheless, after ibuprofen administration, the pre- and post-ischemic levels of PGF2 alpha were again significantly reduced. In the histologic evaluation groups, overall neuronal injury was significantly less in the ibu

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Weight; Brain Ischemia; Caudate Nucleus; Cell Death; Dialysis; Dinoprost; Eicosanoids; Hippocampus; Ibuprofen; Neurons; Prosencephalon; Rats; Rats, Inbred WKY; Stereotaxic Techniques

Immunohistochemical localization of prostaglandin (PG) F2 alpha synthesized during recirculation following experimental forebrain ischemia was studied in Mongolian gerbils. The bilateral carotid arteries were clamped for 5 minutes, and the brains were frozen in situ after 5 minutes of recirculation. Sham-operated gerbils not subjected to arterial occlusion served as controls. Cryostat sections containing dorsal hippocampus 10 microns in thickness were incubated in rabbit anti-PGF2 alpha serum and stained with avidin-biotin-peroxidase complex after fixation in carbodi-imide and Zamboni's solution. In specimens from control animals, blood vessels were faintly stained with anti-PGF2 alpha serum, while neurons and glial cells were less intensely stained or unstained. Specimens from reperfused gerbils demonstrated strongly positive staining for PGF2 alpha in blood vessels, neurons (especially hippocampal pyramidal neurons), and glial cells. Staining for PGF2 alpha in the reperfused animals was substantially diminished by pretreatment with indomethacin (10 mg/kg, i.p.). The results indicate that recirculation after forebrain ischemia results in an increase in PGF2 alpha in neurons, glial cells, and blood vessels.

Topics: Animals; Brain; Brain Ischemia; Dinoprost; Gerbillinae; Immunoenzyme Techniques; Immunohistochemistry; Male; Reperfusion

We explored the temporal and topographic relations between local cerebral blood flow and regional brain prostaglandin profile following prolonged or transient occlusion of the middle cerebral artery in cats. Each experimental group was subjected to a sham operation, prolonged ischemia, or recirculation. Local cerebral blood flow was measured by the hydrogen clearance method. Following in situ freezing, cortical samples were obtained from each gyrus for determination of prostaglandin (PG) F2 alpha, PGE2, 6-keto-PGF1 alpha, and thromboxane (TX) B2 concentrations by radioimmunoassay. During prolonged ischemia, the concentrations of PGF2 alpha and PGE2 within the middle cerebral artery territory were significantly increased. Immediately after recirculation, there was a prominent but transient increase in PGF2 alpha and PGE2 in gyri that had been exposed to moderate ischemia (perifocal area). By contrast, the increases in these prostaglandins were slow and less prominent in gyri that had been exposed to severe ischemia (the focal area). The concentration of 6-keto-PGF1 alpha did not change during prolonged ischemia but transiently increased following recirculation in both the focal and perifocal areas. The TXB2 concentration did not change in any experimental group. Our study revealed a homogeneous increase in the regional brain content of PGE2 or PGF2 alpha in spite of the heterogeneous reduction of local cerebral blood flow during prolonged ischemia. Following recirculation, the focal and perifocal areas exhibited different patterns of prostanoid content. No correlation was found between local cerebral blood flow and the regional concentration of any prostaglandin examined.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Brain; Brain Ischemia; Cats; Cerebral Arteries; Cerebrovascular Circulation; Constriction; Dinoprost; Dinoprostone; Female; Male; Thromboxane B2

Effects of ischemia (20 min) on cerebral cortical prostanoid synthesis and microvascular responses to hypercapnia and topical acetylcholine were examined in anesthetized newborn pigs. Pial arteriolar dilation in response to hypercapnia (10% CO2 ventilation, 10 min) was absent 2 h after ischemia and reversed toward constriction by 24 h postischemia. In sham control piglets, hypercapnia increased cortical periarachnoid fluid prostanoid concentrations. After ischemia, hypercapnia did not affect prostanoid concentrations on the brain surface. Acetylcholine (10(-3) M)-induced pial arteriolar constriction was reversed toward dilation 24 h after cerebral ischemia. Further, acetylcholine-induced prostanoid synthesis was markedly attenuated after ischemia. We conclude that cerebral ischemia-reperfusion alters cerebral prostanoid synthesis and microvascular control in newborn pigs. These abnormalities persist for at least 24 h.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Animals; Animals, Newborn; Brain; Brain Ischemia; Cerebrovascular Circulation; Dinoprost; Dinoprostone; Hypercapnia; Prostaglandins; Swine; Thromboxane B2

The time-dependent release of prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2 alpha), thromboxane (Tx) B2, and 6-keto-PGF1 alpha (6-keto) from brain was measured before, during, and after a 15-min interval of total ischemia (four-vessel occlusion) in halothane-anesthetized cats using the technique of cerebroventricular perfusion. Resting levels of PGE2, PGF2 alpha, 6-keto, and Tx were: 253 +/- 75, 953 +/- 300, 650 +/- 200, and 550 +/- 170 pg/ml, respectively. During the 15-min ischemia, all prostanoids rose significantly, yet the highest levels were not observed until the first 15-60 min of the reflow at which time levels of PGE2, PGF2 alpha, 6-keto, and Tx, as compared with the preischemic baseline, rose approximately 8, 3.4, 3, and 55-fold, respectively. Significantly, although all prostanoids showed increases relative to baseline, the ratios of PGF2 alpha/6-keto and PGE2/6-keto remained stable throughout the experiment in both groups of animals. In contrast, the Tx/6-keto ratio rose from approximately 1 to approximately 30 during the 60 min after reflow in untreated cats. Treatment with zomepirac sodium (5 mg/kg, i.v.), a cyclooxygenase inhibitor, resulted in highly significant reductions in the levels of all prostanoids during the preischemic period. In zomepirac sodium-treated animals, there were also highly significant reductions in the prostanoid response to ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Brain; Brain Ischemia; Cats; Dinoprost; Dinoprostone; Extracellular Space; Female; Fibrinolytic Agents; Male; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Thromboxane B2; Tolmetin

Topics: Animals; Brain Chemistry; Brain Ischemia; Cerebral Cortex; Dinoprost; Female; Male; Prostaglandins F; Rats; Sex Factors; Time Factors

Verapamil and pentobarbital were compared for their actions on isolated canine cerebral (basilar and middle cerebral) and peripheral (mesenteric) arteries of similar diameter. The two agents shared several nonselective actions on canine arteries, but differed widely in potency. Both agents produced direct relaxation of cerebral, but not peripheral, arteries, and both agents inhibited constriction of cerebral and peripheral arteries by KCl and CaCl2 (in K+-depolarizing, Ca2+-deficient media). However, 1 mM pentobarbital was required to produce the same maximal effects as 4 uM verapamil. In addition, verapamil selectively blocked constriction of cerebral arteries by a receptor-mediated agent, prostaglandin F2a, while pentobarbital was nonselective in its blockade. On the basis of their comparative actions on isolated cerebral and peripheral arteries, calcium channel blockers such as verapamil may be a more rational choice in the treatment of cerebral ischemia than the barbiturates.

Topics: Animals; Arteries; Brain Ischemia; Calcium; Cerebral Arteries; Dinoprost; Dogs; Female; In Vitro Techniques; Male; Mesenteric Arteries; Pentobarbital; Potassium Chloride; Prostaglandins F; Vasoconstriction; Verapamil

Regional quantitative studies of brain prostaglandins (PG) in gerbils with bilateral carotid ligation have shown increases in PGF2 alpha in all areas of ischaemia but with no increases in PGE2. Pretreatment of animals with indomethacin (3 mg/kg) reduced this response, whereas dexamethasone (2.5 mg/kg) had no such effect. PGE1 and thromboxane-B2 were found not to be present in our preparation. The significance of these findings lies in the fact that both drugs, which are known to inhibit the development of ischaemic oedema, have now been shown to produce markedly different effects on prostaglandin levels. This may indicate either, that prostaglandins are not involved in ischaemic oedema formation, or, that the drugs have different mechanisms of action.

Topics: Animals; Brain; Brain Ischemia; Dexamethasone; Dinoprost; Dinoprostone; Gerbillinae; Indomethacin; Male; Prostaglandins; Prostaglandins E; Prostaglandins F; Tissue Distribution