leukotriene-b4 and Brain-Edema

Topics: Arachidonic Acid; Arachidonic Acids; Blood-Brain Barrier; Bradykinin; Brain Diseases; Brain Edema; Free Radicals; Histamine; Humans; Leukotriene B4; Serotonin; SRS-A

Topics: Animals; Arachidonic Acids; Brain; Brain Edema; Brain Ischemia; Cerebrovascular Circulation; Cerebrovascular Disorders; Eicosanoic Acids; Epoprostenol; Fatty Acids, Unsaturated; Humans; Indomethacin; Intracranial Embolism and Thrombosis; Ischemic Attack, Transient; Leukotriene B4; Lipid Peroxides; Muscle, Smooth, Vascular; Platelet Aggregation; Prostaglandins; Thromboxanes

Leukotriene B4 (LTB4) is a highly potent neutrophil chemoattractant and neutrophils induces inflammatory response and oxidative stress when they recruit to and infiltrate in the injuried/inflamed site, such as the brain parenchyma after aneurysmal subarachnoid hemorrhage (SAH). This study is to investigate the potential effects of inhibition of LTB4 synthesis on neutrophil recruitment, inflammatory response and oxidative stress, as well as early brain injury (EBI) in rats after SAH. A pre-chiasmatic cistern SAH model of rats was used in this experiment. SC 57461A was used to inhibit LTB4 synthesis via intracerebroventricular injection. The brain tissues of temporal lobe after SAH were analyzed. Neuronal injury, brain edema and neurological function were evaluated to investigate the development of EBI. We found that inhibition of LTB4 synthesis after SAH could reduce the level of myeloperoxidase, alleviate the inflammatory response and oxidative stress, and reduce neuronal death in the brain parenchyma, and ameliorate brain edema and neurological behavior impairment at 24h after SAH. These results suggest that inhibition of LTB4 synthesis might alleviate EBI after SAH possibly via reducing the neutrophil-generated inflammatory response and oxidative stress.

Topics: Animals; beta-Alanine; Blood-Brain Barrier; Brain Edema; Brain Injuries; Disease Models, Animal; Inflammation; Leukotriene B4; Male; Neutrophils; Oxidative Stress; Rats, Sprague-Dawley; Subarachnoid Hemorrhage

Inflammatory preconditioning is a mechanism in which exposure to small doses of inflammatory stimuli prepares the body against future massive insult by activating endogenous protective responses. Phospholipase A2/5-lipoxygenase/leukotriene-B4 (PLA2/5-LOX/LTB4) axis is an important inflammatory signaling pathway. Naja sputatrix (Malayan spitting cobra) venom contains 15% secretory PLA2 of its dry weight. We investigated if Naja sputatrix venom preconditioning (VPC) reduces surgical brain injury (SBI)-induced neuroinflammation via activating PLA2/5-LOX/LTB4 cascade using a partial frontal lobe resection SBI rat model. Naja sputatrix venom sublethal dose was injected subcutaneously for 3 consecutive days prior to SBI. We observed that VPC reduced brain edema and improved neurological function 24 h and 72 h after SBI. The expression of pro-inflammatory mediators in peri-resection brain tissue was reduced with VPC. Administration of Manoalide, a PLA2 inhibitor or Zileuton, a 5-LOX inhibitor with VPC reversed the protective effects of VPC against neuroinflammation. The current VPC regime induced local skin inflammatory reaction limited to subcutaneous injection site and elicited no other toxic effects. Our findings suggest that VPC reduces neuroinflammation and improves outcomes after SBI by activating PLA2/5-LOX/LTB4 cascade. VPC may be beneficial to reduce post-operative neuroinflammatory complications after brain surgeries.

Topics: Animals; Arachidonate 5-Lipoxygenase; Biomarkers; Brain; Brain Edema; Brain Injuries; Elapid Venoms; Hydroxyurea; Inflammation; Intraoperative Complications; Leukocyte Count; Leukotriene B4; Lipoxygenase Inhibitors; Naja; Phospholipase A2 Inhibitors; Phospholipases A2; Rats; Signal Transduction; Skin; Subcutaneous Tissue; Terpenes

Systemic administration of kainic acid causes inflammation and apoptosis in the brain, resulting in neuronal loss. Dual cyclooxygenase/5-lipoxygenase (COX/5-LOX) inhibitors could represent a possible neuroprotective approach in preventing glutamate excitotoxicity. Consequently, we investigated the effects of a dual inhibitor of COX/5-LOX following intraperitoneal administration of kainic acid (KA, 10 mg/kg) in rats. Animals were randomized to receive either the dual inhibitor of COX/5-LOX (flavocoxid, 20 mg/kg i.p.) or its vehicle (1 ml/kg i.p.) 30 min after KA administration. Sham brain injury rats were used as controls. We evaluated protein expression of phosphorylated extracellular signal-regulated kinase (p-ERK1/2) and tumor necrosis factor alpha (TNF-α) as well as levels of malondialdehyde (MDA), prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) in the hippocampus. Animals were also observed for monitoring behavioral changes according to Racine Scale. Finally, histological analysis and brain edema evaluation were carried out. Treatment with the dual inhibitor of COX/5-LOX decreased protein expression of p-ERK1/2 and TNF-α in hippocampus, markedly reduced MDA, LTB4 and PGE2 hippocampal levels, and also ameliorated brain edema. Histological analysis showed a reduction in cell damage in rats treated with the dual inhibitor of COX/5-LOX, particularly in hippocampal subregion CA3c. Moreover, flavocoxid significantly improved behavioral signs following kainic acid administration. Our results suggest that dual inhibition of COX/5-LOX by flavocoxid has neuroprotective effects during kainic acid-induced excitotoxicity.

Topics: Animals; Behavior, Animal; Brain Edema; Catechin; Cyclooxygenase Inhibitors; Dinoprostone; Drug Combinations; Hippocampus; Kainic Acid; Leukotriene B4; Lipid Peroxidation; Lipoxygenase Inhibitors; Male; Malondialdehyde; MAP Kinase Signaling System; Nerve Tissue Proteins; Neuroprotective Agents; Neurotoxins; Phosphorylation; Protein Processing, Post-Translational; Random Allocation; Rats; Rats, Sprague-Dawley; Seizures; Tumor Necrosis Factor-alpha

Lipoxin A(4) (LXA(4)), a biologically active eicosanoid with anti-inflammatory and pro-resolution properties, was recently found to have neuroprotective effects in brain ischemia. As 5-lipoxygenase (5-LOX) and leukotrienes are generally considered to aggravate cerebral ischemia/reperfusion (I/R) injury, we investigated their effects on LXA(4)-mediated neuroprotection by studying middle cerebral artery occlusion (MCAO)/reperfusion in rats and oxygen-glucose deprivation (OGD)/recovery in neonatal rat astrocyte primary cultures. LXA(4) effectively reduced infarct volumes and brain edema, and improved neurological scores in the MCAO/reperfusion experiments; this effect was partially blocked by butoxycarbonyl-Phe-Leu-Phe-Leu-Phe (Boc2), a specific antagonist of the LXA(4) receptor (ALXR). Total 5-LOX expression did not change, regardless of treatment, but LXA(4) could inhibit nuclear translocation induced by MCAO or OGD. We also found that LXA(4) inhibits the upregulation of both leukotriene B(4) (LTB(4)) and leukotriene C(4) (LTC(4)) and the phosphorylation of extracellular signal-regulated kinase (ERK) induced by MCAO or OGD. The phosphorylation of the 38-kDa protein kinase (p38) and c-Jun N-terminal kinase (JNK) was not altered throughout the experiment. These results suggest that the neuroprotective effects of LXA(4) are probably achieved by anti-inflammatory mechanisms that are partly mediated by ALXR and through an ERK signal transduction pathway.

Topics: Animals; Animals, Newborn; Arachidonate 5-Lipoxygenase; Astrocytes; Brain Edema; Brain Ischemia; Disease Models, Animal; Enzyme Inhibitors; Flavonoids; Glucose; Leukotriene B4; Leukotriene C4; Leukotrienes; Lipoxins; Male; MAP Kinase Signaling System; Neuroprotective Agents; Oxygen; Rats; Rats, Sprague-Dawley; Reperfusion Injury; RNA, Messenger

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

We studied the effect of intravascular activation of human neutrophils on the synthesis of cysteinyl leukotrienes (cysLT) and the formation of cerebral edema in guinea-pig brains. Challenge with the chemotactic formylated tripeptide fMLP (0.1 microM) of neutrophil-perfused brain in vitro resulted in blood-brain barrier disruption associated with a significant increase of cysLT. Both events were completely prevented by neutrophil pretreatment with a specific 5-lipoxygenase (5-LO) inhibitor. Perfusion with the 5-LO metabolite leukotriene B4 (10 nM), together with neutrophils treated with the 5-LO inhibitor, did not restore the alteration in permeability observed upon perfusion with untreated and activated neutrophils. The dual cysLT1-cysLT2 receptor antagonist BAYu9773 was more potent and more effective than a selective cysLT1 antagonist in preventing the brain permeability alteration induced by neutrophil activation. RT-PCR showed significant expression of cysLT2 receptor mRNA in human umbilical vein endothelial cells. Intravital microscopy in mice showed that inhibition of leukotriene synthesis significantly reduced firm adhesion of neutrophils to cerebral vessels without affecting rolling. These data support the hypothesis that neutrophil and endothelial cells cooperate toward the local synthesis of cysLT within the brain vasculature and, acting via the cysLT2 receptor on endothelial cells, may represent a contributing pathogenic mechanism in the development of cerebral inflammation and edema.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Arachidonate 5-Lipoxygenase; Benzopyrans; Blood-Brain Barrier; Brain; Brain Edema; Cell Adhesion; Chemotaxis, Leukocyte; Encephalitis; Endothelium, Vascular; Guinea Pigs; Humans; Indoles; Leukotriene A4; Leukotriene B4; Lipoxygenase Inhibitors; Membrane Proteins; Mice; Microcirculation; N-Formylmethionine Leucyl-Phenylalanine; Nerve Tissue Proteins; Neutrophils; Organ Size; Receptors, Leukotriene; SRS-A

The post-traumatic changes of leukotrienes LTC4, LTD4, LTE4, and LTB4 in cerebrospinal fluid of rats from 10 min to 7 days were investigated after controlled cortical impact in relation to brain edema and cellular inflammatory response. LTC4 increased five-fold at 4 h, normalized at 24 h, and showed another four-fold increase at 7 days. The same pattern was observed for LTD4 and LTE4. LTB4 however, behaved differently: concentrations were lower and levels peaked two-fold at 24 h. Edema in the injured hemisphere increased continuously up to 24 h without change contralaterally. Leukocyte infiltration, macrophage presence and microglia activation were most prominent at 24 h, 7 days and 24 h respectively. Leukotriene changes in CSF seem to reflect those in the affected tissue, with a time delay and in lower concentrations, and were not linearly correlated to brain edema. The initially high leukotriene levels are rather likely to contribute to the cytotoxic edema than to enhance a vasogenic edema component. The profile of LTB4 was parallel to the time course of leukocyte infiltration, indicating initiation of infiltration as well as prolonged production by leukocytes themselves. The second leukotriene peak at 7 days is likely to follow a different pathway and might be related to a production in macrophages or activated glia.

Topics: Animals; Brain Edema; Brain Injuries; Leukocytes; Leukotriene B4; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotrienes; Male; Rats; Rats, Sprague-Dawley; Water

LTC4, which enhances vascular permeability and promotes tissue edema, and LTB4, which is a potent chemotactic and activating factor for leukocytes, were measured in rat brain after ischemia and several time periods of reperfusion. Forebrain ischemia was induced by 4-vessel occlusion. LTC4/LTB4 in the brain were measured by RIA. We also studied the effects of a 5-lipoxygenase inhibitor, AA-861 and a PAF antagonist, CV-3988 on LTC4/LTB4 concentrations. LTC4 in brain tissue increased during 30 min forebrain ischemia (p < 0.001). After reperfusion, LTC4 increased further, but at 15 min reperfusion LTC4 returned to the control level. Tissue levels of LTB4 in the brain increased during 30 min ischemia and remained high until 5 min after reperfusion (p < 0.01) returning at 15 min reperfusion to the control level. AA-861 inhibited elevation of LTC4/LTB4 in the reperfusion phase, but was not effective during ischemia. CV-3988 had a similar effect. LTC4 and LTB4 may be involved in the pathogenesis of ischemia brain edema and leukocyte infiltration. Further, PAF and LTs have many similarities of their pathophysiological properties, and may interact therefore in pathologic process.

Topics: Animals; Benzoquinones; Brain Edema; Brain Ischemia; Injections, Intraperitoneal; Leukotriene B4; Leukotriene C4; Lipoxygenase Inhibitors; Male; Phospholipid Ethers; Platelet Activating Factor; Premedication; Prosencephalon; Rats; Rats, Wistar; Reperfusion Injury

Arachidonic acid solution (2 to 15 mg/ml) was infused into the right forebrain white matter of anaesthetised cats over three hours to evaluate its contribution to the genesis and pathophysiology of vasogenic brain oedema. The 0.6 ml infusion increased local white matter water content by a mean of 11.3 ml/100 g tissue but did not increase cortical water content. Histological studies revealed local expansion and trabeculation of the white matter with aggregations of granulocytic neutrophils in the venules and perivenular brain. The adjacent cortical cytoarchitecture was normal. The white matter around the infusion site was stained lightly and over a variable area (15-20 mm2) by intravenously administered Evans Blue dye 2%. Regional cerebral blood flow (rCBF) adjacent to the frontal infusion did not change significantly during the period of infusion and remained similar to rCBF in the contralateral hemisphere. Following the arachidonic acid infusion regional CBF CO2 reactivity was normal and three was no asymmetry of either cortical somatosensory evoked potential (SEP) or motor evoked potential (MEP) waveforms. The increase in brain water content and changes in the ICP and ICP related biodynamics (pressure-volume index, lumped craniospinal compliance and CSF outflow resistance) were similar to those seen following infusion of 0.6 ml saline. These studies suggest that free intraparenchymal arachidonic acid, at concentrations exceeding those occurring in most neuropathological conditions, can increase the normal brain parenchymal capillary permeability but does not disrupt focal cerebrovascular and electrophysiological function. The clinical implications of these findings are discussed.

Topics: Animals; Arachidonic Acid; Blood-Brain Barrier; Brain Edema; Cats; Cerebral Cortex; Cerebrospinal Fluid Pressure; Disease Models, Animal; Evoked Potentials, Somatosensory; Intracranial Pressure; Leukotriene B4; Muscles; Reaction Time; Regional Blood Flow; Specific Gravity; SRS-A; Synaptic Transmission; Vascular Resistance

Mediator compounds such as bradykinin, arachidonic acid, and LT are released in the brain in conditions causing cerebral swelling. The potential of these compounds to enhance this process was studied in the infusion-induced model of brain edema. Cats subjected to chloralose anesthesia were infused with 400 microliters of artificial CSF into the right and left frontal white matter within 2.5 hr. CSF infused into the left hemisphere contained either bradykinin (40 microM), arachidonic acid (3 mM), LTB4 (15 microM), or LTC4 (16 microM), respectively. Evans blue was administered as blood-brain barrier indicator. Water content of gray and white matter was microgravimetrically determined in serial coronal brain slices. Infusion of CSF only led to an increase in water content from 69 to between 75% and 79%. Addition of bradykinin effectively enhanced the infusion edema but did not open the barrier to Evans blue. Arachidonic acid even more effectively led to an increase in water content and opened the barrier to Evans blue, in addition. Infusion of LT (LTB4, as well as LTC4) was not found to increase further the infusion edema and did not open the blood-brain barrier to Evans blue. It is concluded that the infusion edema model is suitable for studying the edema-enhancing potential of mediator compounds. Marked enhancement of vasogenic brain edema by bradykinin or arachidonic acid again demonstrates a pathophysiological function of these compounds as mediators of secondary brain damage, although LT are unlikely to be specifically involved in vasogenic edema formation.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Blood-Brain Barrier; Body Water; Bradykinin; Brain Chemistry; Brain Edema; Cats; Disease Models, Animal; Leukotriene B4; Solutions; SRS-A

Using the bilateral carotid artery occlusion model of cerebral ischemia in the gerbil, we studied the effect of moderate hypothermia (30 to 31 degrees C) on the postischemic production of prostanoids (cyclooxygenase pathway) and leukotrienes (lipoxygenase pathway) and accompanying changes in cerebral edema formation. Hypothermia capable of slowing central evoked potential conduction time was studied over the course of 40 minutes of cerebral ischemia and for up to 2 hours of reperfusion. The successful induction of cerebral ischemia was confirmed by somatosensory evoked potential amplitude changes. Measurements of 6-ketoprostaglandin F1 alpha (PGF1 alpha) and leukotriene B4 (LTB4) (radioimmunoassay) and cerebral edema (specific gravity) were made at early (10 minutes) and late (2 hours) reperfusion times. Although both white and gray matter showed no early significant difference in edema accumulation between normothermic and hypothermic gerbils at 10 minutes of reperfusion, hypothermic animals demonstrated significantly less white matter edema (specific gravity, 1.0397 +/- 0.0010 vs. 1.0341 +/- 0.0012, P less than 0.01) and gray matter edema (specific gravity, 1.0408 +/- 0.0009 vs. 1.0365 +/- 0.0008, P less than 0.01) by 2 hours of reperfusion. Production of PGF1 alpha was not significantly different between normothermic and hypothermic animals during the reperfusion period; however, hypothermic gerbils demonstrated significantly lower production of LTB4 at 10 minutes reperfusion time compared to normothermic animals (1.49 +/- 0.79 vs. 5.28 +/- 1.49 pg/mg of protein, P less than 0.05). This difference between the two groups in LTB4 levels was no longer detectable at 2 hours of reperfusion time.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain Edema; Disease Models, Animal; Evoked Potentials, Somatosensory; Gerbillinae; Hypothermia; Ischemic Attack, Transient; Leukotriene B4; Male; Prostaglandins F

This study examined the changes in cerebral blood flow, water content, and lipoxygenase metabolites (leukotrienes) following bilateral carotid artery occlusion (BCO) and reperfusion in the gerbil. The effect of inhibiting lipoxygenase with nordihydroguaretic acid (NDGA) was also examined. BCO caused cerebral blood flow (measured using H2 clearance) to decline from 23.5 +/- 1.9 to 4.5 +/- 1.9 ml/min/100 gm. Reperfusion increased flow to 27.9 +/- 4 ml/min/100 gm at 10 min, which declined to 13.7 +/- 1.3 ml/min/100 gm at 50 min. Concomitant oedema measurement revealed brain specific gravity decreasing to 1.0402 +/- 0.0014 at 10 min and to 1.0325 +/- 0.0006 at 50 min reperfusion (nonoccluded controls). Leukotriene B4 (LTB4) increased from 26.8 +/- 4.6 to 33.5 +/- 2.1 pg/mg protein 10 min after reperfusion (p less than 0.05), but declined to 21.8 +/- pg/mg protein by 100 min (vs nonischaemic control = 21.3 +/- 2.9 pg/mg protein). Activation of arachidonate metabolism was confirmed by significantly increased 6 keto PGF1 alpha. Pretreatment of the animals with NDGA did not alter CBF, but increased specific gravity above saline-treated controls at 50 min of reperfusion (NDGA = 1.0370 +/- 0.002 vs control = 1.0325 +/- 0.0006, p less than 0.05). Similarly, NDGA blunted the increase in LTB4 formation 10 min after reperfusion (control = 26.8 +/- 4.6 pg/mg protein vs NDGA = 29.7 +/- 2.9 pg/mg protein, p = N.S.). These findings indicate that LTB4 production is stimulated by BCO and reperfusion in the gerbil, and that this stimulation occurs early on in the reperfusion. Further, we observe that the lipoxygenase inhibitor NDGA limits the formation of ischaemic cerebral oedema.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Brain; Brain Chemistry; Brain Edema; Brain Ischemia; Gerbillinae; Leukotriene B4; Lipoxygenase; Regional Blood Flow